Part 7. Developmental Delay and Regression

Menkes disease (MD) and occipital horn syndrome (OHS) are X-linked recessive disorders that affect young infants. They are caused by a defect in copper transportation across the intestinal mucosa, resulting in a copper deficiency and dysfunction of copper-dependent enzymes. The incidence is estimated at 1 in 50,000 to 1 in 250,000 live births; one third of cases result from new mutations. MD usually affects males; however, a few affected females with unfavorable X-lyonization or X chromosome anomalies have been reported.

The genetic defect of MD and OHS is related to ATP7A gene mutations.1 This gene mapped to Xq13.3 and encodes for a P1B-type ATPase, a ubiquitously expressed protein that transports copper across cellular membranes and is critical for copper homeostasis. This protein serves to incorporate copper into copper-dependent enzymes and to remove the excess of copper from the cytosol maintaining the intracellular copper levels. Defects in this P-type ATPase lead to a reduced transport of copper from the intestine into the circulation and central nervous system and to a reduced transport of copper into the Golgi apparatus for incorporation into various copper-dependent enzymes.2 The result is a systemic copper deficiency and a reduced activity of various copper-dependent enzymes, which finally account for the characteristic features of the disease. Deficiencies of enzymes such as cytochrome c-oxidase, superoxide dismutase, and lysyl oxidase may explain the severe neurologic deterioration. Other enzymes implicated are: tyrosinase for the hypopigmentation, lysyl oxidase for defects in connective tissue, ascorbate oxidase for the osteoporosis, dopamine β-hydroxylase for faulty catecholamine production, and sulfhydryl oxidase for the steely hair.

The ATP7A gene is very similar to the gene responsible for Wilson disease, the ATP7B gene, which encodes for another copper-transporting protein. The differential expression of these 2 genes explains the difference in the clinical phenotype. The ATP7A gene is expressed in the intestinal mucosa and other tissues but not liver, whereas the ATP7B gene is expressed in liver and brain.

In classic Menkes disease,2 the neurologic features may begin in utero or shortly after birth (6 to 10 weeks of age) and consist of developmental regression, seizures, retinal degeneration, and later spasticity. Systemic features consist of failure to thrive; hypothermia; osteoporosis; bladder diverticula; sparse, thin hair that is twisted at the shaft (pili torti) and often lightly pigmented (white, silver, or gray); lax skin; tortuous and elongated arterial vessels; distinctive facial features; pectus excavatum; and hernias. Death by 3 years of age is typical.

Occipital horn syndrome (OHS), an allelic variant of Menkes disease (MD), has only minimal neurologic features consisting of mild developmental delay and autonomic instability.3 The systemic features consist of inguinal hernias, bladder diverticula, lax skin and joints, vascular tortuosity and a characteristic calcified occipital horn in the skull.

Differential diagnosis includes infantile-onset neurodegenerative disorders such as biotinidase deficiency, organic acidurias, aminoacidurias, and mitochondrial myopathies. Diagnostic confirmation consists of finding a low serum copper and ceruloplasmin after 2 to 3 weeks of age, when these levels normally rise. Brain MRI shows severe cerebral and cerebellar atrophy with tortuous vessels seen on the magnetic resonance angiography. Subdural hematomas may form following the severe atrophy. Copper-transport studies in cultured fibroblasts show impaired cellular copper exodus, and plasma and cerebral spinal fluid catecholamine analysis shows abnormal catechol concentrations at all ages. Molecular testing for MD and OHS is clinically available, and it is useful as confirmatory diagnostic testing, for carrier testing, or in prenatal diagnosis. The ATP7A gene is the only gene known to be associated with these disorders. The molecular test detects more than 95% of affected individuals.

Management for MD/OHS includes periodic developmental, feeding, nutrition and bladder function evaluations; gastrostomy to manage caloric intake; surgery for bladder diverticula; and developmental intervention. Specific treatment for classic MD patients to correct the copper deficiency has been attempted with early copper-histidine or copper chloride subcutaneous injections. This treatment may improve the outcome of MD if begun before 10 days of age.4 However, unfortunately, no newborn screening is available, and presymptomatic detection is difficult.

Aceruloplasminemia is a disorder of iron metabolism, characterized by iron accumulation in the brain and in the visceral organs associated with undetectable levels of ceruloplasmin. It is a rare autosomal recessive disease described for first time in 1987. It has been reported mainly in Japanese patients, but it has been described in other populations as well; its overall prevalence is unknown.

Aceruloplasminemia is caused by mutations in the CP gene, located at chromosome 3q21–24.5 The CP gene encodes the ceruloplasmin protein, a copper oxidase that carries more than 95% of the plasma copper, and it is also known as ferroxidase and Fe(II) oxygen oxidoreductase. Ceruloplasmin is essential in iron hemostasis, catalyzing the oxidation of ferrous to ferric iron, a change required for the release of iron to plasma transferrin. Ceruloplasmin has two forms: (1) the plasma α-2-glycoprotein form, mainly synthesized in hepatocytes and widely expressed, but unable to enter the brain, and (2) the glycosylphosphatidylinositol–anchored form, generated by a brain-specific alternative splicing expressed mainly in astrocytes but also in visceral organs. Mutations in the CP gene lead to an unstable or nonfunctional ceruloplasmin protein or to retention of ceruloplasmin at the endoplasmic reticulum. As a consequence of absence of ceruloplasmin, cells are unable to oxidize and excrete iron to the extracellular space to be bound by transferrin, and iron accumulates in hepatocytes, astrocytes, retinal neurons, and pancreas, among other sites.

Clinically, aceruloplasminemia is characterized by the triad of diabetes, neurologic disease, and retinal degeneration. This disease usually begins in adults. One of the first manifestations is diabetes mellitus due to the pancreas involvement. Progressive neurologic manifestations consist of ataxia, cognitive dysfunction, dementia, and a complex of extrapyramidal signs including blepharospasm, dystonia, rigidity, tremor, and chorea. Iron accumulation in the retina can cause visual loss. Affected individuals often have a mild to moderate degree of anemia with iron deficiency and elevated serum ferritin.6

Differential diagnosis should be made with other diseases with low serum ceruloplasmin concentrations, such as Wilson disease and Menkes disease, which are disorders of copper metabolism. Wilson disease is characterized by the inability to transfer copper into the ceruloplasmin precursor protein, apoceruloplasmin, resulting in a decreased biliary copper excretion, serum ceruloplasmin deficiency, and excess copper accumulation. In Menkes disease there is a decreased copper absorption from the intestine, resulting in copper and ceruloplasmin deficiencies.

Aceruloplasminemia is suspected in individuals with the characteristic triad, and the diagnosis relies on the demonstration of the absence of serum ceruloplasmin and some combination of low serum copper, low serum iron, high serum ferritin, and high hepatic iron concentrations. There is nondetectable plasma ceruloplasmin ferroxidase activity. The diagnosis is supported by characteristic MRI findings at T1- and T2-weighted images that show abnormal low intensities in liver and in the striatum, thalamus, and dentate nucleus in the brain, reflecting iron accumulation (eFig. 573.1).6 Molecular testing of the CP gene is available on a research basis only.

The management in symptomatic individuals with hemoglobin concentrations higher than 9 g/dL can be done with chelating agents such as desferrioxamine. This treatment can decrease serum ferritin concentration, and brain and liver iron deposits, and can prevent neurologic progression. However, the use of desferrioxamine in combination with fresh-frozen plasma has demonstrated a better outcome, with persistent increase of serum iron concentration, a bigger decrease in liver iron concentration, and can improve the neurologic symptoms. Vitamin E and zinc, along with chelator agents, can prevent tissue damage. Periodically, tests looking for diabetes mellitus are recommended in individuals at risk.

Pantothenate kinase-associated neurodegeneration (PKAN), formerly called Hallervorden-Spatz disease (HSD), is a disorder of iron metabolism and consists of neurodegeneration with brain iron accumulation. It is a rare autosomal recessive disorder; the estimated prevalence in the general population is around 1 to 3 in 1,000,000.

PKAN is caused by mutations in the PANK2 gene,7 which is the only gene currently known to be associated with this disorder. The PANK2 gene is located at chromosome 20p13 and encodes the protein pantothenate kinase 2. The deficiency of this protein is hypothesized to cause accumulation of N-pantothenol-cysteine and pantetheine, leading to cell toxicity directly or via free radical damage as chelators of iron, and also results in coenzyme A depletion and defective membrane biosynthesis. Until now, there has been no clear genotype-phenotype correlation; however, individuals with mutations predicted to have no protein have classic PKAN8 Mutations in PANK2 have been reported in families with HARP syndrome (hypobetalipoproteinemia, acanthocytosis, retinitis pigmentosa, pallidal degeneration), which now is considered part of the PKAN spectrum.

The pathologic findings in PKAN include deposition of iron within astrocytes, microglia, and neurons, which is specific to the globus pallidus and the pars reticulata of the substantia nigra. Focal swelling within axons that are called spheroids is also seen and are not limited just to the areas with iron accumulation. No systemic or global brain increase of iron is seen.

Clinically, PKAN has been classified in 2 forms: the classic form and the atypical form. In the classic form, the onset is usually before age 10 years; the patients present with a rapidly progressive disease with loss of ambulation, often occurring 10 or 15 years after the onset of the disease. The atypical form presents onset during the second decade of life, the progression is slow, and the loss of ambulation is after 15 years of onset.

Pantothenate kinase-associated neurodegeneration (PKAN) is characterized by extrapyramidal dysfunction, with dystonia, rigidity, or choreoathetosis.8 Other neurologic findings are spasticity and extensor toe signs, suggesting corticospinal tract dysfunction. In classic PKAN, 75% of patients develop pigmentary retinopathy that includes flecked retina, bone spicule formation, conspicuous choroidal vasculature, and bull’s-eye annular maculopathy. In atypical PKAN, ocular anomalies are rare, but these patients may have subclinical retinal changes. Mental deterioration indicative of dementia, epilepsy, and acanthocytosis occur in some of these patients. The course is relentless and progressive, extending over several years; death usually occurs in early adulthood.

Differential diagnosis includes other neurodegenerative syndromes with brain iron accumulation, such as infantile neuroaxonal dystrophy associated with mutations in the PLA2G6 gene, neuroferritinopathy associated with mutations in the FTL gene, and aceruloplasminemia associated with mutations in the gene encoding ceruloplasmin. Other disorders to consider are α-fucosidosis, X-linked mental retardation with Dandy Walker malformation, early-onset Parkinson disease, some childhood-onset ataxias and dystonias, among others.

The diagnosis of PKAN often arises in individuals with the suspected clinical features and with characteristic MRI findings. MRI shows iron deposits associated with decreased intensity of the T2-weighted image and a central region of hyperintensity within the globus pallidus that has been called as the “eye of the tiger” sign. This sign is present in all individuals with PANK2 mutations (Fig. 573-1).9 Brain MRI is one of the most helpful tests in determining the diagnosis of PKAN, and it is standard in the evaluation of these patients. Molecular testing is available clinically, and it is useful as a confirmatory diagnostic testing, as a carrier testing or in prenatal diagnosis. Mutations in PANK2 are detected in more than 99% of individuals with PKAN and the “eye of tiger” sign on MRI, and in 50% of individuals with clinical diagnosis of PKAN. Duplications and deletions have been reported in around 3% to 5 % of patients.

The management consists of periodic evaluations by neurology; ophthalmology; physical, occupational, and speech therapy; and developmental assessment. Treatment of manifestations is focused on palliation of symptoms; extrapyramidal movements with oral trihexyphenidyl may be helpful. Treatment for dystonia has been attempted with baclofen, including intrathecal baclofen infusions, intramuscular botulinum toxin, ablative pallidotomy or thalamotomy, and deep brain stimulation. Individuals with some residual enzyme activity have been reported to have improvement in their symptoms while using high doses of pantothenate; however, the efficacy of pantothenate is currently unknown. Docosahexanoic acid may have a role in preventing retinal degeneration, but as yet no studies have been performed. Treatment with chelating agents such as desferrioxamine has not proved effective in reducing the iron load or improving the clinical symptoms.

Lysosomal storage disorders (LSDs) comprise a group of approximately 30 relatively rare inherited diseases that are characterized by defective functioning of one or several lysosomal enzymes. As a result of the enzyme deficiency, a storage material (glycogen, glycoproteins, shingolipids, cholesterol) accumulates in various organs, including central nervous system (CNS), liver, spleen, and kidneys. While most individual LSDs are quite rare, as a group their incidence is estimated to be between 1:5000 to 1:10,000. The prevalence of some of LSDs is higher in certain populations. LSDs are classified based on the type of the enzymatic defect or type of stored substrate product. Clinical symptoms (both somatic and neurological manifestations) tend to progress as the substrate accumulates over time. Several LSDs with CNS involvement are discussed below. These disorders are further discussed in Chapters 160 and 161. Diagnosis is usually made by enzyme assay or mutation analysis. Hematopoietic stem cell transplant (HSCT) has been used for the treatment of several LSDs over the past three decades. Enzyme replacement therapy (ERT) became available for the treatment of few LSDs in the past 15 years. New therapies have emerged in most recent years; small molecule drugs (chaperones) can reduce substrate production (substrate reduction therapy) or increase residual enzyme activity (enzyme enhancing therapy). Gene therapy may become available for the treatment of some LSDs in the future and is under investigation.

Lysosomal Storage Diseases Containing Lipid

GM1 Gangliosidosis

GM1 gangliosidosis is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme, GM1 ganglioside β-galactosidase, a lysosomal enzyme requiring a complex of sphingolipid activator protein (saposin B), protective protein, and neuraminidase enzyme in order to function properly. β-galactosidase deficiency results in accumulation of GM1 ganglioside within the brain and storage of galactose-containing glycoproteins and keratan sulfate within various body organs.

Deficiency of β-galactosidase is expressed clinically as 2 different diseases: GM1 gangliosidosis and Morquio B disease. GM1 gangliosidosis is characterized by a neurodegenerative process with associated visceral involvement. Generalized bone disease without CNS involvement is the hallmark of Morquio B disease. Molecular analysis has confirmed allelic mutations of the same gene in these diseases mapped to chromosome 3 (3p21.33).

The clinical phenotype of GM1 gangliosidosis can be divided into 3 forms: type I (infantile), type II (juvenile), and type III (adult). Type I, or infantile, form presents at birth or during early infancy with characteristic facial appearance of depressed nasal bridge, frontal bossing, epicanthal folds, puffy eyelids, gingival hypertrophy, enlarged tongue, low-set ears, and small jaw. Peripheral and facial edema may be seen. Other features include skeletal dysplasia, manifesting as thoracolumbar kyphoscoliosis and hepatosplenomegaly. Psychomotor delay and hypotonia are apparent early; later neurologic signs include seizures and irritability. Vision is poor; a cherry-red macula develops after several months in at least 50% of children. Bronchopneumonia or cardiac failure often causes death within first few years. MRI may show progressive atrophy and delayed myelination. Skeletal findings include vertebral hypoplasia affecting the thoracolumbar region. Other osseous findings include diaphyseal widening and tapering of digits. Peripheral blood smear analysis frequently shows vacuolated lymphocytes. Patients become vegetative and die within a few years after onset. Type II, or juvenile-onset, disease has onset usually between 1 and 2 years; symptoms consist of mild bony changes without dysmorphic features. The disease primarily affects the CNS and manifests as gradual developmental delay, ataxia, and choreoathetoid movements. The first symptom is usually difficulty with walking, followed by loss of speech. A retinal cherry-red spot is usually not present. The skeletal findings are observed in the thoracolumbar spine region with beaking of the anterior vertebrae and some hypoplasia. There is no hepatosplenomegaly. MRI is usually normal, and EEG may be diffusely slow but not diagnostic. The course is protracted, with death usually occurring within the first decade. Type III adult-onset disease is characterized by late-onset neurologic symptoms. Dysarthria and dystonia, without the ataxia and seizures seen in the other forms, are the main symptoms. There are no dysmorphic features, and funduscopic examination is normal. The neuropathology of the disease is restricted to lipid deposition within the basal ganglia.

Morquio disease type B is also associated with deficiency of β-galactosidase. Patients present with generalized skeletal dysplasia without CNS involvement. Despite the enzymatic defect, the phenotype resembles systemic manifestations of other mucopolysaccharidoses.

Galactosialidosis is a complicated variant of GM1 gangliosidosis involving deficiency not only of GM1 ganglioside β-galactosidase, but also of neuraminidase. The biochemical defect is caused by a deficiency of the protective protein, cathepsin A. The gene for cathepsin A is located on chromosome 20, and several mutations have been identified in this disease. Clinical presentation is frequently a severe infantile onset with dysmorphic and neurologic features similar to infantile GM1 gangliosidosis. Many milder variants have been described, making the phenotype quite heterogeneous.

GM2 Gangliosidoses

The GM2 gangliosidoses are a collection of lysosomal diseases associated with the accumulation of GM2 ganglioside in the lysosomes, predominantly of nervous system cells. The diseases may be caused by a deficiency of β-hexosaminidase A, β-hexosaminidase A and B, or GM2 ganglioside activator protein. Two isoenzymes of β-hexosaminidase exist: Hex A (structure αβ) and Hex B (structure ββ). Tay-Sachs variant is caused by defects in the α-subunit of the enzyme and is associated with deficiency of Hex A and normal activity of Hex B. Sandhoff disease is caused by mutations in the β-subunit gene that result in deficiency of both Hex A and B. The loss of GM2 ganglioside activator protein is more difficult to diagnose because most diagnostic enzyme assays use an artificial substrate with detergent that masks the activator deficiency. The genes encoding the β-hexosaminidase α-subunit (HEXA gene) and β-subunit (HEXB gene) are similar in structure, with nearly 60% nucleotide and amino acid homology, but have been mapped on 2 separate chromosomes, with HEXA localized to 15q23-24 and HEXB to 5q11.2-13.3. The GM2 ganglioside activator protein contains 162 amino acids and was mapped to chromosome 5. All 3 genes have been cloned and mutations identified.

Tay-Sachs Disease (β-Hexosaminidase α-Subunit Deficiency)

The infantile onset of β-hexosaminidase α-subunit deficiency (Tay-Sachs disease) begins within the first few months of life. The first symptom is an excessive startle in response to noise, tactile stimuli, or light flashes. This startle response differs from the Moro response of normal infants and consists of quick extension of the arm and legs, frequently with clonic movements, and does not attenuate with stimulus repetition. As the disease progresses, motor development slows and previously acquired skills are frequently lost, along with decreased vocalizations and loss of awareness of the environment. Axial hypotonia, increased extremity tone, and hyperreflexia are common physical signs. A macular cherry-red spot (Fig. 574-1) occurs in over 90% of infants. Storage of lipids within the retinal ganglion cells causes whitish discoloration of most of the retina except for the fovea, which shows the normal red color. Since the rod and cone cells in the retina do not store the ganglioside, the loss of vision that frequently occurs by the end of the first year is presumed to be due to cerebral pathology. The cherry-red spot may also be observed in other disorders, including Gaucher disease, GM1 gangliosidosis, galactosialidosis, Niemann-Pick disease type A, and Sandhoff disease. Macrocephaly becomes apparent by the second year, presumably caused by intraneuronal storage of gangliosides and other lipids, reactive gliosis, and disturbance of fluid balance. Affected children may develop seizures that can be induced by auditory stimuli. Systemic organs are spared in this form of the disease. Autonomic disturbances, manifesting as fever, circulatory changes in the skin, and cyanosis, frequently accompany disease progression. A vegetative state develops between age 2 and 3 years and is followed by death in a few years, usually from infection. A late-onset (juvenile/adult) variant of GM2 gangliosidosis, with indolent clinical presentation, has been described. It is frequently seen in patients of Ashkenazi Jewish background. This variant has been called the adult-onset variant, but the disease usually begins in childhood. Although early gross motor development is normal, these children are often considered clumsy and awkward. An intention tremor, frequently seen in the first decade, may be the first indication of a neurologic problem. Dysarthria also develops early in many patients, and difficulties in school may be apparent. A specific phenotype of late-onset GM2 gangliosidosis, with slowly progressive dystonia and dementia beginning in the first few years of life, has been described. During adolescence, proximal muscle weakness begins with fasciculations and atrophy and appears similar to juvenile-onset spinal muscular atrophy or early onset amyotrophic lateral sclerosis. Development of a broad-based ataxic gait usually follows, making walking even more difficult. Psychiatric symptoms may occur in nearly 50% of patients and include inattention, anxiety, paranoia, suicidal ideation, postpartum depression, catatonic schizophrenia, and occasionally episodes of hallucinations. These patients frequently are able to ambulate with assistance until the sixth decade. Diagnosis of Tay-Sachs disease (TSD) relies upon the demonstration of absent or extremely low activity of Hex A in white blood cells or other tissues. Before community-based carrier-screening programs were developed in the Ashkenazi Jewish population, the incidence of TSD was about 1 per 3600 births of infants of this descent. The carrier rate for TSD among Jewish Americans of Ashkenazi extraction is about 1 in 30. Extensive counseling and carrier-screening programs reduced the incidence of TSD by 90%.

Sandhoff Disease (β-Hexosaminidase β-Subunit Deficiency)

The age of onset, duration, neurologic symptoms, and ophthalmologic signs in patients with Sandhoff disease are identical to those seen in TSD, but mild hepatosplenomegaly (secondary to storage of globoside) and bony deformities may rarely be present. Deficiencies of both hexosaminidase A and B are present. Bone marrow biopsy results demonstrate foam cells in a few patients. A juvenile-onset variant occurs after age 1 year, beginning with clumsiness and gait ataxia, later dystonic posturing and seizures, but no cherry-red macula. Adult-onset patients follow a similar clinical course to chronic late-onset adult forms of Hex A deficiency.

GM2-Activator Deficiency

Individuals with GM2-activator deficiency have disease course similar to those with infantile-onset TSD or B variant. The storage of glycolipids and the pathologic features are also identical to that found in infantile TSD.

MRI in GM2 gangliosidoses demonstrates atrophy with widening of cerebral sulci, increase in ventricular size, and hyperintensities in the basal ganglia, thalamus, and cerebral cortex. Late-onset forms may have prominent cerebellar atrophy, especially of the vermis, but a normal-appearing cerebral cortex on CT or MRI scans. The EEG in Tay-Sachs disease will frequently show slowing, but when seizures develop, multifocal spikes may occur. In patients with late-onset disease, nerve conduction velocities are normal, but electromyograms will show a neuropathic pattern consisting of denervation with increased spontaneous activity and high-amplitude polyphasic motor units. Treatment is limited to symptomatic and supportive care. Attempts at enzyme replacement therapy were unsuccessful, owing to problems with the delivery of the enzyme to the CNS. The experience in treating patients with bone marrow transplantation is very limited.

Fabry Disease

Fabry disease is an X-linked condition resulting in lysosomal accumulation of various glycosphingolipids with terminal α-galactosyl residues in the cells throughout the body. It is caused by deficiency of the enzyme α-galactosidase A. In affected hemizygous males, enzyme activity is less than 1% of normal.

Clinical Presentation

Clinical symptoms begin in late childhood or adolescence with periodic crises of pain in the extremities, vascular cutaneous lesions (angiokeratomas), hypohydrosis, corneal and lenticular opacities, strokes, left ventricular hypertrophy, and renal insufficiency. The gene encoding α-galactosidase A (GLA) is localized to Xq22.1. The incidence of Fabry disease has been estimated at 1 in 55,000 male births. This figure is almost certainly a substantial underestimate of the true frequency, particularly of milder variants of the disease.

Nervous System Involvement

The most debilitating symptom of Fabry disease is pain in the extremities of 2 types: painful crisis and constant discomfort. The painful crises often begin in childhood or adolescence, last from minutes to several days, and may be accompanied by fever and increased erythrocyte sedimentation rate. They are described as intense burning or lancinating pain felt initially in palms and soles, but frequently radiating to proximal extremities and other body parts. Attacks of abdominal or flank pain may simulate appendicitis or renal colic. In addition to intermittent crises, many patients complain of mild persistent numbness and paresthesias in hands and feet (acroparesthesia). Autonomic nervous system dysfunction manifests as hypohydrosis and anhydrosis (occasionally hyperhidrosis), constipation, chronic diarrhea, and nausea.

Cerebrovascular manifestations include hemipareses, vertigo, diplopia, dysarthria, nystagmus, headache, ataxia, memory loss, and hemisensory loss. These symptoms result from multifocal small vessel involvement. Angiography may reveal tortuosity of brain vessels. Cardiovascular manifestations consist of left ventricular hypertrophy due to the deposition of storage material, mitral valve insufficiency, other valve involvement, arrhythmias, and electro cardiographic changes. Because of endothelial storage in coronary vessels, myocardial ischemia and infarction are a frequent late manifestation of the disorder. Pulmonary symptoms are usually considered not to be a prominent manifestation of Fabry disease, but with age patients complain of dyspnea, cough, and wheezing. This population also has higher incidence of spontaneous pneumothorax and occasionally hemoptysis. Progressive glycosphingolipid accumulation in the kidney results in the development of azotemia and renal insufficiency. Urinary sediment contains casts and “Maltese crosses,” which are birefringent lipid globules. Gradual deterioration of renal function leads to death in the third to fifth decade unless treatment with chronic hemodialysis or renal transplantation is provided. Angiokeratomas appear as clusters of ectatic blood vessels, dark-blue or black-blue, in the superficial layers of the skin. These lesions are flat or slightly raised and do not blanch with pressure. Usually, they are located in the groin, buttocks, upper legs, and umbilical region (Fig. 574-2). The angiokeratomas are often one of the earliest manifestations of Fabry disease. They appear in childhood and gradually increase in number and size over the years. Angioectasias may also occur in the oral mucosa and conjunctiva. Corneal opacity, which can be seen only by slit-lamp examination, is usually the first ocular abnormality and is present in essentially all hemizygous Fabry patients and most heterozygous females. These corneal changes first appear as a mild generalized clouding in the subepithelial corneal layer and may progress to form whorled streaks. Lenticular opacities may occur in approximately 30% of affected males and consist of granular anterior capsular and subcapsular deposits or a characteristic posterior capsular opacity (Fabry cataracts). The corneal and lenticular opacities do not interfere with vision. Dilatation and tortuosity of retinal and conjunctival vessels may occur as a part of a diffuse systemic involvement. Deposition of glycosphingolipids in intestinal small vessels and in the autonomic ganglia of the bowel may cause episodic diarrhea, cramping pain, and intestinal malabsorption. Males with α-galactosidase A activity greater than 1% may have mild phenotypes with either predominantly cardiac or renal involvement. Heterozygous females may have mild symptoms but sometimes can have severe manifestations, similar to affected males, related to a nonrandom chromosome X inactivation. Approximately 70% to 80% of affected females will have corneal opacities, but only rarely they will have the cataracts. In approximately 30% of females, a few angiokeratomas may be present in the characteristic locations, and intermittent pain and paresthesias may occur; rarely, cardiac and renal symptoms develop.

MRI shows hyperintensity in the periventricular white matter early in the disease and development of subcortical and cortical strokes over time. There is also a characteristic “pulvinar sign” seen in many male patients, which consists of an increased signal intensity on T1-weighted MRI images in the pulvinar nucleus of the thalamus.1 Nerve conduction studies reveal an elevated threshold to current perception but no changes in nerve conduction velocities.

Diagnosis and Treatment

Diagnosis is confirmed by low activity of α-galactosidase A in leukocytes in affected males. In females, measurement of enzyme activity is unreliable, as many carrier females have normal levels. GLA is the only gene known to be associated with Fabry disease, with almost 100% of affected males having an identifiable mutation. Molecular genetic testing is the only reliable method that should be used to identify affected females.

Carbamazepine, gabapentin, and diphenylhydantoin are used to reduce frequency and severity of periodic crises of excruciating pain. Chronic hemodialysis and renal transplantation are often required when end-stage renal disease is present. Enzyme replacement therapy (ERT) with Fabrazyme (agalsidase beta) has been approved by the FDA and should be initiated as early as possible in all males with Fabry disease, including children and patients with end-stage renal disease. Female carriers with prominent symptoms are also considered to be candidates for enzyme replacement therapy. Chaperone therapy, an approach aimed to protect and enhance residual enzyme activity by protecting it from misfolding, is under investigation.

Gaucher Disease

Gaucher disease (GD) is an autosomal recessive disease that results from deficiency of the lysosomal enzyme glucocerebrosidase (also termed β-glucosidase, glucosylceramidase), which leads to accumulation of the glycolipid glucosylceramide in the macrophage-monocyte system throughout the body. Previously discrete phenotypes of GD are now felt to be a continuum of clinical findings, from a perinatal lethal form to an asymptomatic form. Nonetheless, clinical classification is used for determining prognosis and treatment approach. Three major clinical types are determined by absence or presence of CNS involvement: type 1, nonneuronopathic; type 2, infantile onset, acute neuronopathic; and type 3, chronic neuronopathic. The presence and rapidity of neurologic symptoms are the major factors in determining the clinical subtype of this disease. Type 1 nonneuronopathic disease does not manifest any neurologic symptoms and often presents in childhood because of massive hepatosplenomegaly. This is the most common form of GD, seen mainly in the Ashkenazi Jewish population. Patients with this form frequently develop osteopenia, lytic or sclerotic bone lesions, and osteonecrosis. Although they do not have primary CNS involvement, neurologic complications may occur secondary to bone disease (eg, spinal cord or root compression due to vertebral disease).

Clinical Presentation of Gaucher Disease (Gd) Affecting the Nervous System

Type 2 (acute neuronopathic) disease is a rare condition presenting in infancy with dramatic brainstem findings, including retroflexion of the neck, opisthotonus, spasticity, strabismus, and trismus. Massive splenomegaly and, to a lesser extent, hepatomegaly are present early in the course. These children become symptomatic usually before 6 months and, because of severe brainstem involvement, frequently die by the age of 2 years. Patients with severe neonatal form may present with hydrops fetalis and/or congenital ichthyosis.

Patients with type 3 GD (chronic neuronopathic) have onset of symptoms ranging from early life to preteen years and may survive into the third and fourth decades. Oculomotor apraxia and problems with saccadic initiation are common features and occasionally may be the only neurologic sign. Generalized and myoclonic seizures are common. Dementia and ataxia are observed in the later stages of the disease.

One rare subgroup of patients with type 3 GD is a genetic isolate from the Norrbotten region of Sweden. These patients present in early childhood with visceral involvement and oculomotor abnormalities and may develop seizures, cognitive disabilities, and dementia.

Another rare subgroup is the patients with the “cardiovascular form,” who develop calcifications of aortic and mitral valves. Additionally these patients have mild hepatosplenomegaly, supranuclear ophthalmoplegia, and corneal opacities.

Because of the slow progression of neurologic symptoms of GD type 3, it may not be possible to differentiate them from individuals with type 1 early in the course of the disease.

Patients with types 2 and 3 GD have nerve cell loss and neuronophagia, primarily in brainstem, cerebellum and spinal cord. The presence of Gaucher cells, specialized cells containing glucosylceramide, has also been recorded from these areas, correlating with the accumulation of glucosylceramide in the brain. These are lipid-engorged cells with characteristic fibrillary appearance to the cytoplasm and eccentrically placed nuclei, derived from a monocyte-macrophage system, distributed throughout the body, and found in spleen, liver, bone marrow, and lymph nodes (Fig. 574-3).

Auditory evoked potentials reveal the presence of only waves I and II in children with severe neurologic involvement. EEG results in children with Gaucher disease (GD) type 3 are typically characterized as having a slow background with multifocal spike-wave discharges and often a photoparoxysmal response.

Patients with GD, including type 3, do not have evidence of lysosomal storage upon examination of skin. Bone marrow aspirates show typical Gaucher cells. Diagnosis may be confirmed through the biochemical study of glucocerebrosidase activity on peripheral blood leukocytes. It is not necessary to perform a bone marrow examination. It is not possible, however, to differentiate individuals with type 1 versus type 3 disease based simply on the enzymatic activity. The gene locus for GD is mapped to 1q21. Various mutations have been reported. There is significant overlap in clinical manifestations among patients with different mutations, and therefore genetic counseling based on molecular diagnosis is difficult. One subgroup of patients with type 3 GD is a genetic isolate from the Norrbotten region of Sweden. It appears that a single founder dating back to at least the 16th century explains the high incidence in this population. The characteristic genotype for type 3 disease is a homozygous mutation in exon 10, a leucine-to-proline substitution in codon 444. Atypical GD due to saposin C deficiency shows phenotypic similarities with neuronopathic GD2 and maps to 10q22.1.

Splenectomy had been used in the past to avoid complications of splenic enlargement in type 1 and 3 GD but is rarely used today because of the increased glycolipid deposition in bone and lung seen following splenectomy. Bone marrow transplantation has been used with successful results in type 1 disease; however, in type 3 patients, conflicting outcomes have been noted, with perhaps the best results occurring in the Norrbottenian form of the disease. Enzyme replacement therapy with recombinant glucocerebrosidase (Imiglucerase, Cerezyme), used with success for treatment of GD type 1, is effective in reversing the visceral and hematologic manifestations of the disease. It appears that in patients with type 3 GD, enzyme replacement therapy reduces glucosylceramide levels in blood and causes a regression of systemic symptoms with stabilization, but not reversal, of neurological deficits.3 Another type of treatment is substrate reduction therapy. The oral agent miglustat (Zavesca), an iminosugar that inhibits glucosylceramide synthase, is the initial enzyme in a series of reactions that result in the synthesis of most glycosphingolipids, including glucocerebroside. Inhibition of this enzyme reduces production of glucocerebrosides, allowing the residual activity of the glucocerebrosidase, deficient in GD, to be more effective.4 Application of small molecules that act as a chaperone increasing residual activity of the lysosomal enzyme (enzyme-enhancing therapy) may represent a future option for patients with GD.3

Niemann-Pick Diseases

Niemann-Pick (NP) disease is not a single disease, but consists of 2 genetically distinct disorders. Because of the historical background, these diseases are likely to continue to be included together. NP types A and B are caused by an autosomal recessive deficiency of the gene that encodes the enzyme acid sphingomyelinase, needed to degrade sphingomyelin. NP type A is associated with severe hepatosplenomegaly and infantile-onset neurologic presentation. NP type B is a slowly progressive disorder that does not appear to affect the nervous system to a great extent. The biochemical defect in NP type C patients is an abnormality in cholesterol transport, which leads to accumulation of sphingomyelin and cholesterol and secondary reduction of acid sphingomyelinase activity with some sphingomyelin storage. In the past, NP type D has been separately described in Acadians from Yarmouth County in Nova Scotia. However, this disease is caused by mutations in the NPC1 gene and represents the same entity.

Niemann-Pick Type a

Niemann-Pick type A is fatal disorder of infancy. Patients present at around age 3 to 4 months with severe vomiting, diarrhea, and failure to thrive. Striking hepatosplenomegaly, which may be present in the neonatal period, rapidly develops. There are no dysmorphic features or skeletal abnormalities. Brownish or ochre pigmentation of the skin may be observed. By 6 months of age, psychomotor retardation becomes evident. The child demonstrates hypotonia, muscular weakness, progressive loss of acquired motor skills, loss of interest in surroundings, and reduction in spontaneous movements. Axial hypotonia and pyramidal signs are usual features. The disease progresses to severe cachexia, blindness, dysphagia, and rigidity. Macular cherry-red spot may be found in about half of the cases. Seizures usually present at the later stages of the disease. Hyperacusis and macrocephaly, typical for Tay-Sachs disease, are not observed. Recurrent pulmonary infections are common, and respiratory failure is usually a cause of death between 1.5 and 3.0 years of age.

The diagnostic finding is a low level of acid sphingomyelinase activity in peripheral blood lymphocytes or cultured skin fibroblasts. Affected individuals typically have less than 10% of activity compared with controls. For individuals of Ashkenazi Jewish background with a clinical picture suggestive of Niemann-Pick type A, targeted mutation analysis is the molecular genetic method of choice. Bone marrow aspiration shows characteristic lipid-containing “foamy” macrophages, and vacuolated lymphocytes are present in peripheral blood smears. These histiocytic cells result from the accumulation of sphingomyelin and other lipids in the monocyte-macrophage system. These cells are also called Niemann-Pick cells, but they are not a pathognomonic feature of Niemann-Pick and may be present in several other lysosomal storage disorders. Niemann-Pick cells can be readily distinguished from Gaucher cells by histologic and histochemical characteristics. MRI and EEG may be abnormal but typically are not diagnostic. CSF is normal. Nerve conduction velocities may be slowed. The gene encoding sphingomyelinase is located on human chromosome 11p15.1-15.4. The full-length cDNA codes for a polypeptide of 630 amino acids. The gene is relatively small, approximately 7 kb, and consists of only 6 exons. A number of mutations have been discovered, with 3 mutations—R496L, L302P, and fsP330—occurring in the Ashkenazi Jewish population The carrier frequency of Niemann-Pick type A in this population is estimated at about 1/80.

Treatments are primarily symptomatic. Hematopoietic cell transplantation and gene therapy for NP type A are under investigation and enzyme replacement for NP type B is currently in phase I studies in patients.

Neimann-Pick Type B

Niemann-Pick (NP) type B is also caused by acid sphingomyelinase deficiency but, in contrast to NP type A, patients with NP type B have minimal or no nervous system involvement; thus, type B is called a nonneuronopathic form of the disease (see Chapter 161). NP type B has a later onset with a milder course. It is characterized by hepatosplenomegaly with stable liver dysfunction and progressive hypersplenism, which in some cases may produce pancytopenia. Most patients are diagnosed in childhood, when enlargement of liver and spleen are detected on routine examination. Gradual deterioration of pulmonary function is characteristic. Patients generally are intellectually normal, although cases with cerebellar and extrapyramidal signs and psychiatric symptoms have been described.

Similarly to NP type A, diagnosis of NP type B is made based on a finding of reduced acid sphingomyelinase activity on lymphocytes and fibroblasts. Foam cells are found in lymph nodes, spleen, and bone marrow. DeltaR608 is a common mutation in NP type B and is frequently found in patients of North African descent.

Niemann-Pick Type C

Niemann-Pick type C (NPC) is not an allelic variant of NP types A and B, but a separate disease not involved in sphingomyelinase metabolism. Because of the foamy macrophages and hepatosplenomegaly, it was placed into the category of NP before molecular genetic studies were able to categorize it as a different disease. It is caused by a unique error in cellular trafficking of exogenous cholesterol that leads to lysosomal accumulation of unesterified cholesterol. The prevalence of NPC in Western Europe is estimated to be 1/150,000 of live births, more frequent than NP types A and B combined. Two genetic isolates have been described: French Acadians in Nova Scotia (former NP type D) and Spanish Americans in southern Colorado. In these populations the incidence is higher.

Neonatal Onset

Approximately 50% of neonates affected with NPC are asymptomatic; in the remaining cases, liver disease is the major sign. Ultrasound examination in late pregnancy may reveal fetal hydrops (rarely) and fetal ascites (more frequently). Prolonged neonatal cholestatic jaundice associated with progressive hepatosplenomegaly is present in about half of the cases. About 10% of the cases may progress into rapidly fatal liver failure. Children with this dramatic, “acute” neonatal, cholestatic, rapidly fatal form die before age 6 months but do not show neurologic symptoms. In children who survive, hepatosplenomegaly may not be detectable later in childhood. Absence of hepatosplenomegaly never eliminates the diagnosis of NPC. Rare cases with severe neonatal respiratory failure due to infiltration of lungs with foam cells have been described. Most cases of NPC are the late-infantile and juvenile neurologic onset forms. In children 3 to 5 years of age, manifestations consist of an ataxic gait, dystonia, and choreoathetoid movements in addition to hepatosplenomegaly. In children 6 to 12 years, poor school performance and impaired fine-motor movements are usually the first symptoms. Seizures or cataplexy may occasionally be the presenting symptom. Cataplexy, which may be accompanied by narcolepsy, is a common sign. Polysomnographic and biochemical studies have demonstrated abnormal sleep and reduction in CSF hypocretin levels, suggesting that the disease may affect hypothalamic secretion of hypocretin.5 The most characteristic sign of NPC is supranuclear vertical gaze palsy, which could be an early manifestation. Children may lose the ability to look downward, upward, or both. Parents may notice compensatory head thrust when the child wants to look downward or upward. In late stages, horizontal saccades may also be impaired. Severe cell loss has been reported in the rostral interstitial nucleus of the medial longitudinal fasciculus (a premotor area of vertical gaze), with lesser degeneration in the paramedian pontine reticular formation, the corresponding center for horizontal saccades.6 As the disease progresses, pyramidal signs and spasticity usually develop. Many patients die in their teenage years from aspiration pneumonia. Adolescent and adult onset may present with features described in the previous section, but with a slower rate of progression. Older patients may present with psychiatric symptoms mimicking depression or schizophrenia.7

There are at least 2 genes involved in NPC. The most common gene for NPC, called NPC1, is mapped to chromosome 18q11 and accounts for at least 95% of cases. About 4% of patients have mutations in NPC2 gene, mapped to chromosome 14q24.3. In some patients with the typical clinical and biochemical phenotype, mutations have not been found in NPC1 or NPC2. More than 100 mutations were described in the NPC1 gene, but genotype-phenotype correlations are poor. All of the 5 mutations found in the NPC2 gene were associated with severe phenotype. The Neimann-Pick type C mutations appear to block intracellular relocation and utilization of lysosomal cholesterol. The synthesis of endogenous cholesterol does not appear to be affected. Imaging and neurophysiologic studies in Niemann-Pick type C are nonspecific. MR and CT scans may be normal or show cerebellar or cortical atrophy. The severe infantile form is characterized by white matter changes. The diagnosis is confirmed by biochemical testing demonstrating impaired cholesterol esterification and positive filipin staining (a probe forming specific complexes with unesterified cholesterol) in cultured fibroblasts. Molecular genetic testing is available on a clinical basis to confirm the diagnosis. Foam cells and sea-blue histiocytes may be present in bone marrow. Sphingomyelinase activity is often partially deficient in cultured skin fibroblasts, but normal in leukocytes.

There is no specific treatment for NPC. Liver transplantation and bone marrow transplant were attempted but did not slow progression of neurologic symptoms. Therapy with cholesterol-reducing medications (cholestyramine, lovastatin, nicotinic acid) has not been effective. Most promising was the trial of miglustat, a small immunosugar molecule that reversibly inhibits glucosylceramide synthase, which catalyses the first committed step of glycosphingolipid synthesis.8 Miglustat can improve or stabilize several clinical markers of NPC, such as impairment of voluntary eye movements, swallowing ability, auditory acuity, and deterioration of ambulation index.

Neuronal Ceroid Lipofuscinoses

Neuronal ceroid lipofuscinoses (NCLs) are a group of progressive hereditary neurodegenerative disorders characterized by the accumulation of autofluorescent material rich in lipid, protein, and carbohydrates in the lysosomes. Although lysosomal accumulation is present in all tissues, only neurons are affected. The incidence of NCL ranges in different countries from 0.1 to 7/100,000 live births. The prevalence is highest in Scandinavian countries, especially Finland. The common name Batten disease strictly refers to juvenile-onset NCL (Batten-Spielmeyer-Vogt disease), but is used sometimes to describe all NCLs.

NCLs may be divided into 4 major groups based on age of onset: infantile neuronal ceroid lipofuscinosis (INCL), late infantile neuronal ceroid lipofuscinosis (LINCL), juvenile neuronal ceroid lipofuscinosis (JNCL), and adult neuronal ceroid lipofuscinosis (ANCL). Late infantile neuronal ceroid lipofuscinosis includes classical cLINCL; Finnish variant fLINCL; vLINCL variant, seen predominantly in patients of Portuguese, Indian, Pakistani and Czech/Gypsy ancestry; and Turkish variant tLINCL. Congenital form has been described.9 A separate form is referred to as Northern epilepsy. The NCLs have an autosomal recessive mode of inheritance, with the exception of adult neuronal ceroid lipofuscinosis, which may be inherited in either an autosomal recessive or dominant manner.

NCLs are characterized by progressive neurodegeneration, with cognitive and motor dysfunction, seizures, and vision loss. Different forms of NCL have distinctive presentations that vary with age of onset. Infantile form is characterized by normal development until age 6 to 12 months. After that age, developmental arrest and regression become apparent. Patients develop ataxia, myoclonic jerks, and occasionally generalized seizures. Vision loss progresses to blindness at age 24 months. Microcephaly is a uniform feature. Most patients die at age 6 to 7 years. Patients with classical late infantile NCL present between ages 2 and 4 years. Seizures, both generalized tonic clonic and myoclonic, are the most prominent feature and are followed by developmental arrest and regression. Vision loss is slow, but blindness eventually develops. Death occurs at age 10 to 15 years. The leading symptom of juvenile NCL is visual impairment, which usually appears between ages 4 and 7 years. Funduscopic examination reveals macular degeneration, retinal degeneration, and optic atrophy. Visual impairment is followed by behavioral/psychiatric problems, sleep disturbance, and seizures. Most patients survive into their late 20s and 30s. In adult neuronal ceroid lipofuscinosis (Kufs disease), initial signs and symptoms usually appear around age 30, with death occurring about 10 years later. This form is characterized by dementia, behavioral abnormalities, ataxia, and pyramidal and extrapyramidal symptoms. Seizures are frequently hard to control. Vision is usually not impaired.

EEG in neuronal ceroid lipofuscinoses shows slowing and large-amplitude polyphasic spikes elicited by low rates of photic stimulation. Visual evoked potential tests show enlarged early component (“giant” waves). Electroretinogram (ERG) is usually abnormal and ERG responses may become undetectable in advanced stages of the disease. MRI shows progressive cerebral atrophy with bilateral periventricular T2 hyperintensities.

NCLs have been defined originally by their age of onset and clinical symptoms; however, they are now classified on the basis of molecular findings (Table 574-1). Several NCL forms overlap. Late infantile NCL is most commonly caused by mutations in the tripeptidyl peptidase 1 (TPP1) gene, but may also be produced by mutations in the palmitoyl-protein thioesterase 1 (PPT), CLN5, CLN6, CLN7, and CLN8 genes. Adult neuronal ceroid lipofuscinosis may result from mutations in the CLN3 and PPT genes.

Storage material (lipopigment) is typically found in sweat glands, conjunctiva, and other tissues revealed by electron microscopy. Granular osmophilic deposits (GROD) are found in infantile neuronal ceroid lipofuscinosis, predominantly curvilinear bodies in late infantile neuronal ceroid lipofuscinosis, and fingerprint inclusions (eFig. 574.1) in juvenile neuronal ceroid lipofuscinosis. Mixed-type inclusions are seen in CLN4, CLN5, CLN6, and CLN8, and in some late infantile forms.

Biochemical analysis of the deposits have demonstrated that subunit c of the mitochondrial ATP synthase complex is the main storage component of curvilinear bodies and fingerprint bodies. GROD consist mostly of saposins A and D, also called sphingolipid activator proteins. In the past, diagnosis was based on a finding of abnormal material (lipopigment) on skin, conjunctival, or rectal biopsy. Current testing strategy includes testing of enzyme activity of palmitoyl-protein thioesterase 1 (PPT) and tripeptidyl peptidase 1 (TPP1) depending on the age of presentation and targeted mutation analysis. These 2 lysosomal enzymes were found to be deficient in neuronal ceroid lipofuscinoses, and their activity can be measured on leukocytes, lymphocytes, and fibroblasts. Both PPT and TPP1 are soluble lysosomal hydrolases hypothesized to function in the degradation of macromolecules.

Therapy for all forms of neuronal ceroid lipofuscinose is mostly symptomatic and consists of generalized care and treatment of seizures with anticonvulsants. Promising new therapies are being investigated, including chaperone therapy, stem cell therapy, and CNS vector-mediated gene therapy.10 A recent report suggests that intracerebral gene therapy with the AAV2 vector containing the CLN2 gene demonstrated a reduction in cognitive decline in an open-label 10-patient phase I trial.11

Farber Disease

Farber lipogranulomatosis is an autosomal recessive disease caused by deficiency of lysosomal acid ceramidase, with accumulation of ceramide in the lysosomes. The condition is extremely rare. Most commonly, patients present soon after birth. The classical form is characterized by a triad of symptoms: subcutaneous nodules, particularly around joints; painful and progressive joint deformity; and hoarseness secondary to laryngeal involvement. Nodules have also been described in conjunctiva, the external ear, nostrils, and mouth. Seizures and psychomotor retardation/decline are characteristic for most cases. The macular cherry-red spot may be observed.12 Illness is progressive and causes death in the first few years of life. Milder phenotypes have been reported with longer survival. Involvement of subcutaneous tissues is explained by the fact that ceramide plays an important role in normal skin, contributing to lipids that preserve the water permeability of skin. Ceramide metabolism is active in the brain, and thus neuronal storage leads to CNS involvement. The gene for Farber disease is localized to 8p22-p21.3. Bone marrow transplantation was attempted in a patient with classic Farber disease without significant success.13

Lysosomal Disorders Containing Sialic Acid

Sialidosis

Sialidosis is a rare autosomal recessive inherited disorder resulting from a deficiency of α-neuraminidase. This disease may present at various ages. Most common is an adolescent-onset form, sialidosis type I, referred to as cherry-red spot myoclonus syndrome. Patients with this form have myoclonic epilepsy and cherry-red macula that typically develops in the third decade; this form is not associated with any significant mental deterioration. Sialidosis type II patients may have a fetal or congenital variant that presents as hydrops fetalis, or a severe infantile onset variant with progressive intellectual retardation, hypotonia, ataxia, sensorineural hearing loss, coarse facies, inguinal hernias, dysostosis multiplex, and cherry-red macula. As mentioned in the section on GM1 gangliosidosis, a subset of GM1 gangliosidosis results from loss of the protective protein cathepsin A, which is required for both β-galactosidase and α-neuraminidase to function; the phenotype that results is similar to the infantile-onset sialidosis. This condition is termed galactosialidosis.

Diagnosis of sialidosis can be made by excess protein-bound sialic acid in urine and, in the case of galactosialidosis, oligosaccharide excretion. Definitive testing requires the analysis of α-neuraminidase enzyme activity in leukocytes or cultured fibroblasts, or both α-neuraminidase and β-galactosidase in the case of galactosialidosis. Genetic testing is available because the gene for α-neuraminidase has been mapped to 6p21.3, and mutations identified. No specific therapies are available. Sialidosis should not be confused with disorders of free sialic acid storage, such as Salla disease, which are due to a defect in the lysosomal transport of free sialic acid.

Sialic Acid Storage Disorders

Salla disease and infantile free sialic acid storage disease (ISSD) are characterized by the accumulation of free sialic acid in the lysosomes. They are allelic variants of the same disease and are secondary to a defect in the lysosomal trafficking of sialic acid. Infants with infantile free sialic acid storage disease may have onset prior to birth with nonimmune hydrops presentation; they have a fulminant presentation and die during the first year of life. Individuals with Salla disease are severely mentally retarded, but their life span is nearly normal. Hypotonia and ataxia are the leading features. Mild coarsening of the features without skeletal changes is typical. Diagnosis is based on increased excretion of free sialic acid in urine and presence of vacuoles in skin and leukocytes. Salla disease is named after a region in northern Finland where most of the cases have been identified. The gene for Salla disease and infantile free sialic acid storage disease was mapped to 6q14-15. No specific treatments are available at present.

Molybdenum cofactor is required for the function of 3 enzymes: sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase. In patients with molybdenum cofactor deficiency, activity of all 3 enzymes is diminished. Both isolated sulfite oxidase deficiency and molybdenum cofactor deficiency are autosomal recessive traits. Patients with isolated sulfite oxidase deficiency have a clinical phenotype similar to that of patients with molybdenum cofactor deficiency. The pathogenesis of the brain damage in these disorders is not known, but it may be caused by sulfite accumulation or lack of sulfate in the CNS. Patients present in the neonatal period with refractory convulsions and severe global developmental delay. Imaging findings are similar to those seen in hypoxia/ischemia and consist of cerebral edema, atrophy, dilated ventricles, calcifications, and cystic encephalomalacia. Clinical features also include facial dysmorphology with narrow bifrontal diameter and deep-set eyes, lens dislocation, abnormal muscle tone, opisthotonus, and myoclonus, with associated feeding and respiratory difficulties. Both disorders are fatal and most patients die in early infancy. The diagnosis should be suspected if urine dipstick is sulfite positive. Urinary thiosulfate can be measured and, if elevated, is diagnostic for both sulfite oxidase deficiency and molybdenum cofactor deficiency. Patients with molybdenum cofactor deficiency may have low plasma uric acid level, whereas the level is normal in those with isolated sulfite oxidase deficiency. Some success was achieved by placing 2 patients with isolated mild sulfite oxidase deficiency on a low-protein diet, with the addition of a synthetic amino acid mixture without sulfur-containing acids cystine and methionine.14

Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder and affects mainly females. The prevalence is 1 in 10,000 girls by the age of 12,1 making it one of the most common genetic causes of severe cognitive impairment in girls. RTT is caused by mutations in the MECP2 gene located at Xq28. MECP2 encodes a nuclear protein (MeCP2) that binds methylated DNA. The function of MeCP2 protein has not been fully elucidated; it is thought to mediate transcriptional silencing and epigenetic regulation of genes in regions of methylated DNA through its association with 5-methylcytosine–rich heterochromatin and may play a role in modulation of RNA splicing as well.2 There are different levels of expression depending on the tissue and developmental stage. Mutations in MECP2 can result in a similar constellation of neuropsychiatric abnormalities with either gain or loss of protein function. For example, MECP2 duplications have been reported in males with severe cognitive impairment.

Approximately 99% of Rett syndrome cases are sporadic, resulting from a de novo mutation in most of the affected children or from inheritance of the mutation from 1 parent with germline mosaicism. In rare cases, it can be inherited from an unaffected or mildly affected mother with a favorably skewed X chromosome inactivation.

Clinical Presentation

Clinically, MECP2-related disorders present a spectrum of phenotypes, including classic RTT, variant RTT, and very mild learning disabilities in females. This variability may be related to the pattern of the X-chromosome inactivation, and depending on a favorable X skewing, some patients can be mildly affected or even asymptomatic. Another source of variability may be somatic mosaicism for the MECP2 mutations.

In males, MECP2 mutations have a range of effects from syndromic or nonsyndromic cognitive impairment to a severe neonatal encephalopathy.3 Mutations leading to a classic RTT in females cause severe encephalopathy and breathing anomalies in males, and these patients usually die before the age of 1 year. A classic RTT phenotype can be seen in patients with 47,XXY karyotype or somatic mosaicism. Some mutations with no phenotypic effect in females can cause severe cognitive impairment or psychiatric disorders.

Classical RTT symptoms appear in stages (eFig. 575.1).4-6 Girls are characterized by an apparent normal prenatal, perinatal, and early infancy period. At 6 to 18 months of age, they start a developmental stagnation period characterized by hypotonia and slow head and general growth. This is followed by regression in language and motor skills; social interaction and cognitive functioning; loss of purposeful hand use, which is replaced with stereotyped hand-wringing or “washing” movements; autistic-like behavior; disturbed sleep; breathing abnormalities; vasomotor changes; limb spasticity and gait ataxia/apraxia. This regression is followed by a pseudostationary stage characterized by amelioration of autistic-like behaviors, weight loss, osteopenia, scoliosis, motor problems, dystonia, rigidity, and foot and hand deformities. About 90% of patients develop seizures. In the late stage, motor deterioration continues, scoliosis is more severe, and finally hypoactivity ends with girls confined to a wheelchair by the adolescent years. Autonomic abnormalities include hypotrophic, cold blue feet, constipation, oropharyngeal anomalies, and cardiac abnormalities, including rhythm anomalies and prolonged QT intervals. In older ages, patients develop parkinsonian features.

Atypical or variant forms of RTT4,5 range from milder forms with a later age of onset to more severe manifestations. These variants include the forme fruste, which is milder, with later progression and hand function, fewer stereotypic movements, and occasional normocephaly. The preserved speech variant is a mild variant. These patients are able to speak few words and are normocephalic, overweight, and kyphotic. More severe variants include the congenital onset variant characterized by significant developmental delay from birth followed by the classical form without evidence of regression; the early seizure onset variant, recognized by seizures before the age of 6 months, followed by a severe RTT-like picture; the Angelman-like variant; the late regression variant characterized by late onset but typical phenotype evolving.

Diagnosis

Differential diagnosis includes Angelman syndrome, autism spectrum disorders, and mental retardation syndromes. Mutations in the CDKL5 gene have been identified in patients with RTT-like phenotype and early-onset seizures.7

The diagnosis of RTT is made based on clinical findings and/or on MECP2 molecular testing. A useful clinical tool is the updated RTT clinical criteria consensus (eTable 575.1).8 Molecular testing is available clinically; MECP2-sequencing analysis mutations and deletions have been identified in up to 95% of classic RTT cases.9 MRI studies demonstrate reduced cerebral volume, especially of the frontal gray matter, basal ganglia, midbrain, and cerebellum.

Treatment

Currently, there are no curative treatments for RTT. The management is mainly symptomatic, focused on predicting and treating problems as they develop and trying to improve the skills and quality of life of patients and their families. Regular follow up is recommended through a multidisciplinary approach, paying attention to growth, nutritional intake, dentition, gastrointestinal function, mobility, communication skills, orthopedic and neurologic complications. Medical therapy includes anticonvulsants for seizures individualized to each patient and melatonin to improve the sleep pattern. Serotonin-uptake inhibitors have been used for agitation. Spasticity and scoliosis need to be treated to improve or maintain mobility. Supplemental nutritional support may be required, including placement of a gastrostomy tube prevent malnutrition. Offering genetic testing to both parents is recommended to determine risks in future pregnancy.

Although there is not yet a specific treatment for RTT for humans, some groups, given the fact that neurons are affected but they do not die, have been working to reverse the phenotype in different mouse models. These studies have demonstrated phenotypic reversal when MeCP2 expression is reactivated, even late in development, leading to a reduction of neurologic symptoms and to a prolonged life span.10,11 These data are very promising in terms of the possibility of restoring neuronal function in Rett syndrome patients, but many caveats exist since perturbation of MeCP2 levels can be highly deleterious. Therefore, identification of the precise molecular mechanisms by which MeCP2 deficiency leads to neurologic problems is still an important goal.

Leukoencephalopathies comprise a clinical and radiographic heterogeneous group of disorders. All these disorders share the common features of neurologic dysfunction and preferential involvement of CNS white matter. Although white matter can be affected by many different processes, the term leukodystrophy is generally reserved for those with an identified or presumed genetic basis that is associated with a loss of previously formed myelin. Acquired causes of white matter dysfunction include infectious (such as encephalitis), inflammatory (such as acute disseminated encephalomyelitis and multiple sclerosis; see Chapter 556, nutritional (such as vitamin B12 deficiency), and neoplastic (such as astrocytoma) etiologies. When evaluating a patient with a suspected leukoencephalopathy, these acquired disorders should be considered and excluded with specific testing when clinically indicated.

MRI can help to distinguish genetic from acquired white matter disorders. Normal myelination starts prenatally and continues for decades, generally proceeding in a caudal-to-rostral and central-to-peripheral pattern.1 Depending on a patient’s age, specific areas are expected to be myelinated, and others are unmyelinated. With myelination, the brain MRI appearance changes, with increasing T1 signal and decreasing T2 signal in the myelinated areas. In general, brain MRI in acquired white matter disorders shows asymmetric disturbances in this process, whereas the leukodystrophies produce a symmetric pattern of abnormalities (see Fig. 556-2).

In the past, treatment of genetic leukoencephalopathies was largely restricted to supportive measures. However, hematopoietic stem cell transplantation (HSCT) has been increasingly used for some of these leukoencephalopathies. For most of these disorders, replacement of the deficient enzyme from donor cells, especially monocytes that can cross the blood-brain barrier, serves as the underlying therapeutic mechanism. This process is slow and inefficient, typically leading to an approximate 6- to 12-month period before CNS symptoms stabilize, and does not typically reverse existing deficits.2 Therefore, although useful in certain disorders, HSCT has also been disappointingly ineffective for patients with advanced symptoms and/or one of the more rapidly progressing leukoencephalopathies. In addition, HSCT is associated with significant potential morbidity and mortality. Thus, as the genetic and molecular bases for the leukoencephalopathy become increasingly delineated, it is hoped that more specific treatments, such as enzyme replacement therapy or gene therapy, will become available. At the time of the writing of this chapter, such therapies have been implemented on a small scale for few of the disorders.

There is a very long list of leukoencephalopathies, which can be broadly divided into disorders in which there is a permanent deficit in myelin deposition (hypomyelinating), disturbances of myelin formation (dysmyelinating), or loss of existing white matter (demyelinating).1 Although useful for defining disease mechanisms, these categories do not readily translate clinically. Therefore, this chapter will use a clinical approach, dividing the leukoencephalopathies primarily based on age of onset, associated symptoms, and MRI appearance (Figs. 576-1, 576-2). Given the frequent heterogeneity within some of the leukoencephalopathies and the ever-expanding list of disorders, this algorithm is an oversimplification, but can nonetheless be a clinically useful initial guide to testing.

With the list narrowed, clinicians can then use the MRI appearance to support or refute their clinical impression, and biochemical and genetic testing to confirm a specific diagnosis. With this approach, the clinician can avoid testing for every leukodystrophy, a costly endeavor that is becoming rapidly impractical due to the growing number of identified leukodystrophies. This chapter will focus on the more common and clinically important leukodystrophies, as well as those whose genetic basis has been recently identified. For an exhaustive review of all white matter disorders, with an emphasis on the radiographic findings, the reader is referred elsewhere.1

X-linked adrenoleukodystrophy (ALD) is an X-linked recessive disorder that affects approximately 1 in 21,000 males and has an overall frequency (male hemizygotes plus female heterozygotes) of approximately 1 in 16,800 in the United States.3 It affects all racial and ethnic groups.

Pathophysiology and Genetics

Mutations in the gene ABCD1 on Xq28 cause ALD. ABCD1 encodes ALD protein, a peroxisomal transmembrane protein that is a member of the ATP-binding cassette transporter family. Most mutations are missense (61%), frameshift (23%), or nonsense (10%) mutations, with less than 10% due to deletions or insertions.4 Ninety-three percent of mutations are inherited, with only 7% forming de novo.4 As of May 2008, nearly 500 unique mutations had been reported to the X-Linked Adrenoleukodystrophy Database (www.x-ald.nl).

Adrenoleukodystrophy protein (ALDP) must dimerize in order to function. It is unclear whether this process occurs as homodimerization or heterodimerization with 1 of 3 other homologous peroxisomal ATP-binding cassette half-transporters (ALD-related protein, PMP69, and PMP70).5 Although its precise activity is unknown, Adrenoleukodystrophy protein (ALDP) plays an essential, although indirect, role in the β-oxidation of very-long-chain fatty acids (VLCFA).5 Its dysfunction in patients with ALD leads to the accumulation of VLCFA in most tissues, particularly the CNS, adrenal cortex, and testes.

The presence of VLCFA in biologic membranes appears to alter their structure and function and may particularly impair myelin stability.6 White matter lesions in patients with ALD contain 3 zones: an outer layer with destruction of myelin but no inflammation, a central layer with demyelination and perivascular inflammation, and an inner layer with gliosis and little inflammation.5 Thus immune responses, particularly CD8+ cytotoxic T lymphocytes targeting oligodendrocytes, are important in ALD pathogenesis.7 Although the levels of VLCFA and the degree of inflammation appears to correlate in postmortem brain tissues of patients with ALD, the mechanisms linking these 2 processes are undefined.6

Clinical Presentation

Although many different phenotypes have been reported, most male patients with ALD present with the childhood cerebral (35% of all affected individuals), adrenomyeloneuropathy (40–45%), or “Addison disease only” (10%) forms.4 The cerebral form can also affect adolescents and adults. Persons with the ALD mutation may also be detected in an asymptomatic or presymptomatic stage during screening of at-risk family members.

The cerebral form is the most common subtype in children and begins between ages 4 and 8, with a mean age of onset of 7.2 years.4 Affected children first develop symptoms suggestive of attention deficit hyperactivity disorder, which are followed by signs of impaired auditory discrimination, cognitive dysfunction, visual abnormalities, ataxia, and, later, signs of corticospinal tract involvement. Seizures occasionally may be the heralding event. Adrenal function is abnormal in 90% of patients.4 After the initial onset, the illness advances rapidly to a vegetative state within a mean of 1.9 years, with death occurring at a mean age of 9.4 years.8

Adrenomyeloneuropathy (AMN) is the most common adult form, with a mean age of onset of 27 years. The main clinical findings are a slowly progressive spastic paraparesis, with sensory disturbances most severe in the distal aspects of the lower extremities and sphincter disturbances. These symptoms reflect the predominant involvement of the spinal cord and peripheral nerves in these patients. Impotence develops in the later stages, although many of these male patients have fathered children. Brain involvement occurs in 40% to 45% of patients with AMN based on clinical exam or MRI and is clinically severe in 10% to 20%.4 The AMN subtype also affects 20% of heterozygote females who develop milder symptoms in the third to fifth decades.

Diagnosis

The initial differential diagnosis of the childhood cerebral form of adrenoleukodystrophy (ALD) mainly includes distinguishing it from primary attention deficit hyperactivity disorder. As symptoms progress, ALD should be distinguished from other childhood-onset leukodystrophies, such as juvenile-onset metachromatic leukodystrophy, on the basis of clinical and MRI findings, with laboratory confirmation. Patients with ALD who present acutely with gadolinium enhancement may be thought to have acquired demyelinating disorders, such as acute disseminated encephalomyelitis or multiple sclerosis; these disorders tend to have much more asymmetric MRI abnormalities. Disorders that can mimic the AMN subtype include multiple sclerosis, vitamin B12 deficiency, and hereditary spastic paraparesis.

The diagnosis of ALD can be confirmed by the detection of elevated levels of very long chain fatty acids (VLCFA) in plasma, particularly C26:0 (hexacosanoic acid), the ratio of C24:0 to C22:0, and the ratio of C26:0 to C22:0. These values are elevated in 99.9% of affected males and 85% of carrier females.4 Although sequencing of the ABCD1 gene can be performed, it is clinically useful only in rare male patients with nondiagnostic VLCFA values and carrier females with normal VLCFA levels.

Gadolinium-enhanced brain MRI should be performed in all patients. Brain MRI shows preferential, symmetric involvement of the parieto-occipital white matter and/or splenium of the corpus callosum (pattern 1) in 66% of patients overall and 80% of patients under 10 years of age (Fig. 576-3).9 Fifteen percent of patients have primary involvement of the frontal lobe white matter and/or genu of the corpus callosum (pattern 2), and 2.5% have diffuse white matter abnormalities (pattern 5). More focal MRI patterns include involvement of the corticospinal tracts (pattern 3) or cerebellar white matter (pattern 4) and correlate with less-severe clinical expression.9 When present, gadolinium enhancement is typically curvilinear and close to the advancing margin, correlating with the middle zone on neuropathology specimens. Enhancement is found in approximately 45% of patients overall and predicts faster clinical and radiographic progression.9

Management

All patients should undergo an assessment of their adrenal function with measurement of plasma adrenocorticotropin hormone (ACTH) levels or cortisol response in an ACTH stimulation test with the assistance of an endocrinologist. Patients with initially normal results should be reevaluated regularly. The first priority of treatment in ALD is to provide adrenal hormone supplementation, if adrenal insufficiency is identified, in order to avoid the morbidity and mortality associated with adrenal crises.

Additional treatment of ALD may include Lorenzo’s oil, a 4:1 mixture of glycerol trioleate and glycerol trierucate that lowers plasma VLCFA levels by approximately 50% in patients with ALD, likely via competitive inhibition of VLCFA synthesis.6 Although it is ineffective in significantly altering clinical progression in patients with cerebral ALD with established neurologic symptoms, it may have a role in disease prevention. In an open-label, single-arm trial involving 89 boys with ALD, no neurologic symptoms, and a normal brain MRI, Lorenzo’s oil therapy appeared to reduce the risk of developing the childhood cerebral form of the disease by twofold over a mean follow-up of 6.9 years. It may also slow progression in adults with adrenomyeloneuropathy; this is currently being tested in placebo-controlled National Institutes of Health trial.6 In 30% to 40% of treated patients, Lorenzo’s oil reduces platelet counts, which should be followed regularly. Very close nutritional and biochemical monitoring must also be carried out.

Hematopoietic stem cell transplantation (HSCT) improves survival and neurologic function in patients with childhood cerebral ALD, particularly those early in the disease course. Although overall 5-year survival was 56% in 94 patients with ALD who received HSCT and 66% in a historical cohort of nontransplanted patients, this figure was significantly higher in patients with mild neurologic deficits and/or MRI findings at the time of HSCT.10,11 In a subgroup of 19 patients with 0 or 1 neurologic deficits and MRI severity score less than 9 on a standardized scale, the 5-year survival rate was 95% compared to 54% in a historical cohort of 30 nontransplanted patients with a similarly mild degree of neurologic deficits.10,11 In addition, 53% of the surviving transplanted patients in this subgroup were neurologically stable at 5 years, compared to only 6% in the historical control group.11 Patients with more significant clinical and MRI disease burden are at high risk of death following HSCT, which is therefore not recommended for this group of patients. In addition, as only 35% to 40% of boys younger than 10 years old with biochemical evidence of ALD will develop childhood cerebral ALD and there are substantial risks associated with HSCT, this treatment is not recommended for patients without MRI evidence of demyelination.2 Therefore, the challenge is to identify the patients who have minimal, but not more advanced, neurologic involvement and to successfully perform HSCT in them quickly. The mechanism by which HSCT affects ALD is uncertain, but probably involves alterations in the immune system, rather than replacement of the defective gene product.

Outcome and Prevention

As described above, the prognosis for ALD depends on the specific clinical phenotype. Within the childhood cerebral subtype, the overall prognosis is poor in the absence of timely HSCT. Unfortunately, plasma levels of VLCFA and specific mutations in ABCD1 do not correlate well with the clinical phenotype, making prognostication difficult. Patients with the same mutation within the same family can have different clinical expression. MRI findings may be more useful, with MRI patterns 1, 2, and 5 carrying a worse prognosis than patterns 3 and 4.9 Early age of onset is also associated with a worse prognosis.9

The diagnosis of ALD can now be made via analysis of newborn blood spots, thus making newborn screening a possibility. It is estimated that at least 50 presymptomatic boys with ALD would be identified each year in the United States.6 Importantly, 92% of boys with ALD with normal brain MRI have normal cognition on detailed neuropsychological testing.12 This finding, combined with the potential efficacy of Lorenzo’s oil in delaying disease expression and the proven efficacy of HSCT in early-stage patients, makes newborn screening an attractive, although challenging, possibility. Early diagnosis would substantially increase the currently narrow therapeutic window of opportunity by allowing advanced preparation for HSCT should it be needed. In families in which the specific mutation is known, prenatal diagnosis is also available.

Patients with Aicardi-Goutieres syndrome develop a subacute, severe encephalopathy within the first year of life, with irritability, developmental regression, and slowing of head growth. This phase usually lasts several months, after which the patient has severe cognitive impairment, spasticity, and microcephaly, but does not continue to regress.13 More than 50% also have seizures and 40% have chilblain lesions on the digits or ears. Fever in the absence of infection is also common. Computerized tomography of the head shows calcification of the basal ganglia and periventricular white matter. Brain MRI reveals hyperintense signal in the periventricular white matter with a frontal predominance on T2-weighted images. Cerebrospinal fluid contains elevated levels of white blood cells, interferon-α, and neopterin, which gradually decline over several years. Mutations in AGS1, 2, 3, or 4 cause approximately 80% of cases of the syndrome, with nearly all patients having homozygous recessive or compound heterozygote mutations.13AGS1 encodes for 3 prime repair exonuclease 1 (TREX1). Mutations in this gene can produce the syndrome at birth, with associated hepatosplenomegaly, transaminitis, and thrombocytopenia. AGS2, 3, and 4 encode for subunits of ribonuclease H. Due to the presence of neurologic abnormalities, microcephaly, and intracranial calcifications, congenital toxoplasmosis, rubella, CMV, and herpes simplex (TORCH) infections should be ruled out with appropriate serologic and virologic studies in patients suspected of having Aicardi-Goutieres syndrome.

Alexander disease is a rare, autosomal dominant leukodystrophy that has been reported in many different racial and ethnic groups. Its exact incidence is uknown.14

Prior to 2001, the definitive diagnosis of Alexander disease required the demonstration of Rosenthal fibers, eosinophilic rodlike intracellular inclusions composed of aggregates of glial fibrillary acidic protein (GFAP) and other proteins, on brain biopsy specimens of affected patients. In 2001, Brenner and colleagues discovered mutations in GFAP on chromosome 17q21 in 10 of 11 patients with Alexander disease.15 Subsequent studies have shown that GFAP mutations account for more than 90% of all cases of Alexander disease.16 Nearly all of the identified mutations are missense mutations involving exons 1, 4, or 6, with hotspots at residues R79 and R239.17 GFAP is the major intermediate filament protein in CNS astrocytes. The exact mechanisms by which alterations in GFAP in astrocytes lead to the myelin abnormalities seen in Alexander disease are unknown.

Three forms of Alexander disease are recognized based on age of onset. The infantile-onset form manifests within the first 2 years of life and comprises approximately 65% of cases.14 Typical symptoms include developmental delay, megalencephaly, and seizures. As the disease progresses, cognitive decline, feeding problems, and spastic quadriparesis become apparent. Some infants present acutely in the first year with hydrocephalus and increased intracranial pressure due to aqueductal stenosis. Death usually occurs between the ages of 2 and 10 years. A more fulminant neonatal form with onset in the first month of life and very rapid progression has also been proposed.

Juvenile-onset Alexander disease (25%) usually begins between the ages of 4 and 10 years. The most common symptoms consist of bulbar or pseudobulbar dysfunction, especially dysphagia. Spasticity, ataxia, and cognitive regression may also occur. Megalencephaly may occur, but is less common than in the infantile-onset form. These children may survive for up to 10 years and frequently longer. Adult-onset forms comprise 10% of all cases with marked variability in presentation.14

The combination of macrocephaly and leukodystrophy in the first 2 years of life is suggestive of Alexander disease. MRI findings and biochemical and genetic testing help to differentiate it from other disorders such as Canavan disease and megalencephalic leukoencephalopathy with subcortical cysts. Juvenile-onset cases can be distinguished from other leukodystrophies with a similar age of onset, such as the juvenile-onset forms of metachromatic leukodystrophy and Krabbe disease, by the lack of peripheral nervous system involvement, as well as MRI features.

MRI in Alexander disease demonstrates extensive, symmetric T2 hyperintense signal in the cerebral white matter with predominant involvement of the frontal lobes (Fig. 576-4). Additional common findings include (1) a periventricular rim of T1 hyperintensity and T2 hypointensity, (2) swelling and later atrophy of the basal ganglia and thalamus, (3) brainstem abnormalities, and (4) contrast enhancement involving various locations. The presence of 4 of 5 of these common findings makes the diagnosis of Alexander disease likely, based on a large, multicenter study.18 However, although frontal-predominant white matter T2 hyperintensities remains the most classic finding, recent studies have demonstrated significant heterogeneity in the MRI appearance.19 Thus, patients suspected of having Alexander disease should undergo sequencing of the GFAP gene, even in the presence of atypical MRI findings.

There is no specific treatment for Alexander disease, although supportive treatment may improve symptoms. The overall prognosis is poor, although significant differences in rates of progression and age at death exist between the different subtypes. Due to its relative rarity, predictive genotype-phenotype correlations do not exist. Prenatal diagnosis is possible in families in which the disease-causing mutation is known.

Canavan disease is an autosomal-recessive neurologic disorder that affects all ethnic groups, but has its highest rate in Ashkenazi Jews. In this group, the carrier rates have been estimated between 1:40 and 1:60.20

Mutations in the ASPA gene on chromosome 17p cause Canavan disease. This gene encodes aspartoacylase, an enzyme that is responsible for hydrolyzing N-acetylaspartic acid to aspartic acid and acetate. Two mutations (E285A and Y231X) account for 98% of alleles in Ashkenazi Jewish patients, while 1 mutation (A305E) is found in approximately 50% of non-Jewish patients.20 Deficiency of the enzyme leads to accumulation of N-acetylaspartic acid in the brain, which in turn causes spongiform degeneration of the white matter via unknown mechanisms. One hypothesis proposes that a secondary reduction in acetate levels causes decreased myelin synthesis,21 and another suggests disturbance in the role of N-acetylaspartic acid as a cerebral osmolyte.22

Following normal initial development, patients with Canavan disease develop the classic triad of macrocephaly, hypotonia, and poor head control.23 Delayed development is apparent by 3 months of age. Macrocephaly may not be apparent within the first few months, but the head enlarges to above the 90th percentile within 6 months to a year of life. Affected children never develop the ability to support the head, sit, or stand independently. Seizures and optic atrophy frequently develop in the second year of life. Over time, hypotonia evolves into spasticity, gastroesophageal reflux becomes prominent, and swallowing deteriorates, leading to feeding difficulties, poor weight gain, and need for gastrostomy tube feeding.20 The rate of overall disease progression is variable.23

The combination of macrocephaly and leukodystrophy with onset at less than 12 months of age raises Canavan disease and Alexander disease as the 2 most likely possibilities, which can be distinguished with magnetic resonance spectroscopy (MRS) and biochemical testing. MRI demonstrates diffuse symmetric white matter changes consisting of increased signal on T2-weighted images (Fig. 576-5A). MRS reveals the characteristic elevation in N-acetylaspartic acid (Fig. 576-5B), which can also be detected in very high levels in urine samples. The diagnosis can be confirmed with analysis of the ASPA gene, starting with targeted mutation screening followed by full sequencing if needed.

Treatment of Canavan disease is supportive. Two patients have undergone intraventricular injection of a liposome/adeno-associated virus–based plasmid in attempt to deliver the ASPA gene.24 A larger trial of such gene therapy is reportedly ongoing, but clinical results have not been published to date. One patient treated with lithium was found to have decreased N-acetylaspartic acid levels in response to treatment, but larger studies have not been reported.25 Acetate supplementation has also gained interest, but has not been formally tested.

The prognosis for Canavan disease is poor, with patients not achieving independent sitting. With improved medical and nursing care, the average life expectancy is into the teens.20 Accurate genotype-phenotype correlations are lacking. Given the high carrier rate in Ashkenazi Jews, population screening has been proposed. Prenatal detection is also available in families in which the pathogenic mutation is known.

Although nearly universally described in adult patients, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) may rarely be diagnosed in childhood.26 The most common symptoms include migraine, usually with aura, developing at a mean age of 26 years, followed by recurrent transient ischemic attacks or strokes, developing at a mean age of 46 years.27 Many patients eventually develop dementia. The MRI pattern consists of symmetric hyperintensities in the periventricular and deep white matter on T2-weighted images, first appearing in the anterior temporal lobes and gradually becoming diffuse over time. The cerebral pathology consists of white matter gliosis and a small-vessel angiopathy with PAS-positive material in the media of the vessel. CADASIL is caused by mutations in NOTCH3 on 19p13.1, which encodes a transmembrane protein with receptor and cell signal transduction function.

Globoid cell leukodystrophy is an autosomal recessive inherited glycosphingolipid storage disorder primarily causing a leukodystrophy. It has an estimated incidence of 1:100,000 in the United States and affects all ethnic groups.28

Pathophysiology and Genetics

Globoid cell leukodystrophy is caused by mutations in the GALC gene on chromosome 14q31 encoding the lysosomal enzyme galactosylceramide β-galactosidase (galactocerebrosidase). GALC produces an 80-kd precursor that is cleaved into 50-kd and 30-kd subunits that aggregate to form the active enzyme. Many different mutations affecting each of the 17 exons have been detected. In patients of European ancestry with infantile onset, a 30-kb deletion starting in exon 10 comprises approximately 45% of mutant alleles.28 This deletion typically results in the classic infantile form, unless it is inherited with the G-to-A mutation at position 809 on the other allele, which invariably results in the late-onset form.

Galactocerebrosidase is required to degrade galactosylceramide, an important glycolipid in myelin structure. Most mutations lead to the production of an unstable, rapidly degraded form of the protein, with residual enzyme activity at 0% to 5% of normal levels.28 The protein is also responsible for the degradation of galactosylsphingosine (pyschosine); resulting elevated levels appear to be toxic to oligodendrocytes.29 Neuropathologic specimens show the accumulation of globoid cells, perivascular multinucleated macrophages with inclusion bodies, as well as loss of oligodendrocytes, white matter rarefaction, and gliosis. The disorder also affects the peripheral nervous system in the form of a diffuse demyelinating sensorimotor polyneuropathy.

Clinical Presentation

The classic infantile form with onset in the first 6 months of life accounts for 90% of all cases.28 This form frequently consists of extreme irritability followed by rigidity, tonic spasms, and progressive neurologic deterioration. Three stages have been proposed. Following a period of a few months of apparently normal development, stage I ensues with irritability, fever in the absence of infection, hypersensitivity to stimuli, and developmental arrest. Although it may not be apparent clinically, peripheral neuropathy is detectable by nerve conduction studies in nearly all patients at this stage.30 Cerebrospinal fluid examination is remarkable for the elevation of protein, typically above 70 mg/dL. Stage II consists of rapid, global deterioration, with severe spasticity resulting in opisthotonic posturing. Epileptic seizures also occur. Finally, the patient is left in a decerebrate state with blindness and immobility in stage III. Death occurs at an average age of 13 months in untreated patients.28

Onset after 6 months of life has been designated as late-onset, which has a variable presentation and subsequent course. This form has been generally divided into late-infantile (onset at 6 months to 4 years of age), juvenile (4 years to 19 years), and adult-onset (> 20 years) subtypes. Common presenting symptoms include weakness and vision loss, followed by progressive deterioration of motor and then cognitive function. In general, patients with onset at a younger age within the late-onset group have a more rapidly progressive course.29 In 1 study of 9 patients with onset between 1.5 and 5 years, the average age of death was 9.5 years.29

The clinical features described above, although nonspecific, should raise suspicion for globoid cell leukodystrophy. The initial presentation will typically lead to a brain MRI that focuses the differential diagnosis on leukodystrophies. Due to the involvement of the peripheral nervous system, late-onset globoid cell leukodystrophy can be confused with metachromatic leukodystrophy. In order to confirm the diagnosis, galactocerebrosidase enzyme activity should be measured in an experienced laboratory. Mutation analysis can be subsequently performed.

More than 95% of patients with the early infantile form have slowed sensory and motor conduction velocities on nerve conduction studies, detectable as early as 1 day of life.30 Although they may be present, nerve conduction study abnormalities are significantly milder in late-onset patients. Nerve conduction studies are more sensitive than other electrophysiologic tests. In the early onset group, abnormal brainstem auditory evoked potentials, electroencephalograms, and visual evoked potential are present in approximately 90%, 65%, and 50% of patients, respectively.31 Such abnormalities are less frequent in the late-onset group.

The CT scan may initially demonstrate nonspecific increased density in the brainstem, thalami, caudate nuclei, corona radiata, cerebellar cortex, and periventricular and capsular white matter (Fig. 576-6A). In patients with the infantile-onset form, MRI reveals large, symmetric, nonenhancing T2 hyperintensities in the brainstem, cerebellum, and centrum semiovale, initially sparing the subcortical fibers.29 Areas of low signal on T2-weighted images, particularly in the thalamus and dentate, may also be present (Fig. 576-6B).29 Patients with later-onset forms often have discrete T2 hyperintense lesions in the corticospinal tracts in the internal capsules and brainstem.29 Over time, the white matter changes become more diffuse in both groups. Rare symptomatic infants have had apparently normal brain MRIs.

Treatment and Outcomes

Hematopoietic stem cell transplantation in the presymptomatic state or in late-onset patients with mild symptoms may be beneficial. The differing rates of progression in the early versus late-onset forms may partially explain the discrepant benefits of stem cell transplantation in these 2 groups.

In 4 patients with late-onset disease, resolution or stabilization of established neurologic deficits, and improvement in electrophysiologic and MRI findings have been reported following bone marrow transplantation.32 Beneficial effects were also reported in 11 “asymptomatic” infants who were diagnosed prenatally or at birth due to prior family history and received umbilical cord blood transplantation at a median age of 28 days.33 These benefits included a survival rate of 100%, developmental progress in cognition and language, and improvements or normalization in brain MRI and electrophysiologic studies. However, these benefits in mortality and morbidity were not observed in 14 symptomatic infants in the same study, and the procedure is therefore not recommend in early-infantile onset patients with established symptoms.33 Umbilical cord blood is preferred over bone marrow as the source of stem cells in the infantile group in order to speed the matching process and time to transplantation.

Although promising, close analysis of the results of umbilical cord blood transplantation in asymptomatic patients suggest that some caution and further study are warranted. Although the reported details are unclear, gross motor delay appears to be present in all of these patients, including 2 patients with progressive symptoms following an initial period of normal function.33,34 Worsening of peripheral nerve function after initial improvement following stem cell transplantation has also been reported.35 At least 33% of transplanted patients also required gastrostomy tube placement.34 Thus, the long-term prognosis of patients who receive stem cell transplantation in the earliest stages of early-infantile Krabbe disease is uncertain.

The prognosis of untreated patients with the early-infantile onset form is poor, with an average age of death of 13 months.28 The prognosis for patients with later-onset forms is variable; in general, those with earlier onset within this group have severe neurologic deficits and death by age 10 years.29

Tandem mass spectrometry can measure galactocerebrosidase enzyme activity in dried newborn blood spots, thus allowing for newborn screening, which has been implemented in New York State.28 This earliest detection may allow for very rapid stem cell transplantation, even in patients without a family history. In addition, prenatal diagnosis via measurement of GALC enzyme activity or gene sequencing in affected families is available.

Although there is a spectrum of clinical severity, the few described patients with hypomyelination with atrophy of the basal ganglia and cerebellum all eventually develop spasticity, cerebellar ataxia, and extrapyramidal movement disorders.36 Brain MRI shows isointense to mildly hyperintense signal on T1-weighted and hyperintense signal on T2-weighted images in all of the cerebral hemispheric white matter, consistent with hypomyelination. There is atrophy of the cerebellum, putamen, and caudate, with striking preservation of the thalamus and globus pallidus. The underlying cause of the syndrome is unknown.

As the name implies, patients with hypomyelination and congenital cataract have bilateral cataracts within the first month of life, as well as neurologic impairment. Frequent neurologic symptoms include developmental delay, mental retardation, hyperreflexia, and cerebellar signs. Brain MRI reveals diffuse isointense to slightly hyperintense T1 signal and hyperintense T2 signal in the supratentorial white matter, consistent with hypomyelination. The disorder is caused by mutations in DRCTNNB1A on chromosome 7p, which encodes for hyccin, a protein of unknown function.

MLC is a rare leukodystrophy that typically presents with increasing head circumference in the first year of life. Additional features include cognitive impairment (which is typically mild to moderate), motor delay and deterioration due to progressive spasticity, and seizures. Brain MRI of affected patients reveals diffuse hyperintense signal in the cerebral white matter on T2-weighted images and temporal lobe cysts. Cysts may also be present in the frontoparietal lobes. The disease is caused by mutations in the MLC1 gene on chromosome 22q, which is a transmembrane protein expressed in astrocytes with unclear function.17

Metachromatic leukodystrophy is an autosomal recessive lysosomal storage disease involving glycosphingolipid metabolism that causes a leukoencephalopathy with an estimated frequency of 1 in 40,000.37 Although the incidence is higher in select small population groups with high rates of consanguinity, it affects all ethnic groups.

Pathophysiology and Genetics

The major cause for metachromatic leukodystrophy (MLD) is mutations in the gene on chromosome 22q13.3 encoding the lysosomal enzyme arylsulfatase A (ASA), which catalyzes cerebroside 3-sulphate (sulfatide). Sulfatide normally composes approximately 5% of myelin lipids. Over 100 mutations have been identified in the ASA gene.38 Mutations have been broadly classified as I alleles, which result in no functional enzyme activity, or A alleles, which retain some activity. Inheritance of 2 I alleles usually causes infantile-onset MLD, and 2 A alleles leads to adult-onset MLD; the combination results in the juvenile-onset form. Most mutations are found in individual patients, but 3 mutations are fairly common among patients of European ancestry: (1) a splice donor-site I type mutation at the exon 2/intron 2 border (25%), (2) a Pro426Leu A type substitution (25%), and (3) an Ile179Ser A type substitution (12%).38 Patients with homozygous P426L mutations typically present with gait disturbance, whereas patients with I179S heterozygous mutations present with neuropsychiatric symptoms.39 However, the overall poor genotype-phenotype correlation in MLD impedes accurate prediction in individual patients and suggests additional, undefined genetic or environmental factors.

Approximately 10% of the normal population carries the so-called arylsulfatase A-pseudodeficiency (ASA-PD) alleles. These alleles result in 5% to 20% of normal ASA enzyme activity but no clinical manifestations, even when inherited in a homozygous state or when inherited with a single MLD allele. The 2 most common mutations are caused by 2 A-to-G transitions; the first results in an N350S substitution and the second alters the polyadenylation signal in the 3 untranslated region. If moderate reductions in ASA activity are found, gene sequencing can be performed to differentiate the disease, carrier and pseudodeficiency states.

Rarely, patients with normal ASA gene structure and enzyme activity have a clinical phenotype compatible with metachromatic leukodystrophy. This situation is caused by mutations in the gene on chromosome 10 encoding the cerebroside sulfate activator protein known as saposin B. This protein is required to solubilize sulfatides so that arylsulfatase A can then hydrolyze them.37 Other rare patients have multiple sulfatase deficiency that combines features of metachromatic leukodystrophy and the mucopolysaccharidoses, including coarse facial features and skeletal abnormalities. Mutations in the gene encoding the formylglycine-generating enzyme, which is needed to activate several sulfatases, cause this disorder.

Regardless of the specific genetic cause, sulfatide accumulation in the liver, kidney, and central and peripheral nervous systems occurs in each of these disorders. When such tissues are stained with cresyl violet or toluidine blue, the excess sulfatides produce a brownish or reddish color compared to the blue color of cell nuclei, leading to the name metachromatic. In the nervous system, sulfatides particularly accumulate in oligodendrocytes and Schwann cells, leading to demyelination via unknown mechanisms. Postulated mechanisms include myelin instability, impaired signaling, and inflammation.40 Psychosine sulfate is also elevated and may have a toxic effect on myelin.

Clinical Presentation and Diagnosis

The clinical phenotype of metachromatic leukodystrophy has been divided based on the age of onset. The late-infantile form (50–60% of cases) manifests with difficulty walking, weakness, and hypotonia between ages 1 and 2, following initially normal development. Eventually, spasticity and loss of speech result in a quadriplegic state and death approximately 3.5 years after onset.37 Juvenile-onset cases (20–30%) develop between 4 and approximately 14 years of age. Within this range, younger patients often present with gait problems related to peripheral nerve involvement, whereas older children tend to initially have school problems and behavioral difficulties. The rate of progression of the disease varies, with survival typically 10 to 20 years after onset. Patients with the adult-onset form (15–20%) usually have psychiatric problems as the major initial feature of the disease.

Some patients may initially present with features restricted to the peripheral nervous system and receive a diagnosis of an isolated peripheral neuropathy, such as chronic inflammatory demyelinating polyneuropathy. However, the eventual development of cerebral involvement should lead to a brain MRI, revealing the leukodystrophy. Patients with symptoms and signs referable to the CNS will undergo brain MRI at the onset. The differential diagnosis in such patients is focused on the leukodystrophies. In particular, given the involvement of the peripheral nervous system, metachromatic leukodystrophy should be distinguished from late-onset globoid cell leukodystrophy via biochemical and genetic testing.

Brain MRI in patients with metachromatic leukodystrophy reveals diffuse, symmetric hyperintense signal on T2-weighted images involving the cerebral white matter, characteristically sparing the immediate subcortical U fibers (Fig. 576-7). These abnormalities may initially start posteriorly and then spread anteriorly as the disease progresses. Atrophy often follows. Nerve conduction studies show diffusely slow motor and sensory conduction velocities indicative of a demyelinating polyneuropathy. In some patients, multifocal slowing, classically indicative of an acquired neuropathy, may be present and does not rule out the diagnosis.41 Measurement of arylsulfatase A enzyme activity narrows the diagnosis to metachromatic leukodystrophy. Urinary excretion of sulfatides is also elevated. Sequencing of the arylsulfatase A gene confirms the diagnosis, with rare patients requiring analysis of the saposin B gene.

Treatment and Outcomes

Treatment for metachromatic leukodystrophy is primarily symptomatic, with treatments directed at spasticity and pain control. A phase I/II trial of enzyme replacement therapy is also underway, but results are currently unknown.38 Bone marrow transplantation (BMT) may be effective to partially ameliorate symptoms if it is used early in the course of juvenile- and adult-onset forms. However, peripheral nervous system involvement is not improved by BMT and patients eventually develop significant motor impairment.42 Although enhancement of BMT with infusion of expanded, donor-derived mesenchymal stem cells led to improved nerve conduction velocity in 4 of 6 patients with metachromatic leukodystrophy (MLD), it did not lead to clinical changes.43 BMT is not recommended for patients with symptomatic late-infantile MLD as the rapid progression of the disease outpaces any potential improvment.2 It is unclear if asymptomatic siblings of patients with late-infantile MLD benefit from BMT. A case report of an asymptomatic 7-week-old infant with MLD whose technically successful BMT did not appreciably alter her neurologic course compared to her older brother, but did lead to major complications, highlights the uncertainties in this area.44

Untreated patients with metachromatic leukodystrophy eventually develop profound motor and cognitive dysfunction leading to early death. The age at which this process starts and the rate of subsequent deterioration depends on the specific subtype as described above. Prenatal diagnosis is available in families with a previously affected member. Tools for newborn screening are also available and may soon allow for very early diagnosis and consideration of BMT prior to symptom onset, even in patients without a family history.

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive hypomyelinating leukoencephalopathy with a prevalence of approximately 1/200,000 to 1/500,000.45

Pathophysiology and Genetics

PMD is caused by abnormalities in the proteolipid protein 1 (PLP1) gene on chromosome Xq22. This gene encodes the transmembrane myelin proteolipid protein, which makes up 50% of the protein content of myelin. The full PLP1 transcript can also be alternatively spliced to form DM20, which lacks residues 117-151 encoded in a portion of exon 3. Mutations in PLP1 appear to cause aberrant folding of myelin proteolipid protein, which in turn triggers the unfolded protein response and oligodendrocyte apoptosis.46 Pathologic specimens show decreased or absent myelin in affected areas, with preservation of axons and scattered areas of preserved but abnormally thin myelin.47

Duplication of PLP1, which can be detected with interphase fluorescent in situ hybridization or quantitative polymerase chain reaction testing, accounts for 50% of all cases. It is usually associated with the classic phenotype described below. More than 100 reported point mutations comprise 15% to 20% of cases.45 Deletions and splice-site or regulatory region mutations account for a small percentage of patients. Mutations in PLP1 can also cause familial spastic paraplegia type 2 (SPG2), which forms a clinical continuum with PMD. Although exact genotype-phenotype correlations do not exist, mutations in the PLP1-specific region in exon 3, which therefore spare DM20, tend to cause SPG2 instead of PMD.48

Approximately 5% to 20% of patients with a PMD phenotype do not have detectable PLP1 mutations, suggesting the involvement of other genes. Such patients are labeled as having PMD-like disease. Mutations in one such gene, GJA12 on chromosome 1q41-42, which encodes gap junction protein α12 (connexin 46.6), account for less than 10% of such cases.49 The remaining genes are unidentified at present.

Clinical Presentation

PLP1-related disorders form a clinical continuum, with connatal PMD at the most severe end and pure SPG2 at the mildest end.45 The connatal form presents at, or shortly after, birth and includes nystagmus, hypotonia, and stridor. As the infant ages, severe spasticity, ataxia, and cognitive impairment develop, and walking is not achieved. Classic PMD manifests with nystagmus, typically in the first 2 months of life. Symptoms are similar to the connatal form, but are generally less severe and progress more slowly. Movement disorders may also be present. Following normal development in the first year of life, pure SPG2 usually starts between ages 2 and 5 with spastic paraparesis and bladder dysfunction. Complicated forms of SPG2 include nystagmus, ataxia, and cognitive dysfunction. Female carriers of PLP1 mutations may develop mild to moderate symptoms later in life. There is an interesting inverse correlation between the likelihood of clinical expression in female carriers and disease severity in their male offspring.

Diagnosis and Treatment

The combination of early-onset nystagmus and leukodystrophy narrows the differential diagnoses significantly, as other leukoencephalopathies such as adrenoleukodystrophy and metachromatic leukodystrophy, do not typically include this symptom. Patients with Salla disease (free sialic acid storage disorders) can also have nystagmus and a diffuse leukodystrophy. This disorder can be considered in patients with negative PLP1 and GLA12 testing.

The MRI appearance of PMD shows a diffuse increase in the signal of white matter on T2-weighted images that is characteristic for children over the age of 1 year (Fig. 576-8). In younger children, the MRI is less specific because the brain has yet to fully myelinate. Patients with spastic paraplegia type 2 may have patchy T2 hyperintensities in the cerebral white matter. Evoked potential studies are also abnormal, and EMG and nerve conduction velocities are usually normal. Patients suspected of having PMD should undergo testing of the PLP1 gene, looking first for duplications and proceeding to sequencing if needed. GJA12 sequencing should be considered in patients with the PMD phenotype and normal PLP1 testing.

Treatment of PMD is supportive, with attention to spasticity and seizures. The prognosis of the PLP1-related disorders depends on the specific phenotype as described above. Although there is some variation, presentations within a single family tend to be similar. Prenatal diagnosis is available if the disease-causing mutation is known in the family.

Vanishing white matter (VWM) disease, also known as childhood ataxia with diffuse CNS hypomyelination, is an important cause of previously undiagnosed leukodystrophies, although its exact incidence is unknown. Mutations in any of the 5 genes (EIF2B1-5) encoding the 5 subunits (α, β, γ, δ, and ε) of eukaryotic translation initiation factor eIF2B cause the disease. Approximately two thirds of mutations are found in EIF2B5.50 eIF2B is involved in the initiation of translation of mRNAs into proteins. Pathologic specimens in patients with VWM disease show marked changes restricted to the white matter, often with frank cavitation, without inflammation. The mechanisms by which the mutations lead to selective, severe white matter injury are uncertain, but may involve the unfolded protein response.50

The most common form of VWM disease presents between ages 2 and 6 years, with chronic progressive ataxia and less severe spasticity and cognitive decline, punctuated by acute deteriorations in the setting of minor head trauma or fever with incomplete or no recovery. Mild epilepsy is also common. In addition to this classic phenotype, a wide spectrum of presentations, ranging from a severe antenatal form to mild adult-onset variants, have been described.50 In addition to brain involvement, primary or secondary ovarian failure can be an important clue in some patients. The acute episodes and white matter changes may prompt consideration of acute disseminated encephalomyelitis (ADEM). However, patients with ADEM typically have more asymmetric white matter lesions and marked or complete recovery from the acute episodes (see also Chapter 556). Encephalitis is also a consideration, but typically involves both gray and white matter on MRI.

MRI demonstrates diffuse confluent abnormality in all of the cerebral white matter early in the course of the disease and even in presymptomatic patients. As the disease progresses, the white matter is replaced by fluid, shown best as the conversion from high to low signal on fluid-attenuated inversion recovery sequences.50 Diagnostic MRI criteria have been developed by van der Knaap and are highly sensitive and specific for the identification of mutations in EIF2B genes.

There is no known treatment for VWM disease, but potential precipitating factors should be avoided and treated promptly if present. Many patients with the childhood onset form die within a few years, but there is overall considerable clinical heterogeneity. Prenatal diagnosis is available for families in which the disease-causing mutation is known.

Patients with deletions in 18q frequently have abnormalities in the cerebral white matter, evident on MRI as poor differentiation between gray and white matter on T1-weighted images and increased white matter signal intensity on T2-weighted images. Such patients always harbor a deletion between 18q22.3 and 18q23, which includes the gene for myelin basic protein, one of the major structural proteins of myelin.51 Most patients have cognitive and motor impairment. The disorder should be suspected in patients with any of the additional variable features of the syndrome, which include craniofacial dysmorphisms, atretic or stenotic external auditory canals, foot deformities, and genitourinary malformations.51 The diagnosis can be made with fluorescent in situ hybridization testing of the 18q locus.

The pediatric neurotransmitter disorders are a fairly recently described group of inherited neurometabolic disorders related to defects in neurotransmitter synthesis or breakdown. These disorders may be divided into defects of γ-aminobutyric acid (GABA), glycine or monoamine metabolism, and secondary neurotransmitter deficiency states. This chapter will primarily discuss disorders of monoamine metabolism; we will focus on the diseases best characterized to date, including GTP cyclohydrolase deficiency, tyrosine hydroxylase deficiency, aromatic l-amino acid decarboxylase deficiency, and monoamine A deficiency.

The monoamine neurotransmitters include biogenic amines or catecholamines (dopamine, norepinephrine, epinephrine) and serotonin. Synthesis of dopamine and serotonin begins with tyrosine and tryptophan. Tyrosine is hydroxylated by tyrosine hydroxylase and tryptophan by tryptophan hydroxylase to form levodopa and 5-hydroxytryptophan, respectively. Levodopa and 5-hydroxytryptophan are then catalyzed to dopamine and serotonin by aromatic l-amino acid decarboxylase (AADC). See Figure 577-1.

Dopamine is converted to norepinephrine via dopamine β-hydroxylase; norepinephrine is then metabolized to epinephrine. Dopamine and serotonin are also deaminated by monoamine oxidase A and B to homovanillic acid and 5-hydroindoleacetic acid, respectively, metabolites that can be measured in CSF. Dopamine is also broken down by catechol-o-methyltransferase to 3-O-methyldopa, also detectable in CSF. See Figure 577-1.

Tetrahydrobiopterin serves as a cofactor for both tyrosine hydroxylase and tryptophan hydroxylase. Similarly, pyridoxine (vitamin B6) is a cofactor for AADC. Thus, impairments in tetrahydrobiopterin or pyridoxine metabolism may result in deficiencies of monoamine neurotransmitters as well.

The disorders in the pathways described above typically affect the basal ganglia due to dopamine deficiency and thus present with hyper- or hypokinetic abnormalities of movement. However, there are widespread effects across the cerebrum causing a broad range of symptoms. Patients may present subtly with global developmental or motor delays, but the presence of abnormalities of tone such as spastic diplegia, dystonia, autonomic dysfunction, or evidence of disease progression should point toward this group of disorders. Deficits in neurotransmitter metabolism should be considered in the differential diagnosis of progressive encephalopathies, particularly those with onset in infancy. The diagnosis of these conditions is often made late due to the lack of awareness of this group of diseases.

Guanosine triphosphate cyclohydrolase (GCH1) catalyzes the rate-limiting step in tetrahydrobiopterin synthesis, thus impairment of this enzyme results in deficiencies of serotonin and dopamine. GCH1 deficiency was first described by Segawa in 1971.1 Also known as Segawa disease, dopa-responsive dystonia, or hereditary progressive dystonia, the disorder is characterized by dystonia or tremor with diurnal fluctuation. Patients typically present in the first decade of life with gait abnormality due to dystonia of the lower extremities. Symptoms are worse later in the day and improved following sleep. Over the course of 10 to 15 years, dystonia gradually spreads to involve all 4 limbs. Postural tremor develops in the upper extremities and spreads to involve the head and neck. By adulthood, parkinsonian signs predominate. Symptoms become static, with less diurnal variation by the fourth decade. The predominant symptoms appear to be determined by a patient’s age, regardless of the age at onset or duration of disease.2 Short stature, sleep disturbances, and psychiatric issues, including increased risk of depression and obsessive-compulsive symptoms, have been reported in association with GCH1 deficiency.2,3

Clinical examination reveals asymmetric dystonia, most prominent in the lower extremities initially. If the examination is early in the day, however, the dystonia may be minimal. Increased lower extremity tone, hyperreflexia, and extensor plantar responses may be present. Cognition remains normal throughout the clinical course.

GCH1 deficiency, as described above, is an autosomal dominant disorder with variable penetrance; over 100 mutations in the GCH1 gene (14q22.1-22.2) have been described. Considerable variability in phenotype has been observed with respect to symptom onset, clinical manifestations, and severity, even within the same family. Symptoms ranging from mild exertion-induced dystonia to severe dystonia and parkinsonism have been described.4 Patients may also present with tremor, spastic paraparesis, or infantile hypokinetic rigid syndromes.5 In sporadic mutations, there is a female-to-male ratio of 4:1; the literature supports a sex effect on phenotype as well, with more severe cases occurring in girls. Genetic testing is clinically available, although a known mutation is not identified in up to 40% to 50% percent of cases.6,7 Note that there is also a less common severe autosomal recessive form of GCH1 deficiency characterized by global developmental impairment, hypotonia, autonomic dysfunction, seizures, dystonia, and oculogyric crises.

CSF evaluation shows low homovanillic acid, low neopterin, and low biopterin concentrations. See Table 577-1 for comparison to other disorders.

The hallmark of the disorder is dramatic sustained responsiveness to low doses of levodopa-carbidopa, which are generally well tolerated. Note that other basal ganglia diseases, such as juvenile parkinsonism, may also respond to levodopa. However, onset in early childhood, diurnal fluctuation, appearance of tremor later in life, and preservation of cognition should help differentiate guanosine triphosphate cyclohydrolase deficiency from other disorders.8,9

Tyrosine hydroxylase catalyzes the conversion of tyrosine to levodopa, the rate-limiting step in the synthesis of catecholamines. Tyrosine hydroxylase deficiency typically presents as a progressive encephalopathy with extrapyramidal and autonomic symptoms. Onset of symptoms generally occurs in the first 2 years of life. Extrapyramidal manifestations include oculogyric crises, dystonia, parkinsonism, tremor, or choreoathetosis. Observed alterations in tone range from truncal hypotonia to rigidity and severe spasticity; even without frank parkinsonism, an overall paucity of movement is observed. The phenotypic spectrum is broad; patients may display infantile parkinsonism, spastic paraparesis, exercise-induced dystonia, or progressive gait disturbance as the main symptoms. In contrast to guanosine triphosphate cyclohydrolase (GCH1) deficiency, the age of onset is earlier, dystonia develops later in the clinical course, and diurnal fluctuation is a less prominent feature. Over the course of the disease, muscle tone increases, contractures develop, and psychomotor retardation and immobilization ensue.10The encephalopathy most commonly manifests as irritability. Tyrosine hydroxylase deficiency may result in mild autonomic dysfunction due to norepinephrine and epinephrine deficiency, causing ptosis, miosis, postural hypotension, temperature instability, and excessive salivation.

In addition to dystonia, physical examination demonstrates truncal hypotonia, appendicular hypertonia, and hyperreflexia with extensor plantar responses.

CSF evaluation demonstrates low homovanillic acid (HVA) and low 3-methoxy-4-hydroxyphenylglycol levels, with normal 5-hydroindoleacetic acid, neopterin, and biopterin. Plasma catecholamine levels are normal, although urine HVA is decreased. See Table 577-1 for comparison to other disorders. Gene sequencing is also available for clinical testing.

Often referred to as an autosomal recessive dopa-responsive dystonia, some patients do respond to treatment with dopamine. However, many have incomplete or absent response to levodopa. Those who present with infantile parkinsonism are the least likely to benefit and tend to have the highest incidence of side effects related to levodopa administration.11 Levodopa appears to be most helpful for later-onset forms, but may take weeks to months to produce an effect, in contrast to GCH1 deficiency, for which benefit is typically observed within days.10 In tyrosine hydroxylase deficiency, prognosis overall remains poor.

Aromatic l-amino acid decarboxylase (AADC) catalyzes the conversion of levodopa to dopamine and 5-hydroxytryptophan to serotonin; defects result in dopamine, norepinephrine, epinephrine, and serotonin deficiencies. First described in 1990, this rare autosomal recessive disorder is characterized by global developmental delay, extrapyramidal symptoms, hypotonia, and severe autonomic dysfunction.12,13 Most patients present in the first 6 months of life, with approximately 50% demonstrating symptoms in the neonatal period.14 Neonatal presentation is characterized by failure to thrive, with poor suck, swallowing dysfunction, hypothermia, lethargy, ptosis, and hypotension. Due to presentation with bradykinesia and athetosis, dystonic cerebral palsy is a common initial diagnosis.13,14 Dystonia, tremor, hypokinesia, and oculogyric crises compose the movement disorder. Truncal hypotonia and hypokinesia can be profound, although deep tendon reflexes are preserved. Limb hypertonia and emotional lability are common, and variable degrees of cognitive impairment are observed.

Of the disorders described in this chapter, AADC deficiency has the most clinically significant autonomic dysfunction, including paroxysmal sweating, hypotension, bradycardia, and hypothermia. The autonomic dysfunction is of particular importance in patients who require anesthesia for procedures or surgeries. Parasympathetic outflow is intact, uncountered by appropriate sympathetic response to stress. Compensatory responses to hypovolemia or blood loss are poor, and patients are at risk for severe bradycardia, refractory hypotension, and apneic episodes with administration of anesthesia or even relatively mild sedation.15

As seen in guanosine triphosphate cyclohydrolase deficiency, there appears to be a divergence of male and female phenotypes. Males tend to demonstrate a better response to treatment, whereas females suffer from frequent adverse treatment effects and experience only minimal or transient treatment response.16

CSF studies show decreased homovanillic acid, 5-hydroindoleacetic acid, and 3-methoxy-4-hydroxyphenylglycol, and elevated levodopa, 5-hydroxytryptophan, and 3-O-methyldopa levels. CSF neopterin and biopterin are normal. Urine organic acid testing shows elevated vanillactic acid, normally absent from urine; hyperdopaminuria from intact kidney AADC may also be present.17 A plasma AADC enzyme assay is also available. See Table 577-1 for comparison to other disorders. Brain MRI is generally unremarkable, but may show progressive cerebral atrophy.14 Gene sequencing is available for clinical testing.

Treatment is very limited, mostly impacting the movement disorder, although patients may demonstrate small benefit from dopamine agonists, monoamine oxidase inhibitors, and vitamin B6 (pyridoxal-5-phosphate is a cofactor for AADC).

Monoamine oxidase A and B (MAO-A and MAO-B) are mitochondrial enzymes that catalyze the deamination of biogenic amines. MAO-A is found mainly in fibroblasts in which its main effects are on the breakdown of serotonin and norepinephrine. A rare X-linked disorder, MAO-A deficiency presents in males with mild mental retardation, aggression, and violent behaviors. In a case series of 14 males with an MAO-A gene mutation, episodes of violent behaviors clustered into 1- to 3-day periods, with decreased sleep and night terrors.18 Measurement of plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) can be used as an index of MAO-A activity; enzyme activity can also be measured in skin fibroblasts.11,19 Urine studies show decreased homovanillic acid, 5-hydroindoleacetic acid, MHPG, and vanillylmandelic acid.18 See Table 577-1 for comparison to other disorders.

Glutamic acid decarboxylase (GAD) converts glutamate to γ–amino butyric acid (GABA). Due to the role of pyridoxal-5-phosphate as a cofactor for GAD, pyridoxine-dependent seizures—presenting typically as refractory epilepsy—were previously thought to be related to GAD deficiency, but thus far the only gene associated with pyridoxine-dependent seizures is ALDH7A1.20 Clinical characteristics of true GAD deficiency are not yet well characterized, but it has been observed that the GAD67 gene and GABA may play a role in facial and palate development.21

Succinic semialdehyde dehydrogenase (SSADH) deficiency, also referred to as 4-hydroxybutyric aciduria, is an autosomal recessive disorder of GABA catabolism. SSADH catalyzes the conversion of succinic semialdehyde to succinic acid. In the absence or deficiency of SSADH, succinic semialdehyde is converted to γ-hydroxybutyrate, as depicted in Figure 577-2. The most frequent clinical features include mental retardation, language delay, hypotonia, and motor delay. Seizures occur in approximately one half of patients, and ataxia is nonprogressive, with isolated reports of improvement with age. A number of ocular abnormalities have been reported, including strabismus and nystagmus.22 Behavioral difficulties are reported in about 30% of patients, including anxiety, aggression, hyperactivity, hallucinations, sleep disturbance, or psychosis.23,24 In contrast to previously discussed neurotransmitter disorders, clinical manifestations do not include encephalopathy. MRI most commonly shows abnormal T2 signal of the subcortical white matter and globus pallidus. This disorder is diagnosed via urine organic acid analysis, which reveals elevated γ-hydroxybutyric acid (4-hydroxybutyric acid); metabolic acidosis is absent. SSADH enzyme activity can also be measured in leukocytes. Treatments with vigabatrin and benzodiazepines have had mixed results. SSADH should be considered during the evaluation of patients presenting with mental retardation and/or ataxia with a history of epilepsy, especially in the setting of consanguinity. (See Chapter 160.)

Glycine functions as an excitatory neurotransmitter in cortical regions and as an inhibitory neurotransmitter in the spinal cord and brainstem. Nonketotic hyperglycinemia, now more commonly referred to as glycine encephalopathy, occurs due to an autosomal recessive defect in mitochondrial glycine cleavage. Several clinical phenotypes have been described, although most publications refer to the classic severe neonatal form. Patients present in the neonatal period with encephalopathy, intractable seizures, and hypotonia. Severe episodes of apnea and myoclonus may result in death. Survivors continue to have refractory epilepsy and severe psychomotor retardation. Seizures may occur in utero, and in retrospect, mothers may report excessive fetal hiccups. Absence or thinning of the corpus callosum and hydrocephalus may be present; a glycine peak may be evident by magnetic resonance spectroscopy.25 Electroencephalographic findings typically evolve from burst suppression to multifocal spikes to hypsarrhythmia over the course of months. In the infantile form, development is normal in the first several months of life, followed by onset of seizures and subsequent variable degrees of cognitive impairment. In contrast to the early-onset forms characterized by refractory seizures, patients with the mild episodic childhood variant demonstrate episodic chorea, delirium, and vertical gaze palsy in the setting of febrile illnesses. Similarly, patients with late-onset forms do not have epilepsy, but may present with spastic diplegia, chorea, or optic atrophy. In a series of 65 patients with all forms of nonketotic hyperglycinemia, clinical outcomes were poorer in girls, including increased rates of early death when compared with boys.26 CSF-to-plasma glycine ratios greater than 0.08 are diagnostic of this disorder. Approximately 80% of cases are due to a mutation in the glycine decarboxylase gene (GLDC). (See Chapter 158.)

Folate serves as an important cofactor for a number of processes, including amino acid metabolism, neurotransmitter synthesis, and formation of myelin.27 Several disorders are related to abnormal total body folate status, including nervous system malformations and other genetic syndromes. Neurologic conditions related to abnormal folate status fall into 1 of 4 categories: (1) disorders of maternal and fetal folate status, such as neural tube defects; (2) cerebral folate deficiency, associated with decreased CSF folate and normal serum folate; (3) folinic acid–responsive seizures, associated with normal CSF folate and normal serum folate levels, but an abnormal peak seen with magnetic resonance spectroscopy; and (4) disorders with decreased CSF and serum folate levels.28

Cerebral folate deficiency (CFD) is characterized by a deficiency of folate in the CSF with normal levels of folate measured peripherally in serum or red blood cells.29 For years, cerebral folate deficiency had been described only in association with other diseases, such as mitochondrial disorders,30 Aicardi-Goutieres syndrome,31 Rett syndrome,32 disorders attributed to chemotherapeutic agents, and enzyme-deficiency states (eg, dihydropteridine reductase deficiency, tetrahydrobiopterin deficiency, 5,10-methylene-tetrahydrofolate reductase deficiency,33 and 3-phosphoglycerate dehydrogenase deficiency).

Only recently has the primary disorder CFD been proposed. Infantile-onset CFD is a distinct disorder characterized by normal initial development followed by acquired microcephaly or deceleration in head growth, seizures, ataxia, dyskinesias, and psychomotor retardation. Signs and symptoms, including seizures, improve with folinic acid administration, as do CSF 5-methyltetrahydrofolate (5-MTHF) levels.34 Antibodies are thought to complex with the folate receptor and impair binding of serum 5-MTHF, inhibiting active transport of folate across choroid plexus epithelial cells. In a case control study of 28 patients clinically diagnosed with the cerebral folate deficiency syndrome, 25 of 28 cases demonstrated folate receptor autoantibodies, whereas none of 28 controls showed positive antibodies.35 Systemic folate metabolism was normal in all cases, and genetic analysis of folate receptors was normal. Similar folate receptor–blocking autoantibodies have been reported in women with pregnancies complicated by neural tube defects.36

In Kearns-Sayre syndrome and other mitochondrial disorders, low CSF folate is hypothesized to be related to an alteration in the energy-dependent transport of folate from serum to CSF across the choroid plexus.37 Folate receptor autoantibodies were not detected in a recent case series of patients with various mitochondrial disorders and low CSF 5-MTHF,30 further evidence that primary cerebral folate deficiency may indeed represent a separate entity, rather than a secondary state. This remains controversial; detection of folate receptor–blocking autoantibodies were recently reported in a 13-year-old girl with rheumatoid arthritis and cerebral folate deficiency.38 Similarly, in a group of 32 patients with Rett syndrome and normal serum folate, 42%were found to have low CSF folate and 24% were found to have blocking antibodies, independent of MECP2 gene mutation status.39 Increased frequency of epilepsy has been suggested in patients with Rett syndrome and low CSF folate compared to those with normal central nervous system folate levels.40

For most patients reported in the literature with both putative primary and secondary cerebral folate deficiency, oral folinic acid replacement in the range of 1 to 3 mg/kg/day resulted in restoration of appropriate CSF 5-MTHF levels and partial clinical improvement, particularly with respect to behavior and seizure control.27,38-41 Folinic acid, a reduced methylfolate metabolite, is used for treatment rather than folic acid, as it does not require use of the folate receptor for transport into the CSF. Although clinical improvement following folinic acid administration has been reported, empiric treatment with folinic acid is not advised due to occasional reports of clinical deterioration with treatment in terms of dyskinesias and seizure frequency.27,42

Primary infantile cerebral folate deficiency remains a somewhat controversial entity, thus secondary causes of cerebral folate deficiency must first be ruled out before arriving at this diagnosis.

Dystonia is a prominent feature of the disorders of monoamine metabolism. Please see Chapter 566 on movement disorders for discussion of dystonia in childhood. If initial studies are negative, then lumbar puncture should be considered. Enzyme assays and urine studies are often insufficient to make a diagnosis, and genetic testing is not clinically available for all disorders. Furthermore, currently available testing may not identify all mutations.

For evaluation of the disorders described in this chapter, analysis of neurotransmitter metabolites in CSF is key, but specimens must be collected in a specific manner. There is a rostrocaudal gradient of tetrahydrobiopterin (BH4) and neurotransmitters in CSF; thus the collection must occur in a standardized manner for accurate comparison to reference values.43 Neurotransmitter samples should be collected first, prior to other CSF specimens, directly into the tubes supplied by the laboratory where analysis will be conducted (not into tubes from a standard lumbar puncture tray). Due to the lability of BH4, the CSF specimen should be frozen immediately on dry ice at the bedside, then transported to the laboratory. The presence of visible blood oxidizes neurotransmitter metabolites; thus traumatic samples need to be centrifuged. CSF can then be transferred to new containers prior to freezing. Analysis should include amine neurotransmitter metabolites and pterins for evaluation of the monoamine neurotransmitter disorders, with the addition of 5-methyltetrahydrofolate and serum folate when considering cerebral folate deficiency, or CSF and serum glycine when evaluating for glycine encephalopathy. MRI is generally nonspecific in the above described disorders, however it is of benefit in exploring alternative diagnoses. EEG should be obtained if suspicion for seizure is present.

This chapter provides an overview conceptualization of neurotransmitter disorders; however, these disorders are numerous and varied and growing in number as our testing and understanding improves. Several of these are beyond the scope of this chapter. We advise using this chapter as a framework for starting to consider this category of disease and considering each of these disorders in consultation with a pediatric neurologist.

The phakomatoses refer to a variety of neurocutaneous syndromes.1 Almost all are multisystem disorders that are embryonal in origin. Neurofibromatosis type 1 and tuberous sclerosis complex are the most common phakomatoses. These disorders are also discussed in Chapter 182.

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders in humans, with an estimated incidence of approximately 1 in 3000 live births. It has diverse manifestations in tissues that are primarily, although not exclusively, of neural crest origin. Clinical findings form the basis of the National Institutes of Health Consensus Statement of diagnostic criteria for neurofibromatosis type 1 (Table 578-1).2 The diagnostic criteria are met in an individual if 2 or more of the features listed are present. Clinical, molecular and management aspects of neurofibromatosis 1 are discussed in Chapter 182.

Optic pathway gliomas are the main central nervous system tumor with a marked increased frequency in neurofibromatosis type 1. Because of their growth, it is recommended that all children age 10 years or younger with neurofibromatosis type 1 undergo annual ophthalmologic examinations. When they progress, visual symptoms are produced because the tumors enlarge and put pressure on the optic nerves-chiasm resulting in impaired visual acuity and visual fields. Extension into the hypothalamus can lead to endocrine deficiencies or failure to thrive.

Although more than 50% of individuals with neurofibromatosis type 1 will have only cutaneous neurofibromas, café au lait spots, or Lisch nodules, an estimated 30% to 40% will develop 1 or more of the serious complications in their lifetime. The major categories of these complications are malignancy, learning disability, cerebrovascular disease, hypertension, and scoliosis. Because of the diverse and unpredictable complications associated with neurofibromatosis type 1, close multidisciplinary follow-up is necessary. Patients with neurofibromatosis type 1 should have regular clinical assessment at least yearly, focusing the history and examination on the potential problems for which they are at increased risk. Laboratory tests and imaging studies should be reserved for investigating specific clinical symptoms and signs. Some of the routine follow-up recommended includes yearly clinical assessment with blood pressure monitoring and yearly ophthalmologic examination.

Tuberous sclerosis complex is an autosomal dominant multisystem disease. It usually presents with seizures, mental retardation, and autism. Tuberous sclerosis complex affects the brain, eye, skin, kidneys, and heart. It is estimated to affect 1 in 6000 to 10,000 newborns. The diagnosis of tuberous sclerosis complex is still based on clinical criteria. To make the definite diagnosis of tuberous sclerosis complex an individual must have 2 major features or 1 major feature plus 2 minor features. (See Tables 578-2 and 578-3 for major and minor features.) The non-neurologic clinical manifestations, molecular aspects and management of tuberous sclerosis complex patients is discussed in Chapter 182.

Neurologic Clinical Presentation

The hallmark of tuberous sclerosis complex is the involvement of the brain. This occurs in 95% of affected individuals. The findings in the brain usually take the form of (1) cortical tubers, (2) subependymal nodules, and (3) subependymal giant cell astrocytomas. It is from the cortical tubers that the origin of the name tuberous sclerosis comes. Tubers are made up of a collection of abnormally large neurons and glia. Tubers are most commonly found in the cerebral cortex. The number, size, and location of the tubers vary tremendously among patients with tuberous sclerosis complex. Brain MRI is the best way of identifying cortical tubers. Based on fetal MRI studies, we know that cortical tubers are formed while in utero in the second trimester.3 Subependymal nodules are lesions found along the wall of the lateral ventricles in the brain. In the past they were referred to as “candle guttering” to convey that their appearance is similar to drippings of wax from a candle. These lesions do not cause any problems; however, in 5% to 10% of cases, these benign lesions can grow into subependymal giant cell astrocytomas. Subependymal giant cell astrocytomas can grow and block the circulation of cerebrospinal fluid around the brain and cause hydrocephalus. Median age of ventricular obstruction due to subependymal giant cell astrocytomas is 9 years. Hydrocephalus requires immediate neurosurgical intervention.

Epilepsy is by far the most common medical condition in tuberous sclerosis complex, occurring in 80% to 90% of patients. In about one third of patients, epilepsy starts out as infantile spasms. Infantile spasms are characterized by brief, but often repetitive, muscle contractions, usually involving the head, trunk, and extremities. The spasms often occur in clusters, and there is usually crying associated with these spells. Often, the children may look like they have colic or abdominal discomfort. The EEG often shows “hypsarrhythmia” (high-voltage, that is, 300–400 mV, chaotic disorganized background with multifocal spikes, and slow waves). However, it is important to remember that one can have hypsarrhythmia without infantile spasms and infantile spasms without hypsarrhythmia, especially in tuberous sclerosis complex patients.

Patients with tuberous sclerosis complex can develop partial or generalized seizures. Depending on the seizure type, there are multiple antiepileptic medications available. If the seizures are intractable despite the use of antiepileptic medications, epilepsy surgery can be an option. Individuals with tuberous sclerosis complex have an increased risk of having neurodevelopmental and behavioral impairment. Although approximately 50% of people with tuberous sclerosis complex have normal intelligence, developmental delay and learning disabilities are commonly found in children with tuberous sclerosis complex. Therefore, early intervention with physical, occupational, and speech therapy is highly recommended.

Some of the behavioral disorders that are common in tuberous sclerosis complex include attention deficit hyperactivity disorder (40–60%), autism spectrum disorder (20–58%), oppositional defiant disorder (25%), and sleep disturbance. Autism is a developmental disability that presents with repetitive behaviors and difficulty with communication and social interactions. The relationship between autism and tuberous sclerosis complex has been an intense area of investigation; however, the underlying cause of autism in patients with tuberous sclerosis complex remains unclear. Autism is associated with temporal lobe epileptiform discharges, seizure onset within the first 3 years of life, and history of infantile spasms.4 An American Academy of Neurology practice5 recommends searching for cutaneous abnormalities associated with tuberous sclerosis complex as a part of the diagnostic evaluation for autism.

von Hippel-Lindau disease is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal cell carcinoma; pheochromocytoma; and endolymphatic sac tumors. Patients present with headache, vomiting, and gait disturbances or ataxia or vision loss. Its incidence is around 1:36,000. It results from an autosomal dominant mutation affecting a tumor suppressor gene, VHL. Around 80% of individuals with von Hippel-Lindau disease syndrome have an affected parent, and around 20% have a de novo gene mutation. Molecular testing is available and detects mutations in almost 100% of probands.6

Incontinentia pigmenti is a disorder that affects the skin, hair, teeth, nails, eyes, and the CNS. Characteristic skin lesions evolve through several stages, from vesicular to hyperpigmented to hypopigmented. Alopecia, hypodontia, abnormal tooth shape, dystrophic nails, and neovascularization of the retina can be seen. The syndrome is inherited as an X-linked dominant disorder with male lethality and can occur due to mutations in NEMO gene, the only gene known to be associated with incontinentia pigmenti. Clinical molecular testing is available, and in 80% of the affected patients a deletion that removes exons 4 through 10 of NEMO can be detected.7 Differential diagnosis includes hypomelanosis of Ito, which presents with similar skin manifestations.

Sturge-Weber syndrome is thought to be a congenital sporadic condition characterized by a vascular birthmark and neurologic abnormalities. The classic symptom of the disease is a port wine stain, often in the distribution of the first division of the trigeminal nerve. Other symptoms can include angiomas on the surface of the brain leading to seizures and hemiparesis on the side of the body opposite the port wine stain and glaucoma on the side of the port wine stain. Although rare, it is possible for a child to have Sturge-Weber syndrome without a facial port wine stain. It is important to note that if a child does have a facial port wine stain, it doesn’t necessarily mean he or she will have neurologic abnormalities. In fact, only 8% of children with a facial port wine stain have neurologic problems. The disorder is diagnosed from the physical and radiographic findings. Therapy is symptomatic, although early surgical excision (lobectomy or hemispherectomy) is sometimes done in the hopes of preventing intellectual decline associated with intractable epilepsy.

Please see Table 578-4 for a list of other neurocutaneous diseases. These are discussed in other sections of this text.