Chapter 23. Metabolic Disorders

Metabolic disorders include a wide array of diseases affecting a number of important pathways that frequently result in neurological consequences. The advances in biochemistry and molecular genetics have revealed much about these disorders. As with most technological advances, as the disorders are better defined, more closely related variants emerge. This further complicates the clinical and diagnostic picture for the pediatrician and subspecialist alike. The introductory section of Chapter 24 discusses these issues in greater detail. The same factors apply to the metabolic disorders, and there is considerable overlap between these two categories of disease.

An often overlooked component of the management of these disorders is a coordinated genetic counseling program. This is more than simply advising a family that a disease is hereditary. There should be coordinated genetic, reproductive, and medical counseling and management.1

Table 23-1 gives an overview of the glycogen storage diseases (GSDs).

Acid Maltase Deficiency—Pompe Disease

Biochemistry and Clinical Characteristics

Acid maltase deficiency (AMD), or Pompe disease (Box 23-1), is an autosomal recessive (AR) glycogen storage disease with several different manifestations.2 Infantile AMD manifests itself within weeks of birth. The clinical manifestations include floppy baby syndrome, generalized and bulbar weakness, macroglossia, cardiomegaly, and hepatomegaly. The symptoms progress to death by age 2 years.

Adult AMD, on the other hand, usually starts in the twenties or thirties. The clinical presentation is different in this population, with the primary findings being respiratory weakness more prominent than limb-girdle weakness and intracranial aneurysms secondary to glycogen accumulation in vessels.

Evaluation and Pathology

The evaluation of AMD reveals increased creatine kinase (CK) with a normal ischemic exercise test. The needle EMG reveals evidence of myopathy and electrical myotonia without clinical myotonia. There is a vacuolar myopathy with accumulation of PAS-positive material in lysosomes on microscopic evaluation (Figure 23-1).

Management

Enzyme replacement may offer an effective treatment for infantile-onset Pompe disease.3,4

Muscle Phosphorylase Deficiency—McArdle Disease

Biochemistry and Clinical Characteristics

Muscle phosphorylase deficiency, or McArdle disease (Box 23-2), is an autosomal recessive glycogen storage disease.5,6 In childhood, it manifests itself with exercise intolerance. In adulthood, cramps and myalgias are more common complaints. Symptoms typically resolve with rest, but permanent weakness occurs in approximately one-third of patients. Acute muscle necrosis can occur but is rare.7

Evaluation and Pathology

The evaluation of muscle phosphorylase deficiency reveals increased creatine kinase (CK) in 90% of patients. The ischemic exercise test is positive with no rise in serum lactate after ischemic exercise. Myoglobinuria with exercise occurs in half the patients. The needle EMG is usually normal. Subsarcolemmal glycogen deposits (blebs) that are PAS positive, intermyofibrillar vacuoles, and immunohistochemical stains showing absent staining for phosphorylase, are evident on microscopic evaluation (Figure 23-2).

Management

Creatine supplementation may offer some treatment benefit for skeletal muscle function in McArdle disease.8

Muscle Phosphofructokinase Deficiency—Tarui Disease

Biochemistry and Clinical Characteristics

Muscle phosphofructokinase deficiency, or Tarui disease (Box 23-3), is an autosomal recessive glycogen storage disease. Tarui disease begins in childhood with premature fatigue, weakness, and stiffness induced by exercise. Myalgias and cramps are common. Symptoms typically resolve with rest.9,10

Evaluation and Pathology

The evaluation of muscle phosphofructokinase deficiency reveals increased creatine kinase (CK) levels.11 The ischemic exercise test is positive, with no rise in serum lactate after ischemic exercise. A mild hemolysis can also occur. The needle EMG is usually normal but some patients have myopathic changes. Subsarcolemmal glycogen deposits (blebs) that are PAS positive, intermyofibrillar vacuoles, and immunohistochemical stains showing absent staining for phosphofructokinase, are the most common findings on microscopic evaluation.

Organic Amino Acidurias

A number of disorders involving amino acid metabolism result in similar symptoms and can be identified via urinary organic acid analysis. A number of different disorders exist and are similar though not directly related. The most important consideration is to recognize the general classification of the disorder by its symptom complex. The urinary organic acid panel can be obtained to identify the exact metabolic defect.12

All the organic acidurias are inherited in an autosomal recessive fashion and begin during infancy. A number of characteristics are common to the organic acidurias including vomiting, anorexia, lethargy, ketoacidosis, dehydration, hyperammonemia, neutropenia, and failure to thrive.13,14 Several neurological manifestations also arise, including seizures, hypomyelination, mental retardation, and coma. Without treatment, these are potentially life-threatening disorders.

Hyperammonemia and hyperglycinemia are common amongst the amino acudurias. Urine and serum organic acid panels can be used to identify the specific disorder.15

Specific Organic Acidurias

Proprionic acidemia is associated with hypotonia, infantile spasms, hypsarrhythmia, and myoclonus in addition to the signs and symptoms common to all the organic acidurias. Treatment includes a diet low in valine, isoleucine, methionine, and threonine. Carnitine supplementation is also necessary.16,17

Methylmalonic aciduria typically becomes symptomatic in the first week of life with vomiting, hypotonia, and metabolic acidosis. This may be followed by spascticity, dystonia, strokes, chorea, and developmental delay. The principle treatment is supplemental vitamin B12. If the patient does not respond to Vitamin B12, then a low-protein diet with supplemental L-carnitine may be required.16,17

Patients with isovaleric aciduria typically have a strong odor of urine and stale perspiration. Pancytopenia may also complicate the clinical course. Oral glycine supplements are the primary treatment.

Glutaric Acidurias

Just as in the organic aminoacidurias, the family of glutaric acidurias is composed of several unrelated diseases.

Glutaric Aciduria Type I

Biochemistry and Clinical Characteristics

Glutaric aciduria type I (Box 23-4) is an autosomal recessive disorder that begins in infancy. The condition presents with a variety of manifestations. Some patients present with an early neurodegenerative disorder with hypotonia, chorea, and seizures. Others have relatively normal early development until the deterioration is suddenly triggered. Macrocephaly is present in 70% and developmental delay is common.16,17

Evaluation and Pathology

The evaluation of glutaric aciduria type I reveals abnormal urine and serum organic acids. Enzyme assays are also helpful in the diagnosis. Neuroimaging reveals cortical atrophy, gliosis in the caudate and putamen, and atrophy of the caudate.

Management

Treatment consists of a low-protein diet, carnitine supplements, and riboflavin supplements. The diet should, however, be high in calories and low in lysine and tryptophan.

Glutaric Aciduria Type II

Biochemistry and Clinical Characteristics

Glutaric aciduria type II (Box 23-5) is also an autosomal recessive (AR) disorder that has several different courses depending on the subtype. There are three subtypes: neonatal with congenital abnormalities, neonatal without congenital abnormalities, and late-onset form. Neonatal glutaric aciduria type II presents with severe metabolic acidosis, cardiomyopathy, and hypoglycemia. The physical features associated with glutaric aciduria type II include macrocephaly, high forehead, flat nasal bridge, and malformed ears.

Evaluation and Pathology

The evaluation of glutaric aciduria type II reveals abnormal urine and serum organic acids. Enzyme assays are also helpful in the diagnosis. Neuroimaging reveals agenesis of the cerebellar vermis and hypoplasia of the temporal lobes.

Management

Treatment consists of a high-carbohydrate, low-fat, low-protein diet. Carnitine supplements and riboflavin supplements may be of benefit.

Phenylketonuria

Biochemistry and Clinical Characteristics

Phenylketonuria (PKU) is an autosomal recessive disorder (Table 23-2, Box 23-6) that results in decreased phenylalanine hydroxylase (conversion of phenylalanine to tyrosine). Patients born with phenylketonuria appear normal at birth, but symptoms begin shortly after birth and after exposure to phenylalanine.18,19 Vomiting is one of the first symptoms. By several months of age, the patients have developmental delay, with seizures in the more severely affected. In untreated patients, a variety of physical signs are noted, including fair skin, blue eyes, blonde hair, hyperreflexia, hyperkinetic activity, photosensitivity, eczema-like rash, and a musty body odor. Malignant PKU, the stiff baby variant, results from dihydropterin reductase (biopterin) deficiency.

Evaluation and Pathology

The phenylalanine screen is positive if phenylalanine level is more than 20 mg/dL. The level should be checked at birth and at 2 weeks of age. If phenylalanine levels are high, a biopterin screen should be obtained. Tyrosine levels are low.

In the untreated, the EEG often reveals paroxysmal activity and hysarrhythmia. The EEG may be normal in the treated patients. Imaging findings remain abnormal even when treated. The MRI reveals atrophy and increased T-2 signal intensity in the posterior deep white matter. There is also decreased metabolism in the caudate and putamen.20

Management

Treatment consists of a low-phenylalanine diet for PKU. Infants with malignant PKU require treatment with supplemental biopterin. Even with treatment, malignant PKU has a poor prognosis.21-23

Nonketotic Hyperglycinemia

Biochemistry and Clinical Characteristics

The nonketotic hyperglycinemias (Box 23-7) are a relatively common group of disorders with widely variable genetics, phenotypes, and severities.24 There are five reported forms of the disease, with four arising during infancy or childhood. The neonatal form is the most common. This form consists of initial hypotonia progressing to hypertonia. Seizures are a common complication. The condition typically progresses to coma, respiratory arrest, and death. Survivors have severe developmental delay and mental retardation.24,25

A rare, transient form appears to occur in some patients who are heterozygous for the disease. These patients have a brief, self-limited syndrome that is clinically similar to the more common neonatal form. The late infantile form typically arises toward the end of the first year, with cognitive decline, decerebrate posturing, and extrapyramidal findings. The juvenile form is associated with mild mental retardation and language dysfunction.

Evaluation and Pathology

Nonketotic hyperglycinemia is rarely identified on newborn screening.26 Laboratory evaluation requires spinal fluid evaluation. Elevation of the CSF glycine/serum glycine ratio (ratio > 0.10) is diagnostic. The EEG can reveal burst suppression, hypsarrhythmia, or focal epileptiform discharges. Neuroimaging reveals atrophy and hypomyelination.27

Management

The principle treatment is supportive care and treatment of the seizures with antiepileptic medication.

Urea Cycle Defects

Biochemistry and Clinical Characteristics

The disorders of the urea cycle all result in hyperammonemia and therefore have similar symptom complexes (Table 23-3).28-30 Symptoms usually arise during the neonatal period. These conditions should always be considered when an infant's ammonia level is elevated. Carbamoyl phosphate synthetase deficiency is the most severe of the urea cycle defects. When the enzyme is completely absent, it is usually fatal. Partial absence or dysfunction of the enzyme results in variable degrees of severity. The clinical presentation includes coma, seizures, hypotonia, respiratory arrest, occasional intracranial hemorrhages, vomiting, and death without treatment. Some patients, especially with milder forms of the disease, may be normal with early treatment.

Evaluation and Pathology

Disorders of the urea cycle are usually associated with dramatic elevations of serum ammonia, often more than 500 mg/dL.31 Increased glutamine levels are found on serum amino acid testing. Hepatic function studies typically reveal elevated AST and ALT levels. Neuroimaging studies reveal cerebral edema with occasional intracranial hemorrhage. A number of findings are common on microscopic pathologic evaluation including cerebral edema, Alzheimer type II cells, decreased myelination, and neuronal loss. Alzheimer type II cells are not common in carbamoyl phosphate synthetase deficiency, most likely because it is often rapidly fatal.

Management

Treatment consists primarily of hemodialysis to decrease ammonia and dietary restriction of nitrogen (low-protein diet). Valproate should be avoided for seizures since this drug increases ammonia production.32

Renal Amino Acid Transport

Hartnup Disease

Biochemistry and Clinical Characteristics

Hartnup disease (Box 23-8) is a familial disorder of renal amino acid transport caused by defective Na-dependent neutral amino acid transport in the small intestine and renal tubules, leading to increased fecal and urinary amino acid excretion.33 The symptoms begin during infancy. The clinical presentation is highly variable, with failure to thrive, a photosensitive scaly rash, intermittent ataxia, personality changes, nystagmus, and a tremor.34 The symptoms tend to improve with age; in some cases there is slow progression.

Evaluation and Pathology

Intermittent cerebral symptoms should suggest the diagnosis. Laboratory studies may reveal low serum tryptophan on neutral amino acid screening.

Management

Treatment includes a high-protein diet with nicotinic acid supplements (niacin). Tryptophan ethylester can also be of benefit. There is, however, a general improvement with increasing age.

Lowe Syndrome (Oculocerebrorenal Syndrome)

Lowe syndrome (Box 23-9), a disorder of renal amino acid transport, is thought to be caused by a membrane transport defect. It is transmitted in an X-linked recessive pattern.35 The symptoms typically begin during the neonatal period. The clinical presentation includes mental retardation and developmental delay, glaucoma, cataracts, myopathy, and pendular nystagmus.36 In addition, punctate cortical lens opacities may be the only sign in heterozygote female carriers. Death usually occurs secondary to renal failure. Pathology reveals loss of both central and peripheral myelinated fibers.

Maple Syrup Urine Disease

Biochemistry and Clinical Characteristics

Maple syrup urine disease (Box 23-10) is a disorder of branched- chain amino acid metabolism secondary to a defect of alpha-ketoacid dehydrogenase deficiency resulting in abnormal oxidative decarboxylation.37 It is inherited in an autosomal recessive pattern. The symptoms typically begin during the neonatal period. The clinical presentation includes hypertonia, opisthotonos, fluctuating ophthalmoplegia that correlates with serum leucine levels, clonus, generalized seizures, and developmental delay.38 The patient eventually becomes flaccid and areflexic. Coma ensues without treatment. Conversely, the prognosis is good and the patient may have a normal IQ if treatment is instituted within 5 days.

Evaluation and Pathology

Laboratory evaluation reveals elevated branched-chain amino acids (leucine, isoleucine, and valine) on serum amino acid screening. Approximately 50% of patients develop severe hypoglycemia. The urine has a characteristic odor and tests positive for 2,4-dinitrophenylhydrazine (DNPH).39 Imaging during the acute phase reveals cerebral edema greatest in cerebellar deep white matter and brainstem. Pathologic specimens reveal white matter cystic degeneration and gliosis.

Management

Treatment consists of thiamine supplementation and dietary restriction of branched-chain amino acids.40

Homocystinuria

Biochemistry and Clinical Characteristics

Homocystinuria (Box 23-11) is a genetic disorder of homocysteine metabolism with AR inheritance (chromosome 21). Cystathionine beta synthase deficiency results in accumulation of homocysteine and methionine.41 There is also impaired methylation of homocysteine to methionine from enzyme deficiency or cofactor B12 deficiency. The onset and severity of symptoms are variable. The clinical presentation includes marfanoid habitus and codfish vertebra (biconcave). Ocular anomalies include ectopia lentis (lens displaced downward) in 90% of patients, myopia, glaucoma, and optic atrophy. Central nervous system complications include mental retardation, seizures, behavioral disorders, and stroke (beginning at age 5 to 9 months).42

Evaluation and Pathology

Laboratory evaluation reveals increased homocysteine on serum and urine amino acids, and a positive methionine challenge test. Pathologic evaluation reveals intimal thickening and fibrosis of blood vessels leading to arterial and venous thrombosis.

Management

Treatment consists of dietary restriction of methionine, pyridoxine supplements, vitamin B12 supplements, and cysteine supplements.

Lesch-Nyhan Syndrome

Biochemistry and Clinical Characteristics

Lesch-Nyhan syndrome (Box 23-12) is a rare disorder of purine metabolism secondary to hypoxanthine-guanine phosphoribosyl transferase deficiency. It is inherited in an X-linked recessive pattern. Symptoms typically begin about age 6 months. The clinical presentation includes developmental delay, choreoathetosis, dystonia, opisthotonos, hyperreflexia, mental retardation, and self-mutilating behavior.43

Evaluation and Pathology

Laboratory evaluation reveals crystalluria and hyperuricemia.44

Management

Treatment includes allopurinol 20 mg/kg/d (blocks uric acid synthesis). L-5-hydroxytryptophan plus L-dopa can help with symptomatic management. Physical restraint may be necessary given the risk of self-mutilating behavior. Fluphenazine may also help decrease self-mutilating behavior.45

Abetalipoproteinemia (Bassen-Kornzweig Disease)

Biochemistry and Clinical Characteristics

Abetalipoproteinemia, or Bassen-Kornzweig disease (Box 23-13), is an AR disorder of lipoprotein metabolism resulting from a decreased posttranslational processing of apolipoprotein B.46 Abetalipoproteinemia typically manifests neurological symptoms by age 12 years. The clinical manifestations include fat malabsorption with diarrhea and steatorrhea; acanthocytosis; retinopathy; vitamins A, D, E, and K deficiency; neuropathy with decreased reflexes, proprioception, and sensation; progressive ataxia; positive Romberg sign; decreased night vision (retinitis pigmentosa); and weakness.47

Evaluation and Pathology

The laboratory evaluation of abetalipoproteinemia reveals acanthocytosis (Figure 23-3); absent beta-lipoproteins (chylomicrons, LDL, VLDL); decreased triglycerides and cholesterol; low vitamin A, D, E, and K levels (fat-soluble vitamins); and increased PT. Nerve conduction velocities are slow. Pathologic findings include loss of large myelinated fibers and spinocerebellar and posterior column degeneration.

Management

Treatment includes dietary restriction of triglycerides. Vitamin E supplements may also be of some benefit.48

Tangier Disease

Biochemistry and Clinical Characteristics

Tangier disease (Box 23-14) is an AR disorder of lipoprotein metabolism resulting from a deficiency of alpha-lipoprotein. The clinical manifestations include large orange tonsils, lymphadenopathy, splenomegaly, corneal infiltrates, relapsing multiple mononeuropathies, and loss of pain and temperature sensation. Peripheral neuropathy occurs in 50% of patients with demyelinating sensory, sensorimotor, or motor neuropathy.

Evaluation and Pathology

The laboratory evaluation of Tangier disease reveals decreased total cholesterol and LDL, triglycerides normal or increased, and very low HDL. Nerve conduction velocities are typically slow in the demeylinating range. Pathologic findings include lipid droplets in Schwann cells and in reticular endothelial system (RES) of other cells, evidence of neuropathy with demyelination/ remyelination, and a syringomyelia-like syndrome with axonal degeneration.

Management

There is no reliable treatment.

Cerebrotendinous Xanthomatosis

Biochemistry and Clinical Characteristics

Cerebrotendinous xanthomatosis (Box 23-15) is an AR disorder of lipoprotein metabolism resulting from absent chenodeoxycholic acid (bile acid).49 The clinical manifestations include dementia, ataxia, seizures, paresis, peripheral neuropathy, juvenile cataracts, xanthoma, atherosclerosis, and mental retardation.

Evaluation and Pathology

The laboratory evaluation of cerebrotendinous xanthomatosis reveals increased cholestanol.50 Nerve conduction velocities are typically slow. Neuroimaging reveals diffuse hypomyelination on MRI and diffuse hypomyelination with hyperdensities in the cerebellum on CT. Pathologic findings include extensive demyelination greatest in the cerebellum and brainstem.

Management

Treatment consists of chenodeoxycholic acid 750 mg/d.50

Biochemistry and Clinical Characteristics

Porphyria occurs in several subtypes, including acute intermittent porphyria (AIP), hereditary coproporphyria, and variegate porphyria.51 The general characteristics of porphyria are outlined in Table 23-4. Porphyria can be challenging to diagnose, especially early in the syndrome. The differential diagnosis includes Guillain–Barré syndrome, lead intoxication, and hereditary tyrosinemia.

Evaluation and Pathology

The laboratory evaluation includes elevated porphobilinogen (PBG) in urine, quantitative aminolevulinic acid (ALA), PBG, and porphyrins in urine and feces.52 There is patchy demyelination and axonal degeneration.

Management

It is of utmost importance to avoid medications and other potential exacerbating factors. Treatment also includes hematin 1.5 to 3 mg/kg IV.52 Symptomatic treatment is very important, but must be administered with care given the risk of some medications exacerbating the porphyria. Pain should be managed with analgesics, morphine, and chlorpromazine. Hyponatremia should be treated with normal saline (NS) + diuretics. Many seizure medications exacerbate porphyria. Valium is usually well tolerated in the patient with porphyria. Several of the newer antiepileptic agents are relatively safe in this population as well.

Wilson Disease (Hepatolenticular Degeneration)

Biochemistry and Clinical Characteristics

Wilson disease, or hepatolenticular degeneration (Box 23-16), is an AR disorder (chromosome 13) of metal metabolism resulting from ATPase deficiency.53 Wilson disease typically manifests itself between ages 11 and 25 years. The clinical manifestations include cirrhosis, tremor (wing-beating), rigidity, dystonia, chorea, Kayser–Fleischer rings (present in 100% of neurological Wilson disease patients; Figure 23-4), seizures, and psychosis.54

Evaluation and Pathology

The laboratory evaluation of Wilson disease reveals low or absent ceruloplasmin (low or absent in 96% of cases).54,55 Aminoaciduria is also common. Kayser–Fleischer rings are present in 100% of neurologic Wilson cases. Neuroimaging reveals caudate and putamen atrophy (lenticular degeneration). Pathologic findings include brick-red basal ganglia, spongy degeneration of the putamen, Alzheimer astrocytes, and neuronal dropout with axonal degeneration.

Management

Treatment includes a copper-poor diet. Sulfide 20 mg tid and penicillamine 500 to 1000 mg tid can also be of some benefit. L-dopa may be effective for the dystonia.

Kinky Hair Disease (Menkes Disease)

Biochemistry and Clinical Characteristics

Kinky hair disease, or Menkes disease (Box 23-17), is disorder of metal metabolism resulting from copper ATPase deficiency.56 The incidence is approximately 1 in 250,000 live births. Kinky hair disease usually becomes clinically apparent during infancy. The clinical manifestations include hypothermia, poor feeding, seizures, hypotonia, a cherubic face, colorless friable kinky hair, and hydronephrosis.

Evaluation and Pathology

The laboratory evaluation of kinky hair disease reveals a falling ceruloplasmin on serial measurements.56,57 Neuroimaging reveals atrophy and focal encephalomalacia. Subdural hematomas are also common. The EEG often reveals hypsarrhythmia. Pathologic findings include focal cortical degeneration, prominent cerebellar neuronal dropout, "weeping willow" dendritic processes, and increased numbers of mitochondria.

Management

The primary treatment is copper histidine.