+++
Lysosomal Storage
Diseases Containing Lipid
++
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.
++
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 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 (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 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.
++
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 (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.
++
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 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 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