| Nonimmune Fetal
Hydrops |
| GM1 gangliosidosis, Niemann-Pick disease, sialidosis, galactosialidosis,
etc | Various | Severe ascites and generalized anasarca, associated with
respiratory distress and disseminated intravascular thrombosis;
often progresses rapidly to death in the first few days of life.
Radiographs may show dysostosis multiplex. Affected infants may
survive, with clearing of the edema and ascites, to present later
in infancy with more classical variants of the diseases. The diagnosis
of a specific lysosomal disorder generally requires analysis of enzyme
activities in cultured skin fibroblasts or tissues obtained at autopsy. | Measurement of lysosomal enzyme activities in peripheral
blood leukocytes or cultured skin fibroblasts, supplemented by specific mutation
analysis of relevant gene. |
| Neonatal Onset |
| Neonatal Gaucher disease | Glucocerebrosidase (β-glucosidase) | Thick, shiny, collodion skin, multiple congenital
anomalies, hepatosplenomegaly, marked paucity of spontaneous movement,
hypertonicity and hyper-reflexia, neck retraction, and poor suck.
In some cases, nonimmune hydrops is severe. Survival is generally
measured in days or weeks. | Demonstration of deficiency of β-glucosidase
in leukocytes or cultured skin fibroblasts |
| GBA mutation analysis |
| Early Infancy (1
to 6 Months) |
| Gaucher disease, type 2 | Glucocerebrosidase (β-glucosidase) | By 2–4 months of age, onset of developmental
delay and feeding difficulties, followed by failure to thrive, protuberant
abdomen, strabismus, difficulty swallowing, and opisthotonic posturing,
associated with massive hepatosplenomegaly and macular cherry-red
spots. Anemia, leukopenia, and marked thrombocytopenia are prominent,
with little radiographic evidence of skeletal involvement. | Bone marrow aspiration shows the presence of
typical “Gaucher storage cells.” |
| Demonstration of deficiency of β-glucosidase
in leukocytes or cultured skin fibroblasts |
| GBA mutation analysis |
| Krabbe globoid cell leukodystrophy | Galactocerebrosidase | In the first few weeks of life, onset of marked
irritability, developmental arrest, generalized hypertonicity, exaggerated
deep tendon reflexes, and feeding difficulties. The liver and spleen
are not enlarged. Seizures are common and typically difficult to
control. CSF protein is elevated, and peripheral nerve conduction
velocities are typically abnormally slow. Death usually occurs before
18 months of age. | Demonstration of deficiency of galactocerebrosidase
in leukocytes or cultured skin fibroblasts. |
| GBA mutation analysis. |
| Niemann-Pick disease, type A | Acid sphingomyelinase | In the first few months of life, onset of
failure to thrive, developmental delay, and marked hepatosplenomegaly,
followed by generalized muscle wasting, weakness, and hypotonia,
though deep tendon reflexes are preserved. Some infants have a macular
cherry-red spot. Death from inanition and pneumonia usually occurs
in the second or third year of life. | Bone marrow aspiration shows the presence of
typical “foamy storage cells.” |
| Demonstration of deficiency of acid sphingomyelinase
in leukocytes or cultured skin fibroblasts |
| ASM mutation analysis |
| GM1 gangliosidosis | β-galactosidase | In the first few weeks of life, onset of failure
to thrive, developmental arrest, coarse facial features, marked
hepatosplenomegaly, dysostosis multiplex with “cloaking” of
long bones, progressing to death within a few months. | Typical abnormalities on analysis of urinary
oligosaccharides |
| Bone marrow aspiration shows the presence of
typical “foamy storage cells.” |
| Demonstration of deficiency of β-galactosidase
in leukocytes or cultured skin fibroblasts |
| GLB1 mutation analysis |
| Farber lipogranulomatosis | Acid ceramidase | In the first few months of life, onset of a hoarse cry; painful,
swollen joints; palpable subcutaneous nodules over the joints; respiratory
problems; dysphagia; recurrent vomiting; pulmonary consolidation;
and fever. Hepatomegaly may be prominent and associated with hepatocellular
dysfunction. Death from progressive neurological deterioration,
inanition, and chronic pulmonary disease usually occurs within several
months of the onset of the disease. | Demonstration of deficiency of acid ceramidase
in leukocytes or cultured skin fibroblasts |
| Late Infancy and
Early Childhood (6 Months to 2 Years) |
| Gaucher disease, type 3 | Glucocerebrosidase (β-glucosidase) | Gaucher disease type 3 is clinically highly heterogeneous.
Patients with type 3a disease typically present in early to middle
childhood with myoclonus, dementia, ataxia, and slowing of horizontal
saccadic eye movements. Smooth-pursuit eye movements may initially
be normal. The spleen and liver are usually enlarged but typically
do not cause the problems seen in patients with type 3b or severe
type 1 disease. Treatment-resistant generalized tonic-clonic seizures
and spasticity develop later. Skeletal lesions, similar to those
seen in patients with type 1 disease, occur in most patients. Ultimately,
the disease ends with death in the second or third decade of life. | Bone marrow aspiration shows the presence of
typical “Gaucher storage cells.” |
| Patients with type 3b Gaucher disease may appear to have
particularly severe type 1 disease, with onset of massive hepatosplenomegaly
at 2–3 years of age, often in the absence of obvious CNS
involvement. Evidence of hepatocellular dysfunction is prominent
and often progresses to cirrhosis. Infiltration of the lungs with
storage cells causes restrictive pulmonary disease. The first sign
of neurological involvement is often oculomotor apraxia. Skeletal
involvement is often severe, with chronic bone pain, multiple acutely
painful “bone crises,” fractures, and avascular
necrosis of large joints. In some patients, severe thoracic kypho-scoliosis
is a prominent feature of the disease. | Demonstration of deficiency of β-glucosidase
in leukocytes or cultured skin fibroblasts |
| A third variant of type 3 Gaucher disease, which is particularly
common in the Middle East, is characterized by mitral valve calcification. | GBA mutation analysis |
| Niemann-Pick disease, type C | Intracellular cholesterol trafficking | Most affected infants have a history of neonatal
hyperbilirubinemia with the histologic characteristics of “giant
cell hepatitis.” Rarely, the neonatal liver involvement
progresses to acute hepatic necrosis and early death. In most infants,
the hepatopathy resolves spontaneously over several days. Typically,
affected infants present in the first 1–3 years of life
with developmental or psychomotor delay, then with slowly progressive
regression, ataxia, dysarthria, dystonia, hepatosplenomegaly, and
a characteristic vertical supranuclear gaze palsy. Dystonia may
be particularly prominent. Myoclonic seizures and cataplexy are
common. Death usually occurs in 3–10 years. | Filipin staining of cultured skin fibroblasts |
| Defect in cholesterol esterification by cultured
skin fibroblasts |
| NPC1 and NPC2 mutation analysis |
| Late-infantile metachromatic leukodystrophy | Arylsulfatase A | Commonly presents in the second year of life
with ataxia, hypotonia, and muscle weakness. Progression is initially
slow but soon becomes more rapid with the development of generalized
spasticity, developmental regression, and ultimately decerebrate
posturing. Ophthalmoscopic examination may show the presence of
atypical cherry-red spots. Seizures are a common but generally a
late manifestation of the disease. Nerve conduction velocities are
slow, and CSF protein concentrations are elevated. CT studies show
progressive attenuation and loss of periventricular white matter,
followed by marked demyelination throughout the CNS. Survival for some
years in a quasivegetative state is not uncommon. | Increased urinary excretion of sulfatide |
| Demonstration of arylsulfatase A deficiency
in leukocytes or cultured skin fibroblasts |
| ARSA mutation analysis |
| Tay-Sachs disease | β-hexosaminidase A | Affected infants generally appear normal at
birth. Mild motor weakness, beginning at 3–5 months of
age, is often associated with an exaggerated startle reaction to noises.
By 6–10 months of age, affected infants show progression
of muscle weakness and hypotonia, poor head control, failure to
achieve gross motor skills, and macrocephaly. Ophthalmoscopic examination
reveals the presence of typical macular cherry-red spots. Seizures
and blindness occur early. Infants with Tay-Sachs disease often
have a strikingly attractive, doll-like facial appearance. CT studies
show a characteristic opacification of the thalami. The course of
the disease is relentlessly progressive, with death by age 3–5
years. | Demonstration of deficiency of β-hexosaminidase
A in serum, leukocytes, or cultured skin fibroblasts |
| HEXA mutation analysis |
| Sandhoff disease | β-hexosaminidase A and B | In most cases, Sandhoff disease is clinically
indistinguishable from Tay-Sachs disease. In some patients, however,
mild-to-moderate enlargement of the liver and spleen occur, and
radiographs may show subtle evidence of dysostosis multiplex. | Demonstration of deficiency of total β-hexosaminidase
in serum, leukocytes, or cultured skin fibroblasts. |
| HEXB mutation analysis |
| Multiple sulfatase deficiency | | Characterized clinically by features of late-infantile metachromatic
leukodystrophy, together with a mild mucopolysaccharide storage
disease and mild generalized ichthyosis. Radiographs show mild dysostosis multiplex,
urinary screening tests for mucopolysaccharides are generally positive,
and urinary excretion of sulfatide is increased. Nerve conduction
velocities are slowed, and CSF protein concentrations are increased.
Retinal dystrophy, with typical pigmentary changes, develops later
in the course of the disease. | Demonstration of deficiency of two or more lysosomal
sulfatases (eg, arylsulfatase A, arylsulfatase B, iduronate 2-sulfatase,
etc) |
| Late Childhood and
Adolescence (2 to 18 Years) |
| Gaucher disease, type 1 | Glucocerebrosidase | Characterized most commonly by painless hepatosplenomegaly. Chronic
bone pain, especially in the legs, is typically worst at night. Patients
may also come to attention as a result of a history
of excessive bleeding occurring as the result of thrombocytopenia
caused by hypersplenism. Children with Gaucher disease may present
with episodes of pain in the lower extremities. The pain is typically
worst at night, sometimes waking the child from sleep. Painful “bone
crises” resembling sickle cell crises may be clinically
indistinguishable from osteomyelitis. Pathological fractures and
avascular necrosis of the hips are common complications of the skeletal
involvement. Severe disease is often associated with growth retardation. | Bone marrow aspiration shows the presence of
typical “Gaucher storage cells.” |
| Demonstration of deficiency of β-glucosidase
in leukocytes or cultured skin fibroblasts |
| Note: The three clinical variants
of Gaucher disease (eTable 161.1) are indistinguishable
by routine enzyme assays. |
| GBA mutation analysis |
| Late-onset metachromatic leukodystrophy | Arylsulfatase A | Generally presents at 4–10 years
of age, often with a history of deteriorating school performance.
It may be associated with personality changes, including obsessiveness,
emotional lability, and social withdrawal, as well as ataxia and
dysarthria. Progression of the disease is usually slow, and seizures
generally occur later in the course of the disease. Survival into
the late teens or later is common. | Increased urinary excretion of sulfatide |
| Demonstration of arylsulfatase A deficiency
in leukocytes or cultured skin fibroblasts |
| ARSA mutation analysis |
| Late-onset GM2 gangliosidosis | β-hexosaminidase A or A and
B | At ages 2–10 years, onset of progressive
ataxia, incoordination, dysarthria, progressive psychomotor regression,
spasticity, seizures, and blindness with retinal pigmentary changes
but no cherry-red spot. The disease may be dominated by progressive
dystonia; choreoathetosis; ataxia; muscle wasting; dementia; dysarthria,
ataxia, and other cerebellar signs; spasticity; muscle wasting;
and pes cavus deformity, with relative preservation of intelligence.
It may also present in adolescence as acute schizophrenia, paranoia,
or recurrent psychotic depression. | Demonstration of deficiency of β-hexosaminidase
A or A+B in serum, leukocytes, or cultured skin fibroblasts |
| HEXA or HEXB mutation analysis |
| Niemann-Pick disease, type B | Acid sphingomyelinase | Presentation in middle or late childhood as
progressive asymptomatic splenomegaly. Hematologic complications
and skeletal involvement similar to but less severe than in Gaucher
disease. Risk of cirrhosis and progressive pulmonary insufficiency. | Bone marrow aspiration shows the presence of
typical “foamy storage cells.” |
| Demonstration of deficiency of acid sphingomyelinase
in leukocytes or cultured skin fibroblasts |
| ASM mutation analysis |
| Fabry disease | α-galactosidase | Presents late in the first decade of life
with episodic, severe, and burning pain in the hands and feet, often
precipitated by extremes of temperature, especially heat; by physical
exertion; fever; or psychological stress. Pain in the joints may
be clinically indistinguishable from pauciarticular arthritis, and
abdominal pain may resemble an acute abdomen or chronic inflammatory
bowel disease. Decreased or absence of sweating is typical. By the
mid to late teens, affected boys develop increasing numbers of tiny
red to black papular lesions (angiokeratomata) in the umbilicus
and on the skin of the buttocks, scrotum, penis, and buccal mucosa.
Slit-lamp examination of the eyes reveals typical corneal verticillata.
Proteinuria, progressive renal impairment, hypertrophic cardiomyopathy,
and stroke occur later in life, though cardiac rhythm disturbances
are common in adolescents. Heterozygous girls may experience painful
crises similar to those occurring in affected boys. Corneal lesions
are common. However, angiokeratomata are unusual in girls. | For males: |
| Demonstration of deficiency of α-galactosidase
in leukocytes, plasma, or cultured skin fibroblasts |
| Demonstration of increased excretion of ceramide
trihexoside in urine |
| GLA mutation analysis |
| Diagnosis in females is difficult: |
| Affected father |
| Demonstration of increased excretion of ceramide
trihexoside in urine |
| GLA mutation analysis |