GM1 gangliosidosis, generalized

Ganglioside beta-galactosidase

Type I (infantile type; 230500*)

Type I onset: 0–6 months

Urine metabolites: None

Clinical features: Coarse facies; clear cornea, cherry-red macular spot, gingival hyperplasia, organomegaly, dysostosis multiplex, hypertrichosis, angiokeratoma corporis diffusum, cerebral degeneration; death in infancy

Treatment: Supportive care

Type II (juvenile type; 230600*)

Type II onset: 6–12 months

Urine metabolites: None

Clinical features: Gait disturbance, spasticity, dystonia, loss of psychomotor milestones, mild visceromegaly and bone abnormality

Treatment: Supportive care

Type III (adult type; 230650*)

Type III onset: 3–50 years

Urine metabolites: None

Clinical features: Angiokeratoma corporis diffusum, spondyloepiphyseal dysplasia, dysarthria, cerebellar dysfunction; no macular red spots or visceromegaly

Treatment: Supportive care

GM2 gangliosidosis

Onset: In types I and II, 5–6 months

In type III, 2–6 years

Urine metabolites: None

Clinical features: Doll-like facies; cherry-red retina; early blindness; exaggerated startle reflex; initial hypotonia followed by hypertonia; psychomotor retardation followed by regression, seizures, and impaired sweating; in types I and II, death by age 5 years; death later in type III

In type I, increased frequency in people of Ashkenazi Jewish ancestry

Treatment: Supportive care

Type I (Tay-Sachs disease; 272800*)

Beta-hexosaminidase A

Type II (Sandhoff disease; 268800*)

Beta-hexosaminidase B

Type III (juvenile type)

Beta-hexosaminidase A

GM2 activator protein deficiency (Tay-Sachs disease AB variant, GM2A; 272750*)

GM2 activator protein

Onset, urine metabolites, and clinical features: Similar to Tay-Sachs

Treatment: Supportive care, stem cell or bone marrow transplantation

Niemann-Pick disease (see also Niemann-Pick disease types C and D in table Other Lipidoses)

Sphingomyelinase

Type A (257200*)

Onset:< 6 months

Clinical features: Growth delay, cherry-red retina, frequent respiratory infections, hepatosplenomegaly, vomiting, constipation, osteoporosis, lymphadenopathy, hypotonia followed by spasticity, sea-blue histiocytes on tissue biopsies, large vacuolated foam cells in bone marrow (NP cells), death by age 3 years

Treatment: Supportive care, stem cell or bone marrow transplantation

Type B (607616*)

Onset: Variable

Clinical features: Much milder symptoms, no neurologic involvement, survival to adulthood

Increased frequency in people of Ashkenazi Jewish ancestry

Treatment: Supportive care, stem cell or bone marrow transplantation

Gaucher disease

Glucosylceramide beta-glucosidase

Type I (adult or chronic form; 230800*)

Onset: Childhood to adulthood

Urine metabolites: None

Clinical features: Hepatosplenomegaly, osteolytic lesions with bone pain, avascular necrosis of the femoral head, vertebral compression, thrombocytopenia, anemia

Increased frequency in people of Ashkenazi Jewish ancestry

Treatment: Supportive care

Splenectomy

Bone marrow or stem cell transplantation

Type II (infantile form; 230900*)

Onset: Infancy

Urine metabolites: None

Clinical features: Infantile hydrops, hepatosplenomegaly, dysphagia, bone lesions, hypertonicity, pseudobulbar palsy, laryngeal spasm, ichthyosis, developmental delay, hypersplenism, death by age 2 years

Treatment: Supportive care

Type III (juvenile form, Norrbottnian type; 231000*)

Onset: 4–8 years

Urine metabolites: None

Clinical features: Similar to type II except milder, possible survival into adulthood

Treatment:

Farber disease (lipogranulomatosis; 228000*)

Ceramidase

Onset: First weeks of life

Urine metabolites: Ceramide

Clinical features: Lipogranulomatosis, periarticular subcutaneous nodules, irritability, hoarse cry, psychomotor and growth delay, respiratory insufficiency, histiocytosis in multiple tissues, nephropathy, hepatosplenomegaly, cherry-red macular spot

Milder variants sometimes divided into 7 subtypes according to severity

Treatment: Supportive care

Fabry disease (301500*)

Onset: Childhood or adolescence

Urine metabolites: Globosylceramide

Clinical features: Painful crisis involving extremities and abdomen precipitated by stress, fatigue, or exercise; angiokeratoma; growth and pubertal delay; corneal dystrophy; renal failure; cardiomyopathy; myocardial infarction and heart failure, hypertension; lymphedema; obstructive lung disease; strokes; seizures; death

Generally, only males affected but occasionally females

Treatment:

Metachromatic leukodystrophy (250100*)

1. Late infantile form

2. Juvenile form

3. Adult form

4. Pseudodeficiency form

Arylsulfatase A

Onset: For late infantile form, 1–2 years

For juvenile form, 4 years to puberty

For adult form, any age after puberty

Urine metabolites: Sulfatides

Clinical features: Optic atrophy, gall bladder dysfunction, urinary incontinence, hypotonia, gait disturbance, hyporeflexia followed by hyperreflexia, bulbar palsies, ataxia, chorea, demyelination and developmental regression, increased cerebrospinal fluid protein

In adult form, also schizophrenia-like symptoms

Pseudodeficiency characterized by mild decrease in enzyme activity without neurologic degeneration

Treatment: Supportive care, consideration of bone marrow or stem cell transplantation in patients who have mildly symptomatic forms

Therapeutic options under investigation, primarily in late infantile forms, include gene therapy, enzyme replacement therapy, substrate reduction therapy, and enzyme enhancement therapy

Mucosulfatidosis (multiple sulfatase deficiency; 272200*)

Sulfatase-modifying factor-1

Onset: Infancy

Urine metabolites: Sulfatides, mucopolysaccharides

Clinical features: Similar to late infantile form of metachromatic leukodystrophy, plus ichthyosis and dysostosis multiplex

Treatment: Supportive care

Krabbe disease (245200*)

1. Infantile form

2. Late infantile form

3. Juvenile form

4. Adult form

Galactosylceramide beta-galactosidase

Onset: In infantile form, 3–6 months

In late infantile and juvenile forms, 15 months–17 years

In adult form, variable

Urine metabolites: None

Clinical features: Growth delay, developmental delay followed by regression, deafness, blindness, vomiting, hyperirritability, hypersensitivity to stimuli, increased deep-tendon reflex, and spasticity; seizures; diffuse cerebral atrophy and demyelination; elevated cerebrospinal fluid protein; peripheral neuropathy; episodic fever

In adult form, mentation generally preserved

Treatment: Supportive care; bone marrow or stem cell transplantation for infantile and late infantile forms prolongs life span and improves functional abilities

Sphingolipid activator protein deficiencies

Onset: Infancy to early childhood

Urine metabolites: Sulfatides

Clinical features: In saposin B deficiency, features similar to those of metachromatic leukodystrophy

In saposin C deficiency, features similar to those of Gaucher disease type III

In prosaposin deficiency, features of saposin B and C deficiencies

Treatment: Supportive care; consideration of bone marrow or stem cell transplantation; for features of Gaucher disease, consideration of enzyme replacement

Prosaposin deficiency (176801*)

Prosaposin

Saposin B deficiency (sulfatide activator deficiency)

Saposin B

Saposin C deficiency (Gaucher activator deficiency)

Saposin C