Sphingolipidoses

Sphingolipidoses are a class of lipid storage disorders or degenerative storage disorders caused by deficiency of an enzyme that is required for the catabolism of lipids that contain ceramide,^[1] also relating to sphingolipid metabolism. The main members of this group are Niemann–Pick disease, Fabry disease, Krabbe disease, Gaucher disease, Tay–Sachs disease and metachromatic leukodystrophy. They are generally inherited in an autosomal recessive fashion, but notably Fabry disease is X-linked recessive. Taken together, sphingolipidoses have an incidence of approximately 1 in 10,000, but substantially more in certain populations such as Ashkenazi Jews. Enzyme replacement therapy is available to treat mainly Fabry disease and Gaucher disease, and people with these types of sphingolipidoses may live well into adulthood. The other types are generally fatal by age 1 to 5 years for infantile forms, but progression may be mild for juvenile- or adult-onset forms.

Sphingolipidoses
Other names	Sphingolipidosis
Diagram showing some of the sphingolipidoses
Specialty	Medical genetics

Accumulated products

• Gangliosides: Gangliosidosis
  • GM1 gangliosidoses
  • GM2 gangliosidoses
    • Tay–Sachs disease
    • Sandhoff disease
    • GM2-gangliosidosis, AB variant
• Glycolipids
  • Fabry's disease
  • Krabbe disease
  • Metachromatic leukodystrophy
• Glucocerebrosides
  • Gaucher's disease

Comparison

Comparison of the main sphingolipidoses

Disease	Deficient enzyme[2]	Accumulated products[2]	Symptoms[2]	Inheritance[2]	Incidence	Generally accepted treatments	Prognosis
Niemann-Pick disease	Sphingomyelinase	Sphingomyelin in brain and RBCs	Mental retardation Spasticity Seizures Hepatosplenomegaly Thrombocytopenia Ataxia	Autosomal recessive	1 in 100,000[3]	Limited	Highly variable, infantile neurovisceral Niemann Pick disease (Type A ASMD) is usually fatal before 3 years of age. Estimasted mortality before adulthood for the Chronic visceral form (type B) is around 15-25%. Many live well into adulthood and may reach a normal lifespan. Diagnosis have been made in the 7th decade of life.[4][5][6]
Fabry disease	α-galactosidase A	Glycolipids, particularly ceramide trihexoside, in brain, heart, kidney	Ischemic infarction in affected organs Acroparesthesia Angiokeratomas hypohidrosis	X-linked[7]	Between 1 in 40,000 to 1 in 120,000 live births for males[8]	Enzyme replacement therapy (but expensive)	Life expectancy among males of approximately 60 years[9]
Krabbe disease	Galactocerebrosidase	Glycolipids, particularly galactocerebroside, in oligodendrocytes	Spasticity Neurodenegeration (leading to death) Hypertonia Hyperreflexia Decerebration-like posture Blindness Deafness	Autosomal recessive	About 1 in 100,000 births[10]	Bone marrow transplant (high risk, potential failure, effectively provides enzyme replacement to the central nervous system from six months post-transplant, if done in the earliest stages; less effective enzyme replacement provision for the peripheral nervous system)	Untransplanted, and in the case of a failed transplant, generally fatal before age 2 for infants
Gaucher disease	Glucocerebrosidase	Glucocerebrosides in RBCs, liver and spleen	Hepatosplenomegaly Pancytopenia Bone pain Erlenmeyer flask deformity	Autosomal recessive	About 1 in 20,000 live births,[11] more among Ashkenazi Jews	Enzyme replacement therapy (but expensive)	May live well into adulthood
Tay–Sachs disease	Hexosaminidase A	GM2 gangliosides in neurons	Neurodegeneration Developmental disability Early death	Autosomal recessive	Approximately 1 in 320,000 newborns in the general population,[12] more in Ashkenazi Jews	None	Death by approx. 4 years for infantile Tay–Sachs[13]
Metachromatic leukodystrophy (MLD)	Arylsulfatase A or prosaposin	Sulfatide compounds in neural tissue	Demyelination in CNS and PNS: Mental retardation Motor dysfunction Ataxia Hyporeflexia Seizures	Autosomal recessive[14]	1 in 40,000 to 1 in 160,000[15]	Bone marrow transplant (high risk, potential failure, effectively provides enzyme replacement to the central nervous system from six months post-transplant, if done in the earliest stages; less effective enzyme replacement provision for the peripheral nervous system)	Untransplanted, and in the case of a failed transplant, death by approx. 5 years for infantile MLD

Metabolic pathways

See also

• Lipid storage disorder