Sphingolipidoses

Sphingolipidoses are a class of lipid storage disorders 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 namesSphingolipidosis
Diagram showing some of the sphingolipidoses
SpecialtyMedical genetics

Accumulated products

Comparison
Comparison of the main sphingolipidoses
DiseaseDeficient enzyme[1]Accumulated products[1]Symptoms[1]Inheritance[1]IncidenceGenerally accepted treatmentsPrognosis
Niemann-Pick disease SphingomyelinaseSphingomyelin in brain and RBCs
  • Mental retardation
  • Spasticity
  • Seizures
  • Hepatosplenomegaly
  • Thrombocytopenia
  • Ataxia
 Autosomal recessive1 in 100,000[2] Limited Usually fatal by the age of approx 1.5 years but may live well into adulthood[3]
Fabry disease α-galactosidase AGlycolipids, particularly ceramide trihexoside, in brain, heart, kidney X-linked[4] Between 1 in 40,000 to 1 in 120,000 live births for males[5] Enzyme replacement therapy (but expensive) Life expectancy among males of approximately 60 years[6]
Krabbe disease GalactocerebrosidaseGlycolipids, particularly galactocerebroside, in oligodendrocytes Autosomal recessive About 1 in 100,000 births[7] 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 GlucocerebrosidaseGlucocerebrosides in RBCs, liver and spleen Autosomal recessive About 1 in 20,000 live births,[8] more among Ashkenazi Jews Enzyme replacement therapy (but expensive) May live well into adulthood
Tay–Sachs disease Hexosaminidase AGM2 gangliosides in neurons
  • Neurodegeneration
  • Developmental disability
  • Early death
 Autosomal recessive Approximately 1 in 320,000 newborns in the general population,[9] more in Ashkenazi Jews None Death by approx. 4 years for infantile Tay–Sachs[10]
Metachromatic leukodystrophy (MLD) Arylsulfatase A or prosaposinSulfatide compounds in neural tissueDemyelination in CNS and PNS:
  • Mental retardation
  • Motor dysfunction
  • Ataxia
  • Hyporeflexia
  • Seizures
 Autosomal recessive[11] 1 in 40,000 to 1 in 160,000[12] 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
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See also

References
  1. If not otherwise specified, reference is: Marks, Dawn B.; Swanson, Todd; Sandra I Kim; Marc Glucksman (2007). Biochemistry and molecular biology. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. ISBN 0-7817-8624-X.
  2. Niemann-Pick disease from Genetics Home Reference. Reviewed: January 2008. Based on an incidence in a general population of 1 in 250,000 for types A and B and 1 in 150,000 for type C
  3. NINDS Niemann-Pick Disease Information Page at the National Institute of Neurological Disorders and Stroke. Last updated October 6, 2011
  4. Banikazemi M, Desnick RJ, Astrin KH (2009-07-08). "Fabry Disease". eMedicine Pediatrics: Genetics and Metabolic Disease. Medscape. Retrieved 2010-12-31.
  5. Mehta, A.; Ricci, R.; Widmer, U.; Dehout, F.; Garcia De Lorenzo, A.; Kampmann, C.; Linhart, A.; Sunder-Plassmann, G.; Ries, M.; Beck, M. (2004). "Fabry disease defined: Baseline clinical manifestations of 366 patients in the Fabry Outcome Survey". European Journal of Clinical Investigation. 34 (3): 236–242. doi:10.1111/j.1365-2362.2004.01309.x. PMID 15025684.
  6. Waldek, S.; Patel, M. R.; Banikazemi, M.; Lemay, R.; Lee, P. (2009). "Life expectancy and cause of death in males and females with Fabry disease: Findings from the Fabry Registry". Genetics in Medicine. 11 (11): 790–796. doi:10.1097/GIM.0b013e3181bb05bb. PMID 19745746.
  7. "Krabbe disease". Genetics Home Reference. United States National Library of Medicine. 2008-05-02. Retrieved 2008-05-07.
  8. Gaucher Disease at National Gaucher Foundation. Retrieved June 2012
  9. GM2 Gangliosidoses – Introduction And Epidemiology at Medscape. Author: David H Tegay. Updated: Mar 9, 2012
  10. Colaianni, Alessandra; Chandrasekharan, Subhashini; Cook-Deegan, Robert (2010). "Impact of Gene Patents and Licensing Practices on Access to Genetic Testing and Carrier Screening for Tay–Sachs and Canavan Disease". Genetics in Medicine. 12 (4 Suppl): S5–S14. doi:10.1097/GIM.0b013e3181d5a669. PMC 3042321. PMID 20393311.
  11. Gieselmann V, Zlotogora J, Harris A, Wenger DA, Morris CP (1994). "Molecular genetics of metachromatic leukodystrophy". Hum. Mutat. 4 (4): 233–42. doi:10.1002/humu.1380040402. PMID 7866401.
  12. Metachromatic leukodystrophy at Genetics Home Reference. Reviewed September 2007
Classification


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