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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.

Accumulated products

Gangliosides: Gangliosidosis
- GM1 gangliosidoses
- GM2 gangliosidoses
  - Tay-Sachs disease
  - Sandhoff disease
Glycolipids
- Fabry's disease
- Krabbe disease
- Metachromatic leukodystrophy
Glucocerebrosides
- Gaucher's disease

Overview

Table

Comparison of the main sphingolipidoses
Disease	Deficient enzyme^[1]	Accumulated products^[1]	Symptoms^[1]	Inheritance^[1]	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^[2]	Limited	Usually fatal by the age of approx 1.5 years.^[3]
Fabry disease	α-galactosidase A	Glycolipids, particularly ceramide trihexoside, in brain, heart, kidney	Ischemic infarction in affected organs Acroparesthesia Angiokeratomas hypohidrosis	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	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.^[7]	Limited	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,^[8] 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,^[9] more in Ashkenazi Jews	None	Death by approx. 4 years for infantile Tay–Sachs ^[10]
Metachromatic leukodystrophy (MLD)	Arylsulfatase A or prosaposin	Sulfatide compounds in neural tissue	Demyelinisation in CNS and PNS: Mental retardation Motor dysfunction Ataxia Hyporeflexia Seizures	Autosomal recessive^[11]	1 in 40,000 to 1 in 160,000^[12]	None	Death by approx. 5 years for infantile MLD

Metabolic pathways

References

^ ^a ^b ^c ^d 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.
^ 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
^ NINDS Niemann-Pick Disease Information Page at the National Institute of Neurological Disorders and Stroke. Last updated October 6, 2011
^ Banikazemi M, Desnick RJ, Astrin KH (2009-07-08). "Fabry Disease". eMedicine Pediatrics: Genetics and Metabolic Disease. Medscape. Retrieved 2010-12-31.
^ 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. edit
^ 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. edit
^ "Krabbe disease". Genetics Home Reference. United States National Library of Medicine. 2008-05-02. Retrieved 2008-05-07.
^ Gaucher Disease at National Gaucher Foundation. Retrieved June 2012
^ GM2 Gangliosidoses - Introduction And Epidemiology at Medscape. Author: David H Tegay. Updated: Mar 9, 2012
^ 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 : Official journal of the American College of Medical Genetics 12 (4 Suppl): S5–S14. doi:10.1097/GIM.0b013e3181d5a669. PMC 3042321. PMID 20393311.
^ 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.
^ Metachromatic leukodystrophy at Genetics Home Reference. Reviewed September 2007

External links

Sphingolipidoses at the US National Library of Medicine Medical Subject Headings (MeSH)
-382402491 at GPnotebook

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English Journal

The chaperone activity and toxicity of ambroxol on Gaucher cells and normal mice.

Luan Z, Li L, Higaki K, Nanba E, Suzuki Y, Ohno K.SourceDivision of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan. Electronic address: nicholasluan@gmail.com.
Brain & development.Brain Dev.2013 Apr;35(4):317-22. doi: 10.1016/j.braindev.2012.05.008. Epub 2012 Jun 7.
Gaucher disease (GD), caused by a defect of acid β-glucosidase (β-Glu), is one of the most common sphingolipidoses. Recently, ambroxol, an FDA-approved drug used to treat airway mucus hypersecretion and hyaline membrane disease in newborns, was identified as a chemical chaperone for GD. In the pre
PMID 22682976

Invariant natural killer T cells are phenotypically and functionally altered in Fabry disease.

Pereira CS, Azevedo O, Maia ML, Dias AF, Sa-Miranda C, Macedo MF.SourceLysosome and Peroxisome Biology Unit (UniLiPe), IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre nº 823, 4150-180, Porto, Portugal. Electronic address: cspereira@ibmc.up.pt.
Molecular genetics and metabolism.Mol Genet Metab.2013 Apr;108(4):241-8. doi: 10.1016/j.ymgme.2013.01.018. Epub 2013 Feb 1.
Fabry disease is a lysosomal storage disease belonging to the group of sphingolipidoses. In Fabry disease there is accumulation of mainly globotriaosylceramide due to deficiency of the lysosomal enzyme α-galactosidase A. The lysosome is an important compartment for the activity of invariant natural
PMID 23433711

The sustained activation of sphingomyelin synthase by 2-hydroxyoleic acid induces sphingolipidosis in tumor cells.

Martin ML, Liebisch G, Lehneis S, Schmitz G, Alonso-Sande M, Bestard-Escalas J, Lopez DH, Garcia-Verdugo JM, Soriano-Navarro M, Busquets X, Escriba PV, Barcelo-Coblijn G.SourceMemorial Sloan-Kettering Cancer Center, United States;
Journal of lipid research.J Lipid Res.2013 Mar 7. [Epub ahead of print]
The mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent antitumor drug, involves the rapid and specific activation of sphingomyelin synthase (SMS), leading to a 4-fold increase in SM mass in tumor cells. In the present study, we investigated the source of the ceramides required to sustain t
PMID 23471028

Japanese Journal

Application of delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry for analysis of sphingolipids in cultured skin fibroblasts from sphingolipidosis patients

Brain & development 24(3), 170-173, 2002-04-01
NAID 10010103744

実地医家のためのゴーシェ病の知識

日本医事新報 (4042), G1-5, 2001-10-13
NAID 40002824020

Application of delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry for analysis of sphingolipids in tissues from sphingolipidosis patients