Metachromatic leukodystrophy 2011
Contents
Summary
Metachromatic leukodystrophy (MLD) is an incurable, autosomal recessive inherited disease, which is caused by a mutation in the enzyme Arylsulfatase A (ARS A). It belongs to the lysosomal storage diseases. The deficiency of the enzyme leads to storage of sulfatides and lysosulfatides, which are usually digested by the enzyme. The storage of the lipids glycosphingolipid sulfatide and lysosulfatide cause a degeneration of the white matter in the brain. This part of the brain mainly consists of myelinated axons, which are needed for the proper function of the brain. <ref name="blomqusit2011">Blomqvist, Maria. Gieselmann,Volkmar. Mansson,Jan-Eric. "Accumulation of lysosulfatide in the brain of arylsulfatase A-deficient mice". Lipids in Health and Disease, 2011</ref> Sulfatide is one of many compomnents of the complex composition of myelin <ref name="jeon2008">Jeon, S. B. and Yoon, H. J. and Park, S. H. and Kim, I. H. and Park, E. J.. "Sulfatide, a major lipid component of myelin sheath, activates inflammatory responses as an endogenous stimulator in brain-resident immune cells. J Immunol, 2008</ref>. ARS A catalyses the breakdown and correct incorporation <ref name="wiesmann1978">Wiesmann, U. N.. "[Pathophysiology of sulfatide metabolism in metachromatic leukodystrophy]". Bull Schweiz Akad Med Wiss, 1978</ref> There is no effective therapy available yet and carries of the disease all die. The progression and symptoms of the disease are in general mental and motoric retardation.
Phenotype
Five different allelic variants have been described. Depending on the variant, onset and type of symptoms and progression of the disease can be different <ref name="wikipedia"> http://en.wikipedia.org/wiki/Metachromatic_leukodystrophy </ref>, <ref name="OMIM"> http://www.ncbi.nlm.nih.gov/omim/250100 </ref>:
- Late infantile: Carriers of the disease causing alleles usually become diseased two years after birth. The patients show motor symptoms, rigidity, mental deterioration, and sometimes convulsions. Death occurs five years after breakout of the disease at the latest.
- Juvenile: Onset is between 3 to 10 years of age. The disease usually begins with impaired school performance, mental deterioration and dementia. Then, symptoms strongly resemble the late infantile form. As the progression is slower than in the juvenile form, patients normally die 10 to 15 years after the start of the symptoms.
- Adult forms: This form of MLD begins after the age of 16. Symptoms are commonly psychiatric and can lead to the diagnosis of schizophrenia. Disorders in movement and posture appear very late. The progression of the disease is even slower than in the "late infantile" and "juvenile" forms and patients may live for another several decades after onset of the symptoms.
- Partial cerebroside sulfate deficiency:
- Pseudoarylsulfatase A deficiency:
Cross-references
See also description of this disease in
- Wikipedia article on MLD
- Wikipedia article on ARS A
- HGMD entry of ARS A
- OMIM entry for MLD
- OMIM Entry for ARS A
- KEGG disease entry for MLD
Biochemical disease mechanism
Arylsulfatase A is located in the Lysosome, where it is responsible for breaking up sulfated Glycosphingolipids (Sulfatides). As the sulfatides are not degraded, they build up and destroy the myelin sheath around the axons.
Cross-references
- KEGG entry of ARS A
- Reactions catalysed by ARS A
- [MetaCyc reaction of ARS A]
- PDB entry of HUMAN ARYLSULFATASE A
Mutations
47 known, disease causing allelic variants are listed in the OMIM database.
Current knowledge about mutations associated with the disease. - Separate into disease causing and neutral mutations.
Reference sequence
Which sequence does not cause the disease and is most often found in the population.
- Create a page for the reference sequence. -- These sequence pages will be the starting point for collecting prediction results and result discussions.
Neutral mutations
Disease causing mutations
References
<references />
