Metachromatic leukodystrophy 2011

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. <ref name="biffi:2008">Biffi, A. and Lucchini, G. and Rovelli, A. and Sessa, M. "Metachromatic leukodystrophy: an overview of current and prospective treatments." Bone Marrow Transplant ,2008 </ref>

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: Carriers of this allele show apparent ARS A enzyme deficiency, but without neurologic abnormalities.
• Pseudoarylsulfatase A deficiency: In this form, the enzyme is partial defected with 10-20 % of normal activity. The symptoms are similar to adult form.

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

Genomic and structural basis of Arylsulfatase A

Gene

The gene coding for Arylsulfatase A is the ARSA gene. It is located on the long arm of chromosome 22 base pair 51,063,448 to base pair 51,066,606. It consists of eight exons. There are more than 100 mutations known until now with different frequencies among ethnic groups.

More than 100 MLD-related ARSA mutations have been described to date, with the frequency differing among ethnic groups. Nevertheless, roughly 50% of the MLD alleles remain unidentified. MLD mutations can be functionally divided into two broad groups: 0 alleles associated with no enzymatic activity and R alleles encoding for ARSA with minimal residual enzymatic activity. The 0 allele 459+1G>A, and the R alleles 1277C>T and 536T>G represent the most frequent mutations encountered in the European population.16, 17, 18, 19 The available epidemiological data are scarce, but all sources indicate that MLD is an extremely rare disorder with an incidence of 0.06–0.25 in 10 000. More recent reports estimated the birth prevalence of MLD to be 1.4–1.8 per 100 000 for all types combined.

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.

Sphingolipid metabolism - Homo sapiens (human) source:http://www.genome.jp/kegg-bin/show_pathway?map00600 highlighting of Arylsulfatase A

Cross-references

• KEGG entry of ARS A
• Reactions catalysed by ARS A
• MetaCyc reaction of ARS A
• PDB entry of HUMAN ARYLSULFATASE A

Treatment

There is no effective therapy avalable yet. Efforts are made to develop and test promising medication for the future <ref name="biffi:2008">Biffi, A. and Lucchini, G. and Rovelli, A. and Sessa, M. "Metachromatic leukodystrophy: an overview of current and prospective treatments." Bone Marrow Transplant ,2008 </ref>:

• Enzyme replacement therapy: The deficient enzyme is replaced, e.g. by infusion and thus restores enzyme activity. Currently this is the most promising approach, because it is already available for the following lysosomal storage diseases: Gaucher disease, Fabry disease, MPS I, MPS VI and Glycogen storage disease type II. Clinical tests of this approach are conducted at the moment.
• Gene therapy: Gene therapy may be used to e.g. repopulate affected tissues with donor-derived myeloid cells. Also here, clinical test are currently performed.

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.

• Nucleotide sequence
• Amino Acid sequence

References

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