Fabry Disease 2011
Fabry disease is a rare genetic disease, that is inherited via the X chromosome and causes a defect in the gene GAL. It is a Lysosomal storage disease and therefore causes a wide range of symptoms. The disease is named after the German Johannes Fabry, who described the disease in 1898 simultaneous with William Anderson from UK.
As the effects caused by the enzymatic dysfunction accumulate over time, the symptoms evolve progressively. The symptoms occuring during childhood, are generally not specific for Fabry disease, thus it is rarely diagnosed at that stage. The most significant symptom for Fabry disease are dark red skin rashes, that usually evolve during adolescence. The most restrictive and dangerous symptoms emerge at an age of ~30-35.<ref name=fabrycom>http://www.fabrycommunity.com/en/Patients/Education/Progression.aspx</ref>
- Pain and burning in the hands and feet
- Impaired sweating
- Psychological and social issues
- Low tolerance for exercise
- Eye abnormalities
- Dark red skin rashes (angiokeratomas)
- Gastrointestinal problems
- Heart problems
- Kidney problems
- Nervous system problems
- Hearing problems
See also description of this disease in
The protein α-galactosidase A is encoded by the gene GLA, which is locacted on the X chromosome (gene map locus: Xq22). The gene has an overall length of 10,222 nucleotides and consists of 7 exons (1,290 nucleotides) and 6 introns (8,932 nucleotides).
α-galactosidase A is a homodimeric protein that consist of 398 amino acids. It is a glycosidase (EC number: 18.104.22.168) and hydrolyses O- and S-glycosidic bonds of glycolipids.
- KEGG: EC 22.214.171.124
- MetaCyc: α-Galactosidase A
- PDB: 1R47
- UniProt: α-galactosidase A
- Wikipedia: α-galactosidase A
Biochemical disease mechanism
Mutations of the gene GLA influence the enzyme α-galactosidase A. These mutations can affect the synthesis<ref name=lemansky>Lemansky et al., "Synthesis and processing of alpha-galactosidase A in human fibroblasts. Evidence for different mutations in Fabry disease.", J Biol Chem. 1987 Feb 15, PubMed</ref>, kinetic properties and stability<ref name=bernstein>Bernstein et al., "Fabry disease: six gene rearrangements and an exonic point mutation in the alpha-galactosidase gene.", J Clin Invest 1989 Apr, PubMed</ref> of the enzyme which leads to a decreased enzyme activity. Hence the catabolization of glycosphingolipids is not done properly which is especially the case for the breakdown of globotriaosylceramide (GL3) to lactosylceramide (GL2) and galactose<ref name=nance>Nance et al., "Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome.", Arch Neurol. 2006 Mar, PubMed</ref>. Since the α-galactosidase A is located in the lysosome, Fabry disease is categorized as an lysosomal storage disorder. The accumulation of glycosphingolipids in the lysosome of blood vessels (endothelial, perithelial and smooth-muscle) and other cell types of heart, kidneys, eyes, cornea and the autonomous nervous system leads to the progressively arising symptoms of the Fabry disease<ref name=kolter>Thomas Kolter, Konrad Sandhoff, Sphingolipid metabolism diseases, Biochimica et Biophysica Acta (BBA) - Biomembranes, Volume 1758, Issue 12, Sphingolipids, Apoptosis and Disease, December 2006, Pages 2057-2079, ISSN 0005-2736</ref>.
Currently there are 494 mutations known of the GLA gene in HGMD (as of 2011/05/15)<ref name=HGMD>HGMD</ref>. 492 of these mutations are associated with Fabry disease, for one mutation there is a uncertainty about the association and one mutation leads to an increased transcription of GLA. A great majority (about 70%) of the associated mutations are missense/nonsense mutations.