Discussion Utilisateur:Dumas69003

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Stephan Kemp, Ph.D., Marc Engelen M.D., and Paul Watkins, M.D., Ph.D.

In retrospect, Haberfeld and Spieler presented the first clinical description of a patient with X-linked adrenoleukodystrophy in 1910 (Haberfeld and Spieler, 1910). A previously healthy 6 year old boy developed a deeply bronzed skin (hyperpigmentation), impaired visual acuity, and his school performance deteriorated. The following months, this boy became incontinent, lost his ability to speak and developed spastic tetraparesis, which eventually progressed to an inability to walk. He was hospitalized at the age of 7, and died 8 months later. An older brother had died of a similar illness at the age of 8. Postmortem histological examination of the brain revealed extensive changes in brain white matter, combined with perivascular accumulation of lymphocytes and plasma cells in the nervous system, indicating an inflammatory response. In 1923, Siemerling and Creutzfeldt reported the case of a boy with a similar disease progression, including the dark skin and neuropathological findings as in the case described by Haberfeld & Spieler in 1910, except that atrophy of the adrenal cortex was documented. By 1963, nine comparable cases had been reported. The fact that all patients were males suggested X-linked recessive inheritance (Fanconi et al., 1963). The name adrenoleukodystrophy was introduced in 1970, based on the striking association of a leukodystrophy with adrenocortical insufficiency (Blaw, 1970). In 1976, a more slowly progressive adult form of the disease characterized by adrenocortical insufficiency, myelopathy and peripheral neuropathy was described (Budka et al., 1976). A year later, five more cases were reported by Griffin et al. who proposed this clinical presentation of X-ALD to be named adrenomyeloneuropathy (AMN) (Griffin et al., 1977). The key to all subsequent knowledge about the disease was the observation made by Powers, Schaumburg, and Johnson that adrenal cells of ALD patients contained characteristic lipid inclusions (fat droplets), followed by the demonstration that these fat droplets consisted of cholesterol esters that contained a striking and characteristic excess of very long-chain fatty acids (VLCFA). Identification of this biochemical characteristic led to the development of assays capable of demonstrating more subtle increases in VLCFA levels in cultured skin cells (fibroblasts), plasma, red blood cells and amniocytes. These techniques have permitted precise postnatal and prenatal diagnosis, the facilitation of genetic studies and gene mapping and the evaluation of therapeutic approaches. Metabolic studies have demonstrated that VLCFA are metabolized (through beta-oxidation) exclusively in subcellular organelles called peroxisomes (see the biochemistry page for more details). Therefore, X-ALD is a peroxisomal disease. Prior to their metabolism, VLCFA must be activated to VLCFA-CoA. The enzyme that performs this reaction is called the very long-chain fatty acyl-CoA synthetase (VLCS). Because the reaction of VLCFA to VLCFA-CoA is diminished in peroxisomes of X-ALD patients, it was hypothesized that genetic changes (mutations) in the VLCS gene are responsible for X-ALD. In 1981, the X-ALD locus was mapped to the terminal segment of the long arm of the X-chromosome, Xq28 (Migeon et al., 1981), and in 1993 Aubourg and co-workers identified the putative gene for X-ALD (ABCD1) using positional cloning strategies (Mosser et al., 1993). It is now absolutely clear that X-ALD is caused by mutations in the X-ALD gene, and not by mutations in the VLCS gene. Of course, this finding was not anticipated. The X-ALD protein (ALDP) has no VLCS activity. One of the many questions that needs to be answered is: "What is the functional relation between ALDP and VLCS?" X-ALD has been identified in all ethnic groups and it is the most common peroxisomal disorder with a minimum incidence ranging from 1:42,000 for hemizygotes only to 1:17,000 for hemizygotes plus heterozygotes combined (Bezman et al., 2001). This makes X-ALD the most common inherited leukodystrophy. The identification of the X-ALD gene enabled the detection of disease causing mutations, prenatal diagnosis and accurate carrier testing (see the diagnosis page for more details). The X-ALD database was initiated in 1999 as a registry for all the mutations identified in the ABCD1 gene.

• www.x-ald.nl/history

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