About Adrenoleukodystrophy

Adrenoleukodystrophy is an X-linked peroxisomal disorder that affects the white matter of the central nervous system, adrenal cortex and testes in boys. The incidence is rare, in that only 1:50,000 males are affected with the disease. People diagnosed with X-linked ALD have elevated plasma levels of saturated very long chain fatty acids (VLCFA – C22 or longer), and for reasons currently not clearly understood, these elevated  levels of VLCFA are toxic to the body, primarily the myelin sheath in the central nervous system. VLCFA are broken down in peroxisomes rather than, like most fatty acids, in the mitochondria due to their large size.

Research has indicated that a gene defect located in Xq28 on the X chromosome is the primary cause of this disease. Xq28 encodes for peroxisomal membrane protein, ALD-P (Adrenoleukodystrophy Protein). ALD-P belongs to the adenosine triphosphate-binding cassette (ABC) superfamily of transmembrane transporters. ABC proteins transport a variety of molecules ranging from ions to proteins across extra- and intra-cellular membranes. An increasing number of mutations (mainly missense) in the ABCD1 gene results in the absence or defective ALD-P, which is responsible for the transfer of VLCFA to peroxisomes for β-oxidation. Furthermore, the metabolism of these fatty acids are activated by their coenzyme A thioesters, acyl-CoA synthetase. Coenzyme activity has also been found to be impaired in ALD patients. Activation of VLCFA by very long chain acyl-CoA synthetase (VLCS) takes place in the peroxisome organelle. Lack of VLCS prevents this organelle from catabolizing VLCFA via β-oxidation.

Due to the inability of VLCFA to be oxidized, an autoimmune or cytokine-mediated inflammatory response normally occurs, leading to cerebral white matter demyelination and scarring due to gliosis.

Nevena V.

References

Kemp S, Pujol A, Waterham HR, van Geel BM, Boehm CD, Raymond GV, Cutting GR, Wanders RJA, Moser HW (2001) ABCD1 Mutations and the X-linked Adrenoleukodystrophy Mutation Database: Role in Diagnosis and Clinical Correlations. Human Mutation. 18(6): 499-515.

Melhem ER, Barker PB, Raymond GV, Moser HW (1999) X-Linked Adrenoleukodystrophy in Children: Review of Genetic, Clinical, and MR Imaging Characteristics. American Journal of Roentgenology. 173(6): 1575-1581.

http://www.x-ald.nl/