Adrenoleukodystrophy: Molecular, Metabolic, Pathologic, and Therapeutic Aspects

Peroxisomal Dysfunction in Inflammatory Childhood White Matter Disorders: An Unexpected Contributor to Neuropathology

“…32 In addition, the observed loss of plasmalogens in inflammatory areas of cALD brain strongly indicates loss of peroxisomal function in those areas 33. This data suggests a relationship between the expression of inflammation mediators, impairment of peroxisomal function, and accumulation of very-long-chain fatty acids in cALD brain 7. Although the expression of mediators of inflammatory disease in cALD have been known since the 1990s,8 the role of very-long-chain fatty acids in the induction of inflammatory disease eluded very many efforts.…”

“…The identification of fatal neurological peroxisomal disorders (Table 1)7-9 encompassing dysfunction in the peroxisomal assembly (biogenesis)9 or individual enzyme functions8,10 highlights the importance of peroxisomes for human health. Peroxisomes are also responsible for turnover of a number of proinflammatory mediators such as metabolite of arachidonic acid and thus participate in inflammatory disease10, and abnormality in very-long-chain fatty acid turnover by peroxisomes, such as in adrenoleukodystrophy, upregulates the expression of inflammatory mediators and thus inflammatory disease 7.…”

“…Peroxisomes are also responsible for turnover of a number of proinflammatory mediators such as metabolite of arachidonic acid and thus participate in inflammatory disease10, and abnormality in very-long-chain fatty acid turnover by peroxisomes, such as in adrenoleukodystrophy, upregulates the expression of inflammatory mediators and thus inflammatory disease 7. Therefore, once peroxisomal functions are affected, a self-amplification cycle perpetuates itself by further inhibiting peroxisomal functions, resulting in further amplification of the inflammatory cascade.…”

“…The most common peroxisomal disorder, X-ALD, is an inherited metabolic disease that affects the nervous system of boys during early childhood (cerebral form, cALD), the severe form of the disease, or early adulthood (adrenomyeloneuropathy, AMN), the mild form of the disease 1,7,8. The affected gene encodes a peroxisomal membrane protein14 that is a member of the ATP-binding cassette family of transporters (ABCD1 or adrenoleukodystrophy protein [ALDP])15 whose function still is unclear.…”

“…Biochemical analysis using cultured skin fibroblasts derived from X-ALD patients demonstrated alteration in the degradation of those fatty acids by peroxisomal β-oxidation16 and an enhanced elongation of fatty acids, an endoplasmic reticulum function 17. Although the precise function of ABCD1 is not understood at present, the fact that transfection of ABCD1 into adrenoleukodystrophy fibroblasts normalizes the fatty acids levels suggests that ABCD1 is involved in the metabolism of very-long-chain fatty acids 7,8. However, lack of correlation between genotype and phenotype as identical mutations can induce the mild or severe form of the disease, indicates that an additional genetic factor (modifier gene) may play a role in the progression of the disease 18,19.…”