Therapy for X-linked adrenoleukodystrophy

Abstract

X-linked adrenoleukodystrophy (X-ALD, OMIM #300100) is caused by defects of the ABCD1 gene on chromosome Xq28 resulting in an impairment of peroxisomal beta-oxidation and the accumulation of saturated very long chain fatty acids (VLCFA).Primary manifestations occur in the central nervous system (CNS), the adrenal cortex and the testes' Leydig cells. The clinical presentation shows a marked variability which is not explained by the different X-ALD genotypes. Phenotypes range from rapidly progressive cerebral disease with childhood (CCALD) or adulthood (ACALD) onset leading to death within a few years, over adult onset adrenomyeloneuropathy (AMN) with or without focal CNS demyelination, AMN converting into a rapidly progressive, cerebral demyelinating phenotype resembling CCALD, to slow disease progression over decades or adrenal insufficiency only. About 50% of female heterozygotes develop moderate spastic paresis resembling the AMN phenotype. This review focuses on current experiences with different therapeutic approaches. Lorenzo's oil did not proof to be effective in cerebral inflammatory disease variants, but asymptomatic patients, and speculatively AMN variants without cerebral involvement, as well as female carriers may benefit from early intake of such oleic and erucic acids in addition to VLCFA restriction. Hormone replacement therapy is necessary in all patients with adrenal insufficiency. Hematopoietic stem cell transplantation has been reported to be effective in presymptomatic or early symptomatic CCALD and may well be a final therapeutic option in early ACALD patients as well. Early detection of mutation carriers and timely initiation of therapy is important for the effectiveness of all therapeutic efforts. Gene therapy of endogenous hematopoietic stem cells, pharmacological up-regulation of other genes encoding proteins involved in peroxisomal beta-oxidation, reduction of oxidative stress, and possibly lovostatin are candidates for future X-ALD therapies.