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 (VLCFAs). Primary manifestations occur in the 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 (childhood cerebral ALD [CCALD]) or adulthood (adult cerebral ALD [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. Approximately 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 prove 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 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 also be a final therapeutic option in early ACALD patients. 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 upregulation of other genes encoding
proteins involved in peroxisomal beta-oxidation, reduction of oxidative stress, and possibly
lovastatin are candidates for future
X-ALD therapies.