Molecular Genetics of X‐linked Adrenoleukodystrophy

Abstract X‐linked adrenoleukodystrophy (X‐ALD), which affects 1 in 17 000 newborns, is one of the most puzzling inborn errors of metabolism of the central nervous system. All X‐ALD patients have mutations in the ABCD1 gene, which affect the function of the encoded protein ALDP, an adenosine triphosphate (ATP) ‐binding cassette transporter located in the peroxisomal membrane protein. ALDP deficiency impairs the peroxisomal beta‐oxidation of very long‐chain fatty acids (VLCFA) and facilitates their further chain elongation by ELOVL1 resulting in the accumulation of VLCFA in the plasma and tissues. The clinical spectrum ranges from progressive myelopathy in adults to fatal cerebral demyelinating disease in boys and adult males (cerebral ALD). In the absence of a genotype–phenotype correlation, the disease course remains completely unpredictable, even within families, and is therefore defined by modifier genes, epigenetics and the environment. For the majority of patients there is no curative therapy. Key Concepts: The clinical spectrum of X‐ALD ranges from a progressive myelopathy (adrenomyeloneuropathy) in adult males and females to a fatal cerebral demyelinating disease in boys and adult males (cerebral ALD). X‐ALD has been diagnosed in all geographic regions and ethnic groups, and there is no evidence that the prevalence varies with ethnic background. Mutations in the ABCD1 gene have no predictive value with respect to the clinical outcome of a patient. Approximately 65% of heterozygous females develop AMN by the age of 60 years. VLCFA accumulating in X‐ALD mostly result from endogenous synthesis through elongation of LCFA by ELOVL1, the VLCFA‐specific elongase. Newborn screening allows prospective monitoring and early intervention.