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  • Updated 12.10.2023
  • Released 02.03.1994
  • Expires For CME 12.10.2026




X-linked adrenoleukodystrophy is a progressive neurodegenerative peroxisomal disorder caused by mutations in the ABCD1 gene, leading to accumulation of very long-chain fatty acids. It is currently the most common leukodystrophy, with the frequency of heterozygotes estimated to be around 1 per 17,000. Despite it being a X-linked disorder, both men and women can be affected. The spectrum of clinical manifestations can be variable, from isolated adrenal involvement and childhood-onset leukodystrophy to adult-onset myeloneuropathy. X-linked adrenoleukodystrophy is included in the Recommended Uniform Screening Panel (RUSP) and, hence, implemented as newborn screening in several states.

Key points

• X-linked adrenoleukodystrophy is currently one of the most common leukodystrophies and is now included in newborn screening in several states.

• The clinical manifestations, age of presentation, and severity of symptoms are variable with no definite genotype-phenotype correlation to date.

• Affected males have three main phenotypes: primary adrenal insufficiency, childhood cerebral adrenoleukodystrophy, or adult-onset myeloneuropathy with or without leukodystrophy.

• Although X-linked, females can also be symptomatic, and the frequency of symptomatic heterozygote women increases sharply with age.

• Treatment is based on presentation, age of onset, and functional status at presentation. If initiated very early in the disease process, it appears that X-linked cerebral adrenoleukodystrophy can be effectively treated using hematopoietic stem cell transplantation, though this does not address the adrenal insufficiency and myeloneuropathy.

Historical note and terminology

In 1987, the first patient with X-linked adrenoleukodystrophy was described by Heubner, a male with rapidly progressive neurologic deterioration (25). In postmortem examinations, diffuse sclerosis in the white matter was evident. Prior to 1970 when the term “adrenoleukodystrophy” was first described, several cases described as “encephalitis periaxialis diffusa” and Schilder disease were associated with symptoms consistent with X-linked adrenoleukodystrophy.

Amidst the plethora of historically based nomenclatures, we recommend that the current designation “adrenoleukodystrophy” be applied to all males who have a pathogenic defect in the X-linked gene that codes for ALDP. All these individuals have demonstrable defects in very long-chain fatty acid metabolism with clinical presentations ranging from asymptomatic, to isolated primary adrenal insufficiency, to various degrees of neurologic involvement. When there is clinical and radiological evidence of involvement of the cerebral hemispheres, we refer to them as childhood, adolescent, or adult cerebral forms of adrenoleukodystrophy. When nervous system involvement affects mainly the spinal cord and peripheral nerves, the condition is referred to as myeloneuropathy.

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