The clinical spectrum of X-linked adrenoleukodystrophy: from Addison's-only in men to middle-age neurologic manifestations in women

Hormones (Athens). 2022 Mar;21(1):33-40. doi: 10.1007/s42000-021-00325-y. Epub 2021 Oct 15.

Abstract

X-linked adrenoleukodystrophy (X-ALD) is caused by a mutation in the ABCD1 gene which encodes for a peroxisomal very long-chain fatty acid (VLCFA) transporter. Clinically, X-ALD can present a wide range of phenotypes, from slowly progressive myelopathy to rapid demyelination of brain white matter (cerebral X-ALD-CALD). Adrenocortical insufficiency (AI) occurs mainly in the pediatric age group, and it can be the first manifestation of the disease. Female carriers may also develop manifestations of myelopathy, but later in life. We present two cases of patients who show the heterogeneous clinical manifestations of X-ALD. Case 1 was a man with AI diagnosed at 6 years old and with the first manifestations of myelopathy at 44 years old, which led to the diagnosis of X-ALD. At 47 years, he developed rapidly progressive CALD. Case 2 was a woman with progressive spastic gait disturbance that started at 49 years old. The diagnosis of X-ALD was confirmed at 54 years old after the discovery of a family history of the disease. Mild progression of the neurologic manifestations was noted, but with no signs of AI nor CALD. She is currently 60 years old and under surveillance. We review the current knowledge on X-ALD as concerns its genetic and pathophysiological mechanisms, clinical presentations, diagnosis, treatment, and follow-up. This condition is a real diagnostic challenge. The early detection of AI and CALD, potentially life-threatening complications in men, is very difficult. The surveillance of these complications in female patients still raises controversy.

Keywords: ATP-binding cassette transporters; Adrenal insufficiency; Adrenoleukodystrophy; Myelopathy; Peroxisomal disorders.

Publication types

  • Review

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily D, Member 1 / genetics
  • Adrenoleukodystrophy* / complications
  • Adrenoleukodystrophy* / diagnosis
  • Adrenoleukodystrophy* / genetics
  • Child
  • Female
  • Heterozygote
  • Humans
  • Male
  • Mutation
  • Phenotype

Substances

  • ATP Binding Cassette Transporter, Subfamily D, Member 1