Adrenoleukodystrophy

Lore & Background

Adrenoleukodystrophy (ALD) is a disease linked to the X chromosome, resulting from failure of peroxisomal fatty acid beta oxidation, which causes accumulation of very long chain fatty acids in tissues. The most severely affected tissues are the myelin in the central nervous system, the adrenal cortex, and the Leydig cells in the testes. The buildup damages the myelin sheath of neurons, leading to seizures, hyperactivity, and problems in speaking, listening, and understanding verbal instructions.

Reader's Guide

ALD presents as a heterogeneous disorder with several distinct phenotypes and no clear genotype–phenotype correlation. As an X-linked disorder, it presents more frequently and severely in males, though approximately 80% of heterozygote females show some symptoms later in life. The childhood cerebral form, the most severe, affects about one third of male patients and is characterized by normal early development followed by rapid degeneration to a vegetative state. Treatment options are limited: for the childhood cerebral form, stem cell transplant and gene therapy are options if detected early, and adrenal insufficiency can be successfully treated. ALD is the most common peroxisomal inborn error of metabolism, with a minimum estimated incidence of 1:42,000 for hemizygotes and 1:16,800 for hemizygotes and heterozygotes, and does not have a significantly higher incidence in any specific ethnic group.

Did You Know?

• ALD is caused by mutations in the ABCD1 gene, located at Xq28, which codes for a peroxisomal membrane transporter protein.
• Approximately one third of male ALD patients present with the childhood cerebral form, the most severe phenotype.
• The level of cerotic acid (26:0) in plasma does not correlate with clinical presentation.
• Almost 600 different mutations in ABCD1 have been identified, with approximately half being missense mutations.