adrenoleukodystrophy

Adrenoleukodystrophy (ALD) is a genetic peroxisomal disorder caused by mutations in the ABCD1 gene on the X chromosome. The defect impairs transport and degradation of very long-chain fatty acids (VLCFAs), leading to their accumulation in the white matter of the brain, the adrenal glands, and other tissues. ALD is inherited in an X-linked pattern; males are typically affected, while female carriers may develop milder symptoms later in life.

Most common is the cerebral form in childhood or adolescence, characterized by inflammatory demyelination and rapid decline in cognition, behavior, vision, and motor function. A later-onset form, known as adrenomyeloneuropathy, presents with spinal cord and peripheral nerve involvement and can include adrenal insufficiency.

Diagnosis begins with elevated plasma VLCFA measurements (eg, increased C26:0 and an elevated C26:1/C22:0 ratio) and is confirmed by sequencing of the ABCD1 gene. MRI typically shows progressive demyelination in the parieto-occipital white matter in early cerebral ALD. Adrenal function testing is also part of initial assessment.

Treatment depends on form and stage. All patients require management of adrenal insufficiency if present. In early cerebral ALD, hematopoietic stem cell transplantation (HSCT) can halt neurologic decline. In 2023, elivaldogene autotemcel (Skysona), a gene therapy using autologous stem cells, received regulatory approval for early cerebral ALD in eligible boys. Lorenzo's oil has been used historically but has not proven to prevent progression. Supportive care and rehabilitation are important.

Without treatment, cerebral ALD progresses to severe disability and death within years. Early identification and intervention improve outcomes; ongoing surveillance with MRI and endocrine assessment is recommended.