X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD), also known as ALD or Siemerling-Creutzfeldt disease, is a genetic peroxisomal disorder caused by mutations in the ABCD1 gene located on the X chromosome. This gene encodes a peroxisomal membrane transporter protein (ALDP) essential for the breakdown of very long-chain fatty acids (VLCFAs). When this protein is deficient or nonfunctional, VLCFAs accumulate in tissues throughout the body, particularly affecting the nervous system (both the brain and spinal cord), the adrenal glands, and the testes. The disease primarily affects males, though female carriers can develop milder symptoms, especially later in life. X-ALD presents with a wide spectrum of clinical phenotypes. The most severe form, childhood cerebral ALD (ccALD), typically manifests between ages 4 and 10 with progressive behavioral changes, cognitive decline, vision loss, hearing impairment, and motor deterioration, often leading to a vegetative state within a few years if untreated. Adrenomyeloneuropathy (AMN), the most common phenotype in adult males, presents in the twenties to forties with progressive stiffness and weakness in the legs (spastic paraparesis), sensory neuropathy, bladder and bowel dysfunction, and sexual dysfunction. Adrenal insufficiency (Addison disease) may occur in isolation or accompany any phenotype and can be life-threatening if unrecognized. Female carriers may develop a milder myelopathy resembling AMN, typically after age 40. Diagnosis is confirmed by elevated VLCFA levels in plasma and genetic testing of the ABCD1 gene. Newborn screening programs using dried blood spot VLCFA analysis have been implemented in many regions, enabling early detection. Treatment includes lifelong adrenal hormone replacement therapy for those with adrenal insufficiency. For boys with early cerebral disease detected by MRI before significant neurological decline, allogeneic hematopoietic stem cell transplantation (HSCT) can halt disease progression. More recently, autologous gene therapy (elivaldogene autotemcel/Skysona) has been approved for early-stage cerebral ALD in boys without a matched donor. Lorenzo's oil (a mixture of oleic and erucic acids) can normalize plasma VLCFA levels but has not been proven to prevent or reverse neurological disease. Supportive care, physical therapy, and management of spasticity are important for patients with AMN.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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