X-linked cerebral adrenoleukodystrophy

X-linked cerebral adrenoleukodystrophy (X-CALD) is the most severe phenotype of X-linked adrenoleukodystrophy (X-ALD), a 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 transport of very long-chain fatty acids (VLCFAs) into peroxisomes for degradation. When this transporter is deficient, VLCFAs accumulate in tissues throughout the body, particularly in the brain white matter, adrenal cortex, and testes, leading to progressive demyelination and adrenal insufficiency. The cerebral form typically presents in boys between ages 4 and 10, though it can occasionally occur in adolescents or adults. Early symptoms often include behavioral changes, declining school performance, vision problems, and difficulty understanding speech. The disease progresses rapidly with inflammatory demyelination of the cerebral white matter, leading to severe neurological deterioration including seizures, spasticity, loss of motor function, blindness, deafness, and eventually a vegetative state. Adrenal insufficiency (Addison disease) may precede or accompany the neurological symptoms and can be life-threatening if untreated. Diagnosis is confirmed by elevated plasma VLCFA levels and ABCD1 gene mutation analysis. MRI of the brain typically shows characteristic white matter lesions, often beginning in the parieto-occipital regions. Newborn screening programs using dried blood spot VLCFA analysis are increasingly being implemented. The primary treatment for early-stage cerebral disease is allogeneic hematopoietic stem cell transplantation (HSCT), which can halt disease progression if performed before significant neurological decline. Gene therapy using autologous CD34+ cells transduced with a lentiviral vector containing a functional ABCD1 gene (elivaldogene autotemcel, marketed as Skysona) has been approved as an alternative for patients without a matched donor. Adrenal insufficiency is managed with corticosteroid replacement therapy. Lorenzo's oil (a mixture of oleic and erucic acids) can normalize plasma VLCFA levels but has not been proven to prevent or halt cerebral disease progression.

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