X-Linked Adrenoleukodystrophy/Adrenomyeloneuropathy

Abstract

X-linked adrenoleukodystrophy (X-ALD) is inherited neuro-endocrine disorder characterized by primary adrenal insufficiency (Addison's disease) and demyelination. The disease has a broad clinical expression with several well-recognized phenotypes defined by the age of onset and the nature of the neurologic symptoms. These phenotypes range from a rapidly progressive, fatal childhood form with inflammatory cerebral demyelination to an Addison's disease variant that lacks neurologic symptoms. The most common phenotype, accounting for approximately 50% of patients, is adrenomyeloneuropathy, which has onset of spastic paraparesis and adrenal insufficiency in the second-to-fourth decade of life. Heterozygous female carriers of X-ALD may develop mild spastic paraparesis later in life. The overall incidence of X-ALD is estimated to be 1 in 18,000. The disease is caused by mutations in ABCD1 on the X chromosome that codes for ALDP, a peroxisomal membrane protein that is necessary for the oxidation of very-long-chain fatty acids (VLCFA). Accumulation of VLCFA in tissues is responsible for the adrenal and neurologic symptoms although the exact pathogenic mechanisms are still unclear. The diagnosis relies on measuring elevated VLCFA in plasma and/or mutation analysis of ABCD1. Newborn screening for X-ALD has recently been initiated in the United States by measuring elevated VLCFA in lipids of dried blood spots and promises to detect all male patients before the onset of symptoms. The adrenal insufficiency is easily treated with hormone replacement and the progressive cerebral demyelination may be halted if treated early with hematopoietic stem cell transplantation and possibly gene therapy.