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X-Linked Adrenoleukodystrophy.


GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.
1999 Mar 26 [updated 2015 Apr 9].



X-linked adrenoleukodystrophy (X-ALD) affects the nervous system white matter and the adrenal cortex. Three main phenotypes are seen in affected males: The childhood cerebral form manifests most commonly between ages four and eight years. It initially resembles attention deficit disorder or hyperactivity; progressive impairment of cognition, behavior, vision, hearing, and motor function follow the initial symptoms and often lead to total disability within two years. Adrenomyeloneuropathy (AMN) manifests most commonly in the late twenties as progressive paraparesis, sphincter disturbances, sexual dysfunction, and often, impaired adrenocortical function; all symptoms are progressive over decades. "Addison disease only" presents with primary adrenocortical insufficiency between age two years and adulthood and most commonly by age 7.5 years, without evidence of neurologic abnormality; however, some degree of neurologic disability (most commonly AMN) usually develops later. Approximately 20% of females who are carriers develop neurologic manifestations that resemble AMN but have later onset (age ≥35 years) and milder disease than do affected males.


The diagnosis of X-ALD is based on clinical findings. MRI is always abnormal in boys with cerebral disease and often provides the first diagnostic lead. Plasma concentration of very long chain fatty acids (VLCFA) is abnormal in 99% of males with X-ALD. Increased concentration of VLCFA in plasma and/or cultured skin fibroblasts is present in approximately 85% of affected females; 20% of known carriers have normal plasma concentration of VLCFA. ABCD1 is the only gene known to be associated with X-ALD.


Treatment of manifestations: Corticosteroid replacement therapy is essential for those with adrenal insufficiency. Affected boys benefit from the general supportive care of parents and psychological and educational support. Physical therapy, management of urologic complications, and family and vocational counseling are of value for men with AMN. Surveillance: For males with X-ALD, periodic reevaluation of adrenocortical function and MRIs for detection of early cerebral disease. Evaluation of relatives at risk: Early identification of asymptomatic or minimally symptomatic at-risk males permits timely treatment of adrenal insufficiency.


X-ALD is inherited in an X-linked manner. About 95% of persons representing index cases have inherited the ABCD1 pathogenic variant from one parent; about 4.1% of individuals with X-ALD have a de novo pathogenic variant. Affected males transmit the ABCD1 pathogenic variant to all of their daughters and none of their sons. Carrier females have a 50% chance of transmitting the ABCD1 pathogenic variant in each pregnancy. Males who inherit the pathogenic variant will be affected; females who inherit it are carriers and will usually not be seriously affected. The phenotypic expression and prognosis of an affected male is unpredictably variable. Carrier testing of at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant in the family is known.

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