Clinical characteristics: X-linked adrenoleukodystrophy (X-ALD) affects the nervous system white matter and the adrenal cortex. Three main phenotypes are seen in affected males: More than 20% of female carriers develop mild-to-moderate spastic paraparesis in middle age or later. Adrenal function is usually normal.
Diagnosis/testing: The diagnosis of X-ALD is established in a male proband with suggestive clinical findings and elevated very long chain fatty acids (VLCFA). MRI is always abnormal in boys with cerebral disease and often provides the first diagnostic lead. The diagnosis of X-ALD is usually established in a female proband with detection of a heterozygous ABCD1 pathogenic variant and elevated VLCFA.
Management: 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 (currently suggested at 6-month intervals) and MRIs for detection of early cerebral disease (yearly until age 3 years and then at 6-month intervals until age 10 years). Evaluation of relatives at risk: Early identification of asymptomatic or minimally symptomatic at-risk males permits timely treatment of adrenal insufficiency.
Genetic counseling: 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; at least 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. Heterozygote (carrier) detection for at-risk female relatives and prenatal testing or preimplantation genetic testing for pregnancies at increased risk are possible if the pathogenic variant in the family is known.
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