Adrenoleukodystrophy: Incidence, new mutation rate, and results of extended family screening

Utilizing the plasma very long chain fatty acid assay, supplemented by muta tion analysis and immunofluorescence assay, we determined the number of X-l inked adrenoleukodystrophy (X-ALD) hemizygotes from the United States ident ified each year in the two laboratories that perform most of the assays in this country: the Kennedy Krieger Institute between 1981 and 1998 and the M ayo Clinic Rochester from 1996 to 1998. The minimum frequency of hemizygote s identified in the United States is estimated to be 1:42,000 and that of h emizygotes plus heterozygotes 1:16,800. Our studies involved 616 pedigrees with a total of 12,787 identified at-risk members. Diagnostic assays were p erformed in 4,169 at-risk persons (33%) and included members of the extende d family. Only 5% of male probands and 1.7% of X-ALD hemizygotes were found to have new mutations. The extended family testing led to the identificati on of 594 hemizygotes and 1,270 heterozygotes. Two hundred fifty of the new ly identified hemizygotes were asymptomatic and represent the group in whic h therapy has the greatest chance of success. Identification of heterozygot es provides the opportunity for disease prevention through genetic counseli ng. Diagnostic tests should be offered to all at-risk relatives of X-ALD pa tients and should include members of the extended family.