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

Utilizing the plasma very long chain fatty acid assay, supplemented by mutation analysis and immunofluorescence assay, we determined the number of X‐linked adrenoleukodystrophy (X‐ALD) hemizygotes from the United States identified 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 Mayo Clinic Rochester from 1996 to 1998. The minimum frequency of hemizygotes identified in the United States is estimated to be 1:42,000 and that of hemizygotes plus heterozygotes 1:16,800. Our studies involved 616 pedigrees with a total of 12,787 identified at‐risk members. Diagnostic assays were performed in 4,169 at‐risk persons (33%) and included members of the extended 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 identification of 594 hemizygotes and 1,270 heterozygotes. Two hundred fifty of the newly identified hemizygotes were asymptomatic and represent the group in which therapy has the greatest chance of success. Identification of heterozygotes provides the opportunity for disease prevention through genetic counseling. Diagnostic tests should be offered to all at‐risk relatives of X‐ALD patients and should include members of the extended family. Ann Neurol 2001;49:512–517