Menkes disease is a lethal X-linked disorder of copper transport caused by defects in a gene that encodes a P-type ATPase (ATP7A). While more than 50 mutations in patients with the classic phenotype have now been reported, only 5 mutations associated with milder phenotypes have been delineated. The latter defects either affected splice junctions (4 families) or the 5′ promoter region (a family), and presumably produced these less severe phenotypes by enabling some normal Menkes message to be transcribed, and some normal protein translated. Here, we report the first missense mutation associated with a mild Menkes phenotype, Ala1362Asp.

Our patients are 2 brothers (ages 8 and 2.5 years) born to healthy parents with no prior family history of Menkes disease. The older boy has abnormal grey-blonde hair and moderate developmental delay but walked by age 2, a finding completely inconsistent with classical Menkes disease. Neither patient has had seizures. Slightly subnormal serum copper, low-normal ceruloplasmin, and abnormal plasma neurochemical patterns were noted in both. RNase protection of lymphoblast mRNA from the older sib showed normal message quantity. RT-PCR and sequencing identified a C to A change at n4230 of the ATP7A coding sequence which predicts substitution of an aspartate residue(hydropathy index -3.5) for an alanine (hydropathy index +1.8) within the 7th and penultimate transmembrane segment of the Menkes ATPase. The base change creates a novel Mbol restriction site that facilitated mutation screening; the alteration segregates with the disease in this family, and was not present on 40 normal X chromosomes tested.

Molecular analysis of patients like these with mild Menkes variants suggests the types of mutations that may be associated with residual copper transport activity, and which therefore may be most likely to benefit from early copper replacement therapy.