Abstract 809 Mechanisms in Hereditary Disease Platform, Tuesday, 5/4

Menkes disease is an X-linked disorder of copper transport caused by mutations in a gene for a copper(Cu)-transporting ATPase. Hemizygotes show dermatological and connective tissue manifestations, progressive neurological deterioration, and death in early childhood. Little is known about the phenotypic effects in heterozygotes. We studied an obligate heterozygote and her sister and daughters to delineate the nature and spectrum of manifestations in heterozygotes carrying the same severe Menkes disease mutation. Linkage studies based on an intragenic polymorphism confirmed heterozygosity in the mother, sister, and two of the three daughters. The oldest daughter was not a carrier and was normal on all evaluations.

On dermatological examination, the two carrier daughters had segmental and patchy areas of skin hypopigmentation. The youngest daughter had focal areas of shorter hair due to breakage. This daughter and the mother exhibited pili torti on microscopic hair examination. On skeletal survey, the mother and sister showed occipital spurring, widened lateral clavicles, periosteal and endosteal changes, and long-bone osteophytes. The youngest daughter showed one widened clavicle. On neurological evaluation the mother had mild ocular dysmetria and subtle choreoathetosis. The sister had cognitive difficulties, oculomotor apraxia, and reinforcible rigidity. The middle daughter had aggressive, oppositional behavior but was neurologically intact. The youngest daughter had cognitive difficulties, ocular dysmetria and apraxia, oromotor apraxia, and mild choreoathetosis. Brain MRI scans showed premature diffuse volume loss in both the mother and sister, plus moderately elongated tortuous vessels in the mother. MRI scans in the daughters are pending. Serum Cu and ceruloplasmin levels were normal in all subjects.

Based on our findings in this family, we draw several conclusions and propose a number of hypotheses regarding Menkes disease phenotypes in heterozygotes. 1) The spectrum of dermatological findings can be ascribed to differential lyonization. 2) Skeletal findings are relatively specific, appear to be more widespread in adults than children, and may reflect localized and long-standing extraskeletal mild lysyl oxidase deficiency. The specificity of the bone findings may serve as a simple initial screen for heterozygosity. 3) The spectrum of similar non-specific neurological features in this family suggests that CNS manifestations in heterozygotes may reflect a more generalized threshold-based CNS Cu deficiency.

Investigations of additional heterozygotes should allow us to further address the hypothesized pathogenic mechanisms and to relate the phenotypic manifestations to specific mutations.