Clinical and Laboratory Observation
Variable clinical expression of an identical mutation in the ATP7A gene for Menkes disease/Occipital horn syndrome in three affected males in a single family

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Abstract

Two maternal half-brothers presented with huge cephalic hematoma, fatal in one. Skin morphology disclosed lack of elastic fibres. Their maternal uncle is moderately mentally handicapped and has extensive connective tissue disorders. In all these patients, an identical missense mutation in the ATP7A gene was found and confirmed Menkes' disease.

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Clinical description

Two maternal half-brothers (patients 1 and 2) were born with skin laxity and large cephalhematoma, which was fatal in patient 1 after disseminated intravascular coagulation. Autopsy demonstrated ruptured vessels with a complete lack of elastic fibers.

In patient 2, skin histology similarly demonstrated many large fibroblasts and rarefaction of elastic fibers. Electron microscopy showed rare fragmented and small elastic fibers located between dense bundles of collagen fibers. Elastin deposits

Mutation analysis

Mutation screening was performed on genomic DNA from cultured skin fibroblasts of patient 2. In exon 20 a single base pair mutation c.3974C>T was identified, leading to the amino acid substitution Ala1325Val. Genomic DNA sequencing of exon 20 from patient 1 (paraffin-embedded tissue) and from patient 3 (fibroblasts) confirmed the presence of the same mutation. Sequencing of the whole coding region excluded a second mutation in both patient 2 and 3. Mosaicism was excluded in the uncle by

Discussion

Classic MD and OHS are two extremes of the same intracellular copper transport and metabolism disorder. Instead of categorizing patients into subgroups, Horn and Tümer3 proposed a disease continuum from the “neurological end” of the spectrum—classic MD—to its connective tissue end—OHS.

To date, about 225 mutations in the ATP7A gene have been identified,3., 4., 5. (unpublished, N. Horn, personal communication 2003). There is, however, poor genotype/phenotype correlation. Even similar splice site

Acknowledgements

We thank the family for participation in the study and Dr Sarioglu and Prof Vogel (Department of Pathology, Charité, Berlin) for the histological findings in patient 1.

References (12)

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    Although genotype/phenotype correlations have been difficult, it is generally accepted that the clinical expression of these diseases and patient response to treatment depends on the type of mutation in ATP7A/ATP7B, which in turn can affect the levels and activity of ATP7A/ATP7B, their post-translational modifications, protein-protein interactions, cellular localization, and/or ability to traffic in response to copper (7–9). For both MD and WD, there are reports of identical mutations, even among siblings, conferring variable clinical expression (10, 11), thus implicating other factors in determining the clinical phenotype. Environmental factors and allelic variants of modifying genes may contribute to the diversity of patient symptoms and onset of disease.

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The molecular studies were supported by The Novo Nordisk Foundation, The Danish Medical Council, and the Foundation of 1870.

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