Molecular diagnosis of Menkes disease: Genotype-phenotype correlation

摘要

Menkes syndrome is an X-linked, fatal neurodegenerative disorder of copper metabolism, caused by mutations in the ATP7A gene, encoding a copper-transporting P1B-type ATPase. To date, a total of approximately 160 different mutations have been reported worldwide. The clinical phenotypes observed in these patients include progressive neuro-degeneration, connective-tissue abnormalities and peculiar hair. There is phenotypic variability. While the majority of the patients do not survive early childhood, milder cases leading to longer survival have been reported. In this review we focus on mutations, identified in patients with milder forms of Menkes disease, and discuss the possibility of establishing a genotype-phenotype correlation. The presence of small amounts of normal protein, or the presence of partly functional protein variants containing a less essential amino acid substitution or a truncation of the N- or C-terminus, might all result in a milder, atypical phenotype. A clear phenotype-genotype correlation is however difficult to establish, clearly illustrated by the presence of inter- and even intra-familial variability.