Premium
Nonsyndromic mental retardation and cryptogenic epilepsy in women with Doublecortin gene mutations
Author(s) -
Guerrini Renzo,
Moro Francesca,
Andermann Eva,
Hughes Elaine,
D'Agostino Daniela,
Carrozzo Romeo,
Bernasconi Andrea,
Flinter Frances,
Parmeggiani Lucio,
Volzone Anna,
Parrini Elena,
Mei Davide,
Jarosz Jozef M.,
Morris Robin G.,
Pratt Polly,
Tortorella Gaetano,
Dubeau François,
Andermann Frederick,
Dobyns William B.,
Das Soma
Publication year - 2003
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.10588
Subject(s) - missense mutation , pachygyria , doublecortin , epilepsy , phenotype , mutation , psychology , genetics , medicine , endocrinology , lissencephaly , gene , psychiatry , biology , central nervous system , dentate gyrus
DCX mutations cause mental retardation in male subjects with lissencephalypachygyria and in female subjects with subcortical band heterotopia (SBH). We observed four families in which carrier women had normal brain magnetic resonance imaging (MRI) and mild mental retardation, with or without epilepsy. Affected male subjects had SBH or pachygyria‐SBH. In two families, the phenotype was mild in both genders. In the first family, we found a tyr138his mutation that is predicted to result in abnormal folding in the small hinge region. In the second family, we found an arg178cys mutation at the initial portion of R2, in the putative β‐sheet structure. Carrier female subjects with normal MRI showed no somatic mosaicism or altered X‐inactivation in lymphocytes, suggesting a correlation between mild mutations and phenotypes. In the two other families, with severely affected boys, we found arg76ser and arg56gly mutations within the R1 region that are predicted to affect DCX folding, severely modifying its activity. Both carrier mothers showed skewed X‐inactivation, possibly explaining their mild phenotypes. Missense DCX mutations may manifest as non‐syndromic mental retardation with cryptogenic epilepsy in female subjects and SBH in boys. Mutation analysis in mothers of affected children is mandatory, even when brain MRI is normal. Ann Neurol 2003