Premium
Corpus callosum agenesis, severe mental retardation, epilepsy, and dyskinetic quadriparesis due to a novel mutation in the homeodomain of ARX
Author(s) -
Conti Valerio,
Marini Carla,
Gana Simone,
Sudi Jyotsna,
Dobyns William B.,
Guerrini Renzo
Publication year - 2011
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.33923
Subject(s) - homeobox , agenesis of the corpus callosum , corpus callosum , epilepsy , mutation , neuroscience , physical medicine and rehabilitation , medicine , biology , genetics , gene , gene expression
We report on a patient with agenesis of the corpus callosum (ACC), severe mental retardation, infantile spasms and subsequent intractable epilepsy, spastic/dyskinetic quadriparesis, severe limb contractures, and scoliosis. This complex, newly described phenotype, is due to a novel non‐conservative missense mutation in the ARX homeodomain (c.1072A>T; p.R358W), inherited from the unaffected mother. Differently from previously reported non‐conservative mutations falling within the same domain, p.R358W did not cause XLAG. It is therefore possible that differences in clinical manifestations between our patient and those with XLAG, are related to the different position of the amino acid substitution in the homeodomain, or to the different chemical properties introduced by the substitution itself. To test the hypothesis that the patient's mother was asymptomatic because of non‐random X chromosome inactivation (XCI), we performed DNA methylation studies of the human androgen receptor gene, demonstrating skewing of the XCI ratio (85:15). The complex phenotype described here combines different traits that had previously been linked to various ARX mutations, including conservative missense mutations in the homeodomain and expansion in the first ARX polyalanine tract and contributes to the expanding pleiotropy associated with ARX mutations. © 2011 Wiley‐Liss, Inc.