Isolated Lissencephaly Sequence and Double-Cortex Syndrome in a German Family with a Novel Doublecortin Mutation

Abstract

Isolated Lissencephaly Sequence (ILS) and Double-Cortex Syndrome (DC) are neuronal heterotopias caused by developmental defects in neuronal precursor cell migration. We report on the clinical and genetic assessment of a German pedigree with DCIILS. Affected males showed clinical symptoms typical of lissencephaly, i.e. seizures, severe mental retardation and extensive physical disability starting in the early postnatal period. Females, however, displayed a milder phenotype with epileptic seizures being the only clinical symptom of note. The MR imaging of a male ILS patient showed a smooth cortex with pachygyria, hydrocephalus and a diffuse, broad distribution of grey matter throughout the brain. In the affected female, a double cortex syndrome in the form of a subcortical bilateral band of grey matter was evident by MR imaging. The molecular and genetic basis of DC/ILS is associated with mutations in the X-linked doublecortin gene (DCX). The genetic assessment of the family revealed a novel missense mutation 211 G-->T in DCX exon 2 in affected family members. This mutation cosegregated with the clinical symptoms and resulted in a non-conservative amino acid substitution A71S. DCX is a microtubule-associated phosphoprotein and mutations in DCX might affect cytoskeletal dynamics and the regulation of cell migration.

Missense mutations resulting in type 1 lissencephaly

“…Similar to the previous mutation, D62N did not bind to phospho-FIGQY neurofascin [89]. An extended family carrying an alanine-to-serine (A71S) mutation was reported [129]. The mutated protein was studied by overexpression in COS-7 cells [125].…”

“…To date, more than 25 missense mutations in DCX were detected in patients [14,15,72,[119][120][121][122][123][124][125][126][127][128][129][130], interestingly, several of these sites were independently mutated several times. Our discussion will focus on those mutations CMLS, Cell.…”

A Novel Missense Mutation of Doublecortin: Mutation Analysis of Korean Patients with Subcortical Band Heterotopia

“…The neuronal migration disorders, X-linked lissencephaly syndrome (XLIS) and subcortical band heterotopia (SBH), also called "double cortex", have been linked to missense, nonsense, aberrant splicing, deletion, and insertion mutations in doublecortin ( DCX ) in families and sporadic cases (1-8). …”

Somatic mosaicism and variable penetrance in doublecortin -associated migration disorders

“…[1][2][3][4][5][6][7][8] Typically, hemizygous mutations in men cause isolated lissencephaly with severe mental retardation, epilepsy, and limited life expectancy, whereas heterozygous mutations in women cause SBH associated with no or moderate mental retardation and epileptic seizures. [1][2][3][4][5][6][7][8] Typically, hemizygous mutations in men cause isolated lissencephaly with severe mental retardation, epilepsy, and limited life expectancy, whereas heterozygous mutations in women cause SBH associated with no or moderate mental retardation and epileptic seizures.…”

“…8 Single strand conformational polymorphism (SSCP) analysis was performed by 10% polyacrylamide/5% glycerol or 6% polyacrylamide gel electrophoresis and silver staining of gels. Patients included fulfilled the following criteria: a family history suggesting X-chromosomal inheritance of SBH/XLIS or sporadic cases with MRI findings characteristic for bilateral SBH or ILS.…”