Molecular heterogeneity in fetal forms of type II lissencephaly

Abstract

Type II lissencephaly (type II LIS) is a group of autosomal recessive congenital muscular dystrophies (CMD) associated with defects in alpha-DG O-glycosylation, which comprises Walker-Warburg syndrome, Fukuyama cerebral and muscular dystrophy, or muscle-eye-brain disease. The most severe forms of these diseases often have a fetal presentation and lead to a pregnancy termination. We report here the first molecular study on fetal type II LIS in a series of 47 fetuses from 41 unrelated families. Sequencing of the different genes known to be involved in alpha-DG O-glycosylation allowed the molecular diagnosis in 22 families: involvement of POMT1 was demonstrated in 32% of cases, whereas POMGNT1 and POMT2 were incriminated in 15% and in 7% of cases, respectively. We found 30 different mutations in these three genes, 25 were described herein for the first time, 15 in POMT1, and five in POMT2 and POMGNT1. Despite sequencing of FKRP, FCMD, and LARGE, no definitive molecular diagnosis could be made for the other half of our cases. Preliminary results concerning genotype-phenotype correlations show that the choice of the first gene sequenced should depend on the clinical severity of the type II LIS; POMT1 and POMT2 for severest clinical picture and POMGNT1 for milder disease. The other genes, FKRP, FCMD, and LARGE, seem not to be implicated in the fetal form of CMD.

Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with a loss-of-function mutation in CDK5

“…Cobblestone lissencephaly is characterized by a nodular brain surface, with a severely disorganized and unlayered cerebral and cerebellar cortex, and a disrupted pial layer. In addition to classical and cobblestone lissencephaly, there are three less common subtypes of the disorder, designated as X-linked lissencephaly with agenesis of the corpus callosum, lissencephaly with cerebellar hypoplasia, and microlissencephaly (Bouchet et al 2007;Verrotti et al 2010;Wynshaw-Boris et al 2010; Barkovich et al 2012;Huang et al 2012 (MIM 236670), POMPT1] and other α-dystroglycanopathies. In addition, there are many newly identified genes associated with various unclassified syndromes within the lissencephaly spectrum.…”

Disturbed Wnt Signalling due to a Mutation in CCDC88C Causes an Autosomal Recessive Non-Syndromic Hydrocephalus with Medial Diverticulum

“…Prognosis critically depends on the presence of additional cerebral and extracranial malformations, which are observed in about 70-80% of the cases [Schrander-Stumpel and Fryns, 1998]. Important syndromal forms of congenital hydrocephalus include the autosomal recessive syndromal lissencephalies type 2 Walker-Warburg syndrome and Muscle-eye-brain disease with additional observation of a hypoplastic cerebellum and brainstem together with cobblestone lissencephaly and agenesis or hypoplasia of the corpus callosum as well as postnatal congenital muscular hypotonia, various eye abnormalities and global developmental delay, which in about half of the cases result from mutations in one of currently 6 genes associated with the O-glycosylation of ␣-dystroglycan [Bouchet et al, 2007]. The most frequent monogenic form of congenital hydrocephalus is due to hemizygous mutations in the L1CAM gene (about 7-15%) and clinically characterised by the distinct combination of a hydrocephalus due to stenosis of the aqueduct of Sylvius commonly in association with adducted thumbs (HSAS) [Tapanes-Castillo et al, 2010;Vos et al, 2010].…”

Dystroglycanopathies: coming into focus

“…Since this study, results from three other populations have been reported in which mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN and FKRP were systematically screened. Each study analysed a defined clinical presentation and detected mutations in a total of 53%, 40% and 51% of CMD and two WWS patient cohorts respectively [9][10][11]. Taken together, these studies strongly implicate novel genes in the pathogenesis of the dystroglycanopathies.…”

“…These studies have firmly established that the clinical spectrum associated with mutations in specific causative dystroglycanopathy genes is in fact far wider than originally appreciated. Hence, in the majority of cases the identity of the defective gene cannot be predicted from the clinical phenotype (Box 1) [9][10][11][12][45][46][47][48].…”