X-linked malformations of neuronal migration (original) (raw)
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Human Molecular Genetics, 1997
While disorders of neuronal migration are associated with as much as 25% of recurrent childhood seizures, few of the genes required to establish neuronal position in cerebral cortex are known. Subcortical band heterotopia (SBH) and lissencephaly (LIS), two distinct neuronal migration disorders producing epilepsy and variable cognitive impairment, can be inherited alone or together in a single pedigree. Here we report a new genetic locus, XLIS, mapped by linkage analysis of five families and physical mapping of a balanced X;2 translocation in a girl with LIS. Linkage places the critical region in Xq21-q24, containing the breakpoint that maps to Xq22.3-q23 by high-resolution chromosome analysis. Markers used for somatic cell hybrid and fluorescence in situ hybridization analyses place the XLIS region within a 1 cM interval. These data suggest that SBH and X-linked lissencephaly are caused by mutation of a single gene, XLIS, that the milder SBH phenotype in females results from random X-inactivation (Lyonization), and that cloning of genes from the breakpoint region on X will yield XLIS.
PloS one, 2017
Neuronal migration disorders are a clinically and genetically heterogeneous group of malformations of cortical development, frequently responsible for severe disability. Despite the increasing knowledge of the molecular mechanisms underlying this group of diseases, their genetic diagnosis remains unattainable in a high proportion of cases. Here, we present the results of 38 patients with lissencephaly, periventricular heterotopia and subcortical band heterotopia from Argentina. We performed Sanger and Next Generation Sequencing (NGS) of DCX, FLNA and ARX and searched for copy number variations by MLPA in PAFAH1B1, DCX, POMT1, and POMGNT1. Additionally, somatic mosaicism at 5% or higher was investigated by means of targeted high coverage NGS of DCX, ARX, and PAFAH1B1. Our approach had a diagnostic yield of 36%. Pathogenic or likely pathogenic variants were identified in 14 patients, including 10 germline (five novel) and 4 somatic mutations in FLNA, DCX, ARX and PAFAH1B1 genes. This ...
Clinical patterns of neuronal migrational disorders and parental consanguinity
Journal of Tropical Pediatrics
The role of inheritance in neuronal migrational disorders is under intense investigation. Studies on neuronal migrational disorders (NMDs) from developing countries that have a high rate of parental consanguinity are lacking. The present study included 29 children (aged 15 days-12 years, mean age 1.4 years) who were diagnosed to have NMDs, from a non-selected population with seizures and non-selected population of cognitive developmental delay, in the period January 1994 to April 1997. Seventeen (58.6 per cent) patients had lissencephaly, four (13.8 per cent) patients had pachygyria, three (10.3 per cent) patients had neuronal heterotopia, four (13.8 per cent) patients had schizencephaly, one patient (3.4 per cent) had hemimegalencephaly, and 14 (48.2 per cent) patients with NMDs had other associated conditions. Lissencephalic patients had a high rate of parental consanguinity (88.2 per cent) and family history of possible similar cases (76.4 per cent). In conclusion, lissencephaly ...
Recent Development in Neuronal Migration Disorders: Clinical, Neuroradiologic and Genetics Aspects
Current Pediatric Reviews, 2008
Disorders of neuronal migration are a heterogeneous group of disorders of nervous system development. One of the most frequent disorders is lissencephaly characterized by a paucity of normal gyri and sulci resulting in a "smooth brain". There are two pathologic subtypes: classical and cobblestone. Classical lissencephaly results from an arrest of neuronal migration, whereas cobblestone lissencephaly results from overmigration.
The location of DCX mutations predicts malformation severity in X-linked lissencephaly
Neurogenetics, 2008
Lissencephaly spectrum (LIS) is one of the most severe neuronal migration disorders that ranges from agyria/pachygyria to subcortical band heterotopia. Approximately 80% of patients with the LIS spectrum carry mutations in either the LIS1 or DCX (doublecortin) genes which have an opposite gradient of severity. The aim of the study was to evaluate in detail the phenotype of DCXassociated lissencephaly and to look for genotype-pheno
X-linked Lissencephaly: a Smooth Brain and a Rough Journey for a 15- Year-Old-Patient
Medicina Moderna - Modern Medicine
Lissencephaly ("smooth brain") is a malformation of cortical development associated with defi cient neuronal migration and abnormal formation of cerebral convolutions or gyri. Although once thought to be rare, malformations of the cerebral cortex are increasingly involved as a major cause of recurrent seizures in children and adults. We described the case of 15-year-old female patient diagnosed with lissencephaly, mental retardation and focal seizures. At 6 months old, the patient developed focal motor seizures. Despite the fact that a CT was performed short after the occurrence of the fi rst seizures, its quality did not allow the identifi cation of cerebral anomalies like subcortical band heterotopia. Genetic testing through multiplex ligation-dependent probe amplifi cation (MLPA) did not reveal any deletion or duplication in genes relevant to the subcortical band heterotopia diagnostic. Thus, in these cases, MRI assessment represents an useful tool to establish the diagnosis.
Apparently novel genetic syndrome of pachygyria, mental retardation, seizure, and arachnoid cysts
American Journal of Medical Genetics Part A, 2007
We report on an apparently new syndrome in a consanguineous family with seven members, three of whom have cerebral anomalies including pachygyria and arachnoid cysts along with mental retardation and seizures. The two patients with seizure disorders also had multiple enlarged perivascular spaces seen in the white matter of the centrum semiovale. Our data provide a contribution to the accumulating knowledge on familial cerebral anomalies including arachnoid cysts and lissencephaly. Given the lack of mutation in known lissencephaly genes such as LIS1, 14-3-3e, and DCX, this syndrome may constitute a new phenotype with autosomal recessive inheritance.
Familial perisylvian polymicrogyria: A new familial syndrome of cortical maldevelopment
Annals of Neurology, 2000
Two familial X-linked dominant syndromes of cortical maldevelopment have recently been described: double cortex/ lissencephaly syndrome and bilateral periventricular nodular heterotopia. We report on 12 kindreds with familial perisylvian polymicrogyria (FPP) presenting at 10 centers, examine the clinical presentation in these familial cases, and propose a possible mode of inheritance. The clinical and radiological pattern was variable among the 42 patients, with clinical differences among the families and even within members of the same family. Pseudobulbar signs, cognitive deficits, epilepsy, and perisylvian abnormalities on imaging studies were not found in all patients. When present, they displayed a spectrum of severity. The only clear correlation in this study was between bilateral imaging findings and abnormal tongue movements and/or pronounced dysarthria. Most of the families provided evidence suggestive of, or compatible with, X-linked transmission. On the other hand, the pedigrees of 2 families ruled out X-linked inheritance. The most likely mode of inheritance for these 2 families was autosomal dominant with decreased penetrance; however, autosomal recessive inheritance with pseudodominance could not be ruled out in 1 family. We conclude that FPP appears to be genetically heterogeneous. However, most of the families probably represent a third previously undescribed X-linked syndrome of cortical maldevelopment.