Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies

Abstract

Cobblestone lissencephaly represents a peculiar brain malformation with characteristic radiological anomalies, defined as cortical dysplasia combined with dysmyelination, dysplastic cerebellum with cysts and brainstem hypoplasia. Cortical dysplasia results from neuroglial overmigration into the arachnoid space, forming an extracortical layer, responsible for agyria and/or 'cobblestone' brain surface and ventricular enlargement. The underlying mechanism is a disruption of the glia limitans, the outermost layer of the brain. Cobblestone lissencephaly is pathognomonic of a continuum of autosomal recessive diseases with cerebral, ocular and muscular deficits, Walker-Warburg syndrome, muscle-eye-brain and Fukuyama muscular dystrophy. Mutations in POMT1, POMT2, POMGNT1, LARGE, FKTN and FKRP genes attributed these diseases to α-dystroglycanopathies. However, studies have not been able to identify causal mutations in the majority of patients and to establish a clear phenotype/genotype correlation. Therefore, we decided to perform a detailed neuropathological survey and molecular screenings in 65 foetal cases selected on the basis of histopathological criteria. After sequencing the six genes of α-dystroglycanopathies, a causal mutation was observed in 66% of cases. On the basis of a ratio of severity, three subtypes clearly emerged. The most severe, which we called cobblestone lissencephaly A, was linked to mutations in POMT1 (34%), POMT2 (8%) and FKRP (1.5%). The least severe, cobblestone lissencephaly C, was linked to POMGNT1 mutations (18%). An intermediary type, cobblestone lissencephaly B, was linked to LARGE mutations (4.5%) identified for the first time in foetuses. We conclude that cobblestone lissencephaly encompasses three distinct subtypes of cortical malformations with different degrees of neuroglial ectopia into the arachnoid space and cortical plate disorganization regardless of gestational age. In the cerebellum, histopathological changes support the novel hypothesis that abnormal lamination arises from a deficiency in granule cells. Our studies demonstrate the positive impact of histoneuropathology on the identification of α-dystroglycanopathies found in 66% of cases, while with neuroimaging criteria and biological values, mutations are found in 32-50% of patients. Interestingly, our morphological classification was central in the orientation of genetic screening of POMT1, POMT2, POMGNT1, LARGE and FKRP. Despite intensive research, one-third of our cases remained unexplained; suggesting that other genes and/or pathways may be involved. This material offers a rich resource for studies on the affected neurodevelopmental processes of cobblestone lissencephaly and on the identification of other responsible gene(s)/pathway(s).

Malformations of Cortical Development and Epilepsy

“…PMG is poorly understood from a brain developmental perspective, partly because the term has been used imprecisely in the literature, and partly because many different processes can result in a thin cortex with many small sulci/ gyri: shunted brains of infants born with severe congenital hydrocephalus (stenogyria) (Miller et al 2008), brains with defects in the PLM (cob-www.perspectivesinmedicine.org blestone cortical malformations) Devisme et al 2012), ciliopathies (Giordano et al 2009;Kheradmand Kia et al 2012), tubulinopathies (Jaglin et al 2009;Jansen et al 2011;Cederquist et al 2012;Guerrini et al 2012;Romaniello et al 2012), inborn errors of metabolism (Gressens et al 2000;van Straaten et al 2005), formation of subcortical heterotopia (Barkovich 2000), and many others. Although it has become accepted that stenogyria and cobblestone cortex differ from "true" PMG, the many different types of irregular cerebral cortices that continue to be labeled as PMG cause considerable confusion and have resulted in some investigators creating a category of "PMG-like" malformations (Cushion et al 2013).…”

Gènes impliqués dans les alpha-dystroglycanopathies

“…La mise en évidence d'une lissencéphalie de type II (LISII), lors de l'examen neuro-foetopathologique, signe le diagnostic chez les foetus. Les syndromes de Walker Warburg (WWS), de Muscle Eye Brain Disease (MEBD) ou de Fukuyama (FCMD) sont les manifestations post-natales de ces formes foetales [2]. Les -DGpathies sans LISII, avec ou sans atteinte cérébrale, sont découvertes au cours des premiers mois de vie pour les patients atteints de dystrophies musculaires congénitales (Congenital Muscular Dystrophy -CMD) ou beaucoup plus tardivement dans le cas des dystrophies musculaires des ceintures (Limb-Girdle Muscular Dystrophy -LGMD).…”

“…Le gène POMGNT1 est le gène historique des MEBD identifié initialement dans la population finlandaise [18]. Il est également impliqué dans des cas de LISII foetale [2]. Le gène GTDC2 est, pour sa part, impliqué dans des formes de LISII sévères, dans des cas de WWS post-natal ou des formes moins sévères de LGMD [19].…”

“…Ces gènes impliqués dans la première étape de la synthèse des chaînes O-mannosylées sont souvent identifiés dans les formes sévères d'-DGpathies [13,14]. Ils sont mis en cause dans près de la moitié des cas foetaux [2]. Toutefois, ils ont également été identifiés, notamment POMT2, dans des formes moins sévères de type CMD [15] ou même LGMD [14,16].…”

Clinical Features and Molecular Characterization of a Patient With Muscle-Eye-Brain Disease

“…The second mutation, c.1469G>A (p.Cys490Tyr), has been described previously in several dystroglycanopathy patients and in a few foetal cobblestone lissencephaly cases. 10,[19][20][21] The two mutations affect residues spanning the catalytic domain of POMGNT1 (Fig. 2B).…”