GPR56-related bilateral frontoparietal polymicrogyria: further evidence for an overlap with the cobblestone complex

Abstract

GPR56 mutations cause an autosomal recessive polymicrogyria syndrome that has distinctive radiological features combining bilateral frontoparietal polymicrogyria, white matter abnormalities and cerebellar hypoplasia. Recent investigations of a GPR56 knockout mouse model suggest that bilateral bifrontoparietal polymicrogyria shares some features of the cobblestone brain malformation and demonstrate that loss of GPR56 leads to a dysregulation of the maintenance of the pial basement membrane integrity in the forebrain and the rostral cerebellum. In light of these findings and other data in the literature, this study aimed to refine the clinical features with the first description of a foetopathological case and to define the range of cobblestonelike features in GPR56 bilateral bifrontoparietal polymicrogyria in a sample of 14 patients. We identified homozygous GPR56 mutations in 14 patients from eight consanguineous families with typical bilateral bifrontoparietal polymicrogyria and in one foetal case, out of 30 patients with bifrontoparietal polymicrogyria referred for molecular screening. The foetal case, which was terminated at 35 weeks of gestation in view of suspicion of Walker Warburg syndrome, showed a cobblestone-like lissencephaly with a succession of normal, polymicrogyric and 'cobblestone-like' cortex with ectopic neuronal overmigration, agenesis of the cerebellar vermis and hypoplastic cerebellar hemispheres with additional neuronal overmigration in the pons and the cerebellar cortex. The 14 patients with GPR56 mutations (median 8.25 years, range 1.5-33 years) were phenotypically homogeneous with a distinctive clinical course characterized by pseudomyopathic behaviour at onset that subsequently evolved into severe mental and motor retardation. Generalized seizures (12/14) occurred later with onset ranging from 2.5 to 10 years with consistent electroencephalogram findings of predominantly anterior bursts of low amplitude a-like activity. Neuroimaging demonstrated a common phenotype with bilateral frontoparietally predominant polymicrogyria (13/13), cerebellar dysplasia with cysts mainly affecting the superior vermis (11/13) and patchy to diffuse myelination abnormalities (13/13). Additionally, the white matter abnormalities showed a peculiar evolution from severe hypomyelination at 4 months to patchy lesions later in childhood. Taken as a whole, these observations collectively demonstrate that GPR56 bilateral bifrontoparietal polymicrogyria combines all the features of a cobblestone-like lissencephaly and also suggest that GRP56-related defects produce a phenotypic continuum ranging from bilateral bifrontoparietal polymicrogyria to cobblestone-like lissencephaly.

Genetics and mechanisms leading to human cortical malformations

“…PMG can affect part of the brain or the whole brain, and there can be overlapping features with COB-LIS as mentioned above [227]. PMG exist also as an isolated malformation or it may be associated with other brain malformations, such as corpus callosum agenesis and hypogenesis, cerebellar hypoplasia, PVH and SBH in patients that may present microcephaly, normocephaly or macrocephaly [237].…”

“…In addition, GPR56 (G protein-coupled receptor) mutations have been reported in 14 patients with bilateral frontoparietal PMG (see below), and the phenotypes associated with these mutations were proposed as COB-like cortical dysgeneses due to the pathophysiological similarities with COB-LIS [227]. Indeed, homozygous or biallelic mutations in the GPR56 ligand, COL3A1 were also recently found associated with a COB-like malformation [228].…”

International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors

“…Magnetic resonance images of BFPP brains reveal bilateral polymicrogyria with an anterior-to-posterior gradient, decreased white matter volume with associated bilateral signal changes, as well as brainstem and cerebellar hypoplasia. Histologic studies in a Adgrg1 (Gpr56) knockout mouse model and a human postmortem BFPP forebrain demonstrate that BFPP is a cobblestone-like cortical malformation, characterized by neuronal overmigration through a breached pial basement membrane (Li et al, 2008;Bahi-Buisson et al, 2010). Studies in Adgrg1 (Gpr56) knockout mice further demonstrated that ADGRG1 (GPR56) is essential for proper morphogenesis of the rostral cerebellum by its regulation of the external granule cell adhesion to the extracellular matrix proteins (Koirala et al, 2009).…”

G protein-coupled receptor 56 and collagen III, a receptor-ligand pair, regulates cortical development and lamination

“…Magnetic resonance imaging of BFPP brains shows numerous (poly) small (micro) gyri, which extend diffusely across the frontal and parietal lobes with a decreasing anterior-to-posterior gradient of severity (17)(18)(19)(20). Further studies in Gpr56 knockout mice and postmortem human BFPP brain specimen revealed that the histopathology of BFPP is a cobblestone-like cortical malformation (21,22). However, the molecular and cellular mechanisms of how GPR56 regulates brain development remain largely unknown.…”