This scientific commentary refers to ‘De novo mutations in GRIN1 cause extensive bilateral polymicrogyria’, by Fry et al. (doi:10.1093/brain/awx358). Malformations of cortical development (MCDs) are a common cause of medically refractory epilepsy and when they extend to span hemispheric, lobar, or bilateral brain areas, are often also associated with intellectual disability and other significant neurological deficits. Polymicrogyria is a complicated and multi-factorial MCD that can be unilateral and focal, or bilateral and extensive, and is defined by the presence of multiple small microgyri, and disordered cortical laminar structure (Stutterd and Leventer, 2014). The excessively small gyral folding pattern may involve only the upper cortical layers or extend throughout all layers, and the laminar arrangement of neurons is disorganized (for review see Squier and Jansen, 2014). Bilateral polymicrogyria is variably associated with epilepsy, intellectual disability, oromotor difficulties, focal motor deficits, and stereotyped movements. In this issue of Brain, Fry and co-workers provide compelling evidence for an association between mutations in GRIN1, which encodes GluN1, an obligatory receptor subunit within the ionotropic N-methyl-d-aspartate (NMDA) receptor, and bilateral polymicrogyria (Fry et al., 2018). The cohort presented provides new insights into how mutations in a wide variety of genes can lead to MCDs, and extends previous work demonstrating that mutations in other NMDA receptor subunits i.e. GRIN2B, are linked to a spectrum of neurodevelopmental disorders such as epileptic encephalopathies, intellectual disability, and autism spectrum disorder (Platzer et al., 2017). Among a cohort of 57 unrelated individuals with polymicrogyria, Fry and colleagues found 11 de novo missense mutations in conserved residues of GRIN1. Clinically, 10/11 patients exhibited polymicrogyria while one showed ‘abnormal thinning and sulcation of the cortex’. There were significant phenotypic similarities across the cohort including profound to severe intellectual delay and disability, microcephaly, medically intractable epilepsy, and cortical visual impairment; a few individuals exhibited stereotypical eye and hand movements. Brain MRI showed extensive bilateral polymicrogyria variably affecting the frontal, parietal, and perisylvian regions. In many cases, the polymicrogyria spared the occipital region. While neuropathological examination was not part of this study, the radiographic polymicrogyria appearance of patients in the cohort was strikingly similar to classically defined polymicrogyria, showing marked disorganization of cortical lamination. Close examination of the GRIN1 variants revealed clustering within the highly conserved S2-region of GluN1, which corresponds to the ligand binding domain and which is deemed intolerant to genomic variation. A small number of mutations were confined to the adjacent extracellular M3 region within a highly conserved domain, the Lurcher motif, which serves as a permeation barrier to the four M3 helices within GRIN1. Finally, a unique subset was identified within the S1-M1 linker region. Three-dimensional analysis of GRIN1 structure and the effects of the identified variants on protein structure revealed no definite association between mutation location and expressed phenotype; a number of mutations affecting similar encoded protein regions have been associated with non-syndromic intellectual disability and epileptic encephalopathy but not polymicrogyria. In addition, Fry et al. noted an increase in the number of functional hydrogen bonds formed by the mutant subunits. An elegant set of experiments assaying the expression of five of the human polymicrogyria GRIN1 variants by site-directed mutagenesis in Xenopus oocytes revealed differential alterations in sensitivity to applied glutamate and glycine. For example, the p.Arg659Trp and p.Arg794Gln mutations showed significantly increased sensitivity to glutamate and glycine whereas the p.Asn674Ile mutant exhibited minimal changes in response to glutamate and reduced potency of glycine. These data suggest complex pharmacodynamics as the mutant subunits combine to form functional receptors. Polymicrogyria can be detected in isolation or in association with other MCDs including lissencephaly and pachygyria, as well as structural abnormalities of the corpus callosum and hippocampus. The most common polymicrogyria phenotype is bilateral perisylvian polymicrogyria, which presents with oral motor dysfunction, intellectual disability and epilepsy (Bahi-Buisson and Guerrini, 2013). The clinical presentation of patients with other forms of polymicrogyria varies widely and depends on the anatomical extent of polymicrogyria and the presence of other brain malformations, such as cerebellar hypoplasia and/or microcephaly. Polymicrogyria can also be observed radiographically in cortical areas serving language or primary motor functions, with minimal deficits. Polymicrogyria has been linked to a number of gene loci, and its causes are quite diverse. For example, polymicrogyria can result from mutations in genes encoding tubulin subtypes, including TUBA1A, TUBB2B, TUBB3 and TUBA8 (Romero et al., 2017). Multiple tubulin subtypes are expressed in post-mitotic neurons, and are essential to cell motility, axon guidance and outgrowth, and cell differentiation. Polymicrogyria has also been linked to mutations in GPR56 and SRPX2, and may be found in association with metabolic disorders such as Zellweger’s syndrome, fumaric aciduria, maple syrup urine disease and certain mitochondrial disorders e.g. Leigh’s disease. Intrauterine infection e.g. cytomegalovirus (CMV) infection, or foetal hypoxic-ischaemic injury are common sporadic causes of polymicrogyria. In view of these diverse causes, Fry et al. propose several compelling ideas to account for the developmental pathogenesis of polymicrogyria based on putative changes induced by GRIN1 variants. First, they propose that either loss- or gain-of-function mutations in NMDA receptor subunits could have direct or indirect effects on neural migration processes, thus limiting the ability of neuroglial progenitor cells in the cortical plate to move effectively and achieve appropriate laminar distribution. This process could explain the characteristic multiple, small, and dysmorphic gyri seen in polymicrogyria. While an interesting hypothesis, there is conflicting evidence from animal models to support it as mice lacking Grin1 exhibit only subtle changes in cerebral cortical structure (Iwasato et al., 2000), and targeted knockdown of Grin2b is associated with delayed cortical migration (Jiang et al., 2015). Alternatively, the functional assays performed by Fry et al. demonstrate that the variants identified do indeed alter the receptor sensitivity to both glutamate and glycine, likely causing inappropriate glutamate signalling, especially enhanced sensitivity to glutamate, that may lead to injury and death of either neural progenitors, migrating neurons, or neurons within the cortical plate. Mechanistically, this notion would fit with prior observations of cell death in polymicrogyria associated with for example, congenital CMV infection and foetal hypoxic-ischaemic injury. While no histopathology was reported by Fry et al., the radiographic pattern looked similar to classical polymicrogyria and suggests a laminar pattern compatible with laminar excitotoxic injury. In terms of clinical phenotype, all patients in the cohort had refractory epilepsy and severe to profound intellectual disability. As has been proposed for many MCDs, the behavioural and neurological phenotypes likely result from combinatorial effects of the gene mutation on protein function, in this case altered pharmacosensitivity to glutamate or glycine as well as altered cerebral cortical structure. The combined effects of altered lamination plus enhanced glutamate sensitivity conceptually yields a dysfunctional network characterized by seizures and impaired cognitive function. One unresolved conundrum in the present analysis is why there was substantial overlap between non-polymicrogyria and polymicrogyria cases both associated with GRIN1 mutations. Thus, with the exception of the M4 mutation cluster, which seemed to be exclusively observed in non-polymicrogyria epileptic encephalopathy, the other variants were roughly equally represented between polymicrogyria and non-polymicrogyria epileptic encephalopathy. These observations speak to the heterogeneity of polymicrogyria and the protean associations with a number of highly variable aetiologies causing polymicrogyria. The authors have presented a compelling story demonstrating how mutations in GRIN1 may simultaneously disrupt cortical lamination and neuronal excitability. Clearly, this avenue of investigation warrants further pursuit. References Bahi-Buisson N, Guerrini R. Diffuse malformations of cortical development. Handb Clin Neurol 2013; 111: 653– 65. Google Scholar CrossRef Search ADS PubMed Fry AE, Fawcett KA, Zelnik N, Yuan H, Thompson BAN, Shemer-Meiri L, et al. De novo mutations in GRIN1 cause extensive bilateral polymicrogyria. Brain 2018; 141: 698– 712. doi: 10.1093/brain/awx358. Google Scholar CrossRef Search ADS Iwasato T, Datwani A, Wolf AM, Nishiyama H, Taguchi Y, Tonegawa S, et al. Cortex-restricted disruption of NMDAR1 impairs neuronal patterns in the barrel cortex. Nature 2000; 406: 726– 31. Google Scholar CrossRef Search ADS PubMed Jiang H, Jiang W, Zou J, Wang B, Yu M, Pan Y, et al. The GluN2B subunit of N-methy-D-asparate receptor regulates the radial migration of cortical neurons in vivo. Brain Res 2015; 1610: 20– 32. Google Scholar CrossRef Search ADS PubMed Platzer K, Yuan H, Schütz H, Winschel A, Chen W, Hu C, et al. GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects. J Med Genet 2017; 54: 460– 70. Google Scholar CrossRef Search ADS PubMed Romero DM, Bahi-Buisson N, Francis F. Genetics and mechanisms leading to human cortical malformations. Semin Cell Dev Biol 2017, in press. pii: S1084-9521(17)30239-2. doi: 10.1016/j.semcdb.2017.09.031. Squier W, Jansen A. Polymicrogyria: pathology, fetal origins and mechanisms. Acta Neuropathol Commun 2014; 2: 80. Google Scholar CrossRef Search ADS PubMed Stutterd CA, Leventer RJ. Polymicrogyria: a common and heterogeneous malformation of cortical development. Am J Med Genet C Semin Med Genet 2014; 166C: 227– 39. Google Scholar CrossRef Search ADS PubMed © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: email@example.com
Brain – Oxford University Press
Published: Mar 1, 2018
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