Article Text
Abstract
Background Malformations of cortical development (MCDs) have been reported in a subset of patients with pathogenic heterozygous variants in GRIN1 or GRIN2B, genes which encode for subunits of the N-methyl-D-aspartate receptor (NMDAR). The aim of this study was to further define the phenotypic spectrum of NMDAR-related MCDs.
Methods We report the clinical, radiological and molecular features of 7 new patients and review data on 18 previously reported individuals with NMDAR-related MCDs. Neuropathological findings for two individuals with heterozygous variants in GRIN1 are presented. We report the clinical and neuropathological features of one additional individual with homozygous pathogenic variants in GRIN1.
Results Heterozygous variants in GRIN1 and GRIN2B were associated with overlapping severe clinical and imaging features, including global developmental delay, epilepsy, diffuse dysgyria, dysmorphic basal ganglia and hippocampi. Neuropathological examination in two fetuses with heterozygous GRIN1 variants suggests that proliferation as well as radial and tangential neuronal migration are impaired. In addition, we show that neuronal migration is also impaired by homozygous GRIN1 variants in an individual with microcephaly with simplified gyral pattern.
Conclusion These findings expand our understanding of the clinical and imaging features of the ‘NMDARopathy’ spectrum and contribute to our understanding of the likely underlying pathogenic mechanisms leading to MCD in these patients.
- Nervous System Malformations
- Genetics
- Pathology
- Radiology
- Pediatrics
Data availability statement
Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Anonymised data from this study will be shared by request from any qualified investigator.
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Data availability statement
Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Anonymised data from this study will be shared by request from any qualified investigator.
Footnotes
Contributors AEF, NB-B and ACJ conceived the work. SB, AL, AEF, SJM and NB-B assisted with data acquisition. SB, AL and AEF drafted the manuscript, which was revised and approved by all. SB and AEF act as guarantor.
Funding The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003). This study makes use of DECIPHER (http://decipher.sanger.ac.uk), which is funded by Wellcome (see Nature PMID: 25533962 or www.ddduk.org/access.html for full acknowledgement). ACJ was funded by an FWO Senior Clinical Investigator Fellowship. SB received funding from the Scientific Fund Willy Gepts. DB is supported by NIHR Research Professorship (RP-2016- 07-011). SFT received funding from the NIH-NINDS (NS111619). YH is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (R01HD082373) and the National Institute of Mental Health (MH127404). SJM is supported by a grant from the National Institute on Aging (R21AG072142). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Competing interests SFT is principal investigator on research grants from Biogen and Janssen to Emory; a member of the Scientific Advisory Board for Eumentis, Sage Therapeutics, GRIN2B Foundation and CureGRIN Foundation; co-founder of NeurOp and Agrithera; and coinventor on Emory-owned intellectual property.
Provenance and peer review Not commissioned; externally peer reviewed.
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