International consensus recommendations on the diagnostic work-up for malformations of cortical development

Abstract

Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from abnormal development of the cerebral cortex in utero. MCDs place a substantial burden on affected individuals, their families and societies worldwide, as these individuals can experience lifelong drug-resistant epilepsy, cerebral palsy, feeding difficulties, intellectual disability and other neurological and behavioural anomalies. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and aetiology, thereby hampering timely and adequate management. In this article, the international MCD network Neuro-MIG provides consensus recommendations to aid both expert and non-expert clinicians in the diagnostic work-up of MCDs with the aim of improving patient management worldwide. We reviewed the literature on clinical presentation, aetiology and diagnostic approaches for the main MCD subtypes and collected data on current practices and recommendations from clinicians and diagnostic laboratories within Neuro-MIG. We reached consensus by 42 professionals from 20 countries, using expert discussions and a Delphi consensus process. We present a diagnostic workflow that can be applied to any individual with MCD and a comprehensive list of MCD-related genes with their associated phenotypes. The workflow is designed to maximize the diagnostic yield and increase the number of patients receiving personalized care and counselling on prognosis and recurrence risk.

ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria

“…The molecular diagnostic yield of polymicrogyria is low, with multiple genes accounting for a small number of diagnoses each, and a relevant number of patients resulting from nongenetic, mainly vascular or infective, prenatal causes Park et al, 2020). The proportion of patients with polymicrogyria related to ATP1A2/A3 remains unknown since available NGS studies on MCDs have been either performed with gene panels which included neither of the two genes (Oegema et al, 2020) or carrying out WES in small series in which no pathogenic variants in either gene emerged Wiszniewski et al, 2018). This study widens the clinical spectrum of ATP1A2/A3-opathies to include profound epilepsy phenotypes, with and without associated polymicrogyria.…”

Molecular diagnostics in drug‐resistant focal epilepsy define new disease entities

“…PMG is a group of highly heterogeneous and difficult to classify MCD (55, 56). Their description is primarily based on their localization (by MRI; e.g., focal, multifocal, or generalized, unilateral or bilateral symmetric/asymmetric) and correlation with clinical aspects including developmental course, growth anomalies, and dysmorphism, seizure history, family history, and genetic testing of blood for PMG‐associated genes (24).…”

Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance

“…In GZ, genes associated with cluster 1 (red) were amongst others involved in DNA damage repair. Indeed, alterations in this pathway can lead to reduced proliferation of neural progenitor cells leading to microcephaly [82,83]. Cluster 2 (green) in GZ was associated with terms related to neurodevelopment and organ morphogenesis.…”