Currently, comprehensive guidelines for diagnosis and management are lacking, adding to the variability in the diagnostic approach between different centres. However, MCD experts usually work individually or in small multidisciplinary teams. The complex nature and high degree of clinical and genetic heterogeneity of MCDs demand highly specialized and multidisciplinary expertise. Next-generation sequencing (NGS) of a selection of genes related to a phenotype (gene panel), the coding exons of the human genes (exome sequencing) or the genome of an individual (genome sequencing) has enabled rapid sequencing of large numbers of genes.Įven following intensive diagnostic assessments, many individuals with an MCD remain without a molecular diagnosis 4, 5, 6.
Rapid advances in molecular genetics and neuroimaging techniques in recent years have substantially increased the number of recognized MCD forms and their associated genes, and have highlighted the considerable genetic heterogeneity associated with these disorders 1. Many MCDs are caused by an underlying genetic defect.
#Xlag 4.0 update
The last update of the developmental and genetic classification for MCDs, which was published in 2012, includes 200 clinical entities and classifies them into three major groups: malformations secondary to abnormal neuronal and glial cell proliferation and apoptosis, including microcephaly and macrocephaly neuronal migration disorders, represented by heterotopia, lissencephaly and cobblestone malformation (COB) and malformations of postmigrational cortical organization and connectivity, represented by conditions such as polymicrogyria, schizencephaly and focal cortical dysplasia (FCD) 3. Although individually rare, as a group MCDs represent a major cause of intellectual disability, autism, epilepsy and cerebral palsy 1, 2. 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.Ībnormal formation of the cerebral cortex in utero leads to neurodevelopmental disorders known as malformations of cortical development (MCDs). 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. We reached consensus by 42 professionals from 20 countries, using expert discussions and a Delphi consensus process. 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. 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. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and aetiology, thereby hampering timely and adequate management. 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. Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from abnormal development of the cerebral cortex in utero. Nature Reviews Neurology volume 16, pages 618–635 ( 2020) Cite this article International consensus recommendations on the diagnostic work-up for malformations of cortical development