MCDs. Malformation of cortical developments are a frequent cause of intractable epilepsies and, if appropriate, surgical resection may be warranted. Malformations represent a wide range of cortical lesions resulting from derangements of normal intrauterine developmental processes affecting the formation of the cortical mantle. Polymicrogyria (PMG) is one of the most common malformations of cortical development. However, while somatic mutations affecting the mTOR pathway are a known cause of certain subtypes of MCD, the polymicrogyrias have remained elusive. The underlying cause remains unknown in more than 80% of cases and, if identified, may be due to a wide range of underlying genetic causes. In a recent publication, mosaic trisomy 1q was identified as a novel and relatively frequent cause of polymicrogyria, emphasizing the role of somatic mutation detection in malformation of cortical development. Continue reading
Tag Archives: polymicrogyria
NMDA receptors and brain malformations: GRIN1-associated polymicrogyria
Ion channels and brain malformations. When the “channelopathy” concept first emerged – the idea that dysfunction of neuronal ion channels leads to neurological disease including epilepsy – it seemed implausible that such dysfunction could lead to malformations of cortical development. However, recent research has suggested that ion channel dysfunction may indeed be linked with brain malformations. In 2017, we saw convincing evidence that germline de novo variants in GRIN2B can cause malformations of cortical development. Some suggestive, but less conclusive, evidence has also linked SCN1A and SCN2A to brain malformations. Now Fry and collaborators demonstrate that de novo pathogenic variants in GRIN1 can also cause significant polymicrogyria, expanding the phenotypic spectrum of GRIN1-related disorders. As a disclaimer, I am also a co-author on the publication by Fry and collaborators. Continue reading
Imbalance of a rare second messenger – FIG4 mutations in polymicrogyria
Brain malformations. Various brain malformations are thought to have a genetic basis, and several genes have already been identified. Polymicrogyria is a particular form of congenital brain malformation due to an excessive number of small and sometimes malformed gyri. In a recent publication in Neurology, mutations in FIG4 are described in a familial form of polymicrogyria. However, the FIG4 gene is no stranger in the field of neurogenetics. Continue reading
Microcephaly, WDR62, and how to analyze recessive epilepsy families
Success rate. What is in an exome? There are lots of rare and unknown variants that are hard to make sense of unless we can ask a specific question or have further data to limit the number of genes that we look at. Genetic studies in recessive diseases with limited candidate genes to consider might represent one of the most straightforward cases. In a recent paper in BMC Neurology, the genetic cause of a recessive epilepsy/intellectual disability syndrome in a consanguineous family presenting with primary microcephaly was solved using a single exome of an affected individual. Was this just lucky or can this strategy be applied to any recessive family with a reasonable chance? Continue reading
C6orf70, neuronal migration and periventricular heterotopia
Radial migration. The fact that neurons find their place in the cortex during development is nothing short of a miracle. Many neurons originate in the subventricular zone, i.e. the area lining the ventricles. During brain development, these neurons subsequently climb outwards to their final positions using radial glia cells as scaffolds. If this delicate process is disturbed, neurons may be misplaced. Periventricular nodular heterotopia (PVNH) is a condition in which defects in neuronal migration result in ectopic neuronal nodules lining the ventricles. These nodules may result in a broad range of epilepsies, ranging from mild seizure disorders to intractable epilepsy with intellectual disability. Many cases of PVNH are assumed to be genetic, and FLNA and ARFGEF2 as known causative genes. However, the cause remains unknown in a significant number of patients. In a recent paper in Brain, C6orf70 is identified as a new candidate for PVNH using a clever combination of array CGH and exome sequencing. Continue reading
