The missing ion channel. A little more than two years ago, we wrote about our discovery of SCN3A as a novel disease gene in epileptic encephalopathies. At the time, SCN3A was the missing ion channel, the only brain-expressed voltage gated sodium channel that did not have a clear gene-disease relationship. However, since the initial discovery of SCN3A as a disease gene, both the phenotypic spectrum and variant landscape have expanded considerably. In a recent publication, we updated our knowledge based on information of 22 individuals with SCN3A-related disorders, which showed brain malformations in more than 75% of individuals and an unusual clustering of pathogenic variants in parts of the Nav1.3 channel. Continue reading
Tag Archives: Brain malformations
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
Publications of the week – SCN8A, CNTNAP4, EML1, and SCN1A
Catching up. This week’s review of recent publications might be relevant for you because it adds new pertinent details to known epilepsy genes and discusses novel gene findings that might be applicable in clinical practice. This post covers publications on SCN8A in epileptic encephalopathy, CNTNAP4 and interneurons, EML1 in brain malformations, and the meaning of SCN1A variants in small epilepsy families. 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
Somatic mutations affecting the mTOR pathway in hemimegalencephaly
Mutations, but not germline. Many of the genetic alterations that we aim to investigate within the EuroEPINOMICS projects are so-called germline mutations. In the case of de novo events, these mutations have occurred in the germ cells themselves or in very early development. In the case of autosomal dominant or recessive inheritance, the mutations have been transmitted from parents. In either case, the mutation can be found in every cell of the body. Cancer research is mainly focussed on somatic mutations, which give rise to malignant transformation in already differentiated tissues. In fact, many of the techniques that we currently use in neurogenetics were developed to study somatic genetic aberrations. Array comparative genomic hybridization for example, had initially been established for these purposes before expanding the focus to germline microdeletions and microduplications. While the role of somatic mutations in cancer research is well established, the role somatic rather than germline genetic alterations play in other disorders is mainly speculative. Some initial evidence for somatic point mutations has recently been found in Proteus syndrome, a rare overgrowth syndrome. Activating somatic mutations in AKT1 have recently been identified in this disorder. A recent paper by Lee and colleagues now identifies mutations in several genes in the mTOR pathway in patients with hemimegalencephaly, a severe form of brain malformation. Continue reading
