The calcium connection. Pathogenic variants in genes encoding voltage-gated ion channels have long been known to cause neurological disorders in people. Dravet syndrome, caused by pathogenic variants in the neuronal sodium channel-encoding gene SCN1A, is one of the most common channelopathies. Although sodium and potassium channels play an established role in childhood-onset epilepsies, the role of voltage-gated calcium channels has been less clear. We have known for over a decade that disease-causing variants in CACNA1A cause a spectrum of neurological disorders, including developmental and epileptic encephalopathies. But evidence of a role for other neuronal calcium channels in epilepsy has been sparse until now. Our publication in the American Journal of Human Genetics now explores the phenotype and functional consequences of de novo variants in CACNA1E, representing a new and unexpectedly frequent disease entity.
The X-factor. Interpreting variants in X chromosome genes in a clinical context is an ongoing diagnostic challenge, regardless of whether the variant is identified in a male or female patient. The majority of X-linked conditions affect hemizygous male individuals, with heterozygous carrier girls and women largely unaffected or much less severely affected. PCDH19-Epilepsy is, of course, a notable rule breaker in this regard. However, we are learning that other X-linked conditions don’t play by the traditional rules either, and affected heterozygous females are being described for some other X-linked conditions. In some cases, including SMC1A– and NEXMIF– (formerly called KIAA2022) related disorders, the phenotypes in males versus females are more or less distinct. However, in other X-linked conditions, including IQSEC2-encephalopathy, both affected males and females share a continuum of similar features. A recent publication in Genetics in Medicine explores and expands the spectrum of IQSEC2-encephalopathy and delves into what is similar – and what is distinct – in affected male and female patients. Continue reading
A successful partnership. Making progress in understanding the genetics of the epilepsies requires a successful partnership involving many players. Researchers, clinicians, patients, and families must work together in order to advance scientific goals. Since the first genetic etiology was discovered in a large family with Autosomal Dominant Nocturnal Frontal Lobe Epilepsy nearly 20 years ago, we have made many strides scientifically, in terms of technologies, our clinical classifications, and our knowledge of genetics. Our views on how we approach research from an ethical perspective is also continuing to evolve. Genetic research hinges on the participation of patients and families, and returning results to participants is increasingly viewed as imperative. A recent paper has used the Epilepsy Phenome/Genome Project (EPGP) and Epi4K studies as a case example of the challenges and opportunities regarding returning genetic results to research participants. Continue reading
ClinGen Epilepsy Gene Curation Expert Panel. For the past year I have been a member of the ClinGen Epilepsy Gene Curation Expert Panel, which has been a rewarding professional experience. I have gotten to know several colleagues within the epilepsy and ClinGen communities, I’ve become familiar with resources for gene curation including MONDO and HPO, and I’ve dived deeply into the existing literature linking genes with a broad spectrum of epilepsies. But working with ClinGen has had another unexpected benefit – it has influenced my approach to writing scientific manuscripts. I have been able to apply this knowledge recently when writing a manuscript about a new causative gene for developmental and epileptic encephalopathies. In this post I would like to share five insider tips about what to include in your genetics manuscript so that it can receive full consideration from the ClinGen Epilepsy Expert Panel.
Somatic mosaicism in focal epilepsy. Recent findings highlighted the role of somatic parental mosaicism in epileptic encephalopathies. However, somatic mosaicism has also emerged over the last few years as a prominent mechanism in the pathogenesis of lesional focal epilepsies, including focal cortical dysplasia (FCD) type 2 and hemimegalencephaly. Previous studies have identified the role of mosaicism of genes such as MTOR, TSC1/TSC2, and genes encoding components of the PI3K/AKT pathway in patients with epilepsy secondary to brain malformations. A recent study in Annals of Neurology has identified a new unrelated genetic cause of refractory non-lesional focal epilepsy, which leads us to wonder what role mosaicism may be playing in focal epilepsies without obvious findings on MRI.
Conventional wisdom. Trio whole exome sequencing has been successful over the last five years in identifying underlying genetic etiologies in nearly 50% of patients with epileptic encephalopathies, which is largely owing to the genetic architecture of these conditions. The vast majority of these genetic epilepsies are caused by apparent de novo variants that are present in the patient but not in the mother or father. The conventional wisdom is that the recurrence risk in future pregnancies for parents of an affected child is low to non-existent and traditionally we have quoted a ~1% recurrence risk for future pregnancies. However, a new study published in the New England Journal of Medicine turns this conventional wisdom on its head, identifying detectable somatic mosaicism in approximately 10% of parents tested, which has implications for how we counsel families of children with epileptic encephalopathies – and potentially other genetic conditions due to de novo variants as well. Continue reading
Unravelling the BAFME mystery. The mystery surrounding Benign Adult Familial Myoclonic Epilepsy (BAFME) – also known as Familial Adult Myoclonic Epilepsy (FAME) or Familial Cortical Myoclonic Tremor and Epilepsy (FCMTE) – has persisted for years. BAFME is an autosomal dominant neurological disorder characterized by adult onset of myoclonic/cortical tremor and infrequent seizures. The clinical course is typically considered to be benign. Linkage studies have shown linkage to several regions including 8q24, 2p11.1-q12.2, 3q26.32-q28, and 5p15. A recent publication identified a variant in CTNND2 segregating with disease in a Dutch family with BAFME3, although it remains to be determined how broadly applicable CTNND2 variants are in other individuals with BAFME. Now in an elegant set of experiments by Ishiura and colleagues, a significant proportion of BAFME appears to be solved and is due to expansions of pentanucleotide intronic sequences in SAMD12.
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
Protocadherins. PCDH19-related epilepsy is the second most common genetic epilepsy, behind Dravet syndrome. PCDH19-related epilepsies display the unusual X-linked inheritance pattern in which heterozygous females are affected but hemizygous males are unaffected. Similarly, somatic mosaic males have also been reported. PCDH19 encodes protocadherin 19, a calcium-dependent cell-cell adhesion molecule that is highly expressed in the central nervous system. The long-hypothesized pathomechanism has been cellular interference, although experimental support has so far been lacking. Now, Pederick and collaborators provide evidence that supports the cellular interference mechanism in PCDH19-related epilepsies, bringing us closer to understanding the biology of this unusual genetic epilepsy. Continue reading
KCNA2. We have previously discussed KCNA2 and that pathogenic variants in this gene can lead to a spectrum of neurological phenotypes. Pathogenic KCNA2 variants were first recognized in individuals with early-onset developmental and epileptic encephalopathies and have subsequently been found also in individuals and families with hereditary spastic paraplegia, episodic ataxia, and milder epilepsies. KCNA2 encodes the Kv1.2 potassium channel, a delayed rectifier class of potassium channel that enables neuronal repolarization after an action potential. A new study by Masnada and colleagues provides clinical and functional data from 23 patients, representing the largest KCNA2 cohort reported to date. Within the KCNA2-related encephalopathy spectrum, it now seems that there may be three distinct phenotypes. Continue reading