Expanding our horizons: Benign Adult Familial Myoclonic Epilepsy and intronic SAMD12 repeat expansions

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.

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The mitochondrial box cutter – an unexpected role for PMPCB in neurodegeneration

MPP. Mitochondria are indispensable for cellular energy production and require constant protein import, as most mitochondrial genes are encoded in the nucleus. In order for proper targeting, mitochondrial proteins have a specific presequence, which is removed once a protein has found its way into the mitochondria. This function is accomplished by the mitochondrial processing peptidase MPP, which is encoded by the PMPCA and PMPCB genes. In a recent publication in the American Journal of Human Genetics, we identified PMPCB as a novel gene for a complex neurodegenerative condition in childhood and discovered a new disease mechanism for neurological disorders. However, epileptic encephalopathy that initially led to the inclusion of our initial RES study was only one extreme of an unusual disease spectrum.  Continue reading

Finding the missing sodium channel – SCN3A in epileptic encephalopathy

Sodium channel. Voltage-gated channels for sodium ions are a crucial component of helping neurons depolarize and repolarize in a way that enables generation of action potentials. However, in order to function properly, voltage-gated ion channels co-exist in a fragile balance, and genetic alterations leading to functional changes in these channels are known causes of disease. SCN1A, SCN2A, and SCN8A have been implicated as causes for human epilepsy. However, SCN3A encoding the Nav1.3 channel, one of the most obvious candidates, could not be linked to disease so far. In a recent publication, we were able identify disease-causing mutations in this major neuronal ion channel. Interestingly, patients with an early onset and the most severe presentation had a prominent gain-of-function effect that responded to known antiepileptic medications. Continue reading

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

PCDH19-related epilepsy: understanding cellular interference

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

SLC6A1 – a generalized epilepsy phenotype emerging

GAT1. When we first identified SLC6A1 in 2015, we were surprised that a significant proportion of patients with disease-causing variants in this gene had a rare epilepsy phenotype referred to as Myoclonic Astatic Epilepsy (MAE). Typically, at the time of gene discovery, it is often unclear how far the phenotypic spectrum expands. In a recent publication in Epilepsia, we reviewed the phenotype of 34 patients with SCL6A1-related epilepsy. Surprisingly, in contrast to many other epilepsy genes that showed a broad and occasionally non-specific phenotypic range, the SLC6A1-related phenotype expands beyond MAE, but remains centered around generalized epilepsies with a predominance of absence seizures and atonic seizures. It is a gene that has started to write its own story. Continue reading

Epilepsy genetics in 2018 – Three things that will happen and three things that won’t

Bomb Cyclone. While the entire US East Cost was held hostage by a weather system that introduced us to new catchy meterological concepts such as bombogenesis, I hope that everybody is staying warm and safe. I wanted to wish all our readers a Happy 2018 and try to give an outlook of the New Year in epilepsy genetics.  Here are three things in epilepsy genetics that will happen in 2018 – and three things that won’t. Continue reading

AES 2017 – Making Sense of Genetic Data in Epilepsy

Controversies. While you are packing your bags for the 71st Annual Meeting of the American Epilepsy Society in Washington, D.C., we wanted to point out one agenda item that may be of interest for you. The AES agenda typically has many parallel sessions, so I wanted to make a plug for our Genetics Special Interest Group (SIG) on Friday, 12/1 at 1:30PM. The topic of our SIG is going to be “Making Sense of Genetic Data in Epilepsy – Consensus and Controversy in 2017”. In contrast to regular sessions and lectures, a SIG is meant to stimulate discussion between SIG members. Therefore, in parallel to previous years, we would like to invite the attendees to use the opportunity to discuss challenging cases within a dedicated AES Special Interest Group. Continue reading

The many faces of KCNA2: a 2017 update

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

The rising role of synaptic transmission: the calcineurin link

Synaptic transmission. Over the last several years, pathogenic variants in multiple genes involved in synaptic transmission have been identified in early-onset epilepsies. STXBP1 and STX1B both encode components of the SNARE complex, a complicated protein complex that mediates the fusion of the plasma membrane of the presynapse and the synaptic vesicle to allow for neurotransmitter release. DNM1, encoding the dynamin-1 protein, plays an essential role in recycling synaptic vesicles back into the presynapse after neurotransmitter release. A new study by Myers and collaborators has identified several patients with de novo variants in PPP3CA, which encodes another protein involved in synaptic vesicle recycling, further highlighting the importance of synaptic transmission in the etiology of severe neurodevelopmental disorders. In the interest of full disclosure, I am also a co-author on this study. Continue reading