GABRB3 – from febrile seizures to epileptic encephalopathies

Beta-3. Even though the gene for the beta-3 subunit of the GABA-A receptor (GABRB3) has not been mentioned frequently in the context of epilepsy genes, it is a gene that is frequently involved in genetic changed that give rise to epilepsy. Given that GABRB3 is one of the genes found within copy number changes on chromosome 15, it may predispose to human epilepsies through various genetic mechanisms including copy number variations and de novo mutations. In a recent publication in Neurology, we reviewed the phenotypes of patients with GABRB3 variants and found an unusual complexity of sporadic and familial cases. Here are three things that I have learned about GABRB3. Continue reading

The Cavatica experience – running epilepsy exomes in the cloud

End of the year. The final weeks of the year are always a time when my curiosity for bioinformatics takes over. Four years ago, I was trying to teach myself sufficient command line and bioinformatics to run Denovogear on my computer. Now the field has moved on, from command line language to solutions that aim at bringing data closer to researchers. I hijacked a platform that was initially built for cancer research, CHOP’s Cavatica platform that was developed with Seven Bridges Genomics. In the same way as a few years ago, I started out with a simple question: Can I take an exome completely apart and then re-analyze it to find the SCN1A mutation in DRA1? Continue reading

FOXG1 – an epilepsy gene involved in brain development

Forkhead. In our Epilepsiome series we are reviewing all major epilepsy genes. This week, we discuss FOXG1, a gene previously described as the cause for a congenital variant of Rett Syndrome. However, since its initial discovery in 2008, a much broader spectrum has been recognized. FOXG1 syndrome typically includes developmental delay and microcephaly. Many patients have severe, early-onset epilepsy and a prominent hyperkinetic movement disorder. In addition, some patients have brain malformations. Here is a brief introduction to our Epilepsiome review of FOXG1, an epilepsy gene that stands out from other causes of genetic epilepsies given its prominent role in forebrain development.

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MECP2 – Rett Syndrome in the era of exome-first studies

Rett. We have written very little about MECP2 on Beyond the Ion Channel. MECP2 is the gene for Rett Syndrome, a neurodegenerative disorder almost exclusively affecting females. Classical Rett Syndrome is characterized by developmental regression in the first two years of life and the development of distinctive hand movements, which historically led to Rett Syndrome being considered a recognizable entity. This blog post is the introduction to our MECP2 Epilepsiome page. However, in 2016, a time when many genes are re-defined by exome studies, I was wondering whether Rett Syndrome is still the classical syndrome that I initially learned about.

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ALG13 – rethinking the glycosylation code

The sugar code. Many proteins in the human body undergo post-translational modification. A common mechanism to modify the function of proteins is a process called glycosylation, the adding of carbohydrate residues to protein. Glycosylation is probably the most complex post-translational modification, critically important to various physiological functions and therefore tightly regulated in cells. Accordingly, genetic disorders that interfere with glycosylation may present as severe, multisystem disorders. However, it is increasingly recognized that many congenital disorders of glycosylation have an exclusively neurological phenotype. Here is an update on ALG13 epileptic encephalopathy, a recently identified disease entity that may account for up to 2% of Infantile Spasms in females. Continue reading

ALDH7A1 beyond pyridoxine-dependent epilepsy – a 2016 overview

Pyridoxine. I still remember when I learned about vitamin B6 deficient epilepsy in medical school. One of the residents quizzed me about the first medication to given to a seizing neonate. I suggested phenobarbital, but he shook his head and said “vitamin B6” – which was something that I had never really heard about before. Technically, pyridoxine is not the first-line treatment in neonatal seizures on most protocols, but vitamin-dependent epilepsies are always on the differential in newborns with seizures. Here are a few things about ALDH7A1 that are new in 2016. Continue reading

SNPs and CNVs in the Golden City – five things I learned in Prague

Prague. I am sitting in my hotel in Dublin on my way back to Philadelphia, trying to collect my thoughts on last week’s European Epilepsy Congress in Prague. For both Katie and me, it was great to catch up with our colleagues from Europe and Australia. For our European RES consortium, this meeting was an important inflection point – in fact, three years after the end of the funding period, RES is alive and kicking. Here are the five things I learned in the City of the Hundred Spires. Continue reading

KCNA2 – an epilepsy gene in hereditary spastic paraplegia

HSP. I have to admit that the hereditary spastic paraplegias are not mentioned all that frequently on our blog.  The main reason is that there is little overlap between early-onset epilepsies and adult-onset progressive neurodegenerative conditions that are characterized by spasticity and weakness in the lower extremities. In a recent publication, we described an epilepsy gene that became an HSP gene, showing an unusual overlap between both groups of conditions and establishing a novel mechanism in HSP pathogenesis. Here is a continuation of the KCNA2 story. Continue reading

SYNJ1 links Parkinson’s disease to epileptic encephalopathy

Duality. Earlier this week, our Luxembourg collaborators came to visit us at CHOP to discuss our current and future projects. We discussed potential overlaps between the diseases that both our groups are mainly involved in, namely Parkinson’s disease and genetic epilepsies. In fact, we had just published on one of the overlapping genes recently, a gene that we accidentally stumbled upon through our genome sequencing projects. Here is the story of SYNJ1, a gene involved in neurodegenerative phenotypes that link early-onset Parkinson’s disease and epileptic encephalopathy. Continue reading

The two faces of GABRA1 – from familial epilepsy to epileptic encephalopathy

Inhibition. GABA is the main inhibitory neurotransmitter in the the Central Nervous System. Given that epilepsy is typically associated with increased excitability, all mechanisms related to GABA signaling are of natural interest to the epilepsy community. Almost 15 years ago, mutations in GABRA1, coding for alpha-1 subunit of the GABA-A receptor, have been identified in familial Juvenile Myoclonic Epilepsy, but there has been relative silence around this gene since. Now, two publications highlight the other side of GABRA1 as a gene for epileptic encephalopathies, putting the GABA receptor into the spotlight again.

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