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.

Continue reading

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

A clinician’s guide to genetic test selection: navigating the Wild West

The Wild West. The diagnostic genetic testing landscape in 2016 is a paradox. In theory genetic testing has never been more widely available clinically, with over 20 diagnostic laboratories in the US alone offering a variety of genetic testing options for patients with epilepsy, ranging from single gene testing to NGS panels to whole exome sequencing. However, access to and reimbursement of genetic services varies widely, with no consensus on an approach to testing or professional guidelines to aide clinicians. Here is our brief guide to epilepsy genetic test selection for busy clinicians. 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

The first Online Symposium: Rare Genetic Variants Associated with Neurodevelopmental Disorders

Online. Last week, we held the first online symposium on “Rare Genetic Variants Associated with Neurodevelopmental Disorders”. The meeting covered seven topics which included different genomic approaches used to unravel the genetic architecture of neurodevelopmental disorders and cognitive traits. In total, 117 participants joined the meeting with a peak of 72 participants listening to a presenter. Continue reading

Shortening the diagnostic odyssey – exome sequencing for white matter abnormalities

Background on whole exome technology. To explain the various ways of obtaining genetic information, I often refer to an encyclopedia set as a representation of our genome. All of the information which makes us who we are is written in a 4 letter code (A, T, G, C) in our genome or ‘encyclopedia set’ and is contained within our chromosomes or ‘volumes’. We have two sets of each volume, one from mom and one from dad. Targeted panels read a select number of genes or ‘chapters’ regarding only those which are known to be associated with white matter changes. Whole exome sequencing (WES) reads all of the coding sections, approximately 20,000 genes in total, but none of the extra information. This noncoding information would represent the appendices, figure legends, and foot notes. Whole genome sequencing (WGS) reads everything cover to cover. 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