Publications of the week: genetics of Infantile Spasms, CERS1, DYRK1A, and hyaluronan

This week in epilepsy genetics. The following publications might be relevant for you, as they demonstrate what happened in the field of epilepsy genetics in the last two weeks. The publications range from basic science studies in extracellular space to novel gene discoveries. I have added a brief comment to each of these studies.

"Wooden neurons" (from under a Creative Commons License)

“Wooden neurons” (from under a Creative Commons License)

Hyaluronan Deficiency, extracellular space, and seizures. I’ll start of with a publication by Arranz and collaborators that was published in the Journal of Neuroscience. They investigate the effect of hyaluronan deficiency in transgenic mice – hyaluronan is a large polysaccharide that keeps water in the extracellular space. If hyaluronan production is disrupted, extracellular space collapses, which results in an intractable seizure phenotype.
Comment: This study reveals a novel mechanism for epileptogenesis and shows the unexpected importance of the extracellular space in neuronal excitability.

The genetic landscape of Infantile Spasms. Sequentially applying CNV analysis, gene panels, and exome sequencing, Michaud and collaborators manage to identify the underlying cause in ~30% of 44 patients with Infantile Spasms. Their study was published in Human Molecular Genetics. Amongst other likely causative genes, they find a de novo mutation in ALG13, a gene previously only identified in the Epi4K cohort. Also they identify two patients with neurometabolic disorders due to mutations in PNPO and ADSL.
Comment: We need studies like this to get a better idea of the overall genetic architecture of IS.

CERS1 and progressive myoclonus epilepsy. Vanni and collaborators identify recessive CERS1 mutations as a cause of familial progressive myoclonus epilepsy in a recent publication in Annals of Neurology. CERS1 codes for ceramide synthetase, which is involved in the generation of sphingomyelin and gangliosides. Defects in the breakdown of these molecules are known to cause Tay-Sachs Disease, Niemann-Pick Disease, and Sialidosis. I’m currently working on a more thorough blog post on this publication.
Comment: There is finally progress in the genetics of the progressive myoclonus epilepsies.

DYRK1A and excitation/inhibition. DYRK1A is one of the main candidate genes for the cognitive phenotype in Trisomy 21/Down Syndrome. In a series of investigations in transgenic mice published in Neurobiological Disorders, Souchet and collaborators demonstrate that DYRK1A gene dosage impacts on synaptogenesis and increased inhibition.
Comment: Even in chromosomal disorders with hundreds of genes involved, specific phenotypic features can be due to individual candidates.

Ingo Helbig

Child Neurology Fellow and epilepsy genetics researcher at the Children’s Hospital of Philadelphia (CHOP), USA and Department of Neuropediatrics, Kiel, Germany

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