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Aug 11, 2013

Childhood Epilepsy Tied to Mutations in Unexpected Genes

  • A large-scale international study supported mostly by the NIH has discovered new mutations in key genes associated with childhood epilepsy. Among those were two genes never before associated with this form of epilepsy, one of which previously had been linked to autism and a rare neurological disorder for which an effective therapy already has been developed.

    The $25 million project, the Epilepsy 4000 (Epi4K), aims to sequence and analyze DNA from 4,000 epilepsy patients and their relatives. NIH researchers organized a team of international research institutions devoted to accomplishing the analyses.

    The results, reported in the August 11 online issue of Nature with the title “De novo mutation in the classic epileptic encephalopathies”, are the first to emerge from the project that involves more than 40 institutions on three continents and about 150 scientists working in different disciplines.

    Noting that “an emerging paradigm in neuropsychiatric disorders is the major impact of de novo mutations on disease risk,” the investigators searched for such mutations associated with epileptic encephalopathies (EE), a heterogeneous group of severe epilepsy disorders characterized by early onset of seizures with cognitive and behavioral features associated with ongoing epileptic activity.

    The global team began with the most severe forms of EE that afflict about 1 in 2,000 children, often before their first birthdays. Many of these children also experience other severe disabilities including autism or cognitive dysfunction. Whether the epilepsy contributes to those, or vice versa, is being addressed in a parallel study.

    The genetic analysis revealed 439 new mutations in the children, with 181 of the children having at least one. Nine of the genes with those mutations appeared in at least two children with EE and five of those had shown up in previous, smaller EE studies. Of the four others, the researchers found, two may have been coincidental. The researchers, in the course of the studies, found two new genes not previously associated with EE: GABRB3 and ALG13. Each appeared with less than a one-in-40-billion statistical chance of being connected to EE by coincidence.

    The findings implicated GABRB3 for the first time as a single-gene cause of EE, and offered the strongest evidence to date for the gene’s role in any form of epilepsy. Elliott Sherr, M.D., Ph.D., UCSF physician-scientist and principal investigator of the Epi4K project, said, “Knowing this about GABRB3, which is also involved with Angelman’s syndrome, also offers the possibility that children with mutations only in this gene might benefit from the existing therapy for Angelman’s. Another new gene, ALG13, is key to putting sugars on proteins, which points to a new way of thinking about the causes of and treatment for epilepsy.”

    The researchers also demonstrated that epilepsy-causing mutations are concentrated in genes that are highly intolerant to changes in their DNA sequence with even the slightest change causing the gene not to function, leading to death or severe forms of diseases.

    UCSF’s Daniel Lowenstein, M.D., further noted that one of the studies most interesting findings was that many of the gene mutations affect molecules “involved in a relatively limited number of cellular pathways.” This suggests, he said, that it may be sufficient to target therapies at a limited set of pathways rather than every mutated protein in every patient.

    In a written statement to GEN, Katrina Gwinn, M.D., a program director at the NIH’s National Institute of Neurological Disorders & Stroke (NINDS), commented, “I consider the pathway study to be a tremendously interesting part of this paper. The study used an unbiased approach to identify and confirm biological pathways that may be involved in severe forms of epilepsy. These pathways may contain new therapeutic targets that have yet to be tested.

    “This study also introduces an important way to think about how to find risk factor genes from an analytical standpoint. This has been a real challenge with rare variants of neurological disorders.

    “Because we suspect some of these variants are related to a gene dosage effect, drug targeting can be considered, which would lower, or raise, the particular dosage of a given gene product or which could impact a pathway without eliminating it. This will allow a much more fine-tuned drug development strategy.”


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