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Impact on GABA systems in monogenetic developmental CNS disorders: clues to symptomatic treatment


Benke, Dietmar; Möhler, Hanns (2017). Impact on GABA systems in monogenetic developmental CNS disorders: clues to symptomatic treatment. Neuropharmacology:Epub ahead of print.

Abstract

Animal studies of several single-gene disorders demonstrate that reversing the molecular signaling deficits can result in substantial symptomatic improvements in function. Focusing on the ratio of excitation to inhibition as a potential pathophysiological hallmark, seven single-gene developmental CNS disorders are reviewed which are characterized by a striking dysregulation of neuronal inhibition. Deficits in inhibition and excessive inhibition are found. The examples of developmental disorders encompass Neurofibromatosis type 1, Fragile X syndrome, Rett syndrome, Dravet syndrome including autism-like behavior, NONO-mutation-induced intellectual disability, Succinic semialdehyde dehydrogenase deficiency and Congenital nystagmus due to FRMD7 mutations. The phenotype/genotype correlations observed in animal models point to potential treatment options and will continue to inspire clinical research. Three drugs are presently in clinical trials: acamprosate and ganoxolon for Fragile X syndrome and SGS-742 for SSADH deficiency.

Abstract

Animal studies of several single-gene disorders demonstrate that reversing the molecular signaling deficits can result in substantial symptomatic improvements in function. Focusing on the ratio of excitation to inhibition as a potential pathophysiological hallmark, seven single-gene developmental CNS disorders are reviewed which are characterized by a striking dysregulation of neuronal inhibition. Deficits in inhibition and excessive inhibition are found. The examples of developmental disorders encompass Neurofibromatosis type 1, Fragile X syndrome, Rett syndrome, Dravet syndrome including autism-like behavior, NONO-mutation-induced intellectual disability, Succinic semialdehyde dehydrogenase deficiency and Congenital nystagmus due to FRMD7 mutations. The phenotype/genotype correlations observed in animal models point to potential treatment options and will continue to inspire clinical research. Three drugs are presently in clinical trials: acamprosate and ganoxolon for Fragile X syndrome and SGS-742 for SSADH deficiency.

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Additional indexing

Item Type:Journal Article, refereed, further contribution
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Congenital nystagmus; Dravet's syndrome; Fragile X syndrome; GABA; Intellectual disability syndrome; NONO; Neurofibromatosis type 1; Rett syndrome; Succinic semialdehyde dehydrogenase deficiency
Language:English
Date:29 July 2017
Deposited On:25 Sep 2017 14:09
Last Modified:26 Sep 2017 07:36
Publisher:Elsevier
ISSN:0028-3908
Publisher DOI:https://doi.org/10.1016/j.neuropharm.2017.07.030
PubMed ID:28764992

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