Journal article
Inherited disorders of gamma-aminobutyric acid metabolism and advances in ALDH5A1 mutation identification
Developmental medicine and child neurology, Vol.57(7), pp.611-617
07/2015
Handle:
https://hdl.handle.net/2376/107757
PMID: 25558043
Abstract
Inherited disorders of gamma-aminobutyric acid (GABA) metabolism include succinic semialdehyde dehydrogenase (SSADH) and gamma-aminobutyric acid transaminase (GABA-T) deficiencies. The clinical features, pathophysiology, diagnosis, and management of both, and an updated list of mutations in the ALDH5A1 gene, which cause SSADH deficiency, are discussed. A database of 112 individuals (71 children and adolescents, and 41 adults) indicates that developmental delay and hypotonia are the most common symptoms arising from SSADH deficiency. Furthermore, epilepsy is present in two-thirds of SSADH-deficient individuals by adulthood. Research with murine genetic models and human participants, using [
C] flumazenil positron emission tomography (FMZ-PET) and transcranial magnetic stimulation, have led to therapeutic trials, and the identification of additional disruptions to GABA metabolism. Suggestions for new therapies have arisen from findings of GABAergic effects on autophagy, with enhanced activation of the mammalian target of rapamycin (mTOR) pathway. Details of known pathogenic mutations in the ALDH5A1 gene, three of which have not previously been reported, are summarized here. Investigations into disorders of GABA metabolism provide fundamental insights into the mechanisms underlying epilepsy, and support the importance of developing biomarkers and clinical trials. Comprehensive definition of phenotypes arising as a result of deficiencies in both SSADH and GABA-T may increase our understanding of the neurophysiological consequences of a hyper-GABAergic state.
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Details
- Title
- Inherited disorders of gamma-aminobutyric acid metabolism and advances in ALDH5A1 mutation identification
- Creators
- Phillip L Pearl - Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USAMahsa Parviz - Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USAKara Vogel - Department of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, WA, USAJohn Schreiber - Department of Neurology, Children's National Medical Center, Washington, DC, USAWilliam H Theodore - Clinical Epilepsy Branch, NINDS, NIH, Bethesda, MD, USAK Michael Gibson - Department of Experimental and Systems Pharmacology, College of Pharmacy, Washington State University, Spokane, WA, USA
- Publication Details
- Developmental medicine and child neurology, Vol.57(7), pp.611-617
- Academic Unit
- Pharmacotherapy, Department of
- Publisher
- England
- Grant note
- UL1 TR001102 / NCATS NIH HHS Z99 NS999999 / Intramural NIH HHS R01 NS082286 / NINDS NIH HHS
- Identifiers
- 99900547481101842
- Language
- English
- Resource Type
- Journal article