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Review
. 2015 Jul;57(7):611-617.
doi: 10.1111/dmcn.12668. Epub 2014 Dec 29.

Inherited disorders of gamma-aminobutyric acid metabolism and advances in ALDH5A1 mutation identification

Phillip L Pearl  1 , Mahsa Parviz  1 , Kara Vogel  2 , John Schreiber  3 , William H Theodore  4 , K Michael Gibson  2
Affiliations
Review

Inherited disorders of gamma-aminobutyric acid metabolism and advances in ALDH5A1 mutation identification

Phillip L Pearl et al. Dev Med Child Neurol. 2015 Jul.

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 [11 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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Figures

Figure
Figure
The metabolic pathway of gamma-aminobutyric acid (GABA) and potential targets for therapeutic trials in SSADH deficiency. GAD = glutamic acid decarboxylase P5P = pyridoxal-5’-phosphate VGB = vigabatrin GABA-T = GABA-transaminase SSADH = succinic semialdehyde dehydrogenase GABABR = GABAB receptor GABAAR = GABAA receptor mTOR = mammalian target of rapamycin
See this image and copyright information in PMC

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