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Inherited disorders of gamma‐aminobutyric acid metabolism and advances in ALDH 5A1 mutation identification
Author(s) -
Pearl Phillip L,
Parviz Mahsa,
Vogel Kara,
Schreiber John,
Theodore William H,
Gibson K Michael
Publication year - 2015
Publication title -
developmental medicine and child neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.658
H-Index - 143
eISSN - 1469-8749
pISSN - 0012-1622
DOI - 10.1111/dmcn.12668
Subject(s) - hypotonia , gamma aminobutyric acid , vigabatrin , genetics , biology , neuroscience , medicine , epilepsy , receptor , anticonvulsant
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 ALDH 5A1 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 GABA ergic effects on autophagy, with enhanced activation of the mammalian target of rapamycin ( mTOR ) pathway. Details of known pathogenic mutations in the ALDH 5A1 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‐ GABA ergic state.