Phenotype of GABA-transaminase deficiency.

Mary Kay Koenig, Ryan Hodgeman, James J Riviello, Wendy Chung, Jennifer Bain, Claudia A Chiriboga, Kazushi Ichikawa, Hitoshi Osaka, Megumi Tsuji, K Michael Gibson, Penelope E Bonnen, Phillip L Pearl

Journal: Neurology 2017;88(20):1919-1924

PMID: 28411234

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Abstract

OBJECTIVE

We report a case series of 10 patients with γ-aminobutyric acid (GABA)-transaminase deficiency including a novel therapeutic trial and an expanded phenotype.

METHODS

Case ascertainment, literature review, comprehensive evaluations, and long-term treatment with flumazenil.

RESULTS

All patients presented with neonatal or early infantile-onset encephalopathy; other features were hypotonia, hypersomnolence, epilepsy, choreoathetosis, and accelerated linear growth. EEGs showed burst-suppression, modified hypsarrhythmia, multifocal spikes, and generalized spike-wave. Five of the 10 patients are currently alive with age at last follow-up between 18 months and 9.5 years. Treatment with continuous flumazenil was implemented in 2 patients. One patient, with a milder phenotype, began treatment at age 21 months and has continued for 20 months with improved alertness and less excessive adventitious movements. The second patient had a more severe phenotype and was 7 years of age at initiation of flumazenil, which was not continued.

CONCLUSIONS

GABA-transaminase deficiency presents with neonatal or infantile-onset encephalopathy including hypersomnolence and choreoathetosis. A widened phenotypic spectrum is reported as opposed to lethality by 2 years of age. The GABA-A benzodiazepine receptor antagonist flumazenil may represent a therapeutic strategy.

Address: From Child and Adolescent Neurology (M.K.K.), University of Texas Medical School, Houston; Neurology (R.H., P.L.P.), Boston Children's Hospital, Harvard Medical School, MA; Child Neurology (J.J.R., W.C., J.B., C.A.C.), Columbia University School of Medicine, New York, NY; Neurology (K.I., M.T.), Kanagawa Children's Medical Center, Yokohama; Pediatrics (H.O.), Jichi Medical School, Tochigi, Japan; Experimental and Systems Pharmacology (K.M.G.), Washington State University, Spokane; and Molecular and Human Genetics (P.E.B.), Baylor College of Medicine, Houston, TX.; From Child and Adolescent Neurology (M.K.K.), University of Texas Medical School, Houston; Neurology (R.H., P.L.P.), Boston Children's Hospital, Harvard Medical School, MA; Child Neurology (J.J.R., W.C., J.B., C.A.C.), Columbia University School of Medicine, New York, NY; Neurology (K.I., M.T.), Kanagawa Children's Medical Center, Yokohama; Pediatrics (H.O.), Jichi Medical School, Tochigi, Japan; Experimental and Systems Pharmacology (K.M.G.), Washington State University, Spokane; and Molecular and Human Genetics (P.E.B.), Baylor College of Medicine, Houston, TX. [email protected].

DOI: 10.1212/WNL.0000000000003936

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MeSH Terms: 4-Aminobutyrate Transaminase, Amino Acid Metabolism, Inborn Errors, Brain, Child, Child, Preschool, Diagnosis, Differential, Female, Flumazenil, Follow-Up Studies, GABA Modulators, Humans, Infant, Male, Phenotype