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

Abstract

Background and Objectives Inherited disorders of GABA metabolism include SSADH and GABA-transaminase deficiencies. The clinical features, pathophysiology, diagnosis, and management of both are discussed, including an updated list of ALDH5A1 mutations causing SSADH deficiency. Methods Our SSADH patient database was analyzed and murine and translational studies leading to clinical trials are reviewed. Results The database containing 112 SSADH-deficient patients (71 pediatric and adolescent subjects, 41 adults) indicates that developmental delay and hypotonia are the most common presenting symptoms. Epilepsy is present in 2/3 of patients by adulthood. Murine genetic model, and human studies using flumazenil-PET and transcranial magnetic stimulation, have led to therapeutic trials and identified additional metabolic disruptions. Suggestions for new therapies have arisen from findings of GABAergic effects on autophagy with enhanced activation of the mTor pathway. A total of 45 pathogenic mutations have been reported in SSADH deficiency including the discovery of three previously unreported. Conclusions Investigations into the disorders of GABA metabolism provide fundamental insights into mechanisms underlying epilepsy and support the development of biomarkers and clinical trials. Comprehensive definition of the phenotypes of both SSADH and GABA-T deficiencies may increase our knowledge of the neurophysiological consequences of a hyperGABAergic state.

mTOR inhibitors rescue premature lethality and attenuate dysregulation of GABAergic/glutamatergic transcription in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism

“…Taurine also possesses diffuse GABA A and GABA B receptor modulatory effects (Gupta et al 2002). An open-label trial of taurine in SSADHD patients was, however, without clinical benefit (Pearl et al 2014). Here, we present new evidence of attenuation of premature lethality in our murine model using mTOR inhibitors, supported by expression array data on GABAergic/glutamatergic systems revealing pharmacological correction with mTOR inhibitors (Donarum et al 2006).…”

“…Mendelian disorders of each catabolic enzyme exist (Pearl et al 2015; Lapalme-Remis et al 2015; Rodan et al 2015). SSADHD presents with non-specific mild to moderate developmental delay, severe expressive language impairment, variable epilepsy (Parviz et al 2014; Pearl et al 2014), and neuropsychiatric problems (i.e., ADHD, OCD, aggression). Metabolically, there is accumulation of glutamate, GABA and the GABA-derivative γ-hydroxybutyrate (GHB; Snead and Gibson 2005), the latter an intermediate with a varied and complex pharmacological history (Maitre et al 2016) (Fig.…”

Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism

“…Further, long-term treatment with VGB is contraindicated due to marked and permanent visual-field impairments (Singh et al 2013; Froger et al 2014; Good et al 2011; Pellock 2011; Escalera et al 2010; Casarano et al 2011; Matern et al 1996; Al-Essa et al 2000). Of further concern is the predicted expectation that VGB will augment brain GABA (Ergezinger et al 2003; Pearl et al 2014a; 2014b), which is a relevant observation in light of recent studies (described above) highlighting GABA-induced impairment of autophagic processes (Vogel et al 2015). The potential use of mTOR inhibitors (e.g., rapamycin, Torin 1 or 2) along with VGB might be an effective intervention, since this would both decrease production of GHB and clear the oxidative-damaging effects of further-enhanced GABA levels.…”

Therapeutic relevance of mTOR inhibition in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism

“…Mendelian disorders of both GABA-T and ALDH5A1 exist [2–4]. ALDH5A1 deficiency (also referred to as succinic semialdehyde dehydrogenase deficiency (SSADHD)) presents with a non-specific neurological phenotype encompassing developmental delay, expressive language impairment, variable epilepsy [5, 6], and neuropsychiatric problems (i.e. ADHD, OCD, aggression).…”