Therapeutic Efficacy of Magnesium Valproate in Succinic Semialdehyde Dehydrogenase Deficiency

Theodore

et al. 2012

J of Inher Metab Disea

Self Cite

Summary This review summarizes a presentation made at the retirement Symposium of Prof. dr. Cornelis Jakobs in November of 2011, highlighting the progress toward clinical trials in succinic semialdehyde dehydrogenase (SSADH) deficiency, a disorder first recognized in 1981. Active and potential clinical interventions, including vigabatrin, L-cycloserine, the GHB receptor antagonist NCS-382, and the ketogenic diet, are discussed. Several biomarkers to gauge clinical efficacy have been identified, including cerebrospinal fluid metabolites, neuropsychiatric testing, MRI, EEG, and measures of GABAergic function including (11C)flumazenil positron emission tomography (PET) and transcranial magnetic stimulation (TMS). Thirty years after its discovery, encompassing extensive studies in both patients and the corresponding murine model, we are now running an open-label trial of taurine intervention, and are poised to undertake a phase II trial of the GABAB receptor antagonist SGS742.

Section: Treatment Strategies For Ssadh Deficiencysupporting

confidence: 70%

Thirty years beyond discovery—Clinical trials in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism

Vogel

Theodore

et al. 2012

J of Inher Metab Disea

Self Cite

“…Characterization of the epileptic phenotype in individuals with SSADH deficiency guides the use of antiepileptic drugs or agents used for seizures in general. Valproate is not used as a first‐line therapy because of inhibition of any residual enzymatic activity, although magnesium valproate treatment was shown to successfully control refractory epilepsy in an SSADH‐deficient individual, and this was associated with improved behavior and EEG findings . Reasonable seizure control was observed in individuals with SSADH deficiency using lamotrigine and carbamazepine.…”

Section: Discussionmentioning

confidence: 99%

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

Develop Med Child Neuro

Parviz

Vogel

et al. 2014

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.

“…A recent case report has identified magnesium valproate as an agent effective in ameliorating behavioral problems and refractory epilepsy (Vanadia et al 2013). This was an unexpected finding since earlier observations by Simler and colleagues (1981) had revealed that valproate is an inhibitor of SSADH.…”

Section: Treatment Of Ssadhdmentioning

confidence: 99%

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

Malaspina

Roullet

Neurochemistry International

et al. 2016

Discovered some 35 years ago, succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a rare, autosomal recessively-inherited defect in the second step of the GABA degradative pathway. Some 200 patients have been reported, with broad phenotypic and genotypic heterogeneity. SSADHD represents an unusual neurometabolic disorder in which two neuromodulatory agents, GABA (and the GABA analogue, 4-hydroxybutyrate), accumulate to supraphysiological levels. The unexpected occurrence of epilepsy in several patients is counterintuitive in view of the hyperGABAergic state, in which sedation might be expected. However, the epileptic status of some patients is most likely represented by broader imbalances of GABAergic and glutamatergic neurotransmission. Cumulative research encompassing decades of basic and clinical study of SSADHD reveal a monogenic disease with broad pathophysiological and clinical phenotypes. Numerous metabolic perturbations unmasked in SSADHD include alterations in oxidative stress parameters, dysregulation of autophagy and mitophagy, dysregulation of both inhibitory and excitatory neurotransmitters and gene expression, and unique subsets of SNP alterations of the SSADH gene (so-called ALDH5A1, or aldehyde dehydrogenase 5A1 gene) on the 6p22 chromosomal arm. While seemingly difficult to collate and interpret, these anomalies have continued to open novel pathways for pharmacotherapeutic considerations. Here, we present an update on selected aspects of SSADHD, the ALDH5A1 gene, and future avenues for research on this rare disorder of GABA metabolism.