Vigabatrin and newer interventions in succinic semialdehyde dehydrogenase deficiency

Abstract

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare disorder characterized by an inborn error of the catabolism of the inhibitory neurotransmitter GABA. Because of the deficiency of SSADH, the final enzyme of the GABA degradation pathway, the substrate, succinic semialdehyde, is shunted towards production of 4-hydroxybutyric acid (gamma-hydroxybutyric acid). Elevations of gamma-hydroxybutyric acid can be detected in the physiologic fluids of patients with SSADH deficiency, and forms the mainstay of diagnosis. The clinical features of SSADH deficiency include nonspecific neurologic manifestations such as mental retardation/developmental delay, absent speech, hypotonia, nonprogressive ataxia, features of autism or pervasive developmental delay, developmental language delay (dyspraxia, receptive, and expressive delays), and occasionally, seizures. Although the metabolic pathway has been established, it is not known whether insufficient GABA and/or excess gamma-hydroxybutyric acid contribute to the disease phenotype. Pharmacological therapy in patients with this disorder has been limited to vigabatrin, an anticonvulsant that blocks GABA transaminase. This review will discuss therapeutic options in SSADH deficiency, on the basis of patient experience, and preliminary work using a murine model. Finally, a discussion of adjunctive therapies will be included.

Therapeutic Efficacy of Magnesium Valproate in Succinic Semialdehyde Dehydrogenase Deficiency

“…Behavioral abnormalities include hyperactivity, aggression, inattention, obsessive-compulsive symptoms and sleep disturbances, and present treatment challenges especially when compounded with seizures. Vigabatrin (VGB), an irreversible inhibitor of GABA transaminase, is predicted to decrease GHB production (Ergezinger et al 2003;Gropman 2003;Gibson et al 1995). Clinical outcomes with VGB, however, have been inconsistent, and progressive retinopathy with consequent peripheral vision loss represents an undesirable long-term adverse effect (Chiron and Dulac 2011).…”

A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype

“…Elevation of these neuroactive compounds is thought to play a role in the psychomotor retardation, ataxia and epilepsy (Gordon, 2004)-with seizure types ranging from absence seizures to convulsive status epilepticus-seen in patients with this disorder (Pearl et al, 2003;Gibson et al, 1998). Currently, there is no effective treatment for human SSADH deficiency (Gropman, 2003;Gibson and Jakobs, 2001).…”

Efficacy of Vigabatrin Intervention in a Mild Phenotypic Expression of Succinic Semialdehyde Dehydrogenase Deficiency

“…Since the first report in 1981 (Jakobs et al 1981), several other patients have been identified (Ziyeh et al 2002;Pearl et al 2003;Gropman 2003;Leuzzi et al 2007;Di Rosa et al 2009), showing marked differences between them regarding GHB concentrations in body fluids, residual enzyme activity, clinical symptoms, and efficacy of therapy. Neurological findings are predominant in SSADH deficiency but the clinical picture shows a wide spectrum from mild to severe developmental delay, especially involving the language.…”

“…The metabolic outcome of this inhibition should yield increased free and total GABA concentration in brain with concomitant reduction of SSA and GHB levels in biological fluids. Therapy with vigabatrin has been tried in a moderate number of patients with good results in some and little efficacy in others (Gibson et al 1989(Gibson et al , 1995Jaeken et al 1989;Matern et al 1996;Gropman 2003;Ergezinger et al 2003;Leuzzi et al 2007).…”