Seizures in a boy with succinic semialdehyde dehydrogenase deficiency treated with vigabatrin (γ‐vinyl‐GABA)

Abstract

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disease involving the catabolism of the neurotransmitter gamma-aminobutyric acid (GABA). The main symptoms include retardation of psychomotor and language development, muscle hypotonia and non-progressive ataxia. Therapy consisting of approximately 75 mg/kg per day of vigabatrin, an irreversible inhibitor of GABA-transaminase, is reported to lead to some improvement of the clinical condition in affected patients. We report on a 12-year-old boy with SSADH deficiency who, when treated with 75 mg/kg per day of vigabatrin, showed marked amelioration of symptoms but also EEG changes and two generalized seizures. On discontinuing vigabatrin therapy, the seizures resolved and the EEG improved, but the patient's clinical condition deteriorated to its pre-treatment state. A stable EEG without the recurrence of seizures as well as renewed improvement of cognitive and behavioural functions was achieved with a reduced vigabatrin dose of 25 mg/kg per day. We conclude that vigabatrin in SSADH deficiency should be administered in a gradually increasing dosage combined with frequent evaluation of the clinical condition and the EEG.

Therapeutic Intervention in Mice Deficient for Succinate Semialdehyde Dehydrogenase (γ-Hydroxybutyric Aciduria)

“…1), since mechanistically it should lead to increased GABA production and decreased GHB output. However, its limited clinical use in human SSADH deficiency has shown inconsistent efficacy (Gibson et al, 1995;Matern et al, 1996). Moreover, VGB intervention has been linked to visual field abnormalities, raising concerns about its chronic use (Spence and Sankar, 2001;Malmgren et al, 2001).…”

Metabolic Causes of Epilepsy

“…Vigabatrin, an irreversible inhibitor of GABAtransaminase, inhibits the formation of succinic semialdehyde and thus is one of the most widely prescribed AEDs in this disorder (Matern et al 1996). However, vigabatrin has shown inconsistent results and MRI signal changes have been observed in patients treated with high doses ).…”

Therapeutic concepts in succinate semialdehyde dehydrogenase (SSADH; ALDH5a1) deficiency (γ‐hydroxybutyric aciduria). Hypotheses evolved from 25 years of patient evaluation, studies in Aldh5a1−/− mice and characterization of γ‐hydroxybutyric acid pharmacology

“…Clinical results are diverse, ranging from improvement in ataxia and speech in some patients to worsening of symptoms (Matern et al 1996). Lower doses (30-50 mg/kg per day) divided into two daily doses in conjunction with monitoring for sideeffects including visual field disturbances (Ergezinger et al 2003;Gibson et al 1997;Gordon 2004) are associated with fewer side effects than high dosage intervention (Matern et al 1996). Although vigabatrin has not been consistently successful in SSADH deficiency, intervention with vigabatrin enhances survival of the Aldh5a1 j/j mouse at very high doses Hogema et al 2001).…”

“…In CSF obtained from patients with SSADH deficiency, GHB concentrations are either static or slightly lower after vigabatrin intervention (Ergezinger et al 2003). Clinical results are diverse, ranging from improvement in ataxia and speech in some patients to worsening of symptoms (Matern et al 1996). Lower doses (30-50 mg/kg per day) divided into two daily doses in conjunction with monitoring for sideeffects including visual field disturbances (Ergezinger et al 2003;Gibson et al 1997;Gordon 2004) are associated with fewer side effects than high dosage intervention (Matern et al 1996).…”