Monitoring of 4‐hydroxybutyric acid levels in body fluids during vigabatrin treatment in succinic semialdehyde dehydrogenase deficiency

Abstract

We report the successful treatment using low-dose vigabatrin (21.5-34 mg/kg/day) of a 10-year-old girl with succinic semialdehyde dehydrogenase (SSADH) deficiency We verified that 4-hydroxybutyric acid (GHB) concentrations in serum, cerebrospinal fluid, and urine continuously decreased in parallel with significant clinical improvement. Our results suggest that GHB quantification in physiological fluids may be a useful laboratory parameter for monitoring efficacy of vigabatrin treatment in SSADH deficiency.

Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

“…Estimates of GHB levels in the brain, both globally and regionally, are on the order of 200-250 mM, with levels in corresponding wild-type mice of 1-4 mM. Although these levels are quite elevated, they are not sufficient to activate GABA(B) receptors, for which the IC 50 for GHB is in the millimolar range (179). Nonetheless, intracellular concentrations of GHB could be significantly larger than those measured above, and could not be estimated without in vivo microdialysis or sensitive spectroscopy methods.…”

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).…”

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

“…Vigabatrin is the most widely used therapy for human SSADH deficiency, although it is expected to exacerbate the hyperGABAergic status (Gibson et al 1989a(Gibson et al , 1997Gropman 2003;Pearl et al 2005b; Table 1). 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).…”

“…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).…”