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

Abstract

We report a patient with succinic semialdehyde dehydrogenase deficiency who presented a mild phenotype including developmental language delay, in association with the typical elevations of 4-hydroxybutyric acid (GHB) in biological fluids and MRI alterations. Two pathogenic mutations were identified one transversion (c.278 G>T) in exon 1 and another (c.1557 T>G) in exon 10. Both parents are carriers of one of the mutations, confirming compound-heterozygosity in their affected child. To reduce the GHB levels in body fluids, a treatment with vigabatrin at low dose (25 mg/kg per day) was started, monitoring its efficacy by clinical and neurochemical follow-up. After 9 months of therapy with vigabatrin, a significant reduction of GHB concentrations in urine and CSF was observed; after 36 months, a significant improvement of communicative skills, not previously reported, was referred. These results support the hypothesis that the clinical improvement is correlated to the reduction in the GHB levels and the importance of considering the SSADH deficiency in the differential diagnosis of patients with mental retardation and language delay.

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

“…As an example, we can see the potential outcome of multifactorial linkages in the treatment of SSADHD with vigabatrin. Biochemical data in the cerebrospinal fluid of patients receiving high-dose vigabatrin supports the biochemical effect (lowered GHB, elevated GABA; Gibson et al 1995), yet the clinical response to vigabatrin is highly variable, with some patients showing benefit, others not showing benefit, and even some patients demonstrating clinical deterioration on this agent (Good 2011; Pellock 2011; Escalera et al 2010; Casarano et al 2011; Matern et al 1996; Al-Essa et al 2000). The recent identification of another aldehyde dehydrogenase in addition to ALDH5A1 (e.g., ALDH1A1) which mediates GABAergic neurotransmission pathway in non-GABAergic neurons of mammalian brain adds another layer to the complexity of understanding of the pathophysiology of SSADHD (Kim et al 2015).…”

“…However, treatment with VGB has resulted in mixed outcomes in SSADHD (Vogel et al 2013). 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).…”

Disorders of GABA metabolism: SSADH and GABA-transaminase deficiencies

“…Patients have responded to lamotrigine and carbamazepine, despite the voltage-sensitive sodium channel blockage effects occasionally associated with exacerbation of generalized seizures. Vigabatrin, an irreversible inhibitor of GABA-transaminase, has been prescribed for seizure control in SSADH [64]; however, the results are inconsistent [65]. In one uncontrolled, nonblinded trial of vigabatrin, plasma GHB concentrations decreased in two pedi-atric patients and verbal communication improved in one [66].…”

Succinic semialdehyde dehydrogenase deficiency – a rare cause of metabolic stroke

“…9 Patients with seizures benefit from vigabatrin and magnesium valproate by causing irreversible inhibition of GABA transaminase, and variable clinical responses have been reported in patients with SSADH deficiency while on treatment with vigabatrin. 10,11 CONCLUSION Metabolic strokes once considered to be unusual are not uncommon entity now. Acute onset encephalopathy, involuntary movements, focal seizures on a background of motor mental delay, similar family history and multisystem involvement are a sufficient clue to think about underlying metabolic defect.…”