Natural history of succinic semialdehyde dehydrogenase deficiency through adulthood

Abstract

We identified patients older than 18 years with SSADH deficiency in our database following identification and review of a patient diagnosed in the seventh decade of life. The illness had a progressive course with escalating seizures in the index case, with fatality at age 63. Diagnosis in adulthood is rare. Epilepsy is more common in the adult than the pediatric SSADH deficiency cohort; neuropsychiatric morbidity remains prominent.

Correlation of blood biomarkers with age informs pathomechanisms in succinic semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism

“…The lowered levels of GHB may track with the onset of neuropsychiatric morbidity in patients (Parviz et al 2014), but further studies are needed to verify this hypothesis. Moreover, we know that a subset of patients with SSADHD has a more severe phenotype, featuring adult-onset epilepsy (Parviz et al 2014), and there have been instances of SUDEP (sudden unexplained death in epilepsy) in adulthood (Lapalme-Remis et al 2015; Knerr et al 2010; Gibson and Pearl, unpublished observation). Previously, Casado and coworkers (2014) documented that GABA levels in cerebrospinal fluid from 55 pediatric controls showed a progressive increase with age.…”

“…This is relevant for several reasons. First, appropriate testing for GHB in order to achieve accurate diagnosis may be overlooked due to the non-specific neurological phenotype (Lapalme-Remis et al 2015). Additionally, clinical trials for SSADHD are either underway or completed (Pearl et al 2014; www.clinicaltrials.gov), and a therapeutic pipeline is under development using the corresponding murine model (Malaspina et al 2016).…”

“…Moreover, Knerr and coworkers have identified a more severe disease course in a subset of patients, in which the epileptic disorder appears more severe (Knerr et al 2007). Importantly, some patients have expired with SUDEP (sudden unexplained death in epilepsy) in adulthood (Lapalme-Remis et al 2015; Knerr et al 2010; Gibson and Pearl, unpublished). To explore the natural history of SSADHD, we have sought to identify biomarkers in physiological fluids which may provide pathophysiological insight into disease evolution.…”

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

“…A number of investigators have noted symmetrically increased T2 signals in the globus pallidi, subthalamic nuclei, and cerebellar dentate nuclei of patients (Pearl et al 2003; Pearl et al 2009; Acosta et al 2010; Lapalme-Remis et al 2015). These hyperintensities are not specific to SSADHD and likely reflect cytotoxic metabolic edema (Pearl et al 2009; Yalcinkaya et al 2000; Ziyeh et al 2002; Horino et al 2016; Gogou et al 2016; Wang et al 2015; Li et al 2015).…”

“…No successful targeted therapy has emerged for SSADHD, and treatment has remained symptomatic and non-specific (e.g., antiepileptics for seizures; SSRIs for OCD; Gropman et al; 2003; Parviz et al 2014; Lapalme-Remis et al 2015). A recent case report has identified magnesium valproate as an agent effective in ameliorating behavioral problems and refractory epilepsy (Vanadia et al 2013).…”