Succinic Semialdehyde Dehydrogenase Deficiency: Review of the Natural History Study

Abstract

Objective: The SSADHD Natural History Study was initiated in 2019 to define the natural course and identify biomarkers correlating with severity. Methods: The study is conducted by 4 institutions: BCH (US clinical), WSU (bioanalytical core), USF (biostatistical core), and Heidelberg (iNTD), with support from the family advocacy group (SSADH Association). Recruitment goals were to study 20 patients on-site at BCH, 10 with iNTD, and 25 as a standard-of care cohort. Results: At this half-way point of this longitudinal study, 28 subjects have been recruited (57% female, mean 9 years, range 18 months–40 years). Epilepsy is present in half and increases in incidence and severity, as do psychiatric symptoms, in adolescence and adulthood. The average Full Scale IQ (FSIQ) was 53 (Verbal score of 56, Non Verbal score of 49), and half scored as having ASD. Although there was no correlation between gene variant and phenotypic severity, there were extreme cases of lowest functioning in one individual and highest in another that may have genotype-phenotype correlation. The most common EEG finding was mild background slowing with rare epileptiform activity, whereas high-density EEG and magnetoencephalography showed reduction in the gamma frequency band consistent with GABAergic dysfunction. MR spectroscopy showed elevations in the GABA/NAA ratio in all regions studied with no crossover between subjects and controls. Conclusions: The SSADH Natural History Study is providing a unique opportunity to study the complex pathophysiology longitudinally and derive electrophysiologic, neuroimaging, and laboratory data for correlation and to serve as biomarkers for clinical trials and prognostic assessments in this ultra-rare inherited disorder of GABA metabolism.

New Therapeutic Approaches to Inherited Metabolic Pediatric Epilepsies

“…44 T2 basal ganglia hyperintensity is often unclear. By contrast, MRS can provide noninvasive measures of metabolite deficiencies or of the build-up of reactants in cases of primary or secondary enzyme deficiencies (e.g., GABA 45 ).…”

Understanding the Molecular Mechanisms of Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): Towards the Development of SSADH-Targeted Medicine

“…First, we begin with understanding the fundamental pathophysiology of the disorder (i.e., ALDH5A1 malfunctions) and its immediate impacts from the systems level down to the molecular level. This is achieved at two parallel fronts: (1) the SSADHD Natural History Study defining the natural course and identify disease correlating biomarkers [ 47 ]. This provides a unique opportunity to study relevant pathophysiology via electrophysiologic (electroencephalography, EEG), neuroimaging (magnetic resonance imaging, MRI), and metabolite analyses in a longitudinally manner.…”

2022 Overview of Metabolic Epilepsies

“…Seizures in metabolic epilepsies may present variably. In some diseases, seizures occur in a subset of patients only (e.g., epilepsy is present in about half of individuals affected with SSADH deficiency [ 26 ]); in other cases, epilepsy is a constant symptom (e.g., GABA-transaminase deficiency [ 27 ]). The age of presentation can be a diagnostic indication in some metabolic epilepsies [ 8 , 28 ]; however, it must be emphasized that there can be a considerable overlap among age groups, many disorders (e.g., mitochondriopathies) may present at any age and there is a general trend for the expansion of the clinical spectrum of many IMDs towards adolescent or adult-onset phenotypes with improved diagnostics [ 29 , 30 ].…”