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.

Keywords: epilepsy; genetics; inborn errors of metabolism; intellectual disability; metabolism; neuroimaging.

Figure 1

The metabolic pathway of gamma-aminobutyric acid (GABA) 1. Glutaminase 2. Glutamic Acid Decarboxylase 3. Homocarnosinase/Carnosinase 4. GABA Transaminase 5. Succinic Semialdehyde Dehydrogenase 6. Tricarboxylic Acid Cycle

Figure 2

Key Milestones in SSADHD Research

Figure 3

Notable Clinical Trials for SSADHD

Figure 4

An Overview of the Natural History Study, stemming from the protean clinical and metabolic alterations of the disease, leading to an international collaborative, assessment of clinical, neurophysiological, and laboratory biomarkers, and development of an SSADH registry and biorepository.

Figure 5

EEG in an 8 year old patient with SSADHD. Mild diffuse background slowing and a paroxysm of diffuse spike-wave with right frontotemporal predominance. Settings: sensitivity 10 uV/mm, HFF 70 Hz, LFF 1.00 Hz

Figure 6

Time-frequency analysis of SEPs for bipolar EEG channel Cz-C4. (a) TFA for healthy controls (n=10); (b) TFA for patients with SSADHD (n=17). (c) Statistical differences between the two groups. Note the significant suppression of signal power in gamma band from ^~40 ms till 50 ms and in beta band from ^~40 ms till 150 ms . Analysis was performed using non-parametric two-tailed t-test [gamma band: p=0.001, corrected for multiple comparisons across normal controls and patients with SSADH over a time span of 70 ms (10-80 ms), t=-4.6074; beta band: p=0.001, t=-3.6018 over a time span of 130 ms (10-140 ms)].