Assessing Prevalence and Carrier Frequency of Succinic Semialdehyde Dehydrogenase Deficiency

Pathogenic variants in ALDH5A1 cause succinic semialdehyde dehydrogenase (SSADH) deficiency, with >180 cases reported worldwide. However, a nonspecific neurologic presentation and inconsistent variant nomenclature have limited diagnoses. In this study, pathogenic variants in ALDH5A1 were curated and variant prevalence assessed in the Genome Aggregation Database (gnomAD) to determine a minimum carrier frequency and to estimate disease prevalence. Stringent population variant analysis, including 98 reported disease-associated ALDH5A1 variants, indicates a pan-ethnic carrier frequency of ∼1/340, supporting a prevalence of SSADH deficiency of ∼1/460 000 worldwide, with highest carrier frequencies observed in East Asian and South Asian populations. Because heterozygous loss of function alleles are rare in gnomAD and >60% of reported disease-causing variants were missense changes that were not present in gnomAD, the pan-ethnic carrier frequency for SSADH deficiency is likely not fully represented in this study. Additional analyses to investigate the potential impact of more common ALDH5A1 variants with reduced but not deficient enzyme activity, including analysis in diverse populations, are needed to fully assess the prevalence of this ultra-rare disease.

Speech Motor Function and Auditory Perception in Succinic Semialdehyde Dehydrogenase Deficiency: Toward Pre–Supplementary Motor Area (SMA) and SMA-Proper Dysfunctions

This study reviews the fundamental roles of pre–supplementary motor area (SMA) and SMA-proper responsible for speech-motor functions and auditory perception in succinic semialdehyde dehydrogenase (SSADH) deficiency. We comprehensively searched the databases of PubMed, Google Scholar, and the electronic journals Springer, PreQuest, and Science Direct associated with keywords SSADHD, SMA, auditory perception, speech, and motor with AND operator. Transcranial magnetic stimulation emerged for assessing excitability/inhibitory M1 functions, but its role in pre-SMA and SMA proper dysfunction remains unknown. There was a lack of data on resting-state and task-based functional magnetic resonance imaging (MRI), with a focus on passive and active tasks for both speech and music, in terms of analysis of SMA-related cortex and its connections. Children with SSADH deficiency likely experience a dysfunction in connectivity between SMA portions with cortical and subcortical areas contributing to disabilities in speech-motor functions and auditory perception. Early diagnosis of auditory-motor disabilities in children with SSADH deficiency by neuroimaging techniques invites opportunities for utilizing sensory-motor integration as future interventional strategies.

Magnetic Resonance Imaging (MRI) and Spectroscopy in Succinic Semialdehyde Dehydrogenase Deficiency

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of γ-aminobutyric acid (GABA) degradation, resulting in elevations of brain GABA and γ-hydroxybutyric acid (GHB). Previous magnetic resonance (MR) spectroscopy studies have shown increased levels of Glx in SSADH deficiency patients. Here in this work, we measure brain GABA in a large cohort of SSADH deficiency patients using advanced MR spectroscopy techniques that allow separation of GABA from overlapping metabolite peaks. We observed significant increases in GABA concentrations in SSADH deficiency patients for all 3 brain regions that were evaluated. Although GABA levels were higher in all 3 regions, each region had different patterns in terms of GABA changes with respect to age. We also report results from structural magnetic resonance imaging (MRI) of the same cohort compared with age-matched controls. We consistently observed signal hyperintensities in globus pallidus and cerebellar dentate nucleus.

Novel ALDH5A1 variants and genotype

ObjectiveTo determine genotype–phenotype correlation in succinic semialdehyde dehydrogenase (SSADH) deficiency.MethodsALDH5A1 variants were studied with phenotype correlation in the SSADH natural history study. Assignment of gene variant pathogenicity was based on in silico testing and in vitro enzyme activity after site-directed mutagenesis and expression in HEK293 cells. Phenotypic scoring used a Clinical Severity Score (CSS) designed for the natural history study.ResultsTwenty-four patients were enrolled (10 male, 14 female, median age 8.2 years). There were 24 ALDH5A1 variants, including 7 novel pathogenic variants: 2 missense, 3 splice site, and 2 frameshift. Four previously reported variants were identified in >5% of unrelated families. There was a correlation with age and presence (p = 0.003) and severity (p = 0.002) of epilepsy and with obsessive-compulsive disorder (OCD) (p = 0.016). The median IQ score was 53 (Q25–Q75, 49–61). There was no overall correlation between the gene variants and the CSS, although a novel missense variant was associated with the mildest phenotype by CSS in the only patient with a normal IQ, whereas a previously reported variant was consistently associated with the most severe phenotype.ConclusionsSeven novel pathogenic and one previously unpublished benign ALDH5A1 variants were detected. There is an age-dependent association with worsening of epilepsy and presence of OCD in SSADH deficiency. Overall, there does not appear to be a correlation between genotype and phenotypic severity in this cohort of 24 patients. We did find a suspected correlation between a novel pathogenic missense variant and high functionality, and a previously reported pathogenic missense variant and maximal severity.

A Missense Variant in ALDH5A1 Associated with Canine Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD) in the Saluki Dog

Dogs provide highly valuable models of human disease due to the similarity in phenotype presentation and the ease of genetic analysis. Seven Saluki puppies were investigated for neurological abnormalities including seizures and altered behavior. Magnetic resonance imaging showed a diffuse, marked reduction in cerebral cortical thickness, and symmetrical T2 hyperintensity in specific brain regions. Cerebral cortical atrophy with vacuolation (status spongiosus) was noted on necropsy. Genome-wide association study of 7 affected and 28 normal Salukis revealed a genome-wide significantly associated region on CFA 35. Whole-genome sequencing of three confirmed cases from three different litters revealed a homozygous missense variant within the aldehyde dehydrogenase 5 family member A1 (ALDH5A1) gene (XM_014110599.2: c.866G>A; XP_013966074.2: p.(Gly288Asp). ALDH5A1 encodes a succinic semialdehyde dehydrogenase (SSADH) enzyme critical in the gamma-aminobutyric acid neurotransmitter (GABA) metabolic pathway. Metabolic screening of affected dogs showed markedly elevated gamma-hydroxybutyric acid in serum, cerebrospinal fluid (CSF) and brain, and elevated succinate semialdehyde in urine, CSF and brain. SSADH activity in the brain of affected dogs was low. Affected Saluki dogs had striking similarities to SSADH deficiency in humans although hydroxybutyric aciduria was absent in affected dogs. ALDH5A1-related SSADH deficiency in Salukis provides a unique translational large animal model for the development of novel therapeutic strategies.