Succinic Semialdehyde Dehydrogenase Deficiency: An Update

Abstract

Succinic semialdehyde dehydrogenase deficiency (SSADH-D) is a genetic disorder that results from the aberrant metabolism of the neurotransmitter γ-amino butyric acid (GABA). The disease is caused by impaired activity of the mitochondrial enzyme succinic semialdehyde dehydrogenase. SSADH-D manifests as varying degrees of mental retardation, autism, ataxia, and epileptic seizures, but the clinical picture is highly heterogeneous. So far, there is no approved curative therapy for this disease. In this review, we briefly summarize the molecular genetics of SSADH-D, the past and ongoing clinical trials, and the emerging features of the molecular pathogenesis, including redox imbalance and mitochondrial dysfunction. The main aim of this review is to discuss the potential of further therapy approaches that have so far not been tested in SSADH-D, such as pharmacological chaperones, read-through drugs, and gene therapy. Special attention will also be paid to elucidating the role of patient advocacy organizations in facilitating research and in the communication between researchers and patients.

Novel genetic tools to model functional enzyme restoration in succinic semialdehyde dehydrogenase deficiency (SSADHD)

“…There are a few things to consider: First , SSADH is a mitochondrial enzyme ( Fig. 1 ) with defined cell-type expression profiles 20,30 . A mitochondria-directed, cell-penetrating SSADH delivery strategy 36 might be necessary to ensure functional SSADH restoration and to avoid off-target effects.…”

“…When bred to a mouse line expressing Cre-recombinase driven by a cell-specific promoter (e.g., Gad2-IRES-Cre mouse 27 ), SSADH will be restored in selective cell types. This will give insight into whether cell targeted SSADH restoration might be viable therapeutic options 28-30 . Details of genomic PCR primers and sequence validation are listed in Fig.…”

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

“…Broad-spectrum anticonvulsants are generally utilized, avoiding valproate which inhibits SSADH which may worsen GHB accumulation and clinical signs [ 50 ]. However, there are many therapeutic options under investigation which include pharmacological (e.g., targeting neurotransmitter receptors), enzyme-replacement therapy, gene therapy and treatment with pharmacological chaperones [ 51 , 52 ].…”

“…In animals, SSADH has been produced in knockout mice; clinical signs are progressive ataxia, failure to thrive, seizure and death at a young age [ 53 , 54 ], and thus they are utilized as a model for the severe and poor survival phenotype in humans. There are no reports of the MR imaging features of SSADH-knockout mice [ 51 ] and, on pathology, there are no reported abnormalities on routine hematoxylin and eosin staining, but detailed neuropathological examinations have not been performed [ 55 ]. There is a single case report of a dog with suspected SSADH deficiency, which had a progressive encephalopathy with profound and persistent lactic acidosis, elevated urine GHB and a 30% reduced activity of SSADH measured in cultured lymphoblasts compared to normal dogs.…”

Succinic Semialdehyde Dehydrogenase Deficiency: In Vitro and In Silico Characterization of a Novel Pathogenic Missense Variant and Analysis of the Mutational Spectrum of ALDH5A1

“…Affected individuals become symptomatic within the first years of life, showing developmental delay (98.5% of all cases), intellectual disability (95.6% of all cases), muscular hypotonia (83.3% of all cases), behavioral difficulties (69.1% of all cases), and variable epileptic semiologies (50% of all cases), some of which are difficult to treat. Individual reports of sudden unexpected death in epilepsy (SUDEP) in SSADH patients exist and indicate an incidence of 15% [ 2 , 3 , 4 , 5 , 6 ]. The diagnosis is based on the biochemical analysis of γ-hydroxybutyrate (GHB) concentrations in the urine, although it can also be measured in the blood and the cerebrospinal fluid (CSF).…”