Abstract
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.
Highlights
Inborn errors of metabolism (IEMs) are a group of diseases caused by an enzymatic deficiency in a metabolic pathway, most commonly caused by a genetic mutation
A pathogenic variant in the canine ALDH5A1 gene associated with recessive Succinic semialdehyde dehydrogenase (SSADH) deficiency, formerly known as status spongiosus in Saluki dogs (SSSD) [13]
Using genome-wide association, followed by whole-genome sequencing, a missense mutation in the ALDH5A1 gene was identified as the presumed cause of status spongiosus in Saluki dogs, previously reported in Saluki puppies [13]
Summary
Inborn errors of metabolism (IEMs) are a group of diseases caused by an enzymatic deficiency in a metabolic pathway, most commonly caused by a genetic mutation. While individually these diseases are rare, as a group they are relatively common, with more than 500 IEM diseases reported in people [1]; in animals, they are becoming increasingly recognized [2,3,4,5,6]. In diseases caused by an IEM, clinical signs are due to the reduced or lack of production of a biochemical product, or accumulation of an abnormal amount of substrate or substrates produced by alternative metabolic pathways, secondary to the enzymatic deficiency. Causes of structural epilepsy include inflammation (e.g., granulomatous meningoencephalitis), neoplasia, nutritional alterations (e.g., thiamine deficiency), infection, anomalous entities (e.g., hydrocephalus), inborn errors of metabolism and trauma [11]
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