Canine GM 2‐Gangliosidosis Sandhoff Disease Associated with a 3‐Base Pair Deletion in the HEXB G ene

Background GM 2‐gangliosidosis is a fatal neurodegenerative lysosomal storage disease ( LSD ) caused by deficiency of either β‐hexosaminidase A (Hex‐A) and β‐hexosaminidase B (Hex‐B) together, or the GM 2 activator protein. Clinical signs can be variable and are not pathognomonic for the specific, causal deficiency. Objectives To characterize the phenotype and genotype of GM 2‐gangliosidosis disease in an affected dog. Animals One affected Shiba Inu and a clinically healthy dog. Methods Clinical and neurologic evaluation, brain magnetic resonance imaging ( MRI ), assays of lysosomal enzyme activities, and sequencing of all coding regions of HEXA , HEXB , and GM 2A genes. Results A 14‐month‐old, female Shiba Inu presented with clinical signs resembling GM 2‐gangliosidosis in humans and GM 1‐gangliosidosis in the Shiba Inu. Magnetic resonance imaging ( MRI ) of the dog's brain indicated neurodegenerative disease, and evaluation of cerebrospinal fluid ( CSF ) identified storage granules in leukocytes. Lysosomal enzyme assays of plasma and leukocytes showed deficiencies of Hex‐A and Hex‐B activities in both tissues. Genetic analysis identified a homozygous, 3‐base pair deletion in the HEXB gene (c.618‐620del CCT ). Conclusions and Clinical Importance Clinical, biochemical, and molecular features are characterized in a Shiba Inu with GM 2‐gangliosidosis. The deletion of 3 adjacent base pairs in HEXB predicts the loss of a leucine residue at amino acid position 207 (p.Leu207del) supporting the hypothesis that GM 2‐gangliosidosis seen in this dog is the Sandhoff type. Because GM 1‐gangliosidosis also exists in this breed with almost identical clinical signs, genetic testing for both GM 1‐ and GM 2‐gangliosidosis should be considered to make a definitive diagnosis.