GM2 Gangliosidosis Variant 0 (Sandhoff Disease) in a Mixed-Breed Dog

Background GM2‐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 GM2 activator protein. Clinical signs can be variable and are not pathognomonic for the specific, causal deficiency.ObjectivesTo characterize the phenotype and genotype of GM2‐gangliosidosis disease in an affected dog.AnimalsOne affected Shiba Inu and a clinically healthy dog.MethodsClinical and neurologic evaluation, brain magnetic resonance imaging (MRI), assays of lysosomal enzyme activities, and sequencing of all coding regions of HEXA, HEXB, and GM2A genes.ResultsA 14‐month‐old, female Shiba Inu presented with clinical signs resembling GM2‐gangliosidosis in humans and GM1‐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.618‐620delCCT).Conclusions and Clinical ImportanceClinical, biochemical, and molecular features are characterized in a Shiba Inu with GM2‐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 GM2‐gangliosidosis seen in this dog is the Sandhoff type. Because GM1‐gangliosidosis also exists in this breed with almost identical clinical signs, genetic testing for both GM1‐ and GM2‐gangliosidosis should be considered to make a definitive diagnosis.

Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 61%

See 1 more Smart Citation

Canine GM2‐Gangliosidosis Sandhoff Disease Associated with a 3‐Base Pair Deletion in the HEXB Gene

Wang

Henthorn

Galban

et al. 2017

“…These abnormal accumulations lead to delayed myelin formation, and swelling and destruction of neurons, axons, and myelin in the central nervous system, resulting in severe neurologic dysfunction . Although GM2 gangliosidoses are thought to affect gray matter primarily, myelin deficiency has been recognized in both the cat and dog . As a corollary of these pathological changes, abnormal signal intensity of the cerebral white matter (WM) on magnetic resonance imaging (MRI) has been documented in humans and domestic animals with GM2 gangliosidoses…”

mentioning

confidence: 99%

“…Sandhoff's disease (SD) is 1 of 3 main variants of GM2 gangliosidoses‐gangliosidosis variant 0, caused by deleterious mutations of the HEXB gene encoding the β‐subunit that is a common component of the lysosomal acid β‐hexosaminidase A and B . In dogs, clinical features and MRI findings in SD have been reported in a Golden Retriever, a family of Toy Poodles, in a mixed‐breed dog and, recently, in Shiba‐Inu dogs . However, long‐term serial changes of MRI and magnetic resonance spectroscopy (MRS), and analysis of cerebrospinal fluid (CSF) in dogs with SD are not established.…”

mentioning

confidence: 99%

Two‐Year Follow‐Up Magnetic Resonance Imaging and Spectroscopy Findings and Cerebrospinal Fluid Analysis of a Dog with Sandhoff's Disease

Ito

Ishikawa

Jeffery

et al. 2018

A 13‐month‐old female Toy Poodle was presented for progressive ataxia and intention tremors of head movement. The diagnosis of Sandhoff's disease (GM2 gangliosidosis) was confirmed by deficient β‐N‐acetylhexosaminidase A and B activity in circulating leukocytes and identification of the homozygous mutation (HEXB: c.283delG). White matter in the cerebrum and cerebellum was hyperintense on T2‐weighted and fluid‐attenuated inversion recovery magnetic resonance images. Over the next 2 years, the white matter lesions expanded, and bilateral lesions appeared in the cerebellum and thalamus, associated with clinical deterioration. Magnetic resonance spectroscopy showed progressive decrease in brain N‐acetylaspartate, and glycine‐myo‐inositol and lactate‐alanine were increased in the terminal clinical stage. The concentrations of myelin basic protein and neuron specific enolase in cerebrospinal fluid were persistently increased. Imaging and spectroscopic appearance correlated with histopathological findings of severe myelin loss in cerebral and cerebellar white matter and destruction of the majority of cerebral and cerebellar neurons.

GM2 Gangliosidosis in Shiba Inu Dogs with an In‐Frame Deletion in HEXB

Kolicheski

Johnson

Villani

et al. 2017

Consistent with a tentative diagnosis of neuronal ceroid lipofuscinosis (NCL), autofluorescent cytoplasmic storage bodies were found in neurons from the brains of 2 related Shiba Inu dogs with a young‐adult onset, progressive neurodegenerative disease. Unexpectedly, no potentially causal NCL‐related variants were identified in a whole‐genome sequence generated with DNA from 1 of the affected dogs. Instead, the whole‐genome sequence contained a homozygous 3 base pair (bp) deletion in a coding region of HEXB. The other affected dog also was homozygous for this 3‐bp deletion. Mutations in the human HEXB ortholog cause Sandhoff disease, a type of GM2 gangliosidosis. Thin‐layer chromatography confirmed that GM2 ganglioside had accumulated in an affected Shiba Inu brain. Enzymatic analysis confirmed that the GM2 gangliosidosis resulted from a deficiency in the HEXB encoded protein and not from a deficiency in products from HEXA or GM2A, which are known alternative causes of GM2 gangliosidosis. We conclude that the homozygous 3‐bp deletion in HEXB is the likely cause of the Shiba Inu neurodegenerative disease and that whole‐genome sequencing can lead to the early identification of potentially disease‐causing DNA variants thereby refocusing subsequent diagnostic analyses toward confirming or refuting candidate variant causality.