GM2 Gangliosidosis Variant 0 (Sandhoff-Like Disease) in a Family of Toy Poodles

Abstract

Background: GM2 gangliosidosis variant 0 (human Sandhoff disease) is a lysosomal storage disorder caused by deficiencies of acid b-hexosaminidase (Hex) A and Hex B because of an abnormality of the b-subunit, a common component in these enzyme molecules, which is coded by the HEXB gene.Objective: To describe the clinical, pathological, biochemical, and magnetic resonance imaging (MRI) findings of Sandhofflike disease identified in a family of Toy Poodles.Animals: Three red-haired Toy Poodles demonstrated clinical signs including motor disorders and tremor starting between 9 and 12 months of age. The animals finally died of neurological deterioration between 18 and 23 months of age. There were some lymphocytes with abnormal cytoplasmic vacuoles detected.Methods: Observational case study.Results: The common MRI finding was diffuse T2-hyperintensity of the subcortical white matter in the cerebrum. Bilateral T2-hyperintensity and T1-hypointensity in the nucleus caudatus, and atrophic findings of the cerebrum and cerebellum, were observed in a dog in the late stage. Histopathologically, swollen neurons with pale to eosinophilic granular materials in the cytoplasm were observed throughout the central nervous system. Biochemically, GM2 ganglioside had accumulated in the brain, and Hex A and Hex B were deficient in the brain and liver. Pedigree analysis demonstrated that the 3 affected dogs were from the same family line.Conclusions and Clinical Importance: The Sandhoff-like disease observed in this family of Toy Poodles is the 2nd occurrence of the canine form of this disease and the 1st report of its identification in a family of dogs.

GM2 gangliosidosis associated with a HEXA missense mutation in Japanese Chin dogs: A potential model for Tay Sachs disease

“…This could reflect a contribution from the degradative pathway initiated by an α-neuraminidase, as described in the knockout mice [39] and/or it could result from the previously described hexosaminidase activity of HexB from affected Japanese Chins on the natural GM2 substrate [6]. Support for this second possibility comes from the observation that the Toy Poodles known to have 0 variant of GM2 gangliosidosis had earlier ages at onset, when they were from 9 to 11 months old [20,22]. After onset, the Japanese Chin disease develops rapidly over several months which could be an advantage for some areas of investigation.…”

“…GM2 gangliosidosis has been previously reported in several animal species including the American flamingo, Muntjak deer, Jacob sheep, Yorkshire pig, pet rabbit, and several breeds of dogs and cats [4,[12][13][14][15][16][17][18][19][20][21][22][23][24][25]. Causal HEXA mutations have been identified in DNA from affected American flamingos and Jacob sheep [21,24].…”

“…In an affected Golden Retriever and in affected members of a Toy Poodle family, marked reductions of β-hexosaminidase activity measured with both MUG and MUGS suggested that these dogs have canine version of the human 0 variant or Sandhoff disease, which is caused by mutations in HEXB [20,22,28], and the causal mutation in HEXB has been identified in the poodles [29]. On the other hand, β-hexosaminidase activities in samples from German Shorthaired Pointers and a mixed breed dog with GM2 gangliosidosis showed normal to elevated hexosaminidase activity with MUG and decreased activity in the German Shorthaired Pointers when assayed with the MUGS substrate [18,19,30].…”

Serial MRI Features of Canine GM1 Gangliosidosis: A Possible Imaging Biomarker for Diagnosis and Progression of the Disease

“…Hyperintensity on T2W of the cerebral white matter is not only specific for GM1 gangliosidosis but has also been found in other lysosomal storage diseases such as globoid cell leukodystrophy [31, 36] and GM2 gangliosidosis [37–42] in humans and animals. In gangliosidoses in domestic animals, diffuse T2W hyperintensity was observed in GM2 gangliosidosis variant 0 (Sandhoff disease) in Japanese domestic cats [41] and Toy Poodles [42], but not in the same disease in a Golden Retriever [43].…”

Rapid and Simple Polymerase Chain Reaction—Based Diagnostic Assays for GM2 Gangliosidosis Variant 0 (Sandhoff-Like Disease) in Japanese Domestic Cats

“…Therefore, deleterious mutations in the HEXB gene encoding the b-subunit of Hex molecules affect both Hex A and Hex B, producing the null (0) variant of GM2 gangliosidosis (human Sandhoff disease) and lysosomal storage of undegraded GM2 ganglioside in neurons as a major storage material. 5 In domestic animals, naturally occurring Sandhoff-like disease has been reported in only 2 canine breeds (i.e., a Golden Retriever 18 and toy Poodles 16 ) and 4 feline breeds or families (i.e., domestic cats in the United States, 4 Korat cats, 13 Japanese domestic cats, 19 and European Burmese cats 3 ). At present, the pathogenic mutations in all 4 feline families have been identified, 3,8,11,12 but not in canine breeds.…”