Inherited lysosomal storage disease associated with deficiencies of β‐galactosidase and α‐neuraminidase in sheep

Abstract

Histopathologic, ultrastructural and Golgi impregnation studies disclosed lesions characteristic of a neuronal lysosomal storage disease in related sheep with onset of neurologic signs at 4-6 months. Biochemical and enzymatic evaluation disclosed storage of GM1 ganglioside, asialo-GM1, and neutral long chain oligosaccharides in brain, urinary excretion of neutral long chain oligosaccharides, and deficiencies of lysosomal beta-galactosidase and alpha-neuraminidase. Retrospective and limited prospective genetic studies suggested autosomal recessive inheritance. A gene-dosage effect on beta-galactosidase levels was documented in fibroblasts from putative heterozygous sheep. Fibroblasts from affected sheep did not have increased beta-galactosidase activity after incubation with the protease inhibitor, leupeptin. In some aspects this disease is similar to GM1 gangliosidosis, but is unique in that a genetic defect in lysosomal beta-galactosidase may cause the deficiency of lysosomal alpha-neuraminidase.

GM1-gangliosidosis in Alaskan Huskies: Clinical and Pathologic Findings

“…Mechanisms resulting in the accumulation of undegraded substrates include diminished enzyme activity due to structurally altered enzymes, lack of enzymes or activator proteins, or alterations in posttranslational processing of lysosomal enzymes. 1,25 Cellular and organ distribution and the amount of storage material determines clinical classifications such as generalized neurovisceral, visceral, or skeletal involvement. 16 GM 1 -gangliosidosis is caused by an acid ␤-galactosidase deficiency.…”

“…38 The disease has been described in a variety of species, including cats, cattle, sheep, mice, and humans. [1][2][3][4][5][6][7][8][9]12,14,16,17,[27][28][29]31,[33][34][35][36][37][38] Until now, the canine form has been found in English Springer Spaniels (ESS), 3,33 Portuguese Water Dogs (PWD), 3,35,36 mixed-breed Beagles, 34 and Alaskan Huskies. 28 In humans, the disorder is classified as infantile (type 1), juvenile (type 2), and adult (type 3) forms.…”

Mouse model for the lysosomal disorder galactosialidosis and correction of the phenotype with overexpressing erythroid precursor cells.

“…Overall, these stud ies establish the validity of suitable animal models, which closely resemble the human disease, to evaluate therapeutic strategies for the correction of disorders like galactosialidosis. Although sheep with a combined p-galactosidase and neuraminidase deficiency have been identified (Ahern-Rindell et al 1988), both the localiza tion of severe storage only to neurons and the enzymatic characteristics differentiate this model from the human disease. Recently, a disease with pathology similar to the adult form of galactosialidosis was described in a Schipperke dog (Knowles et al 1993), but the biochemical data were insufficient to verify the diagnosis.…”

In situ detection of GM1 and GM2 gangliosides using immunohistochemical and immunofluorescent techniques for auxiliary diagnosis of canine and feline gangliosidoses

“…Naturally occurring GM1 gangliosidosis has been reported in dogs, including mixed Beagles [ 4 ], English Springer Spaniels [ 5 ], Portuguese Water dogs [ 6 ], Alaskan Huskies [ 7 ], Shiba Inus [ 8 ], and a mixed-breed dog [ 9 ], and in cats, including Siamese [ 10 , 11 ], Korat [ 12 ], and several families of domestic cats [ 13 – 17 ]. In addition, GM1 gangliosidosis has been reported in ruminants such as Friesian calves [ 17 , 18 ], Suffolk sheep [ 19 ], Coopworth Romny-cross sheep [ 20 ], and Romny sheep [ 21 ], and in wild species such as American black bears [ 22 ] and emus [ 23 ]. Naturally occurring GM2 gangliosidosis has been reported in dogs, including German Shorthair Pointers [ 24 ], Japanese Spaniels (Chins) [ 25 , 26 ], a Golden Retriever [ 27 ], Toy Poodles [ 28 ], and mixed-breed dogs [ 29 , 30 ], and in cats, including Korat [ 31 ], European Burmese [ 32 ], and several families of domestic cats [ 33 – 35 ].…”