title: GM1-gangliosidosis in American black bears: clinical, pathological, biochemical and molecular genetic characterization.
abstract: G(M1)-gangliosidosis is a rare progressive neurodegenerative disorder due to an autosomal recessively inherited deficiency of lysosomal β-galactosidase. We have identified seven American black bears (Ursus americanus) found in the Northeast United States suffering from G(M1)-gangliosidosis. This report describes the clinical features, brain MRI, and morphologic, biochemical and molecular genetic findings in the affected bears. Brain lipids were compared with those in the brain of a G(M1)-mouse. The bears presented at ages 10-14 months in poor clinical condition, lethargic, tremulous and ataxic. They continued to decline and were humanely euthanized. The T(2)-weighted MR images of the brain of one bear disclosed white matter hyperintensity. Morphological studies of the brain from five of the bears revealed enlarged neurons with foamy cytoplasm containing granules. Axonal spheroids were present in white matter. Electron microscopic examination revealed lamellated membrane structures within neurons. Cytoplasmic vacuoles were found in the liver, kidneys and chondrocytes and foamy macrophages within the lungs. Acid β-galactosidase activity in cultured skin fibroblasts was only 1-2% of control values. In the brain, ganglioside-bound sialic acid was increased more than 2-fold with G(M1)-ganglioside predominating. G(A1) content was also increased whereas cerebrosides and sulfatides were markedly decreased. The distribution of gangliosides was similar to that in the G(M1)-mouse brain, but the loss of myelin lipids was greater in the brain of the affected bear than in the brain of the G(M1) mouse. Isolated full-length cDNA of the black bear GLB1 gene revealed 86% homology to its human counterpart in nucleotide sequence and 82% in amino acid sequence. GLB1 cDNA from liver tissue of an affected bear contained a homozygous recessive T(1042) to C transition inducing a Tyr348 to His mutation (Y348H) within a highly conserved region of the GLB1 gene. The coincidence of several black bears with G(M1)-gangliosidosis in the same geographic area suggests increased frequency of a founder mutation in this animal population.
authors.affiliation: Section of Pathology, Department of Biomedical Science, Tufts University Cummings School of Veterinary Medicine, Grafton, MA, USA.
authors.forename: Sureshkumar
authors.initials: S
authors.lastname: Muthupalani
authors.affiliation: Department of Neurology, New York University School of Medicine, New York, NY, USA.
authors.forename: Paola A
authors.initials: PA
authors.lastname: Torres
authors.affiliation: Department of Neurology, New York University School of Medicine, New York, NY, USA.
authors.forename: Betty C
authors.initials: BC
authors.lastname: Wang
authors.affiliation: Department of Neurology, New York University School of Medicine, New York, NY, USA.
authors.forename: Bai Jin
authors.initials: BJ
authors.lastname: Zeng
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Eaton
authors.affiliation: Section of Pathology, Department of Biomedical Science, Tufts University Cummings School of Veterinary Medicine, Grafton, MA, USA.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Erdelyi
authors.affiliation: Section of Pathology, Department of Biomedical Science, Tufts University Cummings School of Veterinary Medicine, Grafton, MA, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ducore
authors.affiliation: Section of Pathology, Department of Biomedical Science, Tufts University Cummings School of Veterinary Medicine, Grafton, MA, USA.
authors.forename: Rajanikarath
authors.initials: R
authors.lastname: Maganti
authors.affiliation: Section of Pathology, Department of Biomedical Science, Tufts University Cummings School of Veterinary Medicine, Grafton, MA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Keating
authors.affiliation: Section of Pathology, Department of Biomedical Science, Tufts University Cummings School of Veterinary Medicine, Grafton, MA, USA.
authors.forename: Bain J
authors.initials: BJ
authors.lastname: Perry
authors.affiliation: Wild Life Clinic, Tufts University Cummings School of Veterinary Medicine, Grafton, MA, USA.
authors.forename: Florina S
authors.initials: FS
authors.lastname: Tseng
authors.affiliation: Wild Life Clinic, Tufts University Cummings School of Veterinary Medicine, Grafton, MA, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Waliszewski
authors.affiliation: Wild Life Clinic, Tufts University Cummings School of Veterinary Medicine, Grafton, MA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Pokras
authors.affiliation: Animal Disease Diagnostic Laboratory, University of Maine, Orono, ME, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Causey
authors.affiliation: Animal Disease Diagnostic Laboratory, University of Maine, Orono, ME, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Seger
authors.affiliation: Department of Clinical Science, Tufts University Cummings School of Veterinary Medicine, Grafton, MA, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: March
authors.affiliation: Department of Clinical Science, Tufts University Cummings School of Veterinary Medicine, Grafton, MA, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Tidwell
authors.affiliation: Department of Pathology, Tufts University School of Medicine, Boston, MA, USA; Tufts Medical Center, Boston, MA, USA.
authors.forename: Rolf
authors.initials: R
authors.lastname: Pfannl
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seyfried
authors.affiliation: Department of Neurology, New York University School of Medicine, New York, NY, USA. Electronic address: ekolc@yahoo.com.
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Kolodny
authors.affiliation: Section of Pathology, Department of Biomedical Science, Tufts University Cummings School of Veterinary Medicine, Grafton, MA, USA; Department of Pathology, Tufts University School of Medicine, Boston, MA, USA; Tufts Medical Center, Boston, MA, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Alroy
mesh_terms: D000818:Animals; D001483:Base Sequence; D002531:Cerebellum / Q000473:pathology / Q000648:ultrastructure; D002855:Chromatography, Thin Layer; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D005732:Gangliosides / Q000378:metabolism; D016537:Gangliosidosis, GM1 / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D005786:Gene Expression Regulation; D016678:Genome / Q000235:genetics; D006801:Humans; D051457:Hyaline Cartilage / Q000473:pathology / Q000648:ultrastructure; D006867:Hydrolases / Q000378:metabolism; D007684:Kidney Tubules / Q000473:pathology / Q000648:ultrastructure; D008279:Magnetic Resonance Imaging; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism; D012160:Retina / Q000473:pathology; D014162:Transfection; D014481:United States; D001503:Ursidae / Q000235:genetics*; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: D018076:DNA, Complementary; D005732:Gangliosides; D050505:Mutant Proteins; D006867:Hydrolases; D001616:beta-Galactosidase
keywords: American black bear; G(M1)-gangliosidosis; GLB1 gene; Neuronal storage; Y348H mutation; β-Galactosidase