A model of mucopolysaccharidosis IIIB (Sanfilippo syndrome type IIIB): N‐acetyl‐α‐D‐glucosaminidase deficiency in Schipperke dogs

Abstract

Mucopolysaccharidosis III (MPS III) is characterized by lysosomal accumulation of the glycosaminoglycan (GAG) heparan sulphate (HS). In humans, the disease manifests in early childhood, and is characterized by a progressive central neuropathy leading to death in the second decade. This disease has also been described in mice (MPS IIIA and IIIB), dogs (MPS IIIA), emus (MPS IIIB) and goats (MPS IIID). We now report on dogs with naturally occurring MPS IIIB, detailing the clinical signs, diagnosis, histopathology, tissue enzymology and substrate levels. Two 3-year-old Schipperke dogs were evaluated for tremors and episodes of stumbling. Examination of the animals found signs consistent with cerebellar disease including dysmetria, hind limb ataxia and a wide-based stance with truncal swaying. There were mildly dystrophic corneas and small peripheral foci of retinal degeneration. Magnetic resonance imaging of the brain and skeletal radiographs were normal. Intracytoplasmic granules were found in the white cells of peripheral blood and cerebral spinal fluid, and in myeloid lineages in bone marrow. Electrophoresis of urinary GAGs indicated the presence of HS, while assays of cultured fibroblasts found N-acetyl-alpha-D-glucosaminidase (Naglu) activity of between 4.3% and 9.2% of normal. Owing to neurological deterioration, both dogs were euthanized, and post-mortem examinations were performed. Biochemical studies of liver and kidney from both animals demonstrated profound deficiency of Naglu activity and abnormally high GAG levels. Pathology of the brain included severe cerebellar atrophy, Purkinje cell loss, and cytoplasmic vacuolation in neurons and perithelial cells throughout the central nervous system. Pedigree analyses and Naglu levels of family members supported an autosomal recessive mode of inheritance. Using an obligate heterozygote, a breeding colony has been established to aid in understanding the pathogenesis of MPS IIIB and testing of potential therapies.

Peripheral Nervous System Neuropathology and Progressive Sensory Impairments in a Mouse Model of Mucopolysaccharidosis IIIB

“…Our data have demonstrated neuropathology in the spinal cord of MPS IIIB mice that is global in distribution with differential cell-type presentation, similar to that observed in previous studies in mice and dogs [4], [5]. While the lysosomal storage lesions are observed in a broad range of cell-types throughout the spinal cord, including neurons, microglia, oligodendrocytes, pericytes and ependymal cells, the neuronal targets are predominantly motor neurons in the ventral horn and autonomic neurons in the lateral horn of grey matter.…”

“…It is known that the lysosomal storage pathology of MPS IIIB is global throughout the CNS and neuropathology studies have focused predominantly on changes in the brain, though previous studies showed lysosomal storage lesions in all parts of the CNS in mice and dogs [4], [5]. Further, it is commonly accepted that in the brain, multiple factors contribute to the neuropathology, secondary to the primary pathology- the lysosomal storage of HS-GAGs [4], [6], [7], [8], [9], [10], [11], [12], [13], [14].…”

Development of Sensory, Motor and Behavioral Deficits in the Murine Model of Sanfilippo Syndrome Type B

“…Characteristic pathologic changes are seen in the brain and other organs of MPS III patients, including lysosomal inclusions, cerebellar atrophy with loss of Purkinje cells [8], [9], [10], cortical and corpus callosum atrophy with white matter changes [11], [5], retinal pigmented epithelium (RPE) pigmentation loss, and photoreceptor degeneration [7], [12]. Usually symptom progression occurs over a decade starting around age 3–5.…”

Canine Models of Inherited Musculoskeletal and Neurodegenerative Diseases

“…MPS IIIb is observed in Schipperkes where the mutant allele is very prevalent (258,259,263). It is typically present in dogs around 2 years of age and leads to euthanasia prior to 5 years of age.…”

“…Initial pathologic studies of Schipperkes showed that the major tissues affected in dogs (liver, kidney, CNS) were consistent with human. The most impressive finding in the Schipperkes with MPS IIIb was an almost complete loss of cerebellar Purkinje cells (263). Humans show varying degrees of cerebellar pathology leading to the belief that this may be a species sensitivity to HS accumulation seen in canines (263).…”