GLYCOGENOSIS TYPE IV IN NORWEGIAN FOREST CATS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Glycogenosis type IV is an autosomal recessive inborn error of carbohydrate metabolism in which the deficiency of branching enzymes results in storage of glycogen with an abnormal structure. The feline homolog of the human disease is characterized by progressive neuromuscular disease. A breeding colony was established and studies of the natural history and pathology of this unique animal model have been published. This will be an important model for studies of therapy of the human disease, which like the feline homolog, causes death before sexual maturity. The cloning of the normal glycogen branching enzyme gene and definition of the mutation in feline GSDIV have been reported by Dr. Fyfe. Most of this colony was transferred to Michigan State University for study by Dr. Fyfe under separate support. A small nucleus of carriers is being maintained by the Referral Center. We previously reported accumulation of abnormal glycogen in sensory and motor neurons, but neurodegeneration in the CNS was not noted. Reevaluation of the feline GSD IV pathology was undertaken to assess the neurologic component of the disorder. Examination of spinal cord of a 5 month-old affected cat revealed degenerative large (motor) neurons and neuronophagia in ventral horns. This was accompanied by astrocytosis in both ventral and dorsal horns. These data indicate that deficiency of branching enzyme activity in the feline nervous system is neuropathic and that the observed muscle disease has at least a component of neurogenic atrophy. Further, these data indicate that effort at long term amelioration of the disease will very likely have to address the tissue specific effects in the CNS.