GLYCOGENOSIS TYPE IV IN NORWEGIAN FOREST CATS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。糖原病IV型是一种常染色体隐性遗传的先天性碳水化合物代谢缺陷，其中分支酶的缺乏导致具有异常结构的糖原储存。人类疾病的猫科同源物的特征是进行性神经肌肉疾病。建立了一个繁殖群，并发表了这种独特动物模型的自然史和病理学研究。这将是人类疾病治疗研究的一个重要模型，这种疾病像猫科动物的同系物一样，在性成熟之前导致死亡。Fyfe博士报告了猫GSDIV中正常糖原分支酶基因的克隆和突变的定义。这个群体的大部分被转移到密歇根州立大学，由法伊夫博士在单独的支持下进行研究。转介中心正在维持一小部分携带者。我们以前曾报道过感觉和运动神经元中异常糖原的积累，但没有注意到中枢神经系统的神经变性。对猫GSD IV病理学进行了重新评价，以评估该疾病的神经学成分。检查脊髓的5个月大的受影响的猫发现变性大（运动）神经元和神经元吞噬在腹角。这是伴随着腹角和背角的星形细胞增多。这些数据表明，猫神经系统中分支酶活性的缺乏是神经性的，并且观察到的肌肉疾病至少具有神经性萎缩的成分。此外，这些数据表明，长期改善疾病的努力很可能必须解决CNS中的组织特异性效应。

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.