Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, Japan Department of Child Neurology, National Center Hospital, NCNP, Kodaira, Tokyo, Japan.
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, Japan Department of Clinical Development, Translational Medical Center, NCNP.
J Neurol Neurosurg Psychiatry. 2015 Mar;86(3):280-7. doi: 10.1136/jnnp-2013-307052. Epub 2014 Jun 17.
Collagen VI is widely distributed throughout extracellular matrices (ECMs) in various tissues. In skeletal muscle, collagen VI is particularly concentrated in and adjacent to basement membranes of myofibers. Ullrich congenital muscular dystrophy (UCMD) is caused by mutations in either COL6A1, COL6A2 or COL6A3 gene, thereby leading to collagen VI deficiency in the ECM. It is known to occur through either recessive or dominant genetic mechanism, the latter most typically by de novo mutations. UCMD is well defined by the clinicopathological hallmarks including distal hyperlaxity, proximal joint contractures, protruding calcanei, scoliosis and respiratory insufficiency. Recent reports have depicted the robust natural history of UCMD; that is, loss of ambulation by early teenage years, rapid decline in respiratory function by 10 years of age and early-onset, rapidly progressive scoliosis. Muscle pathology is characterised by prominent interstitial fibrosis disproportionate to the relative paucity of necrotic and regenerating fibres. To date, treatment for patients is supportive for symptoms such as joint contractures, respiratory failure and scoliosis. There have been clinical trials based on the theory of mitochondrion-mediated myofiber apoptosis or impaired autophagy. Furthermore, the fact that collagen VI producing cells in skeletal muscle are interstitial mesenchymal cells can support proof of concept for stem cell-based therapy.
胶原 VI 广泛分布于各种组织的细胞外基质 (ECM) 中。在骨骼肌中，胶原 VI 特别集中在肌纤维的基底膜及其附近。先天性肌营养不良症（UCMD）是由 COL6A1、COL6A2 或 COL6A3 基因突变引起的，从而导致 ECM 中胶原 VI 缺乏。它通常通过隐性或显性遗传机制发生，后者最常见的是由新生突变引起。UCMD 的临床病理特征包括远端过度伸展、近端关节挛缩、跟骨突出、脊柱侧凸和呼吸功能不全。最近的报告描述了 UCMD 的强大自然病史；即在青少年早期失去行走能力，10 岁时呼吸功能迅速下降，以及早发性、快速进展性脊柱侧凸。肌肉病理学的特征是间质纤维化明显，与坏死和再生纤维的相对缺乏不成比例。迄今为止，针对关节挛缩、呼吸衰竭和脊柱侧凸等症状的治疗方法是支持性的。基于线粒体介导的肌纤维凋亡或自噬受损理论，已经进行了临床试验。此外，骨骼肌中产生胶原 VI 的细胞是间质间充质细胞这一事实，可以支持基于干细胞的治疗的概念验证。
