Objective: To summarize the clinical manifestations and determine the molecular etiology for two collagen type Ⅵ-related myopathy pedigrees. Methods: Two spontaneous collagen type Ⅵ-related myopathy patients were admitted to Department of Neurology, Children's Hospital, Capital Institute of Pediatrics in October 2017. Clinical data of probands and their family members were collected and their genomic DNA was obtained for genetic testing. Next generation sequencing was performed and the variants were verified by the Sanger sequencing in the family members. Results: Target region sequencing indicated that the proband of family 1 has carried a heterozygous variant of COL6A3 gene, c.6229G>C(p.Gly2077Arg), and it was de novo variant confirmed by Sanger-sequencing in the family.The patient 1, a 2-year-three-month old boy, was admitted due to motor retardation at birth. He was defined as early severe Ullrich congenital muscular dystrophy. He never achieved independent ambulation, he had onset of symptoms was found at birth, including diffuse muscle weakness, striking distal joint hyperlaxity, proximal contractures, calcaneal protrusion, kyphosis, and hip dislocation. Serum CK level was elevated slightly and EMG showed neurogenic changes. The patient 2, a 7-year-old girl with a limp for 4 years, carried one de novo variant of COL6A3 gene,c.5169_5177del (p.Glu1724_Leu1726del). This variant results in the deletion of amino acids (1724 to 1726) in α3 chain of collagen Ⅵ, which may disturb the function of this protein.She was diagnosed as Bethlem myopathy with a mild phenotype. She had delayed motor milestones and presented with walking on tiptoe, hypotonia, and ithylordosis. The contracture of proximal joints was not very obvious. Serum CK level was normal and EMG showed myogenic changes.Muscle biopsy revealed muscular dystrophy and muscle magnetic resonance imaging of patient 2 showed vastus lateral is a "sandwich" sign. Immunofluorescence staining for COL6A3 chain in the cultured skin fibroblasts from patients 2 showed decreased deposition compared with control. Conclusions: These two patients were diagnosed as spontaneous collagen type Ⅵ-related myopathy and carried different variants of COL6A3 gene. Different in pathogenetic variants could cause different genetic features and different phenotypes. Collagen type Ⅵ- related myopathy patients have various clinical manifestations. Typical phenotypes include muscular dystrophies, proximal contractures, and distal hyperlaxity. Muscle MRI shows diffuse fatty infiltration of gluteus maximus and thigh muscle. The histological staining showed the low level expression of COL6A3 chain. The seventy of phenotype was related to the genotype.
目的： 分析2例Ⅵ型胶原蛋白缺乏相关肌病的临床和分子遗传学特点。 方法： 对首都儿科研究所附属儿童医院神经内科2017年10月诊治的2例遗传性肌病患儿进行临床资料分析，应用高通量测序技术进行基因检测、家系分析验证，应用免疫荧光染色技术检测患儿皮肤成纤维细胞的COL6A3链表达，确定2例患儿的致病性基因变异，明确患儿的诊断。 结果： 例1男，2岁3月龄，因生后运动发育落后就诊。四肢远端关节松弛，双膝关节挛缩、足跟突出、脊柱后凸、髋关节脱位及下肢为重的肢体近端无力。血肌酸激酶轻度升高。肌电图提示疑似神经源性损害，基因检测发现COL6A3基因存在已知的致病性变异：c.6229G>C(p.Gly2077Arg)，家系验证为新发变异，诊断为Ullrich先天性肌营养不良。例2女，7岁，因走路不稳伴乏力4年就诊。轻微跟腱挛缩步态，下肢肌力轻度下降，腰椎前凸，近端关节挛缩不明显。血肌酸激酶正常，肌电图提示肌源性损害，肌肉活检病理提示肌营养不良样改变，股肌肉磁共振成像见"三明治"样改变，免疫荧光检测皮肤成纤维细胞见COL6A3链的表达减弱。基因检测发现携带1个COL6A3基因的新发变异：c.5169_5177del(p.Glu1724_Leu1726del)，导致Ⅵ型胶原蛋白α3肽链1724-1726位氨基酸的缺失，进而影响蛋白功能，诊断为Bethlem肌病。 结论： 2例Ⅵ型胶原蛋白缺乏相关肌病患儿均携带COL6A3基因变异但是表型复杂多样，主要的临床特点是肌肉无力、远端关节松弛、近端关节挛缩等，肌肉核磁表现为脂肪浸润，组织学检查可见COL6A3链的表达减弱等特征，表型的严重与遗传分子特征相关。.
Keywords: Genetic diseases, inborn; Genotype; Muscular dystrophies.