Naom I, D'Alessandro M, Sewry C A, Philpot J, Manzur A Y, Dubowitz V, Muntoni F
Department of Paediatrics and Neonatal Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
Neuromuscul Disord. 1998 Oct;8(7):495-501. doi: 10.1016/s0960-8966(98)00065-0.
We report two siblings, an 11-year-old boy and his 7-year-old sister, referred to us with a diagnosis of muscular dystrophy. The boy presented at 22 months with delay in walking. A very high serum creatine kinase (CK) level and a dystrophic muscle biopsy lead to a diagnosis of Duchenne muscular dystrophy prior to the identification of the dystrophin gene. Two years later his sister presented with similar problems. A diagnosis of limb-girdle muscular dystrophy was made when they were shown to have inherited different X-chromosomes and normal expression of dystrophin and all sarcoglycans. Their conditions remained static. Recently a slowing of the peripheral motor nerve conduction velocities and T2-weighted brain magnetic resonance imaging showed increased signal of the white matter, both of which are features of merosin-deficient congenital muscular dystrophy. Immunolabelling using a C-terminal laminin alpha 2 chain antibody showed a reduction in expression, while labelling with another antibody that recognises a 300-kDa fragment showed a very significant reduction. Mutational analysis of the LAMA2 gene showed two mutations: one was a G-->C point mutation at position -1 of intron 28 acceptor splicing site. This mutation induced activation of a cryptic splice at nucleotide 4429 of exon 29 and partial skipping of this exon, with conservation of the open reading frame. The other was a nonsense mutation due to a C_T transition at position 5525 of the cDNA sequence (exon 37), resulting in a stop codon. These data confirm that mutations of the LAMA2 gene that do not completely disrupt the production of the protein can give rise to phenotypes considerably milder than classical merosin-deficient congenital muscular dystrophy. Partial laminin alpha 2 deficiency should be considered in the differential diagnosis of limb-girdle muscular dystrophy.
我们报告了两名患有肌肉萎缩症的兄妹，哥哥11岁，妹妹7岁。哥哥22个月大时出现行走迟缓。血清肌酸激酶（CK）水平极高，肌肉活检呈营养不良性改变，在肌营养不良蛋白基因被鉴定出来之前，就诊断为杜氏肌营养不良症。两年后，他的妹妹也出现了类似问题。当发现他们继承了不同的X染色体，且肌营养不良蛋白和所有肌聚糖均正常表达时，诊断为肢带型肌营养不良症。他们的病情保持稳定。最近，外周运动神经传导速度减慢，T2加权脑磁共振成像显示白质信号增强，这两者都是缺乏层粘连蛋白的先天性肌营养不良症的特征。使用C端层粘连蛋白α2链抗体进行免疫标记显示表达减少，而用另一种识别300 kDa片段的抗体标记则显示显著减少。LAMA2基因的突变分析显示有两个突变：一个是内含子28受体剪接位点第-1位的G→C点突变。该突变导致外显子29的核苷酸4429处隐蔽剪接激活，该外显子部分缺失，开放阅读框得以保留。另一个是由于cDNA序列（外显子37）第5525位的C→T转换导致的无义突变，产生了一个终止密码子。这些数据证实，LAMA2基因的突变若未完全破坏蛋白质的产生，可导致比经典的缺乏层粘连蛋白的先天性肌营养不良症明显更轻的表型。在肢带型肌营养不良症的鉴别诊断中应考虑部分层粘连蛋白α2缺乏症。
