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Abstract：
LMNA-related congenital muscular dystrophy (L-CMD) is the most severe phenotypic form of skeletal muscle laminopathies. This paper reports clinical presentation of the disease in 15 Polish patients from 13 families with genetically confirmed skeletal muscle laminopathy. In all these patients floppy infant syndrome was the first manifestation of the disease. The genetic diagnosis was established by next generation sequencing (targeted panel or exome; 11 patients) or classic Sanger sequencing (4 patients). In addition to known pathogenic LMNA variants: c.116A > G (p.Asn39Ser), c.745C > T (p.Arg249Trp), c.746G > A (p.Arg249Gln), c.1072G > A (p.Glu358Lys), c.1147G > A (p.Glu383Lys), c.1163G > C (p.Arg388Pro), c.1357C > T (p.Arg453Trp), c.1583C > G (p.Thr528Arg), we have identified three novel ones: c.121C > G (p.Arg41Gly), c.1127A > G (p.Tyr376Cys) and c.1160T > C (p.Leu387Pro). Eleven patients had de novo mutations, 4 - familial. In one family we observed intrafamilial variability of clinical course: severe L-CMD in the male proband, intermediate form in his sister and asymptomatic in their mother. One asymptomatic father had somatic mosaicism. L-CMD should be suspected in children with hypotonia in infancy and delayed motor development, who have poor head control, severe hyperlordosis and unstable and awkward gait. Serum creatine kinase may be high (~1000IU/l). Progression of muscle weakness is fast, leading to early immobilization. In some patients with L-CMD joint contractures can develop with time. MRI shows that the most frequently affected muscles are the serratus anterior, lumbar paraspinal, gluteus, vastus, adductor magnus, hamstrings, medial head of gastrocnemius and soleus. Ultra-rare laminopathies can be a relatively common cause of generalized hypotonia in children. Introduction of wide genome sequencing methods was a breakthrough in diagnostics of diseases with great clinical and genetic variability and allowed approach \"from genotype do phenotype\". However target sequencing of LMNA gene could be considered in selected patients with clinical picture suggestive for laminopathy.
摘要：
LMNA相关的先天性肌营养不良（L-CMD）是最严重的表型形式的骨骼肌层蛋白病。本文报道了来自13个遗传证实的骨骼肌层病变家庭的15名波兰患者的临床表现。在所有这些患者中，松软的婴儿综合征是该疾病的第一个表现。通过下一代测序(靶向组或外显子组;11名患者)或经典Sanger测序(4名患者)建立遗传诊断。除了已知的致病性LMNA变体外：c.116A>G（p。Asn39Ser)，c.745C>T（p。Arg249Trp),c.746G>A（p。Arg249Gln),c.1072G>A（p。Glu358Lys)，c.147G>A（p。Glu383Lys),c.1163G>C（p。Arg388Pro),c.1357C>T（p。Arg453Trp),c.1583C>G（p。Thr528Arg),我们已经确定了三个新的：c.121C>G（p。Arg41Gly),c.1127A>G（p。Tyr376Cys）和c.1160T>C（第Leu387Pro）。11名患者有从头突变，4-家族。在一个家庭中，我们观察到临床过程的家族内变异性：男性先证者中的严重L-CMD，他妹妹的中间形式，母亲的无症状。一位无症状的父亲患有躯体马赛克。在婴儿期肌张力减退和运动发育迟缓的儿童中应怀疑L-CMD，头部控制能力差的人，严重的过度前凸和不稳定和笨拙的步态。血清肌酸激酶可能较高(~1000IU/l)。肌肉无力的进展很快，导致早期固定。在某些L-CMD患者中，关节挛缩会随着时间的推移而发展。MRI显示最常受累的肌肉是前锯齿肌，腰椎旁,臀肌,vastus,内收肌magnus,腿筋,腓肠肌和比目鱼肌内侧头。超罕见层粘连蛋白病可能是儿童广泛性张力减退的相对常见原因。广泛的基因组测序方法的引入是具有巨大临床和遗传变异性的疾病诊断的突破，并且允许“从基因型做表型”的方法。然而，在具有提示层蛋白病的临床表现的选定患者中，可以考虑对LMNA基因进行靶测序。
