Rare Diseases Research Platform, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland; Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland.
Department of Neurology, Medical University of Warsaw, Poland.
Eur J Paediatr Neurol. 2021 May;32:115-121. doi: 10.1016/j.ejpn.2021.04.005. Epub 2021 Apr 20.
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.
伴 LMNA 基因突变的先天性肌营养不良症（L-CMD）是骨骼肌层板病中最严重的表型形式。本文报告了 13 个家系的 15 例经基因证实的伴骨骼肌层板病的波兰患者的疾病临床表现。在所有这些患者中，松软婴儿综合征是疾病的首发表现。通过下一代测序（靶向panel 或外显子组；11 例）或经典 Sanger 测序（4 例）确定了遗传诊断。除了已知的致病性 LMNA 变异：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），我们还发现了三个新的变异：c.121C>G（p.Arg41Gly），c.1127A>G（p.Tyr376Cys）和 c.1160T>C（p.Leu387Pro）。11 例患者存在新生突变，4 例为家族性。在一个家系中，我们观察到了临床表现的家族内变异性：男性先证者为严重的 L-CMD，其姐姐为中间型，母亲则无症状。一位无症状的父亲存在体细胞嵌合现象。对于婴儿期存在肌无力和运动发育迟缓、头部控制不良、严重脊柱前凸、不稳定和笨拙步态的儿童，应怀疑存在 L-CMD。血清肌酸激酶可能升高（~1000IU/l）。肌无力的进展迅速，导致早期瘫痪。随着时间的推移，一些 L-CMD 患者可能会出现关节挛缩。MRI 显示，最常受累的肌肉为前锯肌、腰椎旁棘突肌、臀肌、股四头肌、大收肌、半腱肌、内侧腓肠肌和比目鱼肌。超罕见的层板病可能是儿童全身性肌无力的常见病因。广泛基因组测序方法的引入是对具有较大临床和遗传变异性疾病进行诊断的突破，使我们能够从“基因型到表型”进行诊断。然而，对于临床表现提示层板病的患者，可考虑对 LMNA 基因进行靶向测序。
