Clinical spectrum and genetic variations of LMNA-related muscular dystrophies in a large cohort of Chinese patients

Abstract

BackgroundLMNA-related muscular dystrophy is caused by mutations in LMNA gene. We aimed to identify genetic variations and clinical features in a large cohort of Chinese patients with LMNA mutations in an attempt to establish genotype-phenotype correlation.MethodsThe clinical presentations of patients with LMNA-related muscular dystrophy were recorded using retrospective and prospective cohort study. LMNA mutation analysis was performed by Sanger sequencing or next-generation sequencing. Mosaicism was detected by personal genome machine amplicon deep sequencing for mosaicism.ResultsEighty-four patients were identified to harbour LMNA mutations. Forty-one of those were diagnosed with LMNA-related congenital muscular dystrophy (L-CMD), 32 with Emery-Dreifuss muscular dystrophy (EDMD) and 11 with limb-girdle muscular dystrophy type 1B (LGMD1B). We identified 21 novel and 29 known LMNA mutations. Two frequent mutations were identified: c.745C>T and c.1357C>T. A correlation between the location of mutation and the clinical phenotype was observed: mutations affecting the head and coil 2A domains mainly occurred in L-CMD, while the coil 2B and Ig-like domains mainly related to EDMD and LGMD1B. We found somatic mosaicism in one parent of four probands. Muscle biopsies revealed 11 of 20 biopsied L-CMD exhibited inflammatory changes, and muscle cell ultrastructure showed abnormal nuclear morphology.ConclusionsOur detailed clinical and genetic analysis of 84 patients with LMNA-related muscular dystrophy expands clinical spectrum and broadens genetic variations caused by LMNA mutations. We identified 21 novel and 29 known LMNA mutations and found two frequent mutations. A correlation between the location of mutation and the clinical severity was observed. Preliminary data suggested that low-dose corticosteroid treatment may be effective.

International retrospective natural history study of LMNA-related congenital muscular dystrophy

“… 7 , 37 , 38 The most common variant our cohort, an Arg249Trp substitution, was primarily associated with congenital and early onset laminopathies and has not been associated with later-onset clinical subttypes (EDMD or LGMD1B) ( www.umd.be/LMNA/ , GB and RBY personal communication ). This finding is similar to the one reported by Fan et al 25 in a large series of Chinese patients with 12/41 of their patients with L-CMD patients carrying this substitution. Other in-frame variants in our cohort (p.Asn39Ser, p.Lys32del, Glu358Lys, p.Arg453Trp) were less exclusively associated with laminopathies showing congenital or early-onset presentations (only 83.3%, 70%, 63.3% and 0% of published carriers showing congenital/early onset laminopathy, respectively).…”

A splicing LMNA mutation causing laminopathies accompanied by aortic valve malformation

“…The disease manifests as slowly progressive scapulahumeroperoneal muscle weakness with rigid spine or scoliosis, childhood-onset contractures of the elbow, posterior cervical and ankle joints, and normal or mildly delayed motor milestones with gait abnormality and difficulty in running and jumping, going up and down stairs, and standing up from squatting. [10][11][12][13] In short, individuals with L-CMD exhibit more severe clinical manifestations and experience more rapid progression and earlier onset than individuals with EDMD do; however, EDMD has a higher risk of cardiac involvement, such as cardiomyopathy, conduction defects, tachyarrhythmias, and even atrial standstill, than that of L-CMD. Moreover, patients with mutations which are at the exon-intron or intron-exon junctions of the LMNA gene always present with an EDMD or DCM phenotype because of the pre-mRNA splicing abnormality.…”

Skeletal and Cardiac Muscle Disorders Caused by Mutations in Genes Encoding Intermediate Filament Proteins

“…Heart is affected in all the three entities, with similar features, except for younger age at onset in L-CMD and EDMD2 than LGMD1B, which also has later presentation of muscle weakness [45,100]. A study involving mainly patients in pediatric age at the end of the follow-up period, showed that cardiac involvement is significantly more frequent in EDMD2 than L-CMD and LGMD1B [101]. Notably, as in desminopathy, cardiac presentation may precede or follow onset of muscle weakness.…”