We recently performed targeted sequencing of 69 selected genes associated with myopathy in the idiopathic muscular dystrophy patient cohort in our hospital.9 Patients were selected by applying the following inclusion criteria: 1) muscular dystrophy, congenital myopathy, congenital muscular dystrophy, metabolic myopathy, or distal myopathy based primarily on clinical phenotypes and secondarily on pathologic findings (if available), 2) genetically undetermined myopathy, and 3) availability of blood or muscle samples. Genomic DNA was extracted from either blood or muscle. A customized panel containing all coding exons and exon–intron junctions of 69 genes that are known to be responsible for myopathy was used, and LMNA and emerin gene (EMD) were included. Sequencing was performed on the HiSeq 2000 Sequencing platform (Illumina, San Diego, CA, USA) platform. Sequencing data were analyzed using an in-house analysis pipeline. All participants had previously signed an informed-consent form to participate in genetic analysis.

Four patients with LMNA-associated muscular dystrophy were included in this study and were confirmed as having an LMNA mutation. The applied variant calling methods were documented previously,9 and validation was performed using Sanger sequencing, for which the concordance rate was 96.3%. We then reviewed the clinical manifestations and findings of neurologic examinations, electromyography, and muscle biopsies from the other hospitals, and compared them with reevaluation findings from our hospital.

Clinical characteristics and laboratory findings of the subjects are presented in Table 1. Four patients who were confirmed as having LMNA mutations visited other hospitals when their first symptom of slow gait speed or waddling gait occurred between the ages of 2 and 5 years. The presence of contracture was not definitive at the time of the first neurologic examination. Two patients (patients 3 and 4) showed hypertrophy of the gastrocnemius muscles. Sequencing of the dystrophin gene was performed in two patients (patients 2 and 3), who were both negative for mutation in that gene. Without follow-up neurologic examination or evaluation, the patients were admitted to our hospital due to progression of weakness (patient 1 at age 29 years), palpitation (patient 2 at age 29 years), scoliosis surgery (patient 3 at age 15 years), or for re-evaluation (patient 4 at age 11 years). In contrast to their first admission, all of the patients showed prominent proximal muscle weakness and various degrees of distal weakness. All patients showed contracture in the ankle, whereas involvement of the neck extensor was prominent in two patients (patients 1 and 4).

Two patients had scoliosis (patients 1 and 3), and one patient had received an Achilles-tendon-lengthening operation (patient 4). None of the family members had any history of muscle weakness or gait disturbance. The serum creatine kinase level was slightly elevated, ranging between 306 and 806 U/L. Electromyography studies were conducted in three patients (patients 1, 2, and 4), and they showed nonspecific generalized myopathic patterns with low-amplitude, polyphasic motor unit action potentials, and early recruitment patterns. Cardiac evaluation including 24-hour Holter monitoring and echocardiography showed a cardiac conduction block but normal cardiac function in three patients (patients 1, 2, and 3). Three patients had a vital capacity of around 50% of the predicted value, and one of them (patient 3) was using noninvasive positive-pressure ventilation. In one patient (patient 1), CT scans of the lower extremities showed symmetric fatty atrophic changes in proximal and distal leg muscles.

We identified a total of four LMNA mutations. The c.1357C>T (patient 1), c.746G>A (patient 3), and c.1583C>G (patient 4) mutations had been previously reported in EDMD patients, while the c.1366A>G mutation found in patient 2 had only been reported in one L-CMD patient.10 Among these mutations, c.746G>A was previously reported in one Korean patient,11 and c.1357C>T has been reported in Chinese patients.12

Three patients (patients 1, 2, and 3) had undergone their first muscle biopsy at other hospitals when their first symptoms occurred, but the samples were not available. Since all of the patients had received a muscle biopsy when they were admitted to our hospital, we reviewed their pathologic records from other hospitals and compared them with the findings from the second muscle biopsy at our hospital. The pathologic findings are presented in Table 2. Nonspecific myopathic changes such as size variations in muscle fibers, increased internal nuclei, and hypertrophic fibers with fiber splitting were the main features evident in the patients. Although a few degenerative fibers were observed in patient 1, suggesting muscular dystrophy, they were still nonspecific dystrophic findings (Fig. 1). The findings of immunohistochemistry investigations using antibodies to lamin A/C and emerin were normal compared to healthy controls (Fig. 2).