Nemaline myopathy: Clinical, pathological, muscle imaging and molecular characterization in a cohort of Brazilian patients

Nemaline myopathy (NM) is one of the most common congenital myopathies with a significant genetic heterogeneity. Pathogenic mutations have been described in the genes NEB, ACTA1, TPM3, TPM2, CFL2, KBTBD13, KBTBD5, KBTBD10, KFHL40, KFHL41, LMOD3 and turn the next generation sequencing more suitable for the screening of NM mutations. The aim of this study is to describe the clinical, muscle imaging and molecular findings in a cohort of 25 Brazilian patients. 25 patients from 19 unrelated families were selected based on the presence of nemaline bodies in the muscle biopsy. Muscle imaging was performed through muscle MRI. Molecular studies were performed using Sanger or the next generation sequencing NGS: whole exome (Nextera – Illumina) or target NGS customized panel of 88 known neuromuscular genes (NGS-NMD). Among the 25 patients, 4 presented the intermediate clinical form, 20 had the typical form and one the juvenile form. From the 19 families, 4 showed mutations in the smaller genes: ACTA1 (2 patients from two families), TPM2 (one patient), and TPM3 (2 patients from one family). 11 families showed NEB mutations, with 9 of them presenting two pathogenic mutations in compound heterozygosis or homozygosis. In the other two families we detected only one pathogenic mutation in NEB gene (truncation mutation). In the remaining four families we could not identify mutations in the known NM genes. Among the NEB mutations here identified we found seven novel mutations (3 frame shift and 4 splicing site mutations). The muscle MRI showed different patterns of muscle involvement related with the affected gene. Considering that mutations in the nebulin gene were detected in 11 of the 19 Brazilian families, this form can be considered the main cause of NM in Brazilian patients.