Nemaline myopathy in Brazilian patients: clinical, muscle imaging and molecular characterization

Background: Nemaline myopathy (NM) is one of the most common structural congenital myopathies, with a significant clinical and genetic heterogeneity. Nowadays, more than 15 genes are related to NM, including TPM3, NEB, ACTA1, TPM2, TNNT1, KBTBD13, CFL2 (COFILIN2), KLHL40, KLHL41, LMOD3, MYO18B, MYPN, RYR3, TTN3, ADSSL1, Filamin C and MYH2. Most of these genes encode structural or regulatory proteins associated with the thin filament in the skeletal muscle fiber. NM is considered a rare condition and there are no national studies with a large choort of Brazilian nemaline patients.

Objective: To characterize the clinical, molecular and muscle MRI data from a Brazilian cohort of patients with nemaline myopathy.

Methods: Patients were clinically evaluated and followed for 2 to 20 years. Exams were performed including muscle biopsy, muscle MRI and next generation sequencing (exome).

Results: 30 patients, 15 males and 15 females, from 25 unrelated families were evaluated. Five families presented more than one affected patient, one of them with a clear autosomal dominant inheritance and 4 with autosomal recessive form. The remaining 20 families presented with sporadic cases. Patients were classified based on the severity of the disease: 24 with the typical form, three with the mild form and three with the severe neonatal form. We identified pathogenic mutations in NM-related genes in all 25 studied families. NEB variants were present in 20 patients from 16 families (all patients had 2 NEB variants and 11 of these variants were novel). Five families showed heterozygous mutations in ACTA1 gene (one mutation was novel), in 4 families, mutations in the following genes were found: TPM2, TPM3, and KLHL40. In 28 patients, the muscle biopsy was performed and showed rods inside of muscle fibers. Type I predominance was present in all patients, and in some there was total predominance. Muscle MRI could show different patterns of muscle involvement associated with the affected gene.

Conclusions: Molecular analysis in the present study showed that mutations in the NEB are the most common cause of NM, followed by mutations in the ACTA1. A total of 12 mutations were novel. The NEB mutation c. 24579 G> C was recurrent in 3 unrelated patients, but from a region with a high frequency of consanguinity, suggesting a common ancestor. Two unrelated patients with severe form of the disease presented the same KLHL40 mutations. Respiratory involvement was very common in NM patients and can be out of proportion to the weakness of the limbs.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
18 September 2023