Nemaline Myopathy in Brazilian Patients: Molecular and Clinical Characterization

Abstract

Nemaline myopathy (NM), a structural congenital myopathy, presents a significant clinical and genetic heterogeneity. Here, we compiled molecular and clinical data of 30 Brazilian patients from 25 unrelated families. Next-generation sequencing was able to genetically classify all patients: sixteen families (64%) with mutation in NEB, five (20%) in ACTA1, two (8%) in KLHL40, and one in TPM2 (4%) and TPM3 (4%). In the NEB-related families, 25 different variants, 11 of them novel, were identified; splice site (10/25) and frame shift (9/25) mutations were the most common. Mutation c.24579 G>C was recurrent in three unrelated patients from the same region, suggesting a common ancestor. Clinically, the “typical” form was the more frequent and caused by mutations in the different NM genes. Phenotypic heterogeneity was observed among patients with mutations in the same gene. Respiratory involvement was very common and often out of proportion with limb weakness. Muscle MRI patterns showed variability within the forms and genes, which was related to the severity of the weakness. Considering the high frequency of NEB mutations and the complexity of this gene, NGS tools should be combined with CNV identification, especially in patients with a likely non-identified second mutation.

Keywords: acta1; congenital myopathy; nebulin; nemaline myopathy.

Figure 1

Muscle biopsy showing the presence and distribution of nemaline bodies inside myofibers: on the left picture, from P1, there are predominantly large rods in subsarcolemmal region; on the right picture, from P20, there are predominantly small intermyofibrillar rods (magnification ×20).

Figure 2

MRI pattern in patients with mutations in the ACTA1 and NEB genes: (A,B) patients with mutations in the ACTA1 gene. In (A), there is a diffuse infiltration in the thigh and legs in P3 (severe form); in (B), there is isolate involvement of tibial anterior in the legs in P2 (typical form). (C,D) patients with nebulin mutations; in (C), we observe a diffuse infiltration in the thigh and legs in a patient with severe weakness who never walked (P21); In (D), we observe that the predominant involvement was in the anterior tibial and soleus muscles, while the thigh muscles were spared (P15).

Figure 3

MRI pattern in patients with mutations in the TPM2 and TPM3 genes. In P6 with TPM2 mutation, the whole-body MRI showed facial involvement, mainly temporal and lateral pterygoid muscles, and distal involvement in lower legs. In P7 with TPM3, the muscle MRI showed fat infiltration in thigh muscles, especially sartorius and adductor magnus, and predominant involvement of the anterior compartment of the leg.