Nemaline myopathy

Nemaline myopathies present with a wide severity spectrum, from severe, generalized muscle weakness and respiratory failure in the neonatal period to mild, distal weakness in young adulthood. Rather than a syndromic vs nonsyndromic distinction, the spectrum is stratified by clinical severity, with subtypes ranging from severe congenital through typical congenital, intermediate, mild childhood-onset, and adult-onset forms. In a contemporary cross-sectional cohort of affected individuals, the typical congenital form accounted for 54%, while 42% presented with more severe phenotypes; mechanical support was required in 58%, with 26% needing wheelchair, tracheostomy, and feeding-tube support. Early clinical markers carry prognostic weight: hypotonia at birth is associated with increased odds of subsequent gastrostomy-tube dependency, and respiratory distress at birth is associated with both gastrostomy-tube dependency and long-term invasive ventilation.

A meta-analytic calculation based on mixed international cohorts estimates the all-age prevalence of nemaline myopathies as approximately 1/500,000 (0.20 per 100,000; 95% CI 0.10-0.35).

A large number of genes have been associated with nemaline myopathies. The genetic forms can be grouped into sarcomeric thin-filament protein defects and additional established NM genes. Sarcomeric thin-filament forms include NEB (nebulin; most common single cause) and ACTA1 (skeletal α-actin; second most common); additional established genes include TPM2, TPM3, CFL2, TNNT1, KBTBD13, KLHL40, KLHL41, LMOD3, and MYPN.

The genetic conditions associated with nemaline myopathies follow heterogeneous inheritance patterns. Both autosomal recessive and autosomal dominant forms occur; pathogenic variants in the most common gene–NEB–are typically inherited in an autosomal recessive form, whereas ACTA1 variants (the second most described gene) follow an autosomal dominant inheritance pattern and frequently arise de novo.

• Where nemaline myopathy is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

• Huang K, Bi FF, Yang H. A systematic review and meta-analysis of the prevalence of congenital myopathy. Front Neurol. 2021;12:761636. PMID: .
• Hildebrandt C, Genetti CA, Logvinenko T, Win W, Barraza-Flores P, Hayes LH, et al. Retrospective cohort analysis of clinical, molecular, and histopathologic characteristics of 275 patients with nemaline myopathy. Neurol Genet. 2025;11(4). PMID: .
• Amburgey K, Acker M, Saeed S, Amin R, Beggs AH, Bönnemann CG, et al. A cross-sectional study of nemaline myopathy. Neurology. 2021;96(10). PMID: .