Clinical and imaging spectrum of non-congenital dominant ACTN2 myopathy.

Background: Alpha-actinin-2, a protein with high expression in cardiac and skeletal muscle, is located in the Z-disc and plays a key role in sarcomere stability. Mutations in ACTN2 have been associated with both hypertrophic and dilated cardiomyopathy and, more recently, with skeletal myopathy.

Methods: Genetic, clinical, and muscle imaging data were collected from 37 patients with an autosomal dominant ACTN2 myopathy belonging to 11 families from Spain and Belgium. Haplotypes were studied to confirm a common ancestry for the two most common recurrent variants identified in this study. A trained machine learning model was used to compare muscle MRI scans in ACTN2 myopathy with other neuromuscular diseases to identify a specific pattern of muscle involvement.

Results: The clinical phenotype ranged from asymptomatic to limb-girdle weakness and facial involvement and was depending on genotype. Cardiac and respiratory involvement were not common. Belgian families carrying the p.Ile134Asn variant and Basque-Spanish families carrying the p.Cys487Arg variant each showed unique haplotypes supporting respective common ancestry. Available muscle biopsies showed non-specific changes. In muscle imaging, the most affected muscles were the glutei minor, glutei medius, hamstrings, tibialis anterior, and soleus. A machine learning model showed that the most differentiating features in dominant ACTN2 myopathy were the involvement of the tibialis anterior and gluteus medius muscles and preservation of the quadratus femoris, gastrocnemius lateralis, and tensor fasciae latae muscles.

Conclusion: We provide new insights into genetic, clinical, and muscle imaging characteristics of non-congenital dominant ACTN2 myopathy, broadening the phenotypic spectrum of muscle disorders caused by ACTN2 variants.