Cytoplasmic body pathology in severe ACTA1-related myopathy in the absence of typical nemaline rod histology

Abstract

Mutations in ACTA1 encoding for α-actin cause a clinical and histopathologically heterogeneous group of myopathies with variable degree of muscle weakness and a spectrum of muscle pathology, including nemaline rods, cores, cap-like structures, fiber type disproportion, and zebra-bodies. Cytoplasmic bodies are a rare finding on muscle pathology that was first described in desmin myopathy. Here we present three patients with severe ACTA1-related myopathy, with typical cytoplasmic bodies in the biopsies but no nemaline rods evident on Gömöri Trichrome staining and electron microscopy. Patients 1 and 2 were fraternal twin boys born to healthy parents. Fetal movements had been reduced. Marked hypotonia and respiratory insufficiency was noted after birth, requiring intubation and ventilation in both. Patients had myopathic faces, generalized hypotonia and severe weakness with minimal limb movements. Both patients passed away at 6 months of age. Exome sequencing identified a heterozygous c.282C > A (p.Asn94Lys) mutation in ACTA1 in both. This mutation was previously reported to cause de-novo dominant severe nemaline myopathy. Parental segregation testing was negative, suggesting parental mosaicism. Patient 3 is a 5-year-old boy with congenital-onset myopathy with severe neonatal weakness and respiratory failure, requiring full-time ventilation. No movements were noted at birth, except for eye movements. Over time he developed minimal movements of fingers and toes. He is currently unable to talk and communicates with eye movements. Exome sequencing identified the same heterozygous c.282C > A (p.Asn94Lys) ACTA1 mutation. This report establishes that severe ACTA1-myopathy can present with the morphologic finding of cytoplasmic bodies in the absence of nemaline rods. These cases also illustrate the successful application of exome sequencing in patients with unknown neuromuscular disease to arrive at a genetic diagnosis, as ACTA1-myopathy had not been suspected clinically.