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

Abstract

Mutations in ACTA1 cause a group of myopathies with expanding clinical and histopathological heterogeneity. We describe three patients with severe ACTA1-related myopathy who have muscle fiber cytoplasmic bodies but no classic nemaline rods. Patient 1 is a five-year-old boy who presented at birth with severe weakness and respiratory failure, requiring mechanical ventilation. Whole exome sequencing identified a heterozygous c.282C>A (p.Asn94Lys) ACTA1 mutation. Patients 2 and 3 were twin boys with hypotonia, severe weakness, and respiratory insufficiency at birth requiring mechanical ventilation. Both died at 6 months of age. The same heterozygous c.282C>A (p.Asn94Lys) ACTA1 mutation was identified by whole exome sequencing. We conclude that clinically severe ACTA1-related myopathy can present with muscle morphological findings suggestive of cytoplasmic body myopathy in the absence of definite nemaline rods. The Asn94Lys mutation in skeletal muscle sarcomeric α-actin may be linked to this histological appearance. These novel ACTA1 cases also illustrate the successful application of whole exome sequencing in directly arriving at a candidate genetic diagnosis in patients with unexpected phenotypic and histologic features for a known neuromuscular gene.

Nemaline myopathies: a current view

“…Examination of resin sections stained with toluidine blue or with electron microscopy is then helpful. An occasional cytoplasmic body may be observed in a few fibres but in three severely affected patients with the same missense ACTA1 mutation (p.Asn94Lys), only dense accumulation of material reported as ‘suggestive of cytoplasmic bodies’ were seen, but no rods (Donkervoort et al 2017). In addition to these patients, rods have not been observed in other patients, although mutations in genes that cause nemaline myopathy may be present.…”

Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies

“…The missense mutations were evenly distributed over exons 2, 3, 4, and 5, and had no predicted impact on splicing. None was listed in the gnomAD public human variant database ( https://gnomad.broadinstitute.org/ ), but c.109G > C (p.Val37Leu; initially described as p.Val35Leu) [ 36 ], c.203C > A (p.Thr68Asn) [ 17 ], c.282C > A (p.Asn94Lys) [ 6 ], c.283G > A (p.Glu95Lys), c.493G > T (p.Val165Leu, initially described as p.Val163Leu) [ 14 , 25 , 36 , 40 ], c.592C > T (p.Arg198Cys) [ 17 ], c.686 T > C (p.Met229Thr) [ 17 , 36 ], and c.11132 T > C (p.Ter378GlnextTer47) [ 39 ] have previously been reported in unrelated NM cases. Furthermore, the LOVD mutation database lists the c.283G > A (p.Glu95Lys) mutation found in patient 5, and also registered different mutations affecting residues Val37, Gly38, Thr68, Asn94, Val165, Arg198, Met229, or the stop codon ( https://databases.lovd.nl/shared/variants/ACTA1/unique ).…”

“…In analogy to nemaline rods, cytoplasmic bodies are also believed to derive from Z-line material. Cytoplasmic bodies are not pathognomonic for a particular neuromuscular disease as they can be found in myofibrillar myopathies, reducing body myopathy, myotonic dystrophy, or periodic paralysis [ 6 , 33 ]. They are however rarely seen in ACTA1 -related NM, and the few described cases were invariably severe [ 6 , 11 , 16 , 37 ].…”

Myopathies with finger flexor weakness: Not only inclusion‐body myositis

“…ACTA1 mutations were initially described in a dominantly inherited nemaline myopathy 48 . Subsequent studies have expanded both the clinical and histological spectrum of ACTA1 ‐myopathy 49–51 . Although ACTA1 ‐myopathy is classified as a congenital myopathy, some patients present in late childhood or adulthood 52 .…”