CONGENITAL MYOPATHIES: NEMALINE AND TITINOPATHIES: P.237Congenital fatal cap-rod myopathy due to a de novo autosomal dominant pathogenic ACTA1 variant

Abstract

Cap disease is a rare structural congenital myopathy (CM) associated with hypotonia, proximal and facial muscle weakness, and frequently scoliosis and respiratory involvement. Mutations in TPM2, TPM3 and ACTA1 have been associated with cap disease, as well as nemaline myopathy. Combined caps and nemaline rods have been reported in the same patient due to a mutation in TPM3. Here, we report the first case of a severe, fatal CM with distinct and separate caps and nemaline rods identified in skeletal muscle biopsies. The patient was born at 37 weeks of gestation, with a history of polyhydramnios, little spontaneous movements at birth, generalised hypotonia, and required immediate ventilatory support. He died 20 days after birth. Ante mortem and post mortem biopsies from the quadriceps, and post mortem biopsies from the biceps and diaphragm showed diffuse fibre hypotrophy without specific structural alterations on light microscopy. Ultrastructural examination of the ante mortem quadriceps biopsy showed several classical cap lesions, and a few of these contained small nemaline rods. The post mortem quadriceps sample showed nemaline rods in several fibres. Both samples showed mitochondrial paracrystalline inclusions in a few interstitial capillary endothelial cells. Ultrastructural findings were key in directing molecular genetic testing. A next generation sequencing panel for 35 congenital myopathy genes identified a de novo ACTA1 c.739G>C p.(Gly247Arg) variant previously reported in the literature in a patient with severe nemaline myopathy, affecting a highly conserved amino acid, and predicted to affect actin function with In Silico analysis. Our case of ACTA1-related cap-rod myopathy is the most severe presentation of a CM with caps or cap-rods described till date. The case further cements the notion of caps and rods being part of the 'nemaline spectrum' and highlights the remarkable heterogeneity of lesions within the same muscle or same group of muscles.