A recurrent homozygous ACTN2 variant associated with core myopathy

Abstract

Recently, Lornage et al. reported a dominantly inherited myopathy associated with monoallelic variants in ACTN2, which is characterized clinically by weakness in distal and/or proximal muscles and pathologically by cores in myofibers [2]. Here, we report eight patients in three unrelated families with muscle weakness, core myopathy, and a biallelic variant in ACTN2. Clinicopathological features of the patients are listed in Table 1. In Family 1, F1-II-6 (Fig. 1a) developed muscle weakness, predominantly in distal muscles from 32-years old. In Family 2, F2-IV-4 (Fig. 1b) had proximal muscle weakness in lower limbs and acquired left exotropia from 60-years old. The latter may be attributable to weakness of the extraocular muscles, as reported previously [2]. He had myocardial diastolic dysfunction and atrial fibrillation at 78-years-old. There was an apparent autosomal dominant family history. Other affected family members reported muscle weakness beginning in their 40 s to 60 s. In Family 3, F3-II-1 (Fig. 1c) developed limb muscle weakness from approximately 60-years-old. Muscle weakness was generalized, but there was asymmetric atrophy in the lower limbs (Fig. 2, online resource). Age at onset of these patients was similar to that of previously reported patients [3]. Muscle images showed fat replacement in the posterior compartment of the thigh, tibialis anterior, and medial head of the gastrocnemius (Fig. 1d–f). By contrast, the anterior compartment of the thigh, particularly the rectus femoris, sartorius, and gracilis, were spared. This pattern of muscle involvement is distinct from that previously described in patients with dominant variants in ACTN2 [2, 3]. Muscle pathology in the three families was similar, showing moderate to marked variation in fiber size, scattered fibers with internal nuclei, and type 1 fiber predominance (Fig. 1g-j). Furthermore, many type 1 fibers had minicore-like structures and some of them looked like lobulated fibers as reported previously [2, 3]. These structures were visible not only by NADH-tetrazolium reductase staining but also by succinate dehydrogenase and cytochrome c oxidase staining, indicating an absence of mitochondria in the cores [4] (Fig. 1k–m). Rimmed vacuoles and nemaline bodies (Table 1 and Fig. 3, online resource) were also observed, similar to previous reports [2, 3].