Clinical and Pathological Features of Korean Patients with DNM2-Related Centronuclear Myopathy

Abstract

Background and purpose: Centronuclear myopathy (CNM) is characterized by the presence of central nuclei within a large number of muscle fibers. Mutations of the dynamin 2 gene (DNM2) are common causes of autosomal dominant or sporadic CNM. The aim of this study was to characterize the clinical and pathological features of CNM relative to the presence of DNM2 mutations.

Methods: Six patients with clinical and pathological features of CNM were recruited. Detailed clinical and pathological findings were analyzed according to the presence of DNM2 mutations.

Results: We detected DNM2 mutations in four of the six sporadic CNM patients, and identified the following distinct clinical and pathological features in those patients with DNM2 mutations: preferential involvement of the distal lower limbs, typical nuclear centralization, and radially distributed sarcoplasmic strands in muscle pathology. In contrast, those without DNM2 mutations exhibited rather diffuse muscular involvement, and nuclear internalization and myofibrillar disorganization were more pronounced features of their muscle pathology.

Conclusions: These findings suggest the presence of specific features in Korean CNM patients. A detailed clinical and pathological examination of CNM patients would be helpful for molecular genetic analyses of this condition.

Keywords: DNM2; central nuclei; centronuclear myopathy; internal nuclei; muscle involvement; sarcoplasmic strands.

Fig. 1

Muscle CT scans of patients 1, 4, and 6. In patient 1, the rectus femoris and biceps femoris were mildly atrophied (arrowheads, A), while the posterior compartment of the lower legs was the most preferentially involved (arrows, B). The hip girdle muscles in patient 1 were somehow affected (C). In patient 4, muscles in the posterior lower legs were more prominently atrophied (arrows, E) and the biceps femoris and vasti muscles were also affected (arrowheads, D); however, the hip girdle muscles were relatively spared (F). In patient 6, the muscles in the thighs (G), lower legs (H), and hip girdle (I) were evenly atrophied.

Fig. 2

Muscle pathology in patients 1 and 4. In patient 1, most of the nuclei were placed in the center of the muscle fibers in hematoxylin and eosin (H&E) staining (A), a nuclear chain was highlighted in a longitudinal H&E-stained section (B), and sarcoplasmic strands were radially arranged in nicotinamide adenine dinucleotide dehydrogenase-tetrazolium reductase (NADH-TR) staining (C). In patient 4, most of the nuclei were centrally placed in H&E staining (D), and radial arrangement of the sarcoplasmic strands and nonreactive regions for the enzyme were demonstrated in NADH-TR staining (E). Accumulation of stain and peripheral halos were observed in some fibers (arrows in E). Electron microscopic observation revealed a central nucleus and radial arrangement of strands in patient 4 (F).

Fig. 3

Muscle pathology in patients 5 and 6. In patient 5, nuclear centralization and internalization were mostly found in the small fibers in H&E staining (A), and nonreactive regions for NADH-TR were observed in some fibers (B). With myofibrillar ATPase stain (pH 10.7), type I fiber atrophy and predominance was noted in patient 5, mimicking the pattern of congenital fiber type disproportion (C). In patient 6, nuclear centralization and internalization were noted, and multiple internal nuclei appeared frequently in H&E staining (D), an abnormal pattern of staining was absent in NADH-TR staining (E), and type 1 fiber predominance was noted in ATPase staining (F; pH 10.7). Radial arrangement of sarcoplasmic strands was not observed around a central nucleus (G), but small areas of myofibrillar disorganization were detected (H) in muscle biopsy tissue from patient 6 in electron microscopy. NADH-TR: nicotinamide adenine dinucleotide dehydrogenase-tetrazolium reductase, ATPase: adenosine triphosphotase.