Access at https://isn-slidearchive.org/?col=ISN&fol=Archive&file=ID-7449113.ome.tif. A 77-year-old woman began experiencing bilateral ptosis without ophthalmoplegia and facial diplegia at 40 years. There was no history of prenatal or neonatal complications, and her motor milestones were achieved on time. Her neurodevelopment was normal, with no signs suggestive of a congenital myopathy during infancy or childhood. She later developed progressive myalgias and muscle weakness affecting both proximal and distal muscles, accompanied by bilateral foot drop and distal amyotrophy. She also reported dysphagia for solids and exertional dyspnea. A broad laboratory work-up was unrevealing, including CBC, biochemistry, thyroid function, serum protein electrophoresis, viral serologies, metabolic screening of very long- and medium-chain fatty acids, and acid maltase enzyme testing. Neuromuscular junction antibodies (AChR, VGCC) were negative. Genetic testing excluded facioscapulohumeral dystrophy type 1 and myotonic dystrophy type 1 (Box 1). Electromyography showed a myopathic pattern, characterized by short-duration, low-amplitude polyphasic motor unit potentials in both lower and upper extremities. A left deltoid muscle biopsy, obtained at the age of 76, revealed myopathic alterations characterized by significant fiber size variation and rounded muscle fibers encircled by fibrotic tissue. Quantitative morphometry revealed a pattern of generalized fiber hypotrophy (49% measuring 6000 μm2) represented a minor fraction (18%). Isolated necrotic and regenerating fibers were present. No endomysial inflammatory infiltrates or neurogenic changes such as angulated atrophic fibers were identified. Type I fibers were hypotrophic and slightly predominant, more grouped in some areas. Approximately 60% of muscle fibers exhibited centrally located nuclei (Figure 1A), predominantly in Type I fibers. Additionally, some fibers displayed nuclear clustering (Figure 1A) and radial sarcoplasmic strands (RSSs), which were evident on nicotinamide adenine dinucleotide reductase (NADH) staining (Figure 1B). Isolated (A (p.Arg369Gln) variant in exon 8 of the DNM2 gene, confirming the diagnosis of a DNM2-related CNM. This case illustrates the polymorphic nature of DNM2-related CNM, demonstrating overlapping myopathological features of other CNMs. In this age group, the phenotype can mimic myasthenia gravis, inclusion body myositis, oculopharyngeal muscular dystrophy, mitochondrial myopathies, lower motor neuron disorders, or neuropathies, making diagnosis challenging. The muscle biopsy provided key diagnostic clues. The markedly increased centralized nuclei strongly suggested a congenital myopathy rather than myotonic dystrophy, which was also excluded by negative genetic testing. Additional structural abnormalities such as RSS and a spoke-like myofibrillar pattern, type I fiber predominance and hypotrophy were characteristic of DNM2-related CNM. Other biopsy findings were considered age-related, including rare ragged-red fibers and a small proportion of COX-negative fibers, with no evidence of primary mitochondrial disease. Although it may reflect the convergence of morphological features, it may reflect age-related amplification of common pathological pathways or, alternatively, the involvement of shared downstream mechanisms in CNM pathogenesis. C5b-9 deposits were confined to isolated viable fibers and MHC-I overexpression occurred without inflammatory infiltrates, arguing against inflammatory myopathy. The integration of clinical data, electrophysiology, detailed myopathological, and genetic confirmation remains essential. EM conceived the study. MT drafted the manuscript. EM and MT performed the histological and immunohistological analysis. AP, GS, and EF revised the manuscript. EM, SS, and LV contributed to the study design and supported the process of drafting and submitting the manuscript. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Tosi et al. (Tue,) studied this question.