A Case of De Novo Dynamin 2-Related Centronuclear Myopathy with Electrical but Not Clinical Myotonia
Centronuclear myopathy (CNM) is a rare congenital myopathy characterized by muscle weakness, atrophy, and the histopathological hallmark of centralized nuclei in muscle fibers. Dynamin 2 (DNM2), a protein involved in membrane trafficking and cytoskeletal organization, is one of the genes implicated in CNM. This article presents a detailed case study of a patient with a de novo DNM2 mutation manifesting electrical myotonia without clinical myotonia, expanding the phenotypic spectrum of DNM2-related disorders.
Clinical Presentation
A 39-year-old male presented with progressive limb atrophy and weakness. His symptoms began in early childhood, marked by generalized muscular hypotonia at birth and difficulties in running during elementary school. By adulthood, the patient exhibited significant facial muscle atrophy and limited left eye adduction, indicative of ophthalmoparesis. Neurological examination revealed proximal muscle atrophy and weakness in the upper limbs, while lower limb weakness was more pronounced distally. Notably, the patient lacked spontaneous or percussion-induced clinical myotonia, and there was no evidence of muscle hypertrophy.
Serum creatine kinase (CK) levels were mildly elevated at 223 IU/L (normal <170 IU/L), consistent with muscle damage but not as markedly elevated as seen in muscular dystrophies.
Electrophysiological Findings
Nerve conduction studies showed normal motor and sensory conduction velocities, ruling out peripheral neuropathy. However, needle electromyography (EMG) revealed fibrillation potentials and positive sharp waves, indicative of active muscle fiber irritability. Myotonic discharges were prominent, characterized by waxing and waning variations in amplitude and frequency. Motor unit potentials in the first dorsal interosseous, tibialis anterior, and quadriceps femoris muscles were of short duration and low amplitude, with early recruitment patterns, confirming a myopathic process.
Muscle Biopsy and Histopathology
A biopsy of the left biceps brachii muscle demonstrated central nuclei in nearly all muscle fibers, a defining feature of CNM. Nicotinamide dehydrogenase tetrazolium reductase (NADH-TR) staining revealed increased perinuclear oxidative activity and radiating sarcoplasmic strands extending from the central nuclei, creating a spoke-like appearance. Similar patterns were observed in immunohistochemical stains for desmin and vimentin, proteins critical for maintaining cytoskeletal integrity. These findings highlighted structural disorganization within muscle fibers, likely contributing to the disease pathophysiology.
Genetic Analysis
Whole-exome sequencing identified a heterozygous c.1565G>A substitution in the DNM2 gene, resulting in an arginine-to-histidine substitution at position 522 (R522H). This mutation has been previously reported as pathogenic in CNM. Parental testing confirmed the mutation was de novo, as neither parent carried the variant. The R522H mutation resides in the pleckstrin homology (PH) domain of dynamin-2, a region essential for membrane interaction and GTPase activity.
Discussion
DNM2 mutations are associated with a spectrum of neuromuscular disorders, including autosomal dominant CNM and Charcot-Marie-Tooth disease (CMT). The current case aligns with CNM due to the absence of neuropathy on electrophysiological studies and the presence of characteristic histopathological features. However, the presence of electrical myotonia without clinical myotonia adds a novel dimension to the DNM2-CNM phenotype.
Electrical Myotonia in CNM
Myotonia, defined by delayed muscle relaxation after contraction, is classically associated with ion channelopathies (e.g., myotonic dystrophy) or non-dystrophic myotonic disorders. Electrical myotonia—detected via EMG as repetitive discharges—without clinical manifestations is rare and has been reported in conditions such as polymyositis and acid maltase deficiency. In CNM, this phenomenon was first described in the 1970s, though earlier cases lacked genetic confirmation. In 2018, Stino and Iyadurai reported a DNM2-R522H patient with electrical myotonia but no clinical myotonia, though muscle biopsy data were unavailable. The current case corroborates this finding and provides histopathological evidence linking DNM2 dysfunction to myotonic discharges.
Pathophysiological Insights
Dynamin-2 plays a critical role in endocytosis, membrane remodeling, and cytoskeletal organization. The R522H mutation likely disrupts these processes, leading to aberrant membrane repair and cytoskeletal instability. The spoke-like sarcoplasmic strands observed in NADH-TR, desmin, and vimentin stains suggest impaired cytoskeletal-mitochondrial interactions, which may contribute to membrane hyperexcitability and electrical myotonia. Desmin, an intermediate filament protein, is vital for maintaining sarcomere integrity; its disorganization may further destabilize muscle membrane potentials.
Genotype-Phenotype Considerations
The R522H variant has been reported in two prior CNM cohorts, neither of which exhibited clinical or electrical myotonia. This discrepancy underscores phenotypic variability even among individuals with identical mutations. Modifying genetic factors, epigenetic influences, or environmental triggers may account for these differences. The current case highlights the importance of comprehensive electrophysiological evaluation in CNM, as myotonic discharges may otherwise go undetected.
Conclusion
This case expands the clinical spectrum of DNM2-related CNM by demonstrating electrical myotonia as a potential feature. The absence of clinical myotonia, coupled with characteristic histopathological and genetic findings, distinguishes this presentation from other myotonic disorders. The structural abnormalities observed in desmin and vimentin staining suggest that cytoskeletal dysfunction contributes to membrane hyperexcitability, though further studies are needed to elucidate the precise mechanisms. Clinicians should consider DNM2 testing in patients with CNM and unexplained electrical myotonia, even in the absence of clinical signs.
doi.org/10.1097/CM9.0000000000000974
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