Myotonia congenita is a disorder in which muscles fail to relax properly after contraction. Patients experience stiffness, particularly after periods of rest, that can make simple movements — opening a door, shaking hands, climbing stairs — feel like a battle against their own bodies. The condition arises from defects in the CLCN1 gene, which encodes a chloride channel called ClC-1 found in skeletal muscle membranes. This channel is essential for regulating the electrical excitability of muscle fibers. When chloride ions cannot flow properly through the channel, muscle fibers become hyperexcitable, firing repetitive action potentials that produce the characteristic stiffness. The CLCN1 gene can be inherited in both dominant and recessive patterns, with recessive cases typically producing more severe symptoms. In the Iranian family studied, the index patient presented with severe myotonia that had a significant impact on daily life, consistent with the more severe end of the myotonia congenita spectrum.

Centronuclear myopathy, by contrast, is a structural muscle disease. The autosomal dominant form (ADCNM) is caused by variants in the DNM2 gene, which encodes dynamin-2, a large GTPase enzyme involved in membrane trafficking, vesicle formation, and the maintenance of muscle fiber architecture. In centronuclear myopathy, muscle fibers display centrally located nuclei — a feature normally seen only in embryonic muscle development — along with progressive weakness. The disease is fundamentally different from myotonia congenita: rather than a problem of electrical excitability, it is a problem of muscle fiber structure and maintenance. Patients with ADCNM typically experience progressive weakness rather than stiffness, and the condition can affect muscles throughout the body, sometimes including those involved in breathing and swallowing.

The Iranian family presented a clinical picture that overlapped both conditions. The index patient showed clinical and electrical myotonia — the hallmark of myotonia congenita — but also displayed myopathic changes on electromyography (EMG), the diagnostic technique that records electrical activity in muscles. Three affected brothers in the family showed myopathic features, suggesting that something beyond simple myotonia congenita was at play. This clinical ambiguity prompted the research team to perform whole-exome sequencing on the index patient, a technique that reads the protein-coding regions of the genome to identify disease-causing variants. The approach is particularly valuable in cases where the clinical picture does not point to a single gene, allowing researchers to scan thousands of genes simultaneously rather than testing one candidate at a time.

The genetic evaluation revealed a remarkable finding: two variants of the CLCN1 gene in a compound heterozygous state, meaning that the patient carried one variant on each copy of the gene. The first variant, c.1012 C > T (p.Arg338Ter), introduces a premature stop codon that truncates the chloride channel protein. The second, c.1355 C > T (p.Pro452Leu), substitutes a proline residue with leucine at position 452, a change that likely disrupts the protein’s structure and function. Compound heterozygosity for CLCN1 variants is consistent with autosomal recessive myotonia congenita, the more severe form of the disease. The finding explains the patient’s severe myotonia: with both copies of the CLCN1 gene compromised, the chloride channels in skeletal muscle membranes cannot function properly, producing the hyperexcitability that underlies the muscle stiffness. Sanger sequencing confirmed the variants, and co-segregation analyses within the family supported the recessive inheritance pattern.

But the story did not end there. In addition to the CLCN1 variants, the researchers identified a heterozygous variant in the DNM2 gene — c.2161G > A (p.Asp721Asn) — in three affected brothers with myopathic features. This variant substitutes an asparagine for an aspartic acid at position 721 of the dynamin-2 protein. Notably, the variant is classified as a variant of uncertain significance (VUS), meaning that its clinical impact cannot yet be determined with confidence. The classification reflects the fact that the variant has not been previously established as disease-causing, and its presence in affected individuals raises the possibility of its involvement in the accompanying myopathic phenotype. However, the researchers are careful to note that its contribution to the clinical manifestations remains uncertain and requires further investigation.

The co-existence of variants in two different neuromuscular disease genes within the same family is extraordinarily rare. Most patients with overlapping myotonia and myopathy carry variants in a single gene, or the overlap reflects the pleiotropic effects of one variant. The Iranian case suggests that the myopathic features in the affected brothers may be attributable to the DNM2 variant, while the severe myotonia stems from the compound heterozygous CLCN1 variants. This dual-hit model — two independent genetic defects producing two independent disease processes — offers a compelling explanation for a phenotype that would otherwise defy classification. The findings underscore the value of comprehensive genetic evaluation in patients with overlapping neuromuscular phenotypes, where a single-gene approach might miss the full genetic picture.

The technical details of the two genes illuminate why their co-existence produces such a distinctive clinical picture. The ClC-1 chloride channel is a voltage-gated channel that allows chloride ions to flow across the muscle membrane, stabilizing the resting potential and preventing repetitive firing. Variants that truncate the protein, such as p.Arg338Ter, typically produce non-functional channels through nonsense-mediated mRNA decay or misfolding. Missense variants, such as p.Pro452Leu, may disrupt the channel’s gating properties or its trafficking to the membrane. Dynamin-2, meanwhile, is a mechanochemical enzyme that assembles into helical polymers around membrane necks, catalyzing membrane fission during vesicle formation. In muscle fibers, dynamin-2 participates in the maintenance of the T-tubule system and nuclear positioning, and variants that alter its GTPase activity or its interactions with binding partners such as amphiphysin and BIN1 can produce the centronuclear architecture characteristic of ADCNM. The two proteins operate in entirely different cellular compartments and pathways, which explains why their co-existence produces a phenotype that combines electrical hyperexcitability with structural muscle disease.

The Iranian context adds another layer of significance to the finding. Consanguineous marriage remains relatively common in parts of Iran, increasing the likelihood of recessive disease within families. The recessive inheritance of myotonia congenita in this family is consistent with this demographic pattern, and the co-existence of a second neuromuscular variant within the same family highlights the diagnostic complexity that can arise in consanguineous populations. The researchers note that the family’s cooperation was essential to the study, and that written informed consent was obtained from all participants or their legal guardians. The study was approved by the Research Ethics Committee of Shahid Sadoughi University of Medical Sciences, and the datasets analyzed are not publicly available due to patient privacy and ethical restrictions.

The case offers a powerful lesson for the field of neuromuscular genetics. Patients with overlapping phenotypes — those whose symptoms do not fit a single disease category — may harbor variants in multiple genes, each contributing a distinct component of the clinical picture. Whole-exome sequencing, by scanning the entire coding genome simultaneously, allows researchers to identify such multi-gene co-existence that single-gene testing would miss. The Iranian family’s case demonstrates that the co-existence of myotonia and myopathy can reflect the co-existence of two independent genetic defects, each producing its own disease process. As genomic medicine becomes increasingly integrated into clinical practice, cases like this one will help clinicians understand that the human genome can produce clinical pictures far more complex than any single-gene model would suggest — and that comprehensive genetic evaluation remains the most powerful tool for unraveling them.

Subject of Research: Co-existence of CLCN1 and DNM2 variants in a phenotype overlapping myotonia and myopathy

Article Title: Co-existence of CLCN1 and DNM2 variants in a phenotype overlapping myotonia and myopathy

Article References: Haghighi, F. S., Kalantar, S. M., Ghasemi, N., Daneshipour, A., Mohammadi, S. A., Poorshekar, S., & Movahedinia, M. (2026). Co-existence of CLCN1 and DNM2 variants in a phenotype overlapping myotonia and myopathy. Molecular Biology Reports, 53(1), Article 1755. https://doi.org/10.1007/s11033-026-12805-8

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12805-8

Keywords: Co-existence, CLCN1, DNM2, variants, phenotype, overlapping, myotonia, myopathy, scientific research

The clinical spectrum of myotonic disorders is broad. Myotonic dystrophy type 1, or DM1, is the most common of them, with prevalence estimates based on clinical diagnosis ranging from one in six to ten thousand, although genetic screening data suggest as many as one in 2,100 people may be affected. DM1 results from an unstable expansion of CTG repeats in the DMPK gene on chromosome 19. The expanded transcripts exert a toxic gain of function, sequestering RNA-binding proteins and disrupting alternative splicing across the genome, which explains why the disease touches so many organ systems. Patients may develop progressive muscle wasting and weakness, cardiac conduction disease and cardiomyopathy, respiratory failure, cataracts, diabetes, thyroid dysfunction and cognitive impairment. Presentation varies enormously: some individuals live nearly normal lives and remain undiagnosed well into adulthood, while others lose ambulation and face shortened life expectancy from cardiorespiratory complications. Myotonic dystrophy type 2, caused by a CCTG expansion in the CNBP gene on chromosome 3, shares the same RNA-mediated spliceopathy mechanism but tends to produce a milder, proximal myopathy without the congenital forms or genetic anticipation seen in DM1.

Distinct from the dystrophies are the non-dystrophic myotonias, pure skeletal muscle channelopathies caused by variants in ion channel genes, with no systemic involvement and a normal life expectancy. Myotonia congenita, the most common with a prevalence of roughly two to seven per 100,000, stems from variants in CLCN1, the gene encoding the ClC-1 voltage-gated chloride channel essential for membrane repolarisation. It is the same channel whose function is secondarily disrupted in myotonic dystrophy. Paramyotonia congenita and sodium channel myotonia are allelic autosomal dominant disorders of SCN4A, the gene for the Nav1.4 sodium channel that generates the action potentials driving contraction. Paramyotonia is notorious for worsening with cold and repeated activity, and can be accompanied by episodic paralysis, while sodium channel myotonia may show both warm-up and paradoxical worsening. For many patients, pain and fatigue are as troublesome as the stiffness itself, and the visible normality of their appearance can make the condition a hidden disability.

The therapeutic mainstay for myotonia has long been sodium channel blockade. In paramyotonia and sodium channel myotonia the mechanism is direct, since the underlying SCN4A variants confer a gain of channel function that the drugs inhibit. In myotonia congenita and the dystrophies the effect is indirect: reducing persistent sodium current partially compensates for impaired chloride-mediated repolarisation. Mexiletine emerged as first-line therapy on the strength of clinical impression, and in 2012 the first randomised controlled trial confirmed its efficacy in non-dystrophic myotonia, with subsequent studies, including aggregated N-of-1 trials, consolidating the evidence. Secondary outcomes consistently showed benefits extending to quality of life, pain, fatigue, independence and emotional well-being. Lamotrigine joined the arsenal in 2017 when a phase 2 crossover trial in 22 patients demonstrated efficacy on the myotonia behaviour score, making these two drugs the only anti-myotonic agents with randomised trial evidence. A head-to-head phase 3 trial failed to show lamotrigine was non-inferior to mexiletine, but it still delivered considerable benefit, giving clinicians two credible options.

Both drugs have also shown efficacy in DM1, with favourable cardiac safety profiles in trials, though these studies were small, short and potentially subject to selection bias in a population where cardiac conduction defects are common. Evidence in DM2 remains far thinner, with no dedicated large randomised trials, forcing treatment strategies to be extrapolated from other populations. Cardiac caution has historically shadowed mexiletine because of its potential pro-arrhythmic properties, yet neither the trials nor 302.4 years of real-world follow-up in non-dystrophic myotonia demonstrated significant electrocardiographic changes, and observational data in myotonic dystrophy show no safety signal on conduction parameters. The FDA has issued a warning on lamotrigine based on in vitro class 1B sodium channel blocker activity, but this has not been replicated by other regulators, including the European Medicines Agency, and has not translated into observable effects on human cardiac conduction. A joint ILAE/AES task force now recommends baseline electrocardiography only for those over 60 or with multiple cardiovascular risk factors, with specialist review mandatory for known cardiac disease. Clinicians must also weigh the rare but serious risk of Stevens-Johnson syndrome with lamotrigine, which a 55-year review of the FDA adverse event database found accounted for nearly ten percent of reported cases.

Practical considerations are also reshaping prescribing. Mexiletine, licensed as Namuscla for adults with non-dystrophic myotonia in several countries and used off-label in children and in myotonic dystrophy, typically requires dosing up to three times daily, which can undermine adherence. Prolonged-release once-daily formulations are now in phase 3 trials: the HERCULES study in DM1 and DM2 and the ACHILLES study in non-dystrophic myotonia. Meanwhile, basic science continues to probe alternative targets. No specific chloride channel activators exist, but intriguing work has shown that niflumic acid, which acutely blocks the ClC-1 channel in transfected cells, paradoxically acts as a pharmacological chaperone that increases channel protein expression when applied over 24 hours. Potassium channel openers such as retigabine, withdrawn from the market in 2017 over blue pigmentation concerns, have inspired next-generation compounds in development.

The most dramatic shift, however, is in DM1, where an era of molecularly targeted clinical trials is underway. Several companies are developing therapies designed to reduce the mutant DMPK transcript or to prevent the sequestration of muscleblind-like protein 1, the key splicing regulator whose loss drives the downstream transcriptional chaos. Delivery strategies range from naked oligonucleotides to targeted conjugates and adeno-associated virus vectors, with studies progressing from early-phase work to phase 3. The most advanced candidate is del-desiran, an antibody-oligonucleotide conjugate that hijacks the transferrin receptor to ferry the drug into muscle. In the phase 2 MARINA trial it demonstrated target engagement and amelioration of aberrant alternative splicing in some patients, a proof of principle that has electrified the field. None of these approaches is curative, and the extent of achievable molecular and clinical correction remains uncertain, but they represent the first credible assault on the underlying pathology rather than its symptoms.

Translational challenges loom large. Many trials use video hand opening time as the primary endpoint, a measure that captures skeletal muscle excitability and likely reflects modulation of MBNL-dependent mis-splicing of ion channel transcripts, making it a useful proof-of-mechanism marker, but its relevance to broader clinical benefit in a multisystem disease is debated. Effects on the heart and brain may not be established for years and will depend on post-marketing surveillance. Delivery poses further difficulties: repeated intravenous infusions at six- to eight-week intervals demand substantial healthcare infrastructure and may limit scalability and central nervous system penetration. Alongside the genetic approaches, repurposed small molecules are advancing. Metformin showed signals of efficacy on the six-minute walk test in the MYOMET phase 2 study, though the primary endpoint was missed in the intention-to-treat population, and the larger phase 3 METFORMYO trial is now underway with the MFM-32 as its primary measure. Tideglusib, a GSK3-beta inhibitor tested in congenital and childhood-onset DM1, showed signals in cognitive and neuromuscular ratings without significant safety concerns, and a phase 2/3 study in children is recruiting. Erythromycin, which modulates MBNL-dependent splicing preclinically, was well tolerated in a phase 2 trial with promising improvements in splicing biomarkers and creatine kinase levels.

Symptomatic care continues to evolve in parallel. Excessive daytime sleepiness affects the majority of people with DM1, yet randomised evidence for psychostimulants such as modafinil remains thin. A phase 2 trial of pitolisant in 30 participants suggested improvements in subjective sleepiness but was not powered for statistical significance, and a small study of intravenous flumazenil found no benefit over placebo. The overall picture that emerges from the review is not one of replacement but of layering: mechanism-based therapies are being built on top of a symptomatic framework that already works reasonably well for myotonia, even as it leaves progressive weakness and multisystem degeneration unaddressed. The recurring theme, the authors note, is the gap between molecular target engagement and clinically meaningful benefit, a gap that applies equally to established drugs and to the new genetic agents. Whether the emerging therapies will ultimately change disease trajectory remains uncertain, but for patients who have waited decades for anything more than symptomatic relief, the pipeline now offers genuine hope, and clinicians are being urged to prepare for a practice landscape that may look radically different within a few years.

Subject of Research: Treatment advances for myotonia in myotonic dystrophy and non-dystrophic muscle channelopathies

Article Title: Treatment updates in myotonic disorders

Article References: Matthews, E., Specterman, M. J., & Mul, K. (2026). Treatment updates in myotonic disorders. Journal of Neurology, 273(10), Article 562. https://doi.org/10.1007/s00415-026-14073-9

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14073-9

Keywords: myotonia, myotonic dystrophy type 1, myotonia congenita, sodium channel blockers, mexiletine, lamotrigine, RNA splicing, oligonucleotide therapy, clinical trials, muscle channelopathies, DMPK gene, disease-modifying therapy

Myotonic dystrophies are autosomal dominant, multisystem disorders caused by toxic repeat expansions in DNA. DM1, the more common and generally more severe form, stems from an expanded CTG repeat in the DMPK gene, while DM2 arises from a CCTG expansion in intron 1 of the CNBP gene, formerly known as ZNF9. In both conditions, the mutant RNA accumulates in cell nuclei and sequesters RNA-binding proteins, producing a splicing defect that disrupts dozens of downstream genes. The result is a bewildering clinical spectrum: myotonia, the delayed relaxation of muscles after contraction; progressive weakness that in DM1 typically begins distally and in DM2 proximally; cataracts; cardiac conduction disturbances; respiratory insufficiency; endocrine dysfunction including diabetes and hypogonadism; and cognitive and gastrointestinal involvement. Because the molecular bottleneck is shared, both diseases overlap in many features, yet they differ markedly in age at onset, severity, and pace of progression, with DM2 often presenting as a milder, later-onset condition.

The Serbian team, led by Ana Azanjac Arsic and Stojan Peric, conducted a cross-sectional analysis of 391 patients with DM1 and 196 with DM2, all enrolled in a national registry whose establishment was approved by the relevant ethics committees. Each participant underwent a comprehensive workup: a detailed neuromuscular examination, electrophysiological testing, cardiac and respiratory evaluation, endocrine and laboratory assessment, skeletal and ophthalmologic examination, and measurement of functional status. Muscle strength was quantified using a modified Medical Research Council score, a standard grading system for assessing power in defined muscle groups. Because the study was explicitly exploratory, the investigators did not apply corrections for multiple statistical comparisons, a point they acknowledge; the results should therefore be viewed as hypothesis-generating signals that will need confirmation in independent cohorts.

In DM1, the sex distribution was nearly even, with a male-to-female ratio of 1.1 to 1, but the clinical burden was not. Men with DM1 carried a distinctly heavier neuromuscular load. They showed weaker grip and hand muscles in the distal upper limbs and weaker proximal lower limb muscles, and their myotonia lasted measurably longer on electrophysiological testing. Speech involvement in the form of dysarthria was more common in men, as was dysphagia, difficulty swallowing that carries a real risk of aspiration. Peripheral polyneuropathy, skeletal deformities, baldness, and infertility were all reported more frequently in male patients, and electrocardiographic abnormalities appeared more often as well. Taken together, the picture in DM1 is one of a more aggressive neuromuscular and cardiac disease in men, consistent with earlier hints from French national databases that male sex predicts greater severity and mortality in this disorder.

DM2 told a strikingly different story. Women outnumbered men in the cohort by a ratio of 1.5 to 1, an imbalance that echoes prior observations in European DM2 registries and remains one of the intriguing epidemiological puzzles of this disease. More importantly, the phenotypic axis of sex difference flipped. Women with DM2 displayed more pronounced weakness in the proximal muscles of the lower limbs, reduced respiratory capacity on pulmonary function testing, and a higher prevalence of cataracts. The cataract finding is particularly interesting because population studies have long suggested that estrogen protects the lens, and the loss of that protection after menopause may interact with the RNA toxicity that drives DM2 pathology. For women with DM2, the practical message is that breathing function and lens status deserve especially close surveillance.

Men with DM2 were not spared, however; their excess burden simply shifted to other systems. Male DM2 patients had longer myotonia duration, more frequent polyneuropathy, and higher rates of baldness and infertility, mirroring some of the male-predominant features seen in DM1. They also showed more hyperglycemia, pointing to a greater metabolic and endocrine load, and they required pacemaker implantation more often, a concrete marker of clinically significant cardiac conduction disease. The authors summarize this asymmetry elegantly: the greater neuromuscular burden falls on DM1 males and DM2 females, while cardiologic and endocrinologic or metabolic complications cluster in males across both disease types.

Why would sex sculpt the phenotype of an RNA-mediated disease so differently depending on which gene harbors the repeat? Several biological mechanisms offer plausible explanations. Sex hormones modulate muscle mass, insulin sensitivity, and cardiac electrophysiology, and estrogen in particular has documented protective effects on lens transparency and vascular function. Alternative splicing, the very process corrupted in myotonic dystrophy, is itself influenced by sex hormone-regulated splicing factors, meaning the toxic RNA may hijack different cellular programs in male and female tissues. Differences in repeat instability dynamics, X-chromosome-linked modifiers, and body composition could also contribute. None of these mechanisms has been definitively proven in humans, and the Serbian authors are careful to frame their study as descriptive; but the consistency of the male cardiac and metabolic signal across both DM1 and DM2 suggests a shared biological substrate rather than statistical noise.

The clinical implications are immediate and practical. A man with DM1, according to these data, warrants particularly vigilant monitoring of swallow function, speech, peripheral nerve status, and cardiac rhythm, with a low threshold for electrophysiological follow-up and pacemaker evaluation. A woman with DM2 should receive focused attention on proximal leg strength, respiratory function, and early cataract screening, while her male counterpart needs closer metabolic surveillance and cardiac follow-up. Risk stratification tools and clinical trial design have historically treated myotonic dystrophy cohorts as homogeneous; this study adds weight to the argument that sex must be incorporated as a stratifying variable, both to balance trial arms fairly and to detect treatment effects that might be masked or amplified in one sex. As antisense oligonucleotide and small-molecule therapies for myotonic dystrophy move toward the clinic, understanding which patients are most vulnerable to which complications could determine who benefits most and when.

The study also highlights the quiet power of national rare disease registries. No single center could have assembled 587 genetically confirmed myotonic dystrophy patients with this depth of phenotyping; a coordinated national effort spanning Belgrade, Kragujevac, Novi Sad, and Nis could. The cross-sectional design cannot establish whether sex differences emerge at disease onset or accumulate over time, and the absence of multiple-comparison correction means individual findings should be interpreted with appropriate caution. Yet the overall pattern, converging with prior reports from France, Germany, and international collaborations, paints a coherent picture: myotonic dystrophy is not one disease experienced identically by all patients, but a family of sex-modified trajectories. For the hundreds of thousands of people worldwide living with DM1 and DM2, that insight moves precision medicine one practical step closer, turning a demographic variable into a roadmap for personalized monitoring and care.

Subject of Research: Sex-related phenotypic differences in genetically confirmed myotonic dystrophy types 1 and 2 in a nationwide Serbian registry cohort

Article Title: Sex-related phenotypic differences in myotonic dystrophy types 1 and 2: a nationwide registry study from Serbia

Article References: Azanjac Arsic, A., Andrejic, N., Viric, V., Gunjic, I., Sreckovic, S., Rajic, S., Jovin, Z., Bozovic, I., Djordjevic, G., Basta, I., & Peric, S. (2026). Sex-related phenotypic differences in myotonic dystrophy types 1 and 2: a nationwide registry study from Serbia. Journal of Neurology, 273(10), Article 645. https://doi.org/10.1007/s00415-026-14190-5

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14190-5

Keywords: myotonic dystrophy type 1, myotonic dystrophy type 2, sex differences, muscle strength, myotonia, cardiac conduction, polyneuropathy, cataracts, respiratory function, infertility, patient registry, Serbia