RARE DISEASE
Myotonic syndrome
Myotonic syndrome
Myotonic syndrome
Drug discovery
1
drug
With orphan designation
Overview
Myotonic dystrophy (DM), the most common adult-onset muscular dystrophy, is an autosomal dominant disorder caused by CTG/CCTG repeat expansions. It manifests with progressive muscle weakness, myotonia, cardiac conduction defects, cataracts, endocrine dysfunction, and multisystem involvement. Clinical severity varies widely, from mild late-onset forms to congenital presentations with significant disability. Management focuses on symptomatic care and surveillance for complications [6][7][13].
Burden
Therapies
Symptomatic control: Mexiletine for myotonia, pacemakers for arrhythmias, CPAP for sleep apnea [3][8].
Rehabilitation: Physiotherapy, speech therapy, and assistive devices to maintain function [3][17].
Monitoring: Regular cardiac/respiratory evaluations to mitigate life-threatening complications [6][15].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
1,074 drug discovery papers about Myotonic syndrome, with 7 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,074 drug discovery papers about Myotonic syndrome, with 7 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-15 | An Ultrastructural and Proteomic Analysis in DM1 Young Adults' Myoblasts: Stressed RER and Mitochondrial Dysfunction Involvement.
Myotonic dystrophy type 1 (DM1) is a progressive muscular disorder caused by the expansion of CTG repeats in the 3' UTR of the DMPK gene. Although the pathogenic mechanisms remain unclear, recent evidence suggests that activation of innate immune responses may contribute to disease progression. In this study, we examined the ultrastructure and proteomic data of myoblasts from young adult DM1 patients carrying approximately 800 and 1300 CTG repeats in order to investigate a link between cellular stress and immune activation. We observed activation of the type I interferon (IFN-I) pathway associated with rough endoplasmic reticulum stress (sRER). The sRER response is likely triggered by the accumulation of toxic RNA species generated from the expanded DMPK allele. Our data suggest that this inappropriate activation of the IFN-I pathway contributes to muscle pathology, not by blocking differentiation directly, but through chronic stress signalling. These findings support a model in which innate immune dysregulation plays a central role in DM1 muscle degeneration and highlight the IFN1 pathway as a potential therapeutic target for restoring normal muscle function.
2026-08-12 | Schwartz-Jampel Syndrome: A Case Report with Clinical and Phenotypic Insights
Schwartz-Jampel Syndrome (SJS) is a rare autosomal recessive disorder characterised by myotonia, craniofacial dysmorphism and skeletal dysplasia, resulting from pathogenic variants in Heparan Sulfate Proteoglycan 2 (HSPG2). Pathogenic variants disrupt perlecan function, resulting in abnormal cartilage development and impaired neuromuscular transmission. A three-year and fivemonth-old male presented with blepharophimosis, generalised muscle stiffness, delayed motor milestones and gait abnormality. Electromyography demonstrated continuous spontaneous myotonic discharges. Radiographs revealed metaphyseal dysplasia with epiphyseal abnormalities. Molecular testing identified three heterozygous HSPG2 variants with parental carrier status, consistent with compound heterozygosity. Carbamazepine and structured rehabilitation were administered. Follow-up demonstrated reduction in myotonia, improved gait parameters and decreased fall frequency. In early-onset myotonic disorders, SJS should be considered with characteristic craniofacial and skeletal features. Symptomatic treatment with sodium-channel–blocking agents and multidisciplinary rehabilitation may confer functional benefit.
2026-07-09 | Tissue-specific CTG•CAG expansion rate and disease severity are modified by DNA repair genes expression levels in myotonic dystrophy type 1 patients.
Myotonic dystrophy type 1 (DM1) is a multisystemic autosomal dominant disorder caused by the expansion of an unstable CTG•CAG repeat in the DMPK gene. This study examined whether differential expression of DNA repair genes in three different tissues from the same DM1 patient contributed to tissue-specific somatic instability of the repeat tract. RNA-Seq was used to quantify expression levels of eight DNA repair genes (MSH2, MSH3, MSH6, MLH1, MLH3, PMS2, LIG1, and FAN1). Results indicate that the expression levels varied significantly across tissues, with no inter-tissue correlations, suggesting independent regulation and patient-specific differences. Somatic expansion of the repeat tract in blood and muscle was effectively predicted by a complex ePALxAge interaction, while in muscle it was further influenced by MSH3 and PMS2 gene expression, confirming their role as tissue-specific genetic modifiers in DM1. Although only marginally significant, muscle expression of PMS2 and FAN1 appeared to affect age-at-onset: higher FAN1 expression was associated with reduced somatic expansion and later onset. Our findings also suggest a complex competitive balance between promoters and stabilizers of repeat instability, shaping muscle expansion dynamics and potentially modifying clinical onset. Overall, these results indicate that certain DNA repair genes exert stronger, tissue-dependent effects on somatic instability. We confirm that MSH3, PMS2, and FAN1 act as key modifiers not only of somatic expansion, especially in skeletal muscle, but also of DM1 severity. Although RT-qPCR data might be required to validate some of these results, these genes therefore represent promising therapeutic targets for modulating disease progression.
2026-07-09 | Elimination of myotonia improves myopathy in a muscleblind-like knockout model of myotonic dystrophy.
A cardinal sign of myotonic dystrophy type 1 (DM1) is myotonia, slow muscle relaxation after voluntary contraction. Myotonia results from mis-regulated splicing of chloride channel 1 (ClC-1), leading to loss of channel function and runs of involuntary action potentials in muscle fibers. Preceding the onset of weakness, myotonia is often the first symptom of DM1, and thus this raises the possibility that muscle hyperexcitability contributes to the subsequent weakness and myopathy. Here, we show that genomic deletion of ClC-1 exon 7a (E7a), a cryptic exon abnormally regulated in DM1, completely rescues of ClC-1 function and yields permanent elimination of myotonia in the muscleblind-like 1 (Mbnl1) knockout mouse model of DM1. The restoration of normal excitability results in normalization of muscle force generation, correction of fiber-type distribution, and improvement of muscle histology. E7a deletion also partially corrects the muscle transcriptome, including changes of differential gene expression and alternative splicing. These results indicate that E7a inclusion is a lynchpin splice event that contributes to myotonic myopathy, and support myotonia reduction as a therapeutic objective in DM1.
2026-07-03 | A simple, sensitive microsample LC-MS assay for quercetin and isorhamnetin in mouse and human plasma: application to EMIQ treatment in myotonic dystrophy type 1.
Quercetin, a dietary flavonoid with emerging therapeutic relevance in myotonic dystrophy type 1 (DM1), has low solubility and poor oral bioavailability. Enzymatically modified isoquercitrin (EMIQ), a water-soluble prodrug, raises systemic quercetin exposure. Pharmacokinetic studies require a sensitive assay that uses minimal sample volume. We developed a single-quadrupole liquid chromatography-mass spectrometry (LC-MS) assay for free quercetin, total quercetin (after enzymatic hydrolysis of glucuronide and sulfate conjugates), and the methylated metabolite isorhamnetin in mouse and human plasma. The method used protein precipitation, 10 µL of plasma, reversed-phase C18 separation, and single-ion recording of [M+H]+ adducts. Validation followed a fit-for-purpose approach consistent with M10 guidelines, and the assay was applied to plasma from EMIQ-treated DM1 and wild-type mice (15 g/L for 6 and 12 weeks). Calibration curves showed r2 > 0.99, with an LLOQ of 0.070 µM for quercetin in both matrices. The assay was successfully validated for quercetin in mouse and human plasma. Total quercetin and isorhamnetin were quantifiable in all treated mice. Exploratory analysis suggested glucuronidation as the major conjugation pathway. This simple, cost-effective microsampling assay suits preclinical and translational studies of EMIQ in DM1, though the conjugation findings remain exploratory.
2026-08-15 | An Ultrastructural and Proteomic Analysis in DM1 Young Adults' Myoblasts: Stressed RER and Mitochondrial Dysfunction Involvement.
Myotonic dystrophy type 1 (DM1) is a progressive muscular disorder caused by the expansion of CTG repeats in the 3' UTR of the DMPK gene. Although the pathogenic mechanisms remain unclear, recent evidence suggests that activation of innate immune responses may contribute to disease progression. In this study, we examined the ultrastructure and proteomic data of myoblasts from young adult DM1 patients carrying approximately 800 and 1300 CTG repeats in order to investigate a link between cellular stress and immune activation. We observed activation of the type I interferon (IFN-I) pathway associated with rough endoplasmic reticulum stress (sRER). The sRER response is likely triggered by the accumulation of toxic RNA species generated from the expanded DMPK allele. Our data suggest that this inappropriate activation of the IFN-I pathway contributes to muscle pathology, not by blocking differentiation directly, but through chronic stress signalling. These findings support a model in which innate immune dysregulation plays a central role in DM1 muscle degeneration and highlight the IFN1 pathway as a potential therapeutic target for restoring normal muscle function.
2026-08-12 | Schwartz-Jampel Syndrome: A Case Report with Clinical and Phenotypic Insights
Schwartz-Jampel Syndrome (SJS) is a rare autosomal recessive disorder characterised by myotonia, craniofacial dysmorphism and skeletal dysplasia, resulting from pathogenic variants in Heparan Sulfate Proteoglycan 2 (HSPG2). Pathogenic variants disrupt perlecan function, resulting in abnormal cartilage development and impaired neuromuscular transmission. A three-year and fivemonth-old male presented with blepharophimosis, generalised muscle stiffness, delayed motor milestones and gait abnormality. Electromyography demonstrated continuous spontaneous myotonic discharges. Radiographs revealed metaphyseal dysplasia with epiphyseal abnormalities. Molecular testing identified three heterozygous HSPG2 variants with parental carrier status, consistent with compound heterozygosity. Carbamazepine and structured rehabilitation were administered. Follow-up demonstrated reduction in myotonia, improved gait parameters and decreased fall frequency. In early-onset myotonic disorders, SJS should be considered with characteristic craniofacial and skeletal features. Symptomatic treatment with sodium-channel–blocking agents and multidisciplinary rehabilitation may confer functional benefit.
2026-07-09 | Tissue-specific CTG•CAG expansion rate and disease severity are modified by DNA repair genes expression levels in myotonic dystrophy type 1 patients.
Myotonic dystrophy type 1 (DM1) is a multisystemic autosomal dominant disorder caused by the expansion of an unstable CTG•CAG repeat in the DMPK gene. This study examined whether differential expression of DNA repair genes in three different tissues from the same DM1 patient contributed to tissue-specific somatic instability of the repeat tract. RNA-Seq was used to quantify expression levels of eight DNA repair genes (MSH2, MSH3, MSH6, MLH1, MLH3, PMS2, LIG1, and FAN1). Results indicate that the expression levels varied significantly across tissues, with no inter-tissue correlations, suggesting independent regulation and patient-specific differences. Somatic expansion of the repeat tract in blood and muscle was effectively predicted by a complex ePALxAge interaction, while in muscle it was further influenced by MSH3 and PMS2 gene expression, confirming their role as tissue-specific genetic modifiers in DM1. Although only marginally significant, muscle expression of PMS2 and FAN1 appeared to affect age-at-onset: higher FAN1 expression was associated with reduced somatic expansion and later onset. Our findings also suggest a complex competitive balance between promoters and stabilizers of repeat instability, shaping muscle expansion dynamics and potentially modifying clinical onset. Overall, these results indicate that certain DNA repair genes exert stronger, tissue-dependent effects on somatic instability. We confirm that MSH3, PMS2, and FAN1 act as key modifiers not only of somatic expansion, especially in skeletal muscle, but also of DM1 severity. Although RT-qPCR data might be required to validate some of these results, these genes therefore represent promising therapeutic targets for modulating disease progression.
2026-07-09 | Elimination of myotonia improves myopathy in a muscleblind-like knockout model of myotonic dystrophy.
A cardinal sign of myotonic dystrophy type 1 (DM1) is myotonia, slow muscle relaxation after voluntary contraction. Myotonia results from mis-regulated splicing of chloride channel 1 (ClC-1), leading to loss of channel function and runs of involuntary action potentials in muscle fibers. Preceding the onset of weakness, myotonia is often the first symptom of DM1, and thus this raises the possibility that muscle hyperexcitability contributes to the subsequent weakness and myopathy. Here, we show that genomic deletion of ClC-1 exon 7a (E7a), a cryptic exon abnormally regulated in DM1, completely rescues of ClC-1 function and yields permanent elimination of myotonia in the muscleblind-like 1 (Mbnl1) knockout mouse model of DM1. The restoration of normal excitability results in normalization of muscle force generation, correction of fiber-type distribution, and improvement of muscle histology. E7a deletion also partially corrects the muscle transcriptome, including changes of differential gene expression and alternative splicing. These results indicate that E7a inclusion is a lynchpin splice event that contributes to myotonic myopathy, and support myotonia reduction as a therapeutic objective in DM1.
2026-07-03 | A simple, sensitive microsample LC-MS assay for quercetin and isorhamnetin in mouse and human plasma: application to EMIQ treatment in myotonic dystrophy type 1.
Quercetin, a dietary flavonoid with emerging therapeutic relevance in myotonic dystrophy type 1 (DM1), has low solubility and poor oral bioavailability. Enzymatically modified isoquercitrin (EMIQ), a water-soluble prodrug, raises systemic quercetin exposure. Pharmacokinetic studies require a sensitive assay that uses minimal sample volume. We developed a single-quadrupole liquid chromatography-mass spectrometry (LC-MS) assay for free quercetin, total quercetin (after enzymatic hydrolysis of glucuronide and sulfate conjugates), and the methylated metabolite isorhamnetin in mouse and human plasma. The method used protein precipitation, 10 µL of plasma, reversed-phase C18 separation, and single-ion recording of [M+H]+ adducts. Validation followed a fit-for-purpose approach consistent with M10 guidelines, and the assay was applied to plasma from EMIQ-treated DM1 and wild-type mice (15 g/L for 6 and 12 weeks). Calibration curves showed r2 > 0.99, with an LLOQ of 0.070 µM for quercetin in both matrices. The assay was successfully validated for quercetin in mouse and human plasma. Total quercetin and isorhamnetin were quantifiable in all treated mice. Exploratory analysis suggested glucuronidation as the major conjugation pathway. This simple, cost-effective microsampling assay suits preclinical and translational studies of EMIQ in DM1, though the conjugation findings remain exploratory.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Myotonic syndrome.
1 orphan drug designation for Myotonic syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
16-base single stranded RNA targeting miR-23b linked to oleic acid | RNAs | EMA | 2022-12-09 | — | Arthex Biotech S.L. |
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