RARE DISEASE
Congenital muscular dystrophy
Congenital muscular dystrophy
Congenital muscular dystrophy
Synonyms: CMD, MDC
Synonyms: CMD, MDC
Synonyms: CMD, MDC
Drug discovery
4
drugs
With orphan designations
Overview
Congenital muscular dystrophy (CMD) comprises rare genetic neuromuscular disorders presenting at birth/infancy with hypotonia, progressive muscle weakness, and dystrophic muscle pathology. Over 30 subtypes exist, classified by affected genes/proteins (e.g., laminin-α2, collagen VI). Clinical features include contractures, respiratory insufficiency, and variable CNS/ocular involvement. Diagnosis combines clinical assessment, muscle biopsy, and genetic testing [1][7][15].
Burden
Mortality: Respiratory/cardiac complications account for 60-80% of deaths, often in early adulthood [1][9]
Economic impact: Annual per-patient costs exceed $100,000 (USD) when accounting for medical care, assistive devices, and lost caregiver productivity [4][5]
Functional decline: >70% develop scoliosis; 40% require wheelchair dependence by adolescence [5][12][15]
Therapies
Supportive care: Respiratory support, physical therapy, orthopedic interventions (spinal fusion, contracture management) [8][19]
Pharmacologic: Corticosteroids for specific subtypes; investigational gene therapies (exon skipping, CRISPR/Cas9) in preclinical stages [3][13][16]
Multidisciplinary management: Cardiac surveillance, nutritional support, and adaptive equipment [5][11]
Categories: rare genetic diseases, rare neurological diseases
Research Papers
625 drug discovery papers about Congenital muscular dystrophy, with 6 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
625 drug discovery papers about Congenital muscular dystrophy, with 6 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-04 | Adenine base editing correction of LMNA c.745C>T (p.R249W) in congenital muscular dystrophy myoblasts improves cellular phenotype while revealing deleterious p.L248P bystander effects
ABSTRACT Background LMNA -related congenital muscular dystrophy (L-CMD) is a rare, life-threatening genetic disorder caused by point mutations in the LMNA gene, for which no effective treatment currently exists. It is characterized by early-onset muscle weakness, dropped-head syndrome, hypotonia, cardiac complications, and restrictive lung disease, frequently leading to premature death. The LMNA c.745C>T (p.R249W) mutation is the most prevalent amongst L-CMD patients. Given its monogenic nature, L-CMD represents a compelling candidate for gene therapy approaches. Results In this study, we investigated the therapeutic potential of adenine base editing (ABE) to correct the pathogenic LMNA c.745C>T (p.R249W) mutation in human myoblasts. We evaluated multiple ABE variants and single-guide RNAs (sgRNAs), identifying optimal combinations that achieved efficient and specific correction of the mutant allele. However, we found that editing can also introduce an adjacent bystander mutation, c.743T>C (p.L248P). To determine the functional consequences of base editing, we established clonal cell lines reverted to wild type or harboring the p.L248P variant. Whereas wild-type edited cells showed a clear correction for all the studied parameters that were abnormal in R249W myoblasts, we found that L248P cells show nuclear abnormalities resembling those of R249W mutant cells, and their cellular function is partially compromised. These results demonstrate that ABE can effectively target the LMNA c.745C>T mutation but also reveal the significant impact of bystander edits on cellular physiology. Conclusions Our findings provide proof-of-concept for the application of base editing as a therapeutic strategy for L-CMD, while underscoring the necessity of precise editing technologies to ensure both efficacy and safety in future clinical translation.
2026-07-31 | Pediatric Ocular Abnormalities: A Pictorial Review of Genetic, Metabolic, and Syndromic Associations. Part 1: Abnormalities of the Globe and Lens
SUMMARY:
This 2-part pictorial review illustrates the spectrum of ocular abnormalities in pediatric imaging and highlights their diagnostic and prognostic implications. Part 1 focuses on globe and lens abnormalities, including the microphthalmos-anophthalmos-coloboma (MAC) complex, macrophthalmos, congenital cataracts, and lens dislocation. Part 2 covers posterior segment and optic pathway abnormalities, ranging from persistent fetal vasculature to optic nerve pathologies. Selected cases demonstrate key associated brain and spine imaging features, syndromic associations, and prognostic significance, showing how orbital imaging can guide targeted genetic testing, improve diagnostic accuracy, and differentiate overlapping conditions. By systematically evaluating the orbits on pediatric brain MRI, radiologists can identify genetic disorders and syndromes early, support clinical and genetic assessment, and improve patient care.
Abbreviations
CHARGE: coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness CIMDAG: cerebellar hypoplasia and cataracts, intellectual disability, congenital microcephaly, dystonia and dyserythropoietic anemia, and growth retardation CS: Cockayne syndrome COACH syndrome: cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, hepatic fibrosis ECCL: encephalocraniocutaneous lipomatosis FCMD: Fukuyama congenital muscular dystrophy JS: Joubert syndrome MAC: microphthalmos-anophthalmos-coloboma MEB: muscle-eye-brain disease MGDA: morning glory disc anomaly OAVS: oculo-auriculo-vertebral spectrum OCCS: oculocerebrocutaneous syndrome PBS: Poretti-Boltshauser syndrome TORCH: toxoplasmosis, other agents (such as HIV, syphilis, and Zika), rubella, cytomegalovirus, and herpes simplex virus WMS: Weill-Marchesani syndrome WWS: Walker-Warburg syndrome
2026-07-30 | Triple-AAV intein-mediated gene therapy ameliorates dystrophic phenotype in MDC1A mice.
Several therapies using adeno-associated viruses (AAVs) as a gene delivery tool have received marketing approval in the past. However, potential applications of AAVs are limited by their restricted gene packaging capacities (<4.7 kb). Many monogenic diseases are caused by large complex genes with hundreds of pathogenic variants that exceed AAV capacity. Merosin-deficient congenital muscular dystrophy type 1A is a severe monogenic recessive disease caused by the absence of functional copies of the LAMA2 gene. To date, no treatment options are available, with the most promising approach being gene replacement therapy to provide a functional copy. The LAMA2 coding sequence, spanning 9.3 kb, encodes laminin-α2, a subunit of the trimeric protein Laminin-211 found in the basement membrane of skeletal muscle cells and Schwann cells. Efforts have been focused on gene or protein replacement along with basement membrane engineering. Here, we exploit the ability of inteins to reconstitute full-length protein in a scarless manner. Using a combination of three AAVs, each encoding one fragment of the laminin-α2 protein flanked by a short split intein, resulted in the complete reconstitution of Laminin-α2 and an improvement of the histopathological features of the dy2j dystrophic mouse model.
2026-07-27 | Cortical organoids from congenital DM1 PSCs reveal MBNL-dependent corticogenesis defects and enable preclinical testing of therapeutic compounds
ABSTRACT Myotonic dystrophy type 1 (DM1) is caused by an expansion of a CTG repeat in the 3′ untranslated region of the DMPK gene, leading to accumulation of toxic CUG-repeat RNAs, sequestration of MBNL proteins and widespread splicing dysregulation. Congenital DM1 (CDM), the most severe form of the disease, is associated with profound muscular and neurodevelopmental defects, yet the mechanisms underlying early human brain involvement remain poorly understood. Here, we generated cortical organoids from patient-derived pluripotent stem cells carrying >1000 CTG repeats, an expansion typically associated with CDM, to model early human neurodevelopment. DM1 molecular and cellular hallmarks were detected at early developmental stages, including nuclear DMPK RNA foci in neural progenitor cells and reduced proliferative capacity. As organoids matured, CDM cultures displayed altered cortical composition, with reduced CTIP2⁺ and SATB2⁺ neuronal populations and increased NFIA⁺/GFAP⁺ glial cells. In parallel, 120-day-old organoids recapitulated splicing abnormalities previously identified in DM1 patient brain tissue. To assess the contribution of MBNL dysfunction, we analyzed cortical organoids derived from MBNL2 and MBNL1/2/3 knockout induced pluripotent stem cells, which reproduced key neurodevelopmental phenotypes observed in CDM organoids, supporting a central role for MBNL loss of function in impaired corticogenesis. Finally, we evaluated the translational relevance of this model using tideglusib and erythromycin, two compounds currently under clinical evaluation in DM1 patients. Both treatments reduced DMPK RNA foci and restored proliferation defects in SOX2⁺ neural progenitors. Together, these findings establish cortical organoids as a robust human model of CDM-associated neurodevelopmental defects, uncover MBNL-dependent mechanisms underlying early corticogenesis impairment and demonstrate the utility of this platform for translational therapeutic discovery in DM1.
2026-07-02 | Muscle-Specific Kinase Signaling and Its Therapeutic Potential.
The function of the neuromuscular junction (NMJ) is compromised in many neuromuscular diseases (NMDs) such as autoimmune or congenital myasthenia gravis (MG), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and muscular dystrophies. The NMJ contains muscle-specific kinase (MuSK), which is a critical regulator of NMJ integrity and function. Activating the MuSK signaling cascade may have therapeutic potential in several of these NMDs that are characterized by impaired neuromuscular communication. The MuSK signaling cascade consists of different components and can be activated with interventions at different levels. In the past years, different therapeutic strategies using an engineered recombinant agrin comprised of the C-terminal fragment of the protein (mini-agrin), gene therapy of key proteins in this pathway, agonist MuSK antibodies, and SRC homology 2 domain-containing phosphotyrosine phosphatase 2 (SHP2) inhibitors have been further developed for this purpose. Each of these strategies engages distinct signaling components: mini-agrin, both as recombinant protein and gene therapy, enhances agrin-Lrp4-MuSK interaction; Dok7 gene therapy amplifies MuSK phosphorylation; Lrp4 gene therapy enhances agrin responsiveness; MuSK agonist antibodies bypass upstream defects and promote downstream signaling; SHP2 inhibitors prolong the duration of active MuSK signaling. These therapeutic strategies have ameliorated NMJ integrity and function in several preclinical models of MG, motor neuron diseases, and muscular dystrophies. In this review, we highlight MuSK signaling as a possible therapeutic target, describe the therapeutic efficacy of intervention in MuSK signaling in different NMDs, and present an outlook on future clinical development.
2026-08-04 | Adenine base editing correction of LMNA c.745C>T (p.R249W) in congenital muscular dystrophy myoblasts improves cellular phenotype while revealing deleterious p.L248P bystander effects
ABSTRACT Background LMNA -related congenital muscular dystrophy (L-CMD) is a rare, life-threatening genetic disorder caused by point mutations in the LMNA gene, for which no effective treatment currently exists. It is characterized by early-onset muscle weakness, dropped-head syndrome, hypotonia, cardiac complications, and restrictive lung disease, frequently leading to premature death. The LMNA c.745C>T (p.R249W) mutation is the most prevalent amongst L-CMD patients. Given its monogenic nature, L-CMD represents a compelling candidate for gene therapy approaches. Results In this study, we investigated the therapeutic potential of adenine base editing (ABE) to correct the pathogenic LMNA c.745C>T (p.R249W) mutation in human myoblasts. We evaluated multiple ABE variants and single-guide RNAs (sgRNAs), identifying optimal combinations that achieved efficient and specific correction of the mutant allele. However, we found that editing can also introduce an adjacent bystander mutation, c.743T>C (p.L248P). To determine the functional consequences of base editing, we established clonal cell lines reverted to wild type or harboring the p.L248P variant. Whereas wild-type edited cells showed a clear correction for all the studied parameters that were abnormal in R249W myoblasts, we found that L248P cells show nuclear abnormalities resembling those of R249W mutant cells, and their cellular function is partially compromised. These results demonstrate that ABE can effectively target the LMNA c.745C>T mutation but also reveal the significant impact of bystander edits on cellular physiology. Conclusions Our findings provide proof-of-concept for the application of base editing as a therapeutic strategy for L-CMD, while underscoring the necessity of precise editing technologies to ensure both efficacy and safety in future clinical translation.
2026-07-31 | Pediatric Ocular Abnormalities: A Pictorial Review of Genetic, Metabolic, and Syndromic Associations. Part 1: Abnormalities of the Globe and Lens
SUMMARY:
This 2-part pictorial review illustrates the spectrum of ocular abnormalities in pediatric imaging and highlights their diagnostic and prognostic implications. Part 1 focuses on globe and lens abnormalities, including the microphthalmos-anophthalmos-coloboma (MAC) complex, macrophthalmos, congenital cataracts, and lens dislocation. Part 2 covers posterior segment and optic pathway abnormalities, ranging from persistent fetal vasculature to optic nerve pathologies. Selected cases demonstrate key associated brain and spine imaging features, syndromic associations, and prognostic significance, showing how orbital imaging can guide targeted genetic testing, improve diagnostic accuracy, and differentiate overlapping conditions. By systematically evaluating the orbits on pediatric brain MRI, radiologists can identify genetic disorders and syndromes early, support clinical and genetic assessment, and improve patient care.
Abbreviations
CHARGE: coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness CIMDAG: cerebellar hypoplasia and cataracts, intellectual disability, congenital microcephaly, dystonia and dyserythropoietic anemia, and growth retardation CS: Cockayne syndrome COACH syndrome: cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, hepatic fibrosis ECCL: encephalocraniocutaneous lipomatosis FCMD: Fukuyama congenital muscular dystrophy JS: Joubert syndrome MAC: microphthalmos-anophthalmos-coloboma MEB: muscle-eye-brain disease MGDA: morning glory disc anomaly OAVS: oculo-auriculo-vertebral spectrum OCCS: oculocerebrocutaneous syndrome PBS: Poretti-Boltshauser syndrome TORCH: toxoplasmosis, other agents (such as HIV, syphilis, and Zika), rubella, cytomegalovirus, and herpes simplex virus WMS: Weill-Marchesani syndrome WWS: Walker-Warburg syndrome
2026-07-30 | Triple-AAV intein-mediated gene therapy ameliorates dystrophic phenotype in MDC1A mice.
Several therapies using adeno-associated viruses (AAVs) as a gene delivery tool have received marketing approval in the past. However, potential applications of AAVs are limited by their restricted gene packaging capacities (<4.7 kb). Many monogenic diseases are caused by large complex genes with hundreds of pathogenic variants that exceed AAV capacity. Merosin-deficient congenital muscular dystrophy type 1A is a severe monogenic recessive disease caused by the absence of functional copies of the LAMA2 gene. To date, no treatment options are available, with the most promising approach being gene replacement therapy to provide a functional copy. The LAMA2 coding sequence, spanning 9.3 kb, encodes laminin-α2, a subunit of the trimeric protein Laminin-211 found in the basement membrane of skeletal muscle cells and Schwann cells. Efforts have been focused on gene or protein replacement along with basement membrane engineering. Here, we exploit the ability of inteins to reconstitute full-length protein in a scarless manner. Using a combination of three AAVs, each encoding one fragment of the laminin-α2 protein flanked by a short split intein, resulted in the complete reconstitution of Laminin-α2 and an improvement of the histopathological features of the dy2j dystrophic mouse model.
2026-07-27 | Cortical organoids from congenital DM1 PSCs reveal MBNL-dependent corticogenesis defects and enable preclinical testing of therapeutic compounds
ABSTRACT Myotonic dystrophy type 1 (DM1) is caused by an expansion of a CTG repeat in the 3′ untranslated region of the DMPK gene, leading to accumulation of toxic CUG-repeat RNAs, sequestration of MBNL proteins and widespread splicing dysregulation. Congenital DM1 (CDM), the most severe form of the disease, is associated with profound muscular and neurodevelopmental defects, yet the mechanisms underlying early human brain involvement remain poorly understood. Here, we generated cortical organoids from patient-derived pluripotent stem cells carrying >1000 CTG repeats, an expansion typically associated with CDM, to model early human neurodevelopment. DM1 molecular and cellular hallmarks were detected at early developmental stages, including nuclear DMPK RNA foci in neural progenitor cells and reduced proliferative capacity. As organoids matured, CDM cultures displayed altered cortical composition, with reduced CTIP2⁺ and SATB2⁺ neuronal populations and increased NFIA⁺/GFAP⁺ glial cells. In parallel, 120-day-old organoids recapitulated splicing abnormalities previously identified in DM1 patient brain tissue. To assess the contribution of MBNL dysfunction, we analyzed cortical organoids derived from MBNL2 and MBNL1/2/3 knockout induced pluripotent stem cells, which reproduced key neurodevelopmental phenotypes observed in CDM organoids, supporting a central role for MBNL loss of function in impaired corticogenesis. Finally, we evaluated the translational relevance of this model using tideglusib and erythromycin, two compounds currently under clinical evaluation in DM1 patients. Both treatments reduced DMPK RNA foci and restored proliferation defects in SOX2⁺ neural progenitors. Together, these findings establish cortical organoids as a robust human model of CDM-associated neurodevelopmental defects, uncover MBNL-dependent mechanisms underlying early corticogenesis impairment and demonstrate the utility of this platform for translational therapeutic discovery in DM1.
2026-07-02 | Muscle-Specific Kinase Signaling and Its Therapeutic Potential.
The function of the neuromuscular junction (NMJ) is compromised in many neuromuscular diseases (NMDs) such as autoimmune or congenital myasthenia gravis (MG), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and muscular dystrophies. The NMJ contains muscle-specific kinase (MuSK), which is a critical regulator of NMJ integrity and function. Activating the MuSK signaling cascade may have therapeutic potential in several of these NMDs that are characterized by impaired neuromuscular communication. The MuSK signaling cascade consists of different components and can be activated with interventions at different levels. In the past years, different therapeutic strategies using an engineered recombinant agrin comprised of the C-terminal fragment of the protein (mini-agrin), gene therapy of key proteins in this pathway, agonist MuSK antibodies, and SRC homology 2 domain-containing phosphotyrosine phosphatase 2 (SHP2) inhibitors have been further developed for this purpose. Each of these strategies engages distinct signaling components: mini-agrin, both as recombinant protein and gene therapy, enhances agrin-Lrp4-MuSK interaction; Dok7 gene therapy amplifies MuSK phosphorylation; Lrp4 gene therapy enhances agrin responsiveness; MuSK agonist antibodies bypass upstream defects and promote downstream signaling; SHP2 inhibitors prolong the duration of active MuSK signaling. These therapeutic strategies have ameliorated NMJ integrity and function in several preclinical models of MG, motor neuron diseases, and muscular dystrophies. In this review, we highlight MuSK signaling as a possible therapeutic target, describe the therapeutic efficacy of intervention in MuSK signaling in different NMDs, and present an outlook on future clinical development.
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Drug Discovery Landscape
4 orphan drug designations for Congenital muscular dystrophy.
4 orphan drug designations for Congenital muscular dystrophy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
adeno associated vector (serotype AAV MYO2) encoding the fukutin related protein (ssAAVMYO2.tMCK.FKRP) | gene therapies | FDA | 2025-09-04 | — | Cure Rare Disease |
Insulin-like Growth Factor-1 | proteins | FDA | 2022-04-11 | — | Sarcomed AB |
Human laminin-111, recombinant | proteins | EMA | 2021-01-06 | — | Maxia Strategies-Europe Limited |
omigapil | small molecules | FDA | 2008-06-24 | — | Santhera Pharmaceuticals (Switzerland) Limited |
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