RARE DISEASE
Collagen VI-related congenital muscular dystrophy
Collagen VI-related congenital muscular dystrophy
Collagen VI-related congenital muscular dystrophy
Synonyms: COL6-RD
Synonyms: COL6-RD
Synonyms: COL6-RD
Drug discovery
1
drug
With orphan designation
Overview
Collagen VI-related congenital muscular dystrophy (COL6-CMD) is a spectrum of rare genetic neuromuscular disorders caused by mutations in COL6A1, COL6A2, or COL6A3 genes. These mutations disrupt collagen VI, a critical extracellular matrix protein, leading to progressive muscle weakness, proximal joint contractures, distal hyperlaxity, and respiratory insufficiency. The disease ranges from Ullrich congenital muscular dystrophy (severe, early-onset) to Bethlem myopathy (milder, later-onset). Diagnosis combines clinical evaluation, genetic testing, muscle imaging, and biopsy. No cure exists, but proactive respiratory, orthopedic, and rehabilitative care improves quality of life [1][2][8][17].
Burden
Categories: rare genetic diseases, rare neurological diseases
Research Papers
61 drug discovery papers related to Collagen VI-related congenital muscular dystrophy, with 4 first-in-class and 0 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
61 drug discovery papers related to Collagen VI-related congenital muscular dystrophy, with 4 first-in-class and 0 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
2026-04-22 | Collagen VI–Related Myopathies: An Educational Overview of Molecular Pathogenesis, Variability of Clinical Presentations Spectrum, Diagnostic Approaches and Management Strategies
Collagen VI–related myopathies (COL6-RM) encompass a broad clinical spectrum of inherited neuromuscular disorders ranging from severe Ullrich congenital muscular dystrophy to milder Bethlem myopathy, caused by pathogenic variants in COL6A1, COL6A2, and COL6A3. The pathogenic disruptions in collagen VI compromise extracellular matrix stability, impair autophagic flux, promote mitochondrial permeability transition, and alter fibroblast–myofiber signaling. These disorders are characterized by proximal muscle weakness, joint contractures, distal hyperlaxity, and respiratory compromise. Advances in basic science have revealed that collagen VI deficiency disrupts extracellular matrix (ECM) integrity, impairs autophagy, induces mitochondrial dysfunction, and alters the myomatrix microenvironment, collectively driving progressive muscle degeneration. Diagnosis relies on a multimodal approach that integrates clinical assessment with muscle MRI, histopathology, and next-generation sequencing. Management remains largely supportive; however, emerging strategies, including autophagy enhancers, mitochondrial permeability transition pore (mPTP) inhibitors, extracellular matrix–targeting agents, and genebased therapies show promise for disease modification. Advances in molecular biology have reshaped the understanding of COL6-RM and opened new avenues for targeted treatment. Robust natural history studies and biomarker development are needed to accelerate translational progress. The objective is to synthesize current evidence regarding pathogenesis, clinical presentation, diagnostic modalities, and evolving therapeutic approaches in COL6-RM. This review integrates and synthesizes findings from molecular pathogenesis, diagnostic tools, clinical spectrum, imaging studies, and evolving management while highlighting future therapeutic directions with emphasis on recent mechanisms involving extracellular matrix dysfunction, autophagy impairment, mitochondrial dysregulation, and myomatrix remodeling.
2026-01-01 | First person – Arístides López-Márquez
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping researchers promote themselves alongside their papers. Arístides López-Márquez is first author on ‘ Col6a1 knock-in mice provide a promising pre-clinical model for collagen-VI-related dystrophies’, published in DMM. Arístides is a senior postdoctoral researcher in the lab of Cecilia Jiménez-Mallebrera at Sant Joan de Deu Research Institute (Barcelona, Spain) investigating advanced personalized therapies based on nucleic acids, such as gene editing or antisense oligonucleotides, for congenital muscular dystrophies and rare genetic diseases.
2025-12-31 | Beyond Genetics: Clinico-Pathological Recognition of Ullrich Muscular Dystrophy in a Resource-Limited Setting
Background: Ullrich congenital muscular dystrophy (UCMD) is a rare collagen VI–related myopathy caused by mutations in COL6A1, COL6A2, or COL6A3 genes. Although traditionally considered an autosomal recessive disorder, recent reports have identified autosomal dominant variants that cause the UCMD phenotype. Clinically, it is characterized by early‐onset muscle weakness, proximal joint contractures, and distal joint hyperlaxity. This condition frequently progresses to restrictive respiratory involvement, while typically sparing cognitive, sensory, and autonomic functions. Given this predictable trajectory, early integration of palliative care is increasingly emphasised to optimize quality of life and reduce crisis-driven interventions. UCMD is extremely rare, with an estimated prevalence of fewer than 1 in 1,000,000 births worldwide, though the exact frequency remains unknown. A definitive diagnosis requires genetic confirmation and immunohistochemistry, but such resources are often limited in low- and middle-income countries. Case summary: A 15-year-old male, born of a third-degree consanguineous marriage, presented to the internal medicine department with recurrent lower respiratory tract infections and respiratory distress. He was first evaluated at age 4 for progressive motor regression, difficulty ambulating, and multiple joint contractures. Over the next decade, he had progressive motor decline and restrictive pulmonary disease, while cognitive, sensory, autonomic, and cardiac functions remained preserved. Physical examination revealed proximal muscle weakness, contractures of elbows and ankles, lumbar lordosis, café-au-lait spots, and a waddling gait. Muscle biopsy demonstrated features consistent with a dystrophic process and mild non-specific myopathic changes. A clinical diagnosis of UCMD was established based on characteristic clinical findings and histopathological correlation due to the unavailability of genetic testing and collagen VI immunohistochemistry. The internal medicine team integrated palliative care principles in his management through holistic assessment, symptom management, caregiver support, advanced care planning, and multidisciplinary coordination. This case illustrates UCMD’s diagnostic challenges, natural history marked by progressive musculoskeletal and respiratory decline, and the imperative for early integration of palliative care principles in management. Conclusion: UCMD is a rare genetic disorder that is often underdiagnosed due to limited awareness and diagnostic challenges, particularly in resource-limited settings. Early diagnosis is essential to initiate supportive care, which can significantly improve quality of life. This case highlights the diagnostic value of comprehensive clinical evaluation and muscle biopsy in identifying UCMD. Increased awareness and expanded diagnostic testing programs are key to uncovering additional cases. Wider access to genetic testing is critical for diagnostic confirmation. Continued research into the molecular and genetic basis of UCMD will help to improve diagnosis and develop novel therapies. Owing to its rare occurrence, comprehensive epidemiological studies are needed to get more knowledge about its global incidence and natural history. Early palliative care integration is recommended to optimize patient and family well-being.
2026-04-22 | Collagen VI–Related Myopathies: An Educational Overview of Molecular Pathogenesis, Variability of Clinical Presentations Spectrum, Diagnostic Approaches and Management Strategies
Collagen VI–related myopathies (COL6-RM) encompass a broad clinical spectrum of inherited neuromuscular disorders ranging from severe Ullrich congenital muscular dystrophy to milder Bethlem myopathy, caused by pathogenic variants in COL6A1, COL6A2, and COL6A3. The pathogenic disruptions in collagen VI compromise extracellular matrix stability, impair autophagic flux, promote mitochondrial permeability transition, and alter fibroblast–myofiber signaling. These disorders are characterized by proximal muscle weakness, joint contractures, distal hyperlaxity, and respiratory compromise. Advances in basic science have revealed that collagen VI deficiency disrupts extracellular matrix (ECM) integrity, impairs autophagy, induces mitochondrial dysfunction, and alters the myomatrix microenvironment, collectively driving progressive muscle degeneration. Diagnosis relies on a multimodal approach that integrates clinical assessment with muscle MRI, histopathology, and next-generation sequencing. Management remains largely supportive; however, emerging strategies, including autophagy enhancers, mitochondrial permeability transition pore (mPTP) inhibitors, extracellular matrix–targeting agents, and genebased therapies show promise for disease modification. Advances in molecular biology have reshaped the understanding of COL6-RM and opened new avenues for targeted treatment. Robust natural history studies and biomarker development are needed to accelerate translational progress. The objective is to synthesize current evidence regarding pathogenesis, clinical presentation, diagnostic modalities, and evolving therapeutic approaches in COL6-RM. This review integrates and synthesizes findings from molecular pathogenesis, diagnostic tools, clinical spectrum, imaging studies, and evolving management while highlighting future therapeutic directions with emphasis on recent mechanisms involving extracellular matrix dysfunction, autophagy impairment, mitochondrial dysregulation, and myomatrix remodeling.
2026-01-01 | First person – Arístides López-Márquez
ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping researchers promote themselves alongside their papers. Arístides López-Márquez is first author on ‘ Col6a1 knock-in mice provide a promising pre-clinical model for collagen-VI-related dystrophies’, published in DMM. Arístides is a senior postdoctoral researcher in the lab of Cecilia Jiménez-Mallebrera at Sant Joan de Deu Research Institute (Barcelona, Spain) investigating advanced personalized therapies based on nucleic acids, such as gene editing or antisense oligonucleotides, for congenital muscular dystrophies and rare genetic diseases.
2025-12-31 | Beyond Genetics: Clinico-Pathological Recognition of Ullrich Muscular Dystrophy in a Resource-Limited Setting
Background: Ullrich congenital muscular dystrophy (UCMD) is a rare collagen VI–related myopathy caused by mutations in COL6A1, COL6A2, or COL6A3 genes. Although traditionally considered an autosomal recessive disorder, recent reports have identified autosomal dominant variants that cause the UCMD phenotype. Clinically, it is characterized by early‐onset muscle weakness, proximal joint contractures, and distal joint hyperlaxity. This condition frequently progresses to restrictive respiratory involvement, while typically sparing cognitive, sensory, and autonomic functions. Given this predictable trajectory, early integration of palliative care is increasingly emphasised to optimize quality of life and reduce crisis-driven interventions. UCMD is extremely rare, with an estimated prevalence of fewer than 1 in 1,000,000 births worldwide, though the exact frequency remains unknown. A definitive diagnosis requires genetic confirmation and immunohistochemistry, but such resources are often limited in low- and middle-income countries. Case summary: A 15-year-old male, born of a third-degree consanguineous marriage, presented to the internal medicine department with recurrent lower respiratory tract infections and respiratory distress. He was first evaluated at age 4 for progressive motor regression, difficulty ambulating, and multiple joint contractures. Over the next decade, he had progressive motor decline and restrictive pulmonary disease, while cognitive, sensory, autonomic, and cardiac functions remained preserved. Physical examination revealed proximal muscle weakness, contractures of elbows and ankles, lumbar lordosis, café-au-lait spots, and a waddling gait. Muscle biopsy demonstrated features consistent with a dystrophic process and mild non-specific myopathic changes. A clinical diagnosis of UCMD was established based on characteristic clinical findings and histopathological correlation due to the unavailability of genetic testing and collagen VI immunohistochemistry. The internal medicine team integrated palliative care principles in his management through holistic assessment, symptom management, caregiver support, advanced care planning, and multidisciplinary coordination. This case illustrates UCMD’s diagnostic challenges, natural history marked by progressive musculoskeletal and respiratory decline, and the imperative for early integration of palliative care principles in management. Conclusion: UCMD is a rare genetic disorder that is often underdiagnosed due to limited awareness and diagnostic challenges, particularly in resource-limited settings. Early diagnosis is essential to initiate supportive care, which can significantly improve quality of life. This case highlights the diagnostic value of comprehensive clinical evaluation and muscle biopsy in identifying UCMD. Increased awareness and expanded diagnostic testing programs are key to uncovering additional cases. Wider access to genetic testing is critical for diagnostic confirmation. Continued research into the molecular and genetic basis of UCMD will help to improve diagnosis and develop novel therapies. Owing to its rare occurrence, comprehensive epidemiological studies are needed to get more knowledge about its global incidence and natural history. Early palliative care integration is recommended to optimize patient and family well-being.
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Drug Discovery Landscape
1 orphan drug designation for Collagen VI-related congenital muscular dystrophy.
1 orphan drug designation for Collagen VI-related congenital muscular dystrophy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Omigapil maleate | small molecules | EMA | 2008-05-08 | — | Santhera Pharmaceuticals (Deutschland) GmbH |
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