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
63 drug discovery papers about Collagen VI-related congenital muscular dystrophy, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
63 drug discovery papers about Collagen VI-related congenital muscular dystrophy, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-29 | Expanding the phenotypic spectrum of COL6-related diseases: Motor neuropathy-like and neuromyopathy associated with COL6A3 c.7447A>G.
Collagen VI is a key component of the extracellular matrix. Murine models suggest that it regulates Schwann cell differentiation, peripheral nerve myelination and regeneration after injury. Neuropathic findings in COL6-related dystrophies (COL6-RDs) have been rarely reported, often based on electromyography findings without nerve conduction abnormalities. We report 37 patients (1.5-79 years), from 32 different families, carrying the COL6A3-c.7447A>G variant, presenting with neuropathic/neuromyopathic findings. Most patients presented in the first decade of life with an abnormal gait and frequent falls (54%), delayed motor milestones (32%) and foot deformities (19%). Predominant distal weakness was present in 46% of patients, whereas 27% exhibited proximo-distal involvement. Foot deformities were present in 32%; joint contractures were present in 83%, exclusively affecting lower limbs in 49%. At last evaluation, mild restrictive respiratory insufficiency was diagnosed in 1 patient and nocturnal hypoventilation requiring non-invasive ventilation in 2. Most patients (89%) remained ambulant at last assessment. Nerve conduction studies (n=29) revealed reduced lower-limb CMAP amplitudes in 79%. Needle EMG (n=31) revealed chronic neurogenic-like features in 84% and mixed neuromyogenic features in 13%. Muscle biopsy (n=12) demonstrated features suggestive of neuropathic involvement in 4 (33%) and mixed neuropathic-myopathic features in 5 (42%). Muscle imaging (n=23) revealed a typical COL6-RD pattern in 48% (with severe distal lower limb atrophy in 65%), and isolated or predominant distal atrophy in 30%. Inheritance was autosomal recessive in all cases. The COL6A3-c.7447A>G variant was present in homozygosity in 24 (65%) and in compound heterozygosity with a second COL6A3 variant in 13 (35%), including 8 previously unreported. We report an expanding phenotypic spectrum associated with COL6-RD, underscoring its relevance in the diagnostic evaluation of distal motor neuropathy-like or neuromyopathic presentations.
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.
2025-12-30 | Tendon Dysfunction in Collagen VI-Related Myopathies: Novel Mechanistic Insights with Therapeutic Potential.
Collagen VI-related myopathies (COL6-RM) encompass a spectrum of disorders characterized by muscle weakness, joint contractures, and connective tissue abnormalities resulting from mutations in the collagen VI genes. While muscle pathology has been extensively studied, tendon dysfunction has emerged as a critical yet underexplored contributor to disease severity, particularly in the development of joint contractures. Tendons from patients and animal models show disrupted collagen fibrillogenesis, altered extracellular matrix (ECM) composition, and impaired cellular mechanotransduction. Various defects in ECM remodeling pathways further exacerbate tendon pathology. Importantly, current clinical management remains limited to orthopedic interventions with modest outcomes, and targeted pharmacological strategies or gene-editing therapies are not yet available for clinical application. Therefore, understanding the basic pathogenic mechanisms underlying tendon dysfunction is essential for identifying novel therapeutic targets. This review provides a comprehensive synthesis of current understanding and recent advances concerning the role of mutated collagen VI in cellular and molecular mechanisms underlying tendon dysfunction. Emphasis is placed on the role of mutated collagen VI in the modulation of key signaling pathways related to mechanotransduction and primary cilium function in COL6-RM. By discussing these multifaceted contributions to disease pathogenesis, this review outlines future research directions in the field and highlights potential pathways for targeted therapeutic interventions.
2025-04-07 | Inter- and intra-familial phenotypic variability of autosomal dominant collagen VI related disorder.
Collagen VI-related disorder (COL6-RD) is an inherited neuromuscular disease characterized by a broad spectrum of phenotypes. Eight families with autosomal dominant COL6-RD were recruited. Clinical manifestations, laboratory findings, electrophysiological results, molecular analyses, and pathological outcomes of eight index patients and their affected family members were systematically collected and reviewed. Pathogenic variants were identified in four families in the COL6A1 gene, one family in the COL6A2 gene, and three families in the COL6A3 gene. Among the index patients, three were classified as moderate progressive Ullrich congenital muscular dystrophy (UCMD), four exhibited mild UCMD or Bethlem myopathy, and one was diagnosed with Bethlem myopathy. The phenotypic presentation was relatively consistent within four families. However, intra-familial phenotypic variability was observed in four families, encompassing a wide range of onset ages, patterns and degrees of muscle weakness, rates of contracture progression, severity of skin changes, and age at loss of ambulation. Inter- and intra-familial phenotypic variability is prevalent in autosomal dominant COL6-RDs. When predicting the clinical course and severity for patients, it is crucial to integrate a comprehensive set of information, including mutation sites and types, family history, and early presenting features.
2025-04-03 | Characterization of severe COL6-related dystrophy due to the recurrent variant COL6A1 c.930+189C>T.
Collagen VI-related dystrophies manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterized by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognized later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and muscle pathology features highly suggestive of collagen VI-related dystrophy, some patients had remained without an identified causative variant in COL6A1, COL6A2 or COL6A3. With combined muscle RNA sequencing and whole-genome sequencing, we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterized an international cohort of 44 patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen VI genes. Patients manifest a consistently severe phenotype characterized by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD, except for one patient with somatic mosaicism for this COL6A1 intron 11 variant who manifests a milder phenotype consistent with Bethlem muscular dystrophy. Partial amelioration of the disease phenotype in this individual provides a strong rationale for the development of our pseudoexon skipping therapy to successfully suppress the pseudoexon insertion, resulting in normal COL6A1 transcripts. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 variant.
2026-07-29 | Expanding the phenotypic spectrum of COL6-related diseases: Motor neuropathy-like and neuromyopathy associated with COL6A3 c.7447A>G.
Collagen VI is a key component of the extracellular matrix. Murine models suggest that it regulates Schwann cell differentiation, peripheral nerve myelination and regeneration after injury. Neuropathic findings in COL6-related dystrophies (COL6-RDs) have been rarely reported, often based on electromyography findings without nerve conduction abnormalities. We report 37 patients (1.5-79 years), from 32 different families, carrying the COL6A3-c.7447A>G variant, presenting with neuropathic/neuromyopathic findings. Most patients presented in the first decade of life with an abnormal gait and frequent falls (54%), delayed motor milestones (32%) and foot deformities (19%). Predominant distal weakness was present in 46% of patients, whereas 27% exhibited proximo-distal involvement. Foot deformities were present in 32%; joint contractures were present in 83%, exclusively affecting lower limbs in 49%. At last evaluation, mild restrictive respiratory insufficiency was diagnosed in 1 patient and nocturnal hypoventilation requiring non-invasive ventilation in 2. Most patients (89%) remained ambulant at last assessment. Nerve conduction studies (n=29) revealed reduced lower-limb CMAP amplitudes in 79%. Needle EMG (n=31) revealed chronic neurogenic-like features in 84% and mixed neuromyogenic features in 13%. Muscle biopsy (n=12) demonstrated features suggestive of neuropathic involvement in 4 (33%) and mixed neuropathic-myopathic features in 5 (42%). Muscle imaging (n=23) revealed a typical COL6-RD pattern in 48% (with severe distal lower limb atrophy in 65%), and isolated or predominant distal atrophy in 30%. Inheritance was autosomal recessive in all cases. The COL6A3-c.7447A>G variant was present in homozygosity in 24 (65%) and in compound heterozygosity with a second COL6A3 variant in 13 (35%), including 8 previously unreported. We report an expanding phenotypic spectrum associated with COL6-RD, underscoring its relevance in the diagnostic evaluation of distal motor neuropathy-like or neuromyopathic presentations.
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.
2025-12-30 | Tendon Dysfunction in Collagen VI-Related Myopathies: Novel Mechanistic Insights with Therapeutic Potential.
Collagen VI-related myopathies (COL6-RM) encompass a spectrum of disorders characterized by muscle weakness, joint contractures, and connective tissue abnormalities resulting from mutations in the collagen VI genes. While muscle pathology has been extensively studied, tendon dysfunction has emerged as a critical yet underexplored contributor to disease severity, particularly in the development of joint contractures. Tendons from patients and animal models show disrupted collagen fibrillogenesis, altered extracellular matrix (ECM) composition, and impaired cellular mechanotransduction. Various defects in ECM remodeling pathways further exacerbate tendon pathology. Importantly, current clinical management remains limited to orthopedic interventions with modest outcomes, and targeted pharmacological strategies or gene-editing therapies are not yet available for clinical application. Therefore, understanding the basic pathogenic mechanisms underlying tendon dysfunction is essential for identifying novel therapeutic targets. This review provides a comprehensive synthesis of current understanding and recent advances concerning the role of mutated collagen VI in cellular and molecular mechanisms underlying tendon dysfunction. Emphasis is placed on the role of mutated collagen VI in the modulation of key signaling pathways related to mechanotransduction and primary cilium function in COL6-RM. By discussing these multifaceted contributions to disease pathogenesis, this review outlines future research directions in the field and highlights potential pathways for targeted therapeutic interventions.
2025-04-07 | Inter- and intra-familial phenotypic variability of autosomal dominant collagen VI related disorder.
Collagen VI-related disorder (COL6-RD) is an inherited neuromuscular disease characterized by a broad spectrum of phenotypes. Eight families with autosomal dominant COL6-RD were recruited. Clinical manifestations, laboratory findings, electrophysiological results, molecular analyses, and pathological outcomes of eight index patients and their affected family members were systematically collected and reviewed. Pathogenic variants were identified in four families in the COL6A1 gene, one family in the COL6A2 gene, and three families in the COL6A3 gene. Among the index patients, three were classified as moderate progressive Ullrich congenital muscular dystrophy (UCMD), four exhibited mild UCMD or Bethlem myopathy, and one was diagnosed with Bethlem myopathy. The phenotypic presentation was relatively consistent within four families. However, intra-familial phenotypic variability was observed in four families, encompassing a wide range of onset ages, patterns and degrees of muscle weakness, rates of contracture progression, severity of skin changes, and age at loss of ambulation. Inter- and intra-familial phenotypic variability is prevalent in autosomal dominant COL6-RDs. When predicting the clinical course and severity for patients, it is crucial to integrate a comprehensive set of information, including mutation sites and types, family history, and early presenting features.
2025-04-03 | Characterization of severe COL6-related dystrophy due to the recurrent variant COL6A1 c.930+189C>T.
Collagen VI-related dystrophies manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterized by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognized later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and muscle pathology features highly suggestive of collagen VI-related dystrophy, some patients had remained without an identified causative variant in COL6A1, COL6A2 or COL6A3. With combined muscle RNA sequencing and whole-genome sequencing, we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterized an international cohort of 44 patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen VI genes. Patients manifest a consistently severe phenotype characterized by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD, except for one patient with somatic mosaicism for this COL6A1 intron 11 variant who manifests a milder phenotype consistent with Bethlem muscular dystrophy. Partial amelioration of the disease phenotype in this individual provides a strong rationale for the development of our pseudoexon skipping therapy to successfully suppress the pseudoexon insertion, resulting in normal COL6A1 transcripts. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 variant.
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 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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