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Background: Collagen VI‐related disorder (COLVI‐RD) is one of the most common congenital muscular dystrophies. However, data is limited in China. Methods: We conducted a retrospective study at two tertiary centers. Clinical presentations, lab findings (including serum creatine kinase levels), muscle biopsy, and molecular test results for patients diagnosed with definite COLVI‐RD were collected. Results: A total of 82 patients were enrolled in the study, including 4 with early–severe Ullrich congenital muscular dystrophy (E–S UCMD) (4.8%), 45 with moderate–progressive Ullrich congenital muscular dystrophy (M–P UCMD, 54.9%), 19 with mild UCMD (23.2%), and 14 with Bethlem myopathy (BM, 17.1%). Feeding difficulty, DDH, and neurogenic damage were more common in E–S and M–P UCMD, while contracture of distal joints, atrophic scars, and hyperkeratosis was more prominent in mild UCMD and BM. Seventy patients harbored 64 pathogenic mutations in COLVI‐related genes: 28 patients in COL6A1 gene, 25 patients in the COL6A2 gene, and 17 patients in the COL6A3 gene, among which 33 mutations were novel. Missense and splicing mutations were predominant for COL6A1 and COL6A3 genes, which were mostly located in N‐terminus of THD, in a dominant pattern, while mutations in the COL6A2 gene were much more polymorphic, which spread throughout the whole length of the gene, in a dominant or recessive pattern. Immunofluorescence dual labeling of Collagen VI/IV in 44 patients showed complete deficiency of Collagen VI in 10 patients (22.7%), sarcolemma‐specific Collagen VI deficiency in 25 patients (56.8%), and normal Collagen VI staining in 9 patients (20.5%). Conclusion: Our study reported the largest cohort of COLVI‐RD in China, which showed M–P UCMD was the most common phenotype, followed by mild UCMD and BM. We identified 30 novel mutations and expanded the genetic spectrum. Missense and splicing mutations were predominant for COL6A1 and COL6A3 genes, while mutations in the COL6A2 gene were much more polymorphic. For severe phenotypes, most mutations are sporadic, while some are AD or recessive inherited. For milder phenotypes, sporadic and AD inherited were both common, while only 1 patient with recessive mutations was observed. [ABSTRACT FROM AUTHOR]

Key Clinical Message: This case highlights the challenges in diagnosing Bethlem myopathy, the need for a high index of suspicion, and the importance of recognizing the diverse clinical presentations of this rare condition. Enhanced understanding can aid in early diagnosis and tailored management. Bethlem myopathy (BM), a rare collagen VI‐related myopathy, is characterized by progressive muscle weakness and contractures, typically affecting the proximal muscles and joints. This case report presents a 15‐year‐old girl from Tehran, Iran, with a 5‐year history of severe limb pain and progressive weakness. Born to consanguineous parents, the patient displayed delayed walking milestones and significant hypotonia, leading to a waddling gait and lumbar hyperlordosis. Neurological examination revealed marked proximal lower limb weakness, a positive Gowers' sign, and absent myotatic reflexes. Elevated creatine phosphokinase (CPK) levels and electromyography (EMG) results indicated myopathy, while nerve conduction studies showed no neuropathy. Genetic testing revealed a novel homozygous variant of c.385C>T (p.Arg129Cys) in the COL6A2 gene, classified as a variant of uncertain significance (VUS) per American College of Medical Genetics and Genomics (ACMG) guidelines due to its rarity and specific phenotype association. Differential diagnosis is essential to distinguish it from other neuromuscular conditions. Management primarily focuses on symptom relief and enhancing patients' quality of life. This case highlights the challenges in diagnosing BM, the need for a high index of suspicion, and the importance of recognizing the diverse clinical presentations of this rare condition. Enhanced understanding can aid in early diagnosis and tailored management. [ABSTRACT FROM AUTHOR]

Abstract Background Bethlem Myopathy is a collagen VI-related myopathy presenting as a rare hereditary muscular disorder with progressive muscular weakness and joint contractures. Despite its milder clinical course relative to other myopathies, anaesthetic management can be challenging. High arched palates and fixed flexion deformities may contribute to a difficult airway. A progressive decline in pulmonary function can present later into adulthood. This respiratory decline can carry secondary cardiovascular consequences due to the progressive nature of restrictive lung disease, including right sided heart disease and pulmonary hypertension. We describe a case of a male patient with Bethlem Myopathy undergoing anaesthesia, to contribute to the limited body of literature on this condition and enhance awareness and guidance amongst anaesthesiologists on approaching patients with this condition. This is the first case report within the literature of its kind. Case presentation This case details a 33-year-old male with Bethlem Myopathy undergoing tonsillectomy. Diagnosed in childhood following developmental delays, the patient had no prior anaesthetic exposure and no family history of anaesthetic complications. Anaesthetic induction was achieved without complications, avoiding depolarizing muscle relaxants and careful airway management. Extreme care was taken in patient positioning to prevent complications. The surgery proceeded without incident and muscle paralysis was reversed with Suggammadex, resulting in no adverse post-operative respiratory complications. The patient was discharged on the first post-operative day without any respiratory or cardiovascular compromise. Conclusions Bethlem Myopathy, while often exhibiting a mild clinical course, can present anaesthetic challenges. Awareness of potential complications including a difficult airway, cardiovascular and respiratory implications as well as the need for specialised monitoring and positioning is crucial to ensure a safe peri-operative course.

Background: Bethlem Myopathy is a collagen VI-related myopathy presenting as a rare hereditary muscular disorder with progressive muscular weakness and joint contractures. Despite its milder clinical course relative to other myopathies, anaesthetic management can be challenging. High arched palates and fixed flexion deformities may contribute to a difficult airway. A progressive decline in pulmonary function can present later into adulthood. This respiratory decline can carry secondary cardiovascular consequences due to the progressive nature of restrictive lung disease, including right sided heart disease and pulmonary hypertension. We describe a case of a male patient with Bethlem Myopathy undergoing anaesthesia, to contribute to the limited body of literature on this condition and enhance awareness and guidance amongst anaesthesiologists on approaching patients with this condition. This is the first case report within the literature of its kind. Case presentation: This case details a 33-year-old male with Bethlem Myopathy undergoing tonsillectomy. Diagnosed in childhood following developmental delays, the patient had no prior anaesthetic exposure and no family history of anaesthetic complications. Anaesthetic induction was achieved without complications, avoiding depolarizing muscle relaxants and careful airway management. Extreme care was taken in patient positioning to prevent complications. The surgery proceeded without incident and muscle paralysis was reversed with Suggammadex, resulting in no adverse post-operative respiratory complications. The patient was discharged on the first post-operative day without any respiratory or cardiovascular compromise. Conclusions: Bethlem Myopathy, while often exhibiting a mild clinical course, can present anaesthetic challenges. Awareness of potential complications including a difficult airway, cardiovascular and respiratory implications as well as the need for specialised monitoring and positioning is crucial to ensure a safe peri-operative course. [ABSTRACT FROM AUTHOR]

Key Clinical Message This case highlights the challenges in diagnosing Bethlem myopathy, the need for a high index of suspicion, and the importance of recognizing the diverse clinical presentations of this rare condition. Enhanced understanding can aid in early diagnosis and tailored management. Abstract Bethlem myopathy (BM), a rare collagen VI‐related myopathy, is characterized by progressive muscle weakness and contractures, typically affecting the proximal muscles and joints. This case report presents a 15‐year‐old girl from Tehran, Iran, with a 5‐year history of severe limb pain and progressive weakness. Born to consanguineous parents, the patient displayed delayed walking milestones and significant hypotonia, leading to a waddling gait and lumbar hyperlordosis. Neurological examination revealed marked proximal lower limb weakness, a positive Gowers' sign, and absent myotatic reflexes. Elevated creatine phosphokinase (CPK) levels and electromyography (EMG) results indicated myopathy, while nerve conduction studies showed no neuropathy. Genetic testing revealed a novel homozygous variant of c.385C>T (p.Arg129Cys) in the COL6A2 gene, classified as a variant of uncertain significance (VUS) per American College of Medical Genetics and Genomics (ACMG) guidelines due to its rarity and specific phenotype association. Differential diagnosis is essential to distinguish it from other neuromuscular conditions. Management primarily focuses on symptom relief and enhancing patients' quality of life. This case highlights the challenges in diagnosing BM, the need for a high index of suspicion, and the importance of recognizing the diverse clinical presentations of this rare condition. Enhanced understanding can aid in early diagnosis and tailored management.

Collagen type VI-related dystrophies (COL6-RD) are rare diseases with a wide phenotypic spectrum ranging from severe Ullrich’s congenital muscular dystrophy Ullrich congenital muscular dystrophy to much milder Bethlem myopathy Both dominant and recessive forms of COL6-RD are caused by pathogenic variants in three collagen VI genes (COL6A1, COL6A2 and COL6A3). The prognosis of these diseases is variable and difficult to predict during early disease stages, especially since the genotype-phenotype correlation is not always clear. For this reason, studies with long-term follow-up of patients with genetically confirmed COL6-RD are still needed. In this study, we present phenotypic and genetic data from 25 patients (22 families) diagnosed with COL6-RD and followed at a single French center, in both adult and pediatric neurology departments. We describe three novel pathogenic variants and identify COL6A2:c.1970-9G>A as the most frequent variant in our series (29%). We also observe an accelerated progression of the disease in a subgroup of patients. This large series of rare disease patients provides essential information on phenotypic variability of COL6-RD patients as well as on frequency of pathogenic COL6A gene variants in Southern France, thus contributing to the phenotypic and genetic description of Collagen type VI-related dystrophies. [ABSTRACT FROM AUTHOR]

Pericytes are a distinct type of cells interacting with endothelial cells in blood vessels and contributing to endothelial barrier integrity. Furthermore, pericytes show mesenchymal stem cell properties. Muscle-derived pericytes can demonstrate both angiogenic and myogenic capabilities. It is well known that regenerative abilities and muscle stem cell potential decline during aging, leading to sarcopenia. Therefore, this study aimed to investigate the potential of pericytes in supporting muscle differentiation and angiogenesis in elderly individuals and in patients affected by Ullrich congenital muscular dystrophy or by Bethlem myopathy, two inherited conditions caused by mutations in collagen VI genes and sharing similarities with the progressive skeletal muscle changes observed during aging. The study characterized pericytes from different age groups and from individuals with collagen VI deficiency by mass spectrometry-based proteomic and bioinformatic analyses. The findings revealed that aged pericytes display metabolic changes comparable to those seen in aging skeletal muscle, as well as a decline in their stem potential, reduced protein synthesis, and alterations in focal adhesion and contractility, pointing to a decrease in their ability to form blood vessels. Strikingly, pericytes from young patients with collagen VI deficiency showed similar characteristics to aged pericytes, but were found to still handle oxidative stress effectively together with an enhanced angiogenic capacity.

Collagen type VI-related dystrophies (COL6-RD) are rare diseases with a wide phenotypic spectrum ranging from severe Ullrich’s congenital muscular dystrophy Ullrich congenital muscular dystrophy to much milder Bethlem myopathy Both dominant and recessive forms of COL6-RD are caused by pathogenic variants in three collagen VI genes (COL6A1, COL6A2 and COL6A3). The prognosis of these diseases is variable and difficult to predict during early disease stages, especially since the genotype-phenotype correlation is not always clear. For this reason, studies with long-term follow-up of patients with genetically confirmed COL6-RD are still needed. In this study, we present phenotypic and genetic data from 25 patients (22 families) diagnosed with COL6-RD and followed at a single French center, in both adult and pediatric neurology departments. We describe three novel pathogenic variants and identify COL6A2:c.1970-9G>A as the most frequent variant in our series (29%). We also observe an accelerated progression of the disease in a subgroup of patients. This large series of rare disease patients provides essential information on phenotypic variability of COL6-RD patients as well as on frequency of pathogenic COL6A gene variants in Southern France, thus contributing to the phenotypic and genetic description of Collagen type VI-related dystrophies.

Pathogenetic mechanism recognition and proof-of-concept clinical trials were performed in our patients affected by collagen VI-related myopathies. This study, which included 69 patients, aimed to identify innovative clinical data to better design future trials. Among the patients, 33 had Bethlem myopathy (BM), 24 had Ullrich congenital muscular dystrophy (UCMD), 7 had an intermediate phenotype (INTM), and five had myosclerosis myopathy (MM). We obtained data on muscle strength, the degree of contracture, immunofluorescence, and genetics. In our BM group, only one third had a knee extension strength greater than 50% of the predicted value, while only one in ten showed similar retention of elbow flexion. These findings should be considered when recruiting BM patients for future trials. All the MM patients had axial and limb contractures that limited both the flexion and extension ranges of motion, and a limitation in mouth opening. The immunofluorescence analysis of collagen VI in 55 biopsies from 37 patients confirmed the correlation between collagen VI defects and the severity of the clinical phenotype. However, biopsies from the same patient or from patients with the same mutation taken at different times showed a progressive increase in protein expression with age. The new finding of the time-dependent modulation of collagen VI expression should be considered in genetic correction trials. [ABSTRACT FROM AUTHOR]

Collagen VI exerts several functions in the tissues in which it is expressed, including mechanical roles, cytoprotective functions with the inhibition of apoptosis and oxidative damage, and the promotion of tumor growth and progression by the regulation of cell differentiation and autophagic mechanisms. Mutations in the genes encoding collagen VI main chains, COL6A1, COL6A2 and COL6A3, are responsible for a spectrum of congenital muscular disorders, namely Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM) and myosclerosis myopathy (MM), which show a variable combination of muscle wasting and weakness, joint contractures, distal laxity, and respiratory compromise. No effective therapeutic strategy is available so far for these diseases; moreover, the effects of collagen VI mutations on other tissues is poorly investigated. The aim of this review is to outline the role of collagen VI in the musculoskeletal system and to give an update about the tissue-specific functions revealed by studies on animal models and from patients' derived samples in order to fill the knowledge gap between scientists and the clinicians who daily manage patients affected by collagen VI-related myopathies. [ABSTRACT FROM AUTHOR]

Bethlem myopathy (BM) is a disease that is caused by mutations in the collagen VI genes. It is a mildly progressive disease characterized by proximal muscle weakness and contracture of the fingers, the wrist, the elbow, and the ankle. BM is an autosomal dominant inheritance that is mainly caused by dominant COL6A1, COL6A2, or COL6A3 mutations. However, a few cases of collagen VI mutations with bilateral facial weakness and Beevor's sign have also been reported. This study presents a 50-year-old female patient with symptoms of facial weakness beginning in childhood and with the slow progression of the disease with age. At the age of 30 years, the patient presented with asymmetrical proximal muscle weakness, and the neurological examination revealed bilateral facial weakness and a positive Beevor's sign. Phosphocreatine kinase was slightly elevated with electromyography showing myopathic changes and magnetic resonance imaging (MRI) of the lower limb muscles showing the muscle MRI associated with collagen VI (COL6)-related myopathy (COL6-RM). The whole-genome sequencing technology identified the heterozygous mutation c.6817-2(IVS27)A>G in the COL6A3 gene, which was in itself a novel mutation. The present study reports yet another case of BM, which is caused by the recessive COL6A3 intron variation, widening the clinical spectrum and genetic heterogeneity of BM. [ABSTRACT FROM AUTHOR]

Abstract Background Collagen VI-related dystrophy spans a clinical continuum from severe Ullrich congenital muscular dystrophy to milder Bethlem myopathy. This disease is caused by causative variants in COL6A1, COL6A2, or COL6A3. Most reported causative variants are de novo; therefore, to identify possible associated causative variants, comprehensive large cohort studies are required for different ethnicities. Methods We retrospectively reviewed clinical information, muscle histology, and genetic analyses from 147 Japanese patients representing 130 families, whose samples were sent for diagnosis to the National Center of Neurology and Psychiatry between July 1979 and January 2020. Genetic analyses were conducted by gene-based resequencing, targeted panel resequencing, and whole exome sequencing, in combination with cDNA analysis. Results Of a total of 130 families with 1–5 members with collagen VI-related dystrophy, 120 had mono-allelic and 10 had bi-allelic variants in COL6A1, COL6A2, or COL6A3. Among them, 60 variants were in COL6A1, 57 in COL6A2, and 23 in COL6A3, including 37 novel variants. Mono-allelic variants were classified into four groups: missense (69, 58%), splicing (40, 33%), small in-frame deletion (7, 6%), and large genomic deletion (4, 3%). Variants in the triple helical domains accounted for 88% (105/120) of all mono-allelic variants. Conclusions We report the causative variant profile of a large set of Japanese cases of collagen VI-related dystrophy. This dataset can be used as a reference to support genetic diagnosis and variant-specific treatment.

Objectives: Collagen-VI-related myopathies are caused by both dominant and recessive mutations in the three collagen-VI-related genes (COL6A1, COL6A2, and COL6A3) and present as two different major clinical entities; Bethlem myopathy and Ullrich congenital muscular dystrophy. Methods: In this study, we evaluated the clinical, pathologic, and genetic features of 8 patients with Bethlem myopathy from 3 families. Results: We inspected disease course differences with age and mutations. Different variants in COL6A1 and COL6A2 genes were detected. Muscle MRI of the lower limbs showed a specific pattern of muscle involvement with variable severity of fatty infiltration. One family had essential hypertension. Conclusion: Genotype-phenotype correlation studies are critical in determining gene or mutation-targeted therapies, patient follow-up, severity and progression prediction, and genetic counselling.

Pericytes are a distinct type of cells interacting with endothelial cells in blood vessels and contributing to endothelial barrier integrity. Furthermore, pericytes show mesenchymal stem cell properties. Muscle-derived pericytes can demonstrate both angiogenic and myogenic capabilities. It is well known that regenerative abilities and muscle stem cell potential decline during aging, leading to sarcopenia. Therefore, this study aimed to investigate the potential of pericytes in supporting muscle differentiation and angiogenesis in elderly individuals and in patients affected by Ullrich congenital muscular dystrophy or by Bethlem myopathy, two inherited conditions caused by mutations in collagen VI genes and sharing similarities with the progressive skeletal muscle changes observed during aging. The study characterized pericytes from different age groups and from individuals with collagen VI deficiency by mass spectrometry-based proteomic and bioinformatic analyses. The findings revealed that aged pericytes display metabolic changes comparable to those seen in aging skeletal muscle, as well as a decline in their stem potential, reduced protein synthesis, and alterations in focal adhesion and contractility, pointing to a decrease in their ability to form blood vessels. Strikingly, pericytes from young patients with collagen VI deficiency showed similar characteristics to aged pericytes, but were found to still handle oxidative stress effectively together with an enhanced angiogenic capacity.

Objectives: Collagen-VI-related myopathies are caused by both dominant and recessive mutations in the three collagen-VI-related genes (COL6A1, COL6A2, and COL6A3) and present as two different major clinical entities; Bethlem myopathy and Ullrich congenital muscular dystrophy. Methods: In this study, we evaluated the clinical, pathologic, and genetic features of 8 patients with Bethlem myopathy from 3 families. Results: We inspected disease course differences with age and mutations. Different variants in COL6A1 and COL6A2 genes were detected. Muscle MRI of the lower limbs showed a specific pattern of muscle involvement with variable severity of fatty infiltration. One family had essential hypertension. Conclusion: Genotype-phenotype correlation studies are critical in determining gene or mutation-targeted therapies, patient follow-up, severity and progression prediction, and genetic counselling. [ABSTRACT FROM AUTHOR]

Background: Collagen VI-related dystrophy spans a clinical continuum from severe Ullrich congenital muscular dystrophy to milder Bethlem myopathy. This disease is caused by causative variants in COL6A1, COL6A2, or COL6A3. Most reported causative variants are de novo; therefore, to identify possible associated causative variants, comprehensive large cohort studies are required for different ethnicities.Methods: We retrospectively reviewed clinical information, muscle histology, and genetic analyses from 147 Japanese patients representing 130 families, whose samples were sent for diagnosis to the National Center of Neurology and Psychiatry between July 1979 and January 2020. Genetic analyses were conducted by gene-based resequencing, targeted panel resequencing, and whole exome sequencing, in combination with cDNA analysis.Results: Of a total of 130 families with 1-5 members with collagen VI-related dystrophy, 120 had mono-allelic and 10 had bi-allelic variants in COL6A1, COL6A2, or COL6A3. Among them, 60 variants were in COL6A1, 57 in COL6A2, and 23 in COL6A3, including 37 novel variants. Mono-allelic variants were classified into four groups: missense (69, 58%), splicing (40, 33%), small in-frame deletion (7, 6%), and large genomic deletion (4, 3%). Variants in the triple helical domains accounted for 88% (105/120) of all mono-allelic variants.Conclusions: We report the causative variant profile of a large set of Japanese cases of collagen VI-related dystrophy. This dataset can be used as a reference to support genetic diagnosis and variant-specific treatment. [ABSTRACT FROM AUTHOR]

Abstract Background Collagen VI-related myopathies are a spectrum of muscular diseases with features of muscle weakness and atrophy, multiple contractures of joints, distal hyperextensibility, severe respiratory dysfunction and cutaneous alterations, attributable to mutations in the COL6A1, COL6A2, and COL6A3 genes. However, no case of collagen VI mutations with hematuria has been reported. We report a 14-year-old boy who had both Bethlem myopathy and recurrent hematuria and who carried a known de novo COL6A1 missense mutation c.877G > A (p.G293R). Case presentation The patient was a 14-year-old boy presenting with muscle weakness from 3 years of age without any family history. Six months before admission, he developed recurrent gross hematuria, three bouts in total, with the presence of blood clots in the urine. Next-generation sequencing of his whole-exome was performed. The result of sequencing revealed a de novo heterozygous G-to-A nucleotide substitution at position 877 in exon 10 of the COL6A1 gene. After treatment, the hematuria healed, but the muscle weakness failed to improve. Conclusions Hematuria in Bethlem myopathy can be caused by COL6 mutations, which may be related to the aberrant connection between collagen VI and collagen IV.

Mutations in the genes that code for type VI collagen can lead to what are known as the collagenopathies (collagen VI myopathies), such as Bethlem myopathy (BTHLM1), which affect structural tissues like muscles and tendons. We present the case of a young female and her two relatives, who were discovered to share the autosomal dominant COL6A3 mutation and whose presentation in clinic varied from mild to severe. Type VI collagenopathies represent a clinically and genetically heterogeneous spectrum of disorders generally characterized by muscle weakness and joint contractures. We highlight the importance of examining close relatives whenever possible and documenting a pedigree prior to proceeding with further electromyography (EMG) and lab work up, which includes obtaining genetic testing in order to reach a unifying diagnosis. The proband (L.C.) reported challenges with activities of daily living due to distal hand weakness, had significant findings on neuromuscular exam, and had abnormalities on needle EMG testing. Five of her relatives were reported to have weakness and trouble with day-to-day function. Her mother (M.C.) and her maternal grandfather (W.C.) were able to be examined in person and had the condition genetically confirmed.

The combination of autosomal dominant, early onset Paget disease of bone (PDB) and muscular dystrophy is an unusual disorder. We recently mapped the disorder in a large family from central Illinois with PDB and proximal limb-girdle type of muscular dystrophy (LGMD), and in 3 additional families with hereditary inclusion body myopathy (HIBM), Paget disease of bone and frontotemporal dementia, to a unique locus on chromosome 9p21.1-q12. The present study describes an unrelated 10-member family with autosomal dominant PDB and a scapuloperoneal type of muscular dystrophy. Clinical, biochemical, and radiological evaluations were performed to delineate clinical features in this family. Progression of the muscular dystrophy begins with weakness in the distal muscles of the legs accompanied by foot drop. EMG and muscle biopsy are compatible with a primary dystrophy. Onset of Paget disease is early, at a mean age of 41 years, with initial distribution in the long bones and eventual infiltration of the spine and pelvis. Creatine phosphokinase (CPK) and alkaline phosphatase levels are elevated in affected individuals. Molecular analyses excluded all known loci for Paget disease of bone, scapuloperoneal muscular dystrophy (SPMD), fascioscapulohumeral muscular dystrophy (FSH), amyotrophic lateral sclerosis (ALS), Bethlem myopathy, two forms of autosomal dominant limb-girdle muscular dystrophy (LGMD), and the critical region for LGMD or HIBM/PDB on chromosome 9p21.1-q12, thus providing evidence for genetic heterogeneity among families with the unique combination of muscular dystrophy and Paget disease of bone.

Collagen VI-related myopathy is a group of disorders affecting skeletal muscles and connective tissue. The most common symptoms are muscle weakness and joint deformities which limit the movement and progress over time. Several forms of collagen VI-related myopathies have been described: Bethlem myopathy, an intermediate form and Ullrich congenital muscular dystrophy, which is the most severe. Here we report a novel de novo c.1056+3A>C substitution in intron 14 of the COL6A1 gene encoding alpha-chains of collagen VI in a 13-year-old girl suffering from collagen VI (ColVI) myopathy. Analysis performed on cDNA generated from the RNA obtained from the patient’s blood cells showed that the reported variant leads to the entire exon 14 skipping and probably results in an in-frame deletion of 18 amino acids of the COL6A1 protein. Clinical presentation, abnormal secretion of the collagen demonstrated in muscle biopsy and the COL6A1 c.1056+3A>C mutation justify classification of the presented case as ColVI myopathy with moderate-progressive course. Analysis of the literature indicates that the donor splice site of COL6A1 intron 14, associated with the phenotype of Bethlem myopathy or intermediate form, is a hot spot for ColVI myopathies.

Mutations in collagen VI genes cause two major clinical myopathies, Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), and the rarer myosclerosis myopathy. In addition to congenital muscle weakness, patients affected by collagen VI-related myopathies show axial and proximal joint contractures, and distal joint hypermobility, which suggest the involvement of tendon function. To gain further insight into the role of collagen VI in human tendon structure and function, we performed ultrastructural, biochemical, and RT-PCR analysis on tendon biopsies and on cell cultures derived from two patients affected with BM and UCMD. In vitro studies revealed striking alterations in the collagen VI network, associated with disruption of the collagen VI-NG2 (Collagen VI-neural/glial antigen 2) axis and defects in cell polarization and migration. The organization of extracellular matrix (ECM) components, as regards collagens I and XII, was also affected, along with an increase in the active form of metalloproteinase 2 (MMP2). In agreement with the in vitro alterations, tendon biopsies from collagen VI-related myopathy patients displayed striking changes in collagen fibril morphology and cell death. These data point to a critical role of collagen VI in tendon matrix organization and cell behavior. The remodeling of the tendon matrix may contribute to the muscle dysfunction observed in BM and UCMD patients.

Collagen VI‐related myopathy, caused by pathogenic variants in the genes encoding collagen VI, represents a clinical continuum from Ullrich congenital muscular dystrophy (UCMD) to Bethlem myopathy (BM). Clinical data of 60 probands and their family members were collected and muscle biopsies of 26 patients were analyzed. COL6A1, COL6A2 and COL6A3 exons were analyzed by direct sequencing or next generation sequencing (NGS). Sixty patients were characterized by delayed motor milestones, muscle weakness, skin and joint changes with 40 UCMD and 20 BM. Muscle with biopsies revealed dystrophic changes and showed completely deficiency of collagen VI or sarcolemma specific collagen VI deficiency. We identified 62 different pathogenic variants in these 60 patients, with 34 were first reported while 28 were previously known; 72 allelic pathogenic variants in COL6A1 (25/72, 34.7%), COL6A2 (33/72, 45.8%) and COL6A3 (14/72, 19.4%). We also found somatic mosaic variant in the parent of 1 proband by personal genome machine amplicon deep sequencing for mosaicism. Here we provide clinical, histological and genetic evidence of collagen VI‐related myopathy in 60 Chinese patients. NGS is a valuable approach for diagnosis and accurate diagnosis provides useful information for genetic counseling of related families. [ABSTRACT FROM AUTHOR]

Collagen VI-related myopathy is a group of disorders affecting skeletal muscles and connective tissue. The most common symptoms are muscle weakness and joint deformities which limit the movement and progress over time. Several forms of collagen VI-related myopathies have been described: Bethlem myopathy, an intermediate form and Ullrich congenital muscular dystrophy, which is the most severe. Here we report a novel de novo c.1056+3A>C substitution in intron 14 of the COL6A1 gene encoding alpha-chains of collagen VI in a 13-year-old girl suffering from collagen VI (ColVI) myopathy. Analysis performed on cDNA generated from the RNA obtained from the patient's blood cells showed that the reported variant leads to the entire exon 14 skipping and probably results in an in-frame deletion of 18 amino acids of the COL6A1 protein. Clinical presentation, abnormal secretion of the collagen demonstrated in muscle biopsy and the COL6A1 c.1056+3A>C mutation justify classification of the presented case as ColVI myopathy with moderate-progressive course. Analysis of the literature indicates that the donor splice site of COL6A1 intron 14, associated with the phenotype of Bethlem myopathy or intermediate form, is a hot spot for ColVI myopathies. [ABSTRACT FROM AUTHOR]

Bethlem myopathy and Ullrich congenital muscular dystrophy form a spectrum of collagenopathies caused by genetic mutations encoding for any of the three subunits of collagen VI. Bethlem phenotype is relatively benign and is characterized by proximal dominant myopathy, keloids, contractures, distal hyperextensibility, and follicular hyperkeratosis. Three patients from a single family were diagnosed to have Bethlem myopathy based on European Neuromuscular Centre Bethlem Consortium criteria. Affected father and his both sons had slowly progressive proximal dominant weakness and recurrent falls from the first decade. Both children aged 18 and 20 years were ambulant at presentation. All had flexion contractures, keloids, and follicular hyperkeratosis without muscle hypertrophy. Creatinine kinase was mildly elevated and electromyography revealed myopathic features. Muscle imaging revealed severe involvement of glutei and vasti with "central shadow" in rectus femoris. Muscle biopsy in the father showed dystrophic changes with normal immmunostaining for collagen VI, sarcoglycans, and dysferlin.

Ullrich congenital muscular dystrophy (UCMD), due to mutations in the collagen VI genes, is an autosomal recessive form of CMD, commonly associated with distal joints hyperlaxity and severe course. A mild or moderate involvement can be occasionally observed. OBJECTIVE: To evaluate the clinical picture of CMD patients with Ullrich phenotype who presented decreased or absent collagen VI immunoreactivity on muscular biopsy. RESULTS: Among 60 patients with CMD, two had no expression of collagen V and their clinical involvement was essentially different: the first (3 years of follow-up) has mild motor difficulty ; the second (8 years of follow-up) never acquired walking and depends on ventilatory support. A molecular study, performed by Pan et al. at the Thomas Jefferson University, demonstrated in the first a known mutation of Bethlem myopathy in COL6A1 and in the second the first dominantly acting mutation in UCMD and the first in COL6A1, previously associated only to Bethlem myopathy, with benign course and dominant inheritance. CONCLUSION: Bethlem myopathy should be considered in the differential diagnosis of UCMD, even in patients without fingers contractures; overlap between Ullrich and Bethlem phenotypes can be supposed.A distrofia muscular congênita (DMC) com hiperextensibilidade articular distal (fenótipo Ullrich) associa-se a mutações nos genes do colágeno VI e corresponde a um grave quadro congênito de herança autossômica recessiva e curso progressivo, ocasionalmente mostrando menor gravidade. OBJETIVO: Avaliar o quadro clínico dos pacientes com DMC tipo Ullrich que apresentam imunoexpressão baixa ou ausente do colágeno VI na biópsia muscular. RESULTADOS: Entre 60 pacientes com DMC, dois mostravam imunomarcação negativa do colágeno VI. Mostravam-se clinicamente essencialmente diferentes: o primeiro, com 8 anos de idade e três de seguimento mostra leve dificuldade motora; o segundo, com 14 anos de idade e 8 de seguimento, não deambula e apresenta insuficiência respiratória. O estudo molecular, realizado na Thomas Jefferson University por Pan et al., revelou no primeiro, no gene COL6A1, mutação típica da miopatia de Bethlem, que tem curso benigno e herança autossômica dominante; e no segundo a primeira mutação de efeito dominante e do gene COL6A1, previamente associado apenas à miopatia de Bethlem. CONCLUSÃO: A miopatia de Bethlem deve constar no diagnóstico diferencial da DMC tipo Ullrich, mesmo na ausência das típicas contraturas dos dedos; pode existir sobreposição dos fenótipos Ullrich e Bethlem.

Bethlem myopathy and Ullrich congenital muscular dystrophy form a spectrum of collagenopathies caused by genetic mutations encoding for any of the three subunits of collagen VI. Bethlem phenotype is relatively benign and is characterized by proximal dominant myopathy, keloids, contractures, distal hyperextensibility, and follicular hyperkeratosis. Three patients from a single family were diagnosed to have Bethlem myopathy based on European Neuromuscular Centre Bethlem Consortium criteria. Affected father and his both sons had slowly progressive proximal dominant weakness and recurrent falls from the first decade. Both children aged 18 and 20 years were ambulant at presentation. All had flexion contractures, keloids, and follicular hyperkeratosis without muscle hypertrophy. Creatinine kinase was mildly elevated and electromyography revealed myopathic features. Muscle imaging revealed severe involvement of glutei and vasti with "central shadow" in rectus femoris. Muscle biopsy in the father showed dystrophic changes with normal immmunostaining for collagen VI, sarcoglycans, and dysferlin. [ABSTRACT FROM AUTHOR]

Summary: The collagen VI-related myopathies comprise two major forms, Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), which show a variable combination of muscle wasting and weakness, joint contractures, distal laxity, and respiratory compromise. Specific diagnosis requires molecular genetic testing showing mutation in one of the three genes involved. This review summarizes current treatments, in particular indication for physiotherapy, orthopedic treatment for correction of foot deformity, scoliosis, and flexion contractures of elbows, and treatment of respiratory failure. The turning point in basic research on collagen VI myopathies was the discovery of an unexpected mitochondrial dysfunction as a pathogenetic mechanism underlying the myopathic syndrome seen in Col6a1 null mice. Treatment of Col6a1 −/− mice with cyclosporin A (CsA) rescued the mitochondrial dysfunction and decreased apoptosis. Similar mitochondrial defects were revealed in cultures of UCMD patients. The results of an open pilot trial with CsA in five patients with collagen VI-related myopathies are summarized and discussed. With the availability of new potential effective treatments, several challenges must be addressed in conducting trials in orphan diseases and in neuromuscular disorders in particular. Outcome measures are discussed in the context of the expected effect of the cure. Randomized clinical trials often are not feasible for rare diseases, and sometimes would be ethically inappropriate. The need to develop alternative outcome measures or biomarkers using platforms such as genomics and proteomics is stressed in this context. [Copyright &y& Elsevier]