New Clinical and Immunofluorescence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients

Merlini, Luciano; Sabatelli, Patrizia; Gualandi, Francesca; Redivo, Edoardo; Di Martino, Alberto; Faldini, Cesare

doi:10.3390/ijms241512474

Cited by 6 publications

(6 citation statements)

References 76 publications

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“…Merlini et al conducted a cohort study in patients affected by collagen VI-related myopathies, providing clinical and genetic information and presenting quantitative data on muscle strength and contractures that can be valuable in clinical trials [17]. Their results show that respiratory failure can be a part of the clinical spectrum even in ambulatory patients, confirming the relationship between FVC and the three common collagen VI-related myopathies phenotypes acknowledged in previous studies [20,21].…”

Section: Discussionmentioning

confidence: 75%

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A Diagnostic Challenge in an Adolescent with Collagen VI-Related Myopathy and Emotional Disorder—Case Report

Oros,

Baranga,

Glangher

et al. 2023

JPM

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Collagen VI-related disorders constitute a spectrum of severities from the milder Bethlem myopathy (BM) to the Ullrich congenital muscular dystrophy (UCMD), which is more severe, and an intermediate form characterized by muscle weakness that begins in infancy. Affected children are able to walk, although walking becomes increasingly difficult starting in early adulthood. They develop contractures in the ankles, elbows, knees, and spine in childhood. In some affected cases, the respiratory muscles are weakened, requiring mechanical ventilation, particularly during sleep. Individuals with collagen VI-related myopathy are at risk of restrictive lung disease and sleep-disordered breathing due to the development of scoliosis associated with neuromuscular weakness. Typical signs of respiratory failure are not always present, and some patients are unaware that their respiratory muscles have become weaker. Here, we report a case of an intermediate form of collagen VI-related myopathy confirmed by next-generation sequencing. The girl presented morning headache, irritability, and aggressiveness, and because of these main symptoms, she was referred by the neurologist for respiratory evaluation. The result of spirometry was associated with hypoventilation shown during sleep studies, indicating the necessity to initiate home non-invasive ventilation (NIV) with immediate improvement in the symptoms. Neuromuscular disorders (NMDs) have a great impact on sleep, but only very few studies evaluating sleep quality in young patients with collagen VI-related myopathy have been described. Daytime symptoms of sleep-disordered breathing may include irritability, emotional lability, and poor attentiveness, but these can be overseen by the severity of other complex medical problems in patients with collagen VI-related myopathy. We underline the importance of the close monitoring of respiratory function, sleep evaluation, and decision making to support the NIV treatment of other collagen VI-related myopathy variant-specific patients. Early recognition of sleep disturbances and initiation of respiratory support can preserve or enhance the quality of life for patients and their caregivers. Routine screening for identification of emotional distress should be instituted in the clinical practice using validated psychological measures in a multidisciplinary approach with different intervention strategies for both patient and parent when necessary.

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Section: Discussionmentioning

confidence: 75%

“…Highly developed research centers have contributed to the discovery of the connection between mitochondrial dysfunction [17,18] and defective autophagy [17,19] in the pathogenesis of collagen VI-related myopathies.…”

Section: Discussionmentioning

confidence: 99%

A Diagnostic Challenge in an Adolescent with Collagen VI-Related Myopathy and Emotional Disorder—Case Report

Oros,

Baranga,

Glangher

et al. 2023

JPM

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“…Tendon biopsies of four unaffected donors and three genetically characterized UCMD patients [ 7 ] were used for the study. Biopsies were isolated from the pedidium tendons of two UCMD patients carrying a heterozygous c.896G>A mutation in COL6A1 (p.Gly299Glu, UCMD1), and a homozygous c.2572C>T mutation in COL6A2 (p.Gln858X, UCMD2), respectively, and from the Achilles tendon of one UCMD patient with a heterozygous c.850G>A mutation in COL6A1 (p.Gly284Arg, UCMD3).…”

Section: Methodsmentioning

confidence: 99%

“…In addition to variable muscle weakness, patients affected by COL6-RM display different degrees of axial and proximal joint contractures together with distal joint hypermobility, which worsen motor capability and deeply affect patients’ quality of life [ 7 ]. Therefore, understanding the mechanisms underlying the onset of contractures is crucial for the development of effective therapeutic strategies in COL6-RM.…”

Section: Introductionmentioning

confidence: 99%

Collagen VI Deficiency Impairs Tendon Fibroblasts Mechanoresponse in Ullrich Congenital Muscular Dystrophy

Cenni,

Sabatelli,

Di Martino

et al. 2024

Cells

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The pericellular matrix (PCM) is a specialized extracellular matrix that surrounds cells. Interactions with the PCM enable the cells to sense and respond to mechanical signals, triggering a proper adaptive response. Collagen VI is a component of muscle and tendon PCM. Mutations in collagen VI genes cause a distinctive group of inherited skeletal muscle diseases, and Ullrich congenital muscular dystrophy (UCMD) is the most severe form. In addition to muscle weakness, UCMD patients show structural and functional changes of the tendon PCM. In this study, we investigated whether PCM alterations due to collagen VI mutations affect the response of tendon fibroblasts to mechanical stimulation. By taking advantage of human tendon cultures obtained from unaffected donors and from UCMD patients, we analyzed the morphological and functional properties of cellular mechanosensors. We found that the length of the primary cilia of UCMD cells was longer than that of controls. Unlike controls, in UCMD cells, both cilia prevalence and length were not recovered after mechanical stimulation. Accordingly, under the same experimental conditions, the activation of the Hedgehog signaling pathway, which is related to cilia activity, was impaired in UCMD cells. Finally, UCMD tendon cells exposed to mechanical stimuli showed altered focal adhesions, as well as impaired activation of Akt, ERK1/2, p38MAPK, and mechanoresponsive genes downstream of YAP. By exploring the response to mechanical stimulation, for the first time, our findings uncover novel unreported mechanistic aspects of the physiopathology of UCMD-derived tendon fibroblasts and point at a role for collagen VI in the modulation of mechanotransduction in tendons.

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“…Three patients were included in a report of a cohort of patients with COL6-RD in Italy. 21 Phenotypic data on the clinical presentation of patients with a phenotype of UCMD due to causative variants in the COL6 genes other than the COL6A1 c.930+189C>T variant were evaluated to serve as a comparison cohort to the COL6A1 c.930+189C>T specific cohort. Seventeen patients with UCMD, 12 females and 5 males evaluated at the National Institutes of Health (NIH) were included in this comparison cohort (Supplementary Table 1).…”

Section: Clinical Presentationmentioning

confidence: 99%

The recurrent deep intronic pseudoexon-inducing variantCOL6A1c.930+189C>T results in a consistently severe phenotype of COL6-related dystrophy: Towards clinical trial readiness for splice-modulating therapy

Foley,

Bolduc,

Guirguis

et al. 2024

Preprint

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Collagen VI-related dystrophies (COL6-RDs) manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterised by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognised later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and immunohistochemical features highly suggestive of COL6-RD, 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 characterised an international cohort of forty-four 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 characterised 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. Characterisation of this individual provides a robust validation for the development of our pseudoexon skipping therapy. 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 causative variant to a Bethlem muscular dystrophy phenotype.

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New Clinical and Immunofluorescence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients

Cited by 6 publications

References 76 publications

A Diagnostic Challenge in an Adolescent with Collagen VI-Related Myopathy and Emotional Disorder—Case Report

A Diagnostic Challenge in an Adolescent with Collagen VI-Related Myopathy and Emotional Disorder—Case Report

Collagen VI Deficiency Impairs Tendon Fibroblasts Mechanoresponse in Ullrich Congenital Muscular Dystrophy

The recurrent deep intronic pseudoexon-inducing variantCOL6A1c.930+189C>T results in a consistently severe phenotype of COL6-related dystrophy: Towards clinical trial readiness for splice-modulating therapy

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