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Newsletter

Spring 2021
Dear Registry Participants,

Welcome to our spring newsletter! 

In this newsletter we highlight a number of publications, share the registry poster which is currently being featured at the the 14th Annual Neuromuscular Translational Research Conference  and detail a couple of funding awards.
If you have any stories you would like to share in our next newsletter, please let us know.   

I would like to take the opportunity to thank you for your participation in the project thus far, I have enjoyed my communications with you and I wish you all the very best.  Thank you also to our steering committee members and current funders for their essential role in developing the registry.

Best wishes,
Lucy

Registry Coordinator

 
News
 
The Orphan Disease Centre has granted two funding awards for work in Collagen6
 
Novel tools for drug repurposing in COL6 myopathies: accelerating the route towards therapy.
Feb 1

Awardee: Paolo Bonaldo

Institution: University of Padova, Department of Molecular Medicine

Award Amount: $42,406

Funding Period: February 1, 2021 - January 31, 2022



Targeting muscle stem cells for the treatment of Collagen VI muscular dystrophies
Feb 1

Awardee: Nicholas Dumont

Institution: CHU Sainte-Justine research center (University of Montreal)

Award Amount: $42,406

Funding Period: February 1, 2021 - January 31, 2022



The Speak Foundation have a new magazine! Find out more, and subscribe to the magazine, here
 
Publications

Association of Initial Maximal Motor Ability With Long-term Functional Outcome in Patients With COL6-Related Dystrophies

https://pubmed.ncbi.nlm.nih.gov/33441455/
 
Abstract

Objective: To accurately categorize the phenotypes of individuals with collagen VI-related dystrophies (COL6-RDs) during the first years of life to predict long-term motor function and pulmonary function, to provide phenotype-specific anticipatory care, and to improve clinical trial readiness.

Methods: This retrospective, multicenter, international study analyzed the relationship of long-term motor and pulmonary function with the initial maximal motor ability achieved in individuals with COL6-RD.

Results: We studied 119 patients with COL6-RD from Spain (n = 54) and the United States (n = 65). The early maximal motor milestones of ability to rise from the floor unassisted and ability to climb 4 steps without holding onto a railing demonstrated reliability in distinguishing between 3 COL6-RD phenotypic subgroups: (1) Ullrich congenital muscular dystrophy, (2) intermediate COL6-RD, and (3) Bethlem myopathy. Long-term motor function and pulmonary function are strongly correlated with the maximal motor ability achieved during the first years of life. Maximal motor capacity can predict other disease-relevant events such as the age at loss of ambulation and the need for the initiation of nocturnal noninvasive ventilation.

Conclusion: This work proposes a prospective phenotypic classification for COL6-RDs that will enable an accurate prediction of a patient's COL6-RD phenotype during the first years of life. The ability to establish a patient's COL6-RD phenotypic classification early will enable a more accurate prognosis of future motor and pulmonary function, thus improving anticipatory clinical care, and it will be instrumental in aiding the design of future clinical trials by allowing early stratification of trial cohorts.

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A novel variant in the COL6A1 gene causing Ullrich congenital muscular dystrophy in a consanguineous family: a case report


https://pubmed.ncbi.nlm.nih.gov/33750322/
 
Abstract

Background: Collagen VI-related dystrophies are a subtype of congenital muscular dystrophy caused by pathogenic variants in COL6A1, COL6A2 or COL6A3 genes affecting skeletal muscles and connective tissue. The clinical phenotype ranges from the milder Bethlem myopathy to the severe Ullrich congenital muscular dystrophy (UCMD). Herein, we report the first consanguineous Sri Lankan family with two children affected with UCMD due to a novel variant in the COL6A1 gene.

Case presentation: Two sisters, aged 10-years and 7-years, presented with progressive, bilateral proximal muscle weakness. Both probands had delayed motor milestones and demonstrated difficulty in standing from a squatting position, climbing stairs and raising arms above the shoulders. Cognitive, language and social development were age appropriate. Examination showed proximal muscle weakness of the upper and lower extremities and hyperlaxity of the wrist and fingers in both with some variability in clinical severity noted between the two siblings. Serum creatine kinase levels were elevated, and electromyography showed low polyphasic motor unit potentials in the 10-year-old and myopathic features with short duration motor unit potentials with no polyphasia in the 7-year-old. Whole exome sequencing (WES) was performed and a novel, homozygous missense, likely pathogenic variant in exon 25 of COL6A1 gene [NM_001848: c.1667G > T;NP_001839.2:p.Gly556Val] was identified in both probands. This variant was validated by Sanger sequencing in proband 1 as well as proband 2, and the parents and an unaffected sibling were found to be heterozygote carriers for the same variant.

Conclusions: The findings in this family add to the expanding number of COL6A1 variants identified and provides a better understanding of the genotype-phenotype correlations associated with UCMD.

Keywords: COL6A1; Case report; Collagen type VI; Consanguineous; Myopathy; Phenotypic heterogeneity; Ullrich congenital muscular dystrophy.

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Harnessing the Membrane Translocation Properties of ABToxins for Therapeutic Applications

Abstract: Over the last few decades, proteins and peptides have become increasingly more com-mon as FDA-approved drugs, despite their inefficient delivery due to their inability to cross theplasma membrane. In this context, bacterial two-component systems, termed AB toxins, use variousprotein-based membrane translocation mechanisms to deliver toxins into cells, and these mechanismscould provide new insights into the development of bio-based drug delivery systems. These toxinshave great potential as therapies both because of their intrinsic properties as well as the modularcharacteristics of both subunits, which make them highly amenable to conjugation with various drugclasses. This review focuses on the therapeutical approaches involving the internalization mecha-nisms of three representative AB toxins: botulinum toxin type A, anthrax toxin, and cholera toxin. Weshowcase several specific examples of the use of these toxins to develop new therapeutic strategiesfor numerous diseases and explain what makes these toxins promising tools in the development ofdrugs and drug delivery systems.

Keywords: botulinum toxin; anthrax toxin; cholera toxin; membrane translocation; endocytosis;therapeutic applications; drug delivery

Key Contribution:This paper showcases the mechanisms and several therapeutic applications ofbotulinum toxin, anthrax toxin, and cholera toxin.

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Intrafamilial Phenotypic Variability of Collagen VI-Related Myopathy Due to a New Mutation in the COL6A1 Gene

https://content.iospress.com/articles/journal-of-neuromuscular-diseases/jnd200476
 
Abstract

A family of five male siblings (three survivors at 48, 53 and 58 years old; two deceased at 8 months old and 2.5 years old) demonstrating significant phenotypic variability ranging from intermediate to the myosclerotic like Bethlem myopathy is presented. Whole-exome sequencing (WES) identified a new homozygous missense mutation chr21:47402679 T > C in the canonical splice donor site of the second intron (c.227 + 2T>C) in the COL6A1 gene. mRNA analysis confirmed skipping of exon 2 encoding 925 amino-acids in 94–95% of resulting transcripts. Three sibs presented with intermediate phenotype of collagen VI-related dystrophies (48, 53 and 2.5 years old) while the fourth sibling (58 years old) was classified as Bethlem myopathy with spine rigidity. The two older siblings with the moderate progressive phenotype (48 and 53 years old) lost their ability to maintain a vertical posture caused by pronounced contractures of large joints, but continued to ambulate throughout life on fully bent legs without auxiliary means of support. Immunofluorescence analysis of dermal fibroblasts demonstrated that no type VI collagen was secreted in any of the siblings’ cells, regardless of clinical manifestations severity while fibroblast proliferation and colony formation ability was decreased. The detailed genetic and long term clinical data contribute to broadening the genotypic and phenotypic spectrum of COL6A1 related disease.

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Survey on patients’ organisations’ knowledge and position paper on screening for inherited neuromuscular diseases in Europe
Background

The development of new genetic testing methods and the approval of the first treatments raises questions regarding when and how to perform screening for inherited neuromuscular conditions. Screening directives and access to the different techniques is not uniform across Europe. The patient advisory board of the European reference network for rare neuromuscular diseases (NMD) conducted a qualitative study to understand the state of play of screening for inherited NMD in Europe and patients’ needs.

Results

We collected answers from 30 patient organisations (POs) from 18 European countries. Fifteen acknowledge the existence of pre-implantation genetic diagnosis in their country. Regarding prenatal screening, we had 25 positive answers and 5 negative ones. Twenty-four POs mentioned that newborn screening was available in their country. We had some contradictory answers from POs from the same country and in some cases; diseases said to be part of the screening programmes were not hereditary disorders. Twenty-eight organisations were in favour of screening tests. The reasons for the two negative answers were lack of reimbursement and treatment, religious beliefs and eventual insurance constrains. Most POs (21) were in favour of systematic screening with the option to opt-out. Regarding the timing for screening, “at birth”, was the most consensual response. The main priority to perform screening for NMDs was early access to treatment, followed by shorter time to diagnostic, preventive care and genetic counselling.

Conclusions

This is the first study to assess knowledge and needs of POs concerning screening for NMDs. The knowledge of POs regarding screening techniques is quite uneven. This implies that, even in communities highly motivated and knowledgeable of the conditions they advocate for, there is a need for better information. Differences in the responses to the questions “how and when to screen” shows that the screening path depends on the disease and the presence of a disease modifying treatment. The unmet need for screening inherited NMDs should follow an adaptive pathway related to the fast moving medical landscape of NMDs. International coordination leading to a common policy would certainly be a precious asset tending to harmonize the situation amongst European countries.


 
The Burden of Rare Diseases, Clinical Trials and Pediatric Vaccines

As part of its mission to empower the rare disease patient community to advocate for impactful, science-driven legislation and policy that advances the equitable development of and access to lifesaving diagnoses, treatments and cures, the EveryLife Foundation undertook aninitiative to understand the economic burden of RDbycommissioningthe Lewin Group to estimate the economic impact of RD in the U.S. in 2019. This study aims to provide the most comprehensive assessment of the total burden of RD to date, including filling the knowledge gap in some of the less well-understood cost components(such as productivity loss in both the labor market as well as in social life)and caregiver economic burden.



Find out more, and the full summary document here https://everylifefoundation.org/burden-study/

Join theShare4Rare Neuromuscular Disease Study!

 


"Impact of neuromuscualr diseases on education and working opportunities of patients and carers"
 
During the last 10 years, there has been a growing interest in developing research related to neuromuscular diseases. There are therapies that have been tested in clinical trials and some of them are already available for patients in the United States and the European Union.
However, very little is known about the impact of neuromuscular diseases on the education and employment opportunities of both patients and their caregivers, and this can have a significant impact on their quality of life and their access to potential treatments in the future. 
The diseases included in this study are the following:
Muscular dystrophies (MD)
Myotonic dystrophy (MD1 and MD2)
Fascioscapulohumeral MD (FSHD)
Limb girdle MD (LGMD)
Congenital muscular distrophies
Amyotrophic Lateral Sclerosis (ALS)
Peripheral neuropathies
Charcot Marie Tooth (CMT)
Chronic inflammatory demyelinating polyneuropathy (CIDP)
Congenital myasthenias
Myasthenia gravis
Congenital myopathies
Objectives
Information provided directly by patients and their caregivers will allow us to understand the impact of rare neuromuscular diseases on the employment opportunities and the education of these patients and their families.
Method
Questionnaires developed and designed by the John Walton Muscular Dystrophy Research Centre at Newcastle University (UK) and the World Duchenne Organization.
Analysis of the data to understand the impact of neuromuscular diseases on the education and employment opportunities of patients and their families.
 
Join here
 

Collagen 6 poster at the 14th Annual Neuromuscular Translational Research Conference





A further conference report will follow in the next newsletter.
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Global Registry for COL6-related dystrophies · International Centre for Life · Newcastle Upon Tyne, Net NE3 1BZ · United Kingdom

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