MRI-phenotyping of Patients With Pathogenic Anoctamin 5 Variants (ANO5 MRI)

A large cohort of MRI scans from patients with pathogenic variants in the anoctamin 5 gene will be collected through an international collaboration to better describe muscle involvement.

Study Overview

• Status: Recruiting
• Conditions: Limb Girdle Muscular Dystrophy
• Intervention / Treatment: Other: No intervention

Detailed Description

Background:

The anoctamin 5 gene (ANO5) encodes the anoctamine 5 protein that act as a calcium-sensitive chloride channel. The protein is preferentially expressed in skeletal and cardiac muscle and bone and likely acts in the repair of the cell membrane. Pathogenic ANO5 variants inherited in a autosomal recessive trait give rise to three main phenotypes: Limb-girdle muscular dystrophy type R12 (LGMDR12, formerly classified as LGMD2L), Miyoshi distal muscular dystrophy type 3 (MMD3), and asymptomatic hyperCKemia). As the name implies, patients with LGMDR12 are affected more proximally and patients with MMD3 more distally, but the definition and distinction between the two entities is unclear. Men with anoctaminopathy are more severely affected than women. Cardiac disease such as arrhythmias and cardiomyopathy as well as bulbar symptoms or respiratory failure are very rare in anoctaminopathies. Onset is in adulthood and disease progression is slow, generally with a later onset and disease progression than seen in other LGMDs. Ambulation is preserved until late in the disease course.

However, only few studies based on small case series have investigated the phenotype of patients with ANO5 mutations using MRI. There is therefore a need to investigate a larger international group of patients using MRI to properly describe which muscles are affected in men and women with anoctaminopathy.

The spectrum of phenotypes in anoctaminopathies resembles that seen in dysferlinopathies, and in the latter group, it has been shown that the former division into LGMDR2 (formally LGMD2B) and Miyoshi distal muscular dystrophy type 2 (MMD2) is rather arbitrary. Our hypothesis is that this may very well also be the case for LGMDR12 and MMD3. A large MRI study would be able to shed light on this question. Muscle involvement in patients with ANO5 mutations is said to be asymmetric based on clinical assessments (7,8,10). The proposed study will also elucidate this by studying symmetry of muscle affection. Finally, the diseases severity is said to be marked between the two sexes, but this has not been quantified in any detail before. The proposed study will also be able to shed light on this.

Aim:

The aims of the project are:

• To describe the muscle MRI phenotype in around 200 patients from multiple countries around the world.
• To investigate if it makes sense to group patients with pathogenic ANO5 variants into proximal and distal myopathies.
• To investigate to what extent the disease is asymmetric.
• To investigate the difference in disease severity between sexes.
• To investigate whether a phenotype-genotype correlation exists.

Methods:

Sites from all over the world will share an eCRF and their MRI data with Copenhagen Neuromuscular Center through the platform MyoShare.

• Study Type: Observational
• Enrollment (Estimated): 200

Contacts and Locations

• Study Contact: Name: Nanna S Poulsen, MD; Phone Number: +4535454346; Email: Nanna.scharff.poulsen@regionh.dk
• Study Contact Backup: Name: John Vissing, MD, DMSc; Email: john.vissing@regionh.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Nanna Scharff Poulsen
    • Contact: Nanna S Poulsen, MD
    • Contact: Nanna S Poulsen, MD; Phone Number: +4535454346; Email: Nanna.scharff.poulsen@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

MRIs of patients with pathogenic variants in the anoctamin 5 gene will be examined. The MRIs are obtained from either former studies or as part of clinical evaluation in the collaborating countries.

Description

Inclusion Criteria:

• Two pathogenic variants in the anoctamin-5 gene
• T1-weighted MR-images of lower back and leg muscles.

Exclusion Criteria:

- Concomitant other disorders that also can result in muscular atrophy, i.e. polyneuropathy, other muscle diseases, recent long-term stay in intensive care, among others.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Anoctaminopathies; Anoctaminopathies including Limb Girdle Muscular Dystrophy R12, Miyoshi distal Muscular Dystrophy type 3 and asymptomatic hyperCKemia	Other: No intervention; No intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Qualitative fat fraction lower back and legs	Qualitative muscle fat fraction analyses of lower back and legs evaluated from T1-weighted images using the Mercury score (score: 0-4)	15 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Qualitative fat fraction of whole body	Qualitative fat fraction analyses of the rest of the body evaluated from T1-weighted images using the Mercury score (score: 0-4)	15 minutes
Quantitative fat fraction of axial and leg muscles	Qualitative fat fraction analyses of axial and leg muscles evaluated from Dixon images	60 minutes
Inflammatory evaluation of axial and leg muscles	Quantitative analysis of inflammation in axial and leg muscles from STIR images	60 minutes

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark

Publications and helpful links

General Publications

• Little AA, McKeever PE, Gruis KL. Novel mutations in the Anoctamin 5 gene (ANO5) associated with limb-girdle muscular dystrophy 2L. Muscle Nerve. 2013 Feb;47(2):287-91. doi: 10.1002/mus.23542. Epub 2012 Nov 21.
• Witting N, Duno M, Petri H, Krag T, Bundgaard H, Kober L, Vissing J. Anoctamin 5 muscular dystrophy in Denmark: prevalence, genotypes, phenotypes, cardiac findings, and muscle protein expression. J Neurol. 2013 Aug;260(8):2084-93. doi: 10.1007/s00415-013-6934-y. Epub 2013 May 14.
• Sarkozy A, Deschauer M, Carlier RY, Schrank B, Seeger J, Walter MC, Schoser B, Reilich P, Leturq F, Radunovic A, Behin A, Laforet P, Eymard B, Schreiber H, Hicks D, Vaidya SS, Glaser D, Carlier PG, Bushby K, Lochmuller H, Straub V. Muscle MRI findings in limb girdle muscular dystrophy type 2L. Neuromuscul Disord. 2012 Oct 1;22 Suppl 2:S122-9. doi: 10.1016/j.nmd.2012.05.012.
• Ten Dam L, van der Kooi AJ, Rovekamp F, Linssen WH, de Visser M. Comparing clinical data and muscle imaging of DYSF and ANO5 related muscular dystrophies. Neuromuscul Disord. 2014 Dec;24(12):1097-102. doi: 10.1016/j.nmd.2014.07.004. Epub 2014 Aug 1.
• Silva AMS, Coimbra-Neto AR, Souza PVS, Winckler PB, Goncalves MVM, Cavalcanti EBU, Carvalho AADS, Sobreira CFDR, Camelo CG, Mendonca RDH, Estephan EDP, Reed UC, Machado-Costa MC, Dourado-Junior MET, Pereira VC, Cruzeiro MM, Helito PVP, Aivazoglou LU, Camargo LVD, Gomes HH, Camargo AJSD, Pinto WBVDR, Badia BML, Libardi LH, Yanagiura MT, Oliveira ASB, Nucci A, Saute JAM, Franca-Junior MC, Zanoteli E. Clinical and molecular findings in a cohort of ANO5-related myopathy. Ann Clin Transl Neurol. 2019 Jul;6(7):1225-1238. doi: 10.1002/acn3.50801. Epub 2019 Jun 11.
• Mahjneh I, Bashir R, Kiuru-Enari S, Linssen W, Lamminen A, Visser Md. Selective pattern of muscle involvement seen in distal muscular dystrophy associated with anoctamin 5 mutations: a follow-up muscle MRI study. Neuromuscul Disord. 2012 Oct 1;22 Suppl 2:S130-6. doi: 10.1016/j.nmd.2012.02.007.
• Khawajazada T, Kass K, Rudolf K, de Stricker Borch J, Sheikh AM, Witting N, Vissing J. Muscle involvement assessed by quantitative magnetic resonance imaging in patients with anoctamin 5 deficiency. Eur J Neurol. 2021 Sep;28(9):3121-3132. doi: 10.1111/ene.14979. Epub 2021 Jul 11.
• Willis TA, Hollingsworth KG, Coombs A, Sveen ML, Andersen S, Stojkovic T, Eagle M, Mayhew A, de Sousa PL, Dewar L, Morrow JM, Sinclair CD, Thornton JS, Bushby K, Lochmuller H, Hanna MG, Hogrel JY, Carlier PG, Vissing J, Straub V. Quantitative muscle MRI as an assessment tool for monitoring disease progression in LGMD2I: a multicentre longitudinal study. PLoS One. 2013 Aug 14;8(8):e70993. doi: 10.1371/journal.pone.0070993. eCollection 2013.
• Penttila S, Vihola A, Palmio J, Udd B. ANO5 Muscle Disease. 2012 Nov 29 [updated 2019 Aug 22]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from http://www.ncbi.nlm.nih.gov/books/NBK114459/

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2021
• Primary Completion (Estimated): February 1, 2026
• Study Completion (Estimated): August 1, 2026

Study Registration Dates

• First Submitted: October 20, 2021
• First Submitted That Met QC Criteria: October 20, 2021
• First Posted (Actual): November 2, 2021

Study Record Updates

• Last Update Posted (Actual): April 6, 2025
• Last Update Submitted That Met QC Criteria: April 2, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Anoctaminophathies
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Muscular Disorders, Atrophic; Muscular Dystrophies; Muscular Dystrophies, Limb-Girdle
• Other Study ID Numbers: 1928485

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No