MRI-phenotyping of Patients With Pathogenic Anoctamin 5 Variants

Overview

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.

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.

Interventions

• Other No intervention
  No intervention

Primary outcome measures

• Qualitative fat fraction lower back and legs [Time frame: 15 minutes]

Secondary outcome measures (3)

• Qualitative fat fraction of whole body [Time frame: 15 minutes]
• Quantitative fat fraction of axial and leg muscles [Time frame: 60 minutes]
• Inflammatory evaluation of axial and leg muscles [Time frame: 60 minutes]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Denmark · 1 center

• Nanna Scharff Poulsen — Copenhagen

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. PMID 23169617
• 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. PMID 23670307
• Palmio J, Penttila S, Jokela M. ANO5-Related Muscle Disease. 2012 Nov 29 [updated 2025 May 15]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK114459/ PMID 23193613
• 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. PMID 22980763
• 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. PMID 25176504
• 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 PMID 31353849
• 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. PMID 22980764
• 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. PMID 34145687

Identifiers

NCT: NCT05102799 · 1928485

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗