Congenital myopathies: revising and revisiting nomenclature and diagnostic guidelines

277th ENMC International Workshop:

Location: Hoofddorp, The Netherlands

Title: Congenital myopathies: revising and revisiting nomenclature and diagnostic guidelines

Date: 21-23 June 2024

Organisers:
Dr J. Dowling (CA)
Dr C. Bönnemann (US)
Dr E. Oates (AU)
Dr A. Ferreiro (FR)

Early Career Researchers:
Dr L. Hayes (USA), N. Villar (France), S. Raga (South Africa)

Translations of this report:
Dutch:  Prof. N. Voermans
German: Prof. U. Schara-Schmidt
Italian: Prof. E. Malfatti
Spanish: Dr N. Villar
French: Dr N. Villar
Japanese: Dr I. Nishino

Participants:
Dr J. Dowling (Canada), Dr E. Oates (Australia), Dr C. Bönnemann (USA), Dr A. Ferreiro (France), Prof. E. Malfatti (France), Prof. V. Straub (UK), Dr A. Sarkozy (UK), Prof. A. Beggs (USA), Dr I. Nishino (Japan), Prof. H. Jungbluth (UK), Prof. N. Voermans (Netherlands), Prof. U. Schara-Schmidt (Germany), Prof. J. Wilmshurst (South Africa), Prof. S. Quijano-Roy (France), Dr S.  Donkervoort (USA), Dr P. Agrawal (USA), Dr L. Hayes (USA), Dr N. Villar (France), Dr S. Raga (South Africa), Mrs A. Lennox (patient representative, UK), Mrs S. Foye (patient representative, USA), Mr M. Guillet (patient representative, USA), Dr M. De Carvalho (France), Prof. G. Ravenscroft (Australia); Mr M. Goldberg (patient representative, USA), Dr M. Davis (Australia), Dr A. Hamosh (USA).

ENMC hosted a group of experts on Congenital Myopathies from June 21-23, 2024 in Hoofddorp, The Netherlands.

Workshop summary:

26 individuals including clinical and research experts, curation specialists, and patient advocates and representing 8 countries from 5 continents met in Amsterdam on 21-23 June for the 277^th ENMC workshop. The goals of the workshop were to establish an updated nomenclature for congenital myopathies, and to revise the diagnostic guidelines. The group began with agreement that the term “Congenital myopathy” (CMYO) should remain the umbrella term used to describe a heterogeneous group of genetic muscle disorders that typically present at birth (even prenatally) or during infancy with hypotonia and muscle weakness. They are typically nonprogressive or only slowly progressive. The initially defining histopathological findings are distinctive structural abnormalities in skeletal muscle fibres without overt dystrophic features. While this describes the majority of patients, it was importantly acknowledged that congenital myopathies may come to clinical attention at any age. In addition, individuals with congenital myopathy may have experience an age-related evolution of their disease features. Of note, agreement was reached on a short-hand acronym to be used in clinical care, academic literature and online databases: CMyo

Originally, definitions of CMYOs were based on characteristic muscle biopsy findings. However, given the now evident variability of biopsy findings, the primacy of genetics in current diagnostic approach to this group of disorders, and the fact that many patients with CMYOs may not have had a biopsy, an update/revision of the existing classification and nomenclature of CMYOs is required. That stated, a gene only approach to nomenclature has its limitations, as pathogenic variants in one gene can be associated with multiple clinical presentations, multiple muscle biopsy features, and different modes of inheritance. Therefore, a new classification and nomenclature that encompasses these features (gene, mode of inheritance, histotype, unique clinical presentations) is essential, as nomenclature has important mechanistic, treatment-related, and counseling/guidance implications.  In addition, patient organizations have expressed the importance of establishing a clear system of classification and nomenclature, because in the current situation there is a lack of consistency and specificity that is resulting in confusion within the patient community as well as the broader medical community. A precise and accurately named diagnosis is part of each patient’s identity and also has implications for the development of therapies, clinical trials, and access to resources.

The group concluded that while the designation as “congenital myopathy” is the common starting point, mode of inheritance, gene, and muscle biopsy features, if known, should be part of an individual's more specific diagnosis. Based on this, they formulated a framework for a new nomenclature and companion classification incorporating these features. An illustrative example of this new nomenclature is as follows: “autosomal recessive RYR1-congenital myopathy with cores”. The components incorporated in this nomenclature will depend on what clinical, genetic, and histopathological knowledge is available for each affected individual. In cases where the gene is unknown and/or the biopsy is unavailable or nonspecific, the diagnosis of congenital myopathy alone may be used, though by definition the term congenital myopathy should be applied only to individuals who either have a confirmed genetic basis (i.e. pathogenic variant(s) in a known CMYO gene) or consistent muscle features. The group requested that online databases (e.g. ClinGen, OMIM, Orphanet) coordinate their classification and nomenclature to establish a minimum core of consistent/compatible systems that the academic communities can work with and to reflect the recommendations from this meeting.

Additional clinical information regarding motor function, distribution of weakness, and comorbidities are important but would not be part of the diagnostic term. There was also a proposal to conceptualize congenital myopathies around three axes: (1) Gene +molecular mechanism, (2) Clinical “class” or syndrome with biopsy findings if available, and (3) Disease impact on function. A classification system, distinct from but consistent with the nomenclature, was proposed to include key features as follows: 1) Congenital myopathy; 2) Gene; 3) Inheritance pattern; 4) Main histopathological (or other phenotypical) features (i.e., Congenital myopathy, RYR1-related, AR, with cores. The specifics of additional phenotypic and histologic classification will be formalized by a virtual working group.

The second aim of the workshop was to update recommendations for the diagnostic evaluation of a suspected congenital myopathy. To begin, the diagnosis of CMYO can be made when there are compatible clinical symptoms and either a confirmed genetic diagnosis that accounts for the clinical presentation or muscle biopsy supporting the diagnosis of a congenital myopathy. In cases where neither are available nor have not been obtained yet, a probable or possible congenital myopathy could be referenced, though such patients more accurately belong in a broader category of congenital muscle disease that allows for consideration of alternative diagnoses. The group emphasized the importance of a genetic diagnosis, when possible, to facilitate focused screening for subtype-specific comorbidities (for example, cardiomyopathy in patients with genetically confirmed TTN-congenital myopathy), family planning, and clinical trials.

The diagnostic evaluation always begins with a comprehensive and often multidisciplinary clinical evaluation with careful attention to family history and ancestry. Genetic testing is generally the next step in the case of a suspected congenital myopathy, with age-appropriate exclusion of alternative diagnoses. The type of genetic testing may vary with the age of the patient. The advantages and potential disadvantages of each MPS-based testing strategy will be clearly described in our final diagnostic guideline publication to ensure fully informed decision making around clinical genetic testing options in the setting of suspected/likely congenital myopathy-genome level sequencing (next generation sequencing based approaches - including exome, genome, or comprehensive panel sequencing) is considered the gold standard. Ultimately, the choice of genetic testing is highly dependent on availability and expertise in each environment. The group emphasized that appropriate pre and post-test counseling must be performed prior to and after all forms of genetic testing. In some countries, additional counselling around insurance implications of testing options may be warranted. In the adolescent and adult population, additional diagnostic tests such as electromyography (EMG), imaging, and muscle biopsy may be performed ahead of genetic testing for the purposes of excluding other (treatable) disorders that are more common in the adult population. When genetic testing is not informative or is inconclusive, additional investigations should be performed initially using clinically available testing (biopsy, imaging) and may go on to include research-based technologies for example muscle RNA sequencing. Moving forward, an updated diagnostic algorithm and supporting guidelines manuscript will be completed by an expert working group.

The meeting concluded by emphasizing the need for education and increased awareness of congenital myopathies within the patient and medical community. Patient advocacy organizations and key leaders will help to disseminate this information world-wide. We must improve our engagement with low- and middle-income countries that are often underrepresented in these academic meetings. Future discussions around nomenclature, diagnostics, and treatment in CMYOs must include patient advocates and global representation.

A full report will be published in Neuromuscular Disorders.