Diagnostic criteria and outcome measures in primary mitochondrial myopathies

280^th ENMC International Workshop

Location: Hoofddorp, The Netherlands

Title: Diagnostic criteria and outcome measures in primary mitochondrial myopathies

Date: 22-24 November 2024

Organisers: Prof. M. Mancuso (Italy), Prof. C. Kornblum (Germany)

Early Career Researchers (ECR): Dr. P. Lopriore (Italy), Dr. L. Semmler (Germany)

Translations of this report by:
German by Dr. Luisa Semmler
Italian by Dr. Piervito Lopriore
Spanish by Dr. Marcello Bellusci
French by Dr. Manuel Schiff
Danish by Prof. John Vissing
Dutch by Dr. Mirian Janssen
Hungarian by Prof. Rita Horvath

Participants: Prof. M. Mancuso (Italy), Prof. C. Kornblum (Germany), Dr. R. Artuch (Spain), Dr. M. Bellusci (Spain), Prof. E. Bertini (Italy), Prof. V. Carelli (Italy), Dr. J. van den Ameele (United Kingdom), Prof. F. Distelmaier (Germany), Prof. M. Hirano (USA), Prof. R. Horvath (United Kingdom), Dr. M. Janssen (Netherlands), Prof. A. Karaa (France/ USA), Prof. T. Klopstock (Germany), Dr. C. Lamperti (Italy), Prof. R. McFarland (United Kingdom), Dr. Y. Ng (United Kingdom), Prof. M. Schiff (France), Prof. S. Servidei (Italy), Prof. T. Taivassalo (USA), Prof. J. Vissing (Denmark), Dr. P. Lopriore (Italy), Dr. L. Semmler (Germany), K. Waller (patient representative, United Kingdom), Dr. V. Stoyanova-Beninska (Netherlands)

Background and aims:

Primary mitochondrial diseases (PMDs) are a diverse and complex group of genetic disorders that affect the structure or function of the mitochondrial oxidative phosphorylation (OXPHOS) system. They arise from mutations in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) and are considered one of the most common inborn errors of metabolism, with an estimated prevalence of approximately 1 in 5,000 adults. PMDs often involve peripheral nerves and muscles, making them a significant group of inherited neuromuscular disorders. The clinical diagnosis of PMDs is challenging due to their multi-systemic nature, which requires the involvement of various medical specialties. Additionally, the field faces significant barriers, including a lack of comprehensive information about the natural history of PMDs and the current biomarkers used for diagnosis and severity prediction, which lack sensitivity and specificity.

Primary mitochondrial myopathies (PMM) represent a subset of PMDs that predominantly affect skeletal muscle. These disorders can present at any age, but more severe phenotypes often manifest earlier in life. In November 2016, most of the proposed attendees to this workshop met in Rome and published a consensus paper on "Outcome measures and clinical trial readiness in primary mitochondrial myopathies in children and adults."¹ Within this meeting, PMM was for the first time clearly defined as a specific entity and recommendations on outcome measures were provided for both children and adults. Numerous clinical trials, based on these outcome measures, have been performed, are ongoing, or are about to start and several observational studies have already been published on PMM since then. In addition, over ten pharmaceutical companies have announced the development of new molecules targeting PMM.

Regarding this beneficial development, the consensus on PMM needed to be updated and expanded to include new outcome measures (OMs), patient-reported outcome measures (PROMs), and new potential biomarkers for PMM natural history studies and interventional clinical trials. In addition, guidance on the use of new digital health technologies (DHTs) in PMM is needed to harness their potential. Thus, the primary aims of the workshop were:
- to review and update the definition of PMM, harmonizing criteria for diagnosing PMM and its phenotypes;
- to share and review natural history data in both adults and children;
- to explore OMs and real-life challenges expanding experiences from the previous consensus paper, and drawing lessons from past and current clinical trials;
- to reach a consensus on an optimal set of OMs, PROMs, functional outcome measures, disease biomarkers, and measures of disease burden for natural history studies and investigational trials;
- to explore new DHTs to be applied in the field.

Workshop outcomes

Before this meeting, our group conducted a thorough review of the literature focusing on studies on PMM from 2017 onwards (the year the previous consensus was published). Especially studies on outcome measures used in PMM were analysed. Additionally, we searched for relevant papers from related fields such as metabolic myopathies and neuromuscular diseases in general. As preparatory work, we conducted several online suryeys following the so called “Delphi process” to prepare the meeting and facilitate consensus finding.

At the workshop, the sessions started with an overview of the current state of European and US registries, ongoing projects (especially international collaborations), and the structure of national and international networks.
Afterwards, a general discussion on the clinical trials on PMM conducted in recent years has been held. Further, the Patient Engagement and Advocacy Manager of the Lily Foundation gave an overview of the patients' perspective regarding useful parameters for inclusion in clinical trials and respective burdens with which patients are confronted in terms of clinical trial participation. Moreover, an expert from the European Medical Agency explained in detail what is needed to implement clinical trials in rare and ultra-rare diseases and how to reach progress in identifying new drugs.

Definition of PMM

PMM were defined as “genetically determined mitochondrial disorders with prominent skeletal muscle involvement. Other diseases, with secondary involvement of mitochondria, are not considered PMM”. Two main types of PMM were proposed, based on whether or not the person has progressive external ophthalmoplegia (PEO), which is a condition that affects the eye muscles. There was a uniform agreement, that normal respiratory chain enzyme activities do not exclude PMM, as in adult PMM enzyme activities could be normal. If PMM is suspected, genetic testing of DNA from blood is an appropriate first-line approach. However, if negative, or for the confirmation of the diagnosis, muscle biopsy may be needed in some cases. In the case of a maternal family history or a typical PMM presentation, testing for specific common mtDNA mutations/deletion may be useful before exome or genome sequencing. Single-large scale deletions of mtDNA in adults can be detected in muscle and urine sediment, and these are better sources for DNA extraction than blood.

Clinical outcome measures for PMM

PROMS

Some of the previously endorsed scales, such as NMDAS/NPMDS Section IV, Fatigue severity scale (FSS) etc. were discussed. Some of them were validated in real-world cohorts, some others specifically created for PMM or PMDs. A set of different PROMs, covering different topics such as pain, fatigue, exercise intolerance, activity of daily living, caregiver burden, also coming from experience in other neuromuscular diseases such as myasthenia gravis and metabolic myopathies, was proposed.

Clinical scales

Several scales have been designed specifically for mitochondrial diseases, including the Newcastle Mitochondrial Disease Adult Scale (NMDAS), the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS), and the International Paediatric Mitochondrial Disease Scale (IPMDS). Additionally, other scales have been adopted from the broader field of neuromuscular research. The participants accepted the PMM-specific scales for use in PMM studies. We also concluded that several other scales, predominantly covering motor symptoms, would be valuable. These include the Hammersmith Functional Motor Scale Expanded and the Gait, Stair, Gower Manoeuvre and Chair (GSGC) composition score. Furthermore, we agreed on scales with a broader scope, including two multi-dimensional scales: the Physician Global Assessment (PhGA) and the Clinical Global Impression (CGI). We also endorsed a scale for assessing fatigue in adult PMM patients and the Pediatric Quality of Life Inventory (PedsQL) for evaluating quality of life in children with PMM.

Functional tests and performance outcome measures

Although functional tests and performance outcome measures were discussed in two separate groups, we all acknowledged significant overlap between them. We agreed on the following tests to assess walking capacity: 6-minute walking test, 6-minute walking test with slope (meters walked/minute), the 12-minute walk test and the spontaneous gait speed. For adults only, we recommend the Quick Motor Function Test (QMFT), the Timed Up-and-Go test and the Five Times Sit-to-Stand test for assessing motor function. Additionally, we recommend assessing balance under different conditions, such as the tandem stance with eyes open and closed. For children, we positively evaluated assessment batteries such as the North Star Ambulatory Assessment (NSAA) and the Hammersmith Infant Neurological Examination (HINE).

Regarding performance outcome measures, we concluded that Cardiopulmonary Exercise Testing (CPET) is appropriate for adults and children above the age of 6 years. If a participant is not compliant with CPET, a submaximal exercise test assessing blood lactate and heart rate can be performed instead. Furthermore, performing the 30 seconds sit-to-stand test might be useful in both adults and children. When respiratory weakness is suspected, we agreed on measuring the Maximal Inspiratory Pressure (MIP).

Biomarkers

Currently, clinical practice employs various methods to distinguish mitochondrial diseases from other pathologies, including laboratory testing of blood and urine, analysis of cerebrospinal fluid, muscle biopsy, and imaging techniques. Recent studies have explored potential new biomarkers, particularly two blood markers: Growth Differentiation Factor 15 (GDF-15) and Fibroblast Growth Factor 21 (FGF-21). These parameters were investigated for their utility in the differential diagnosis of PMM and as clinical endpoints. However, all studied parameters lacked the high specificity and sensitivity expected of reliable biomarkers. We concluded that more data needs to be collected before recommending the comprehensive use of any of these new biomarkers. In our opinion, a biomarker for differentiating phenotypes is unnecessary, as this distinction is already achieved through clinical investigations

DHTs

All the members agreed that there are no validated DHTs for PMM assessment to date, with no pivotal studies on this topic published. More studies need to be done to further develop and validate such tools in PMM. Based on the research literature and experience coming from other neuromuscular diseases, the group proposed a set of DHTs which could be used in future studies focused on PMM. Specifically, the group focused on gait and movement analysis using wearable (such as accelerometer to capture remote physical activity), non-wearable technologies (such as gait mat), customized foot sensor inserts or smartphone-based monitoring tools (for children). Moreover, digital tools evaluating sleep parameters, pharyngeal weakness and breathing were endorsed.

Impact for the patients and their families

Our workshop defined PMM and its related phenotypes, evaluated useful outcome measures for natural history assessment, and discussed which of these measures to implement in clinical trials. Gathering more data on the natural history of PMM is crucial for patients and their families as it lays the foundation for future therapies. Moreover, understanding the patient's and family's burden and viewpoint is particularly important, as it can help select appropriate parameters for clinical trials. Thereby, we ensure that trials measure not only the 'academic advances' of investigational medications but also focus on parameters that capture noticeable benefits for patients in their daily lives. This collaborative effort between researchers and patients is essential for meaningful progress in the field of mitochondrial medicine.

Reference

Mancuso, M., McFarland, R., Klopstock, T., Hirano, M., & consortium on Trial Readiness in Mitochondrial Myopathies (2017). International Workshop:: Outcome measures and clinical trial readiness in primary mitochondrial myopathies in children and adults. Consensus recommendations. 16-18 November 2016, Rome, Italy. Neuromuscular disorders : NMD, 27(12), 1126–1137. https://doi.org/10.1016/j.nmd.2017.08.006

A full report will be published in Neuromuscular Disorders (PDF)