Genetic Epidemiology and Clinical Trial Readiness in Encephalomyopathy of Leigh Syndrome Spectrum, virtual meetings; first (16 October 2020) second (4 December 2020) third (9 July 2021) fourth -hybrid- meeting (25 – 27 March 2022)

Location: Amsterdam, The Netherlands (Hybrid Meeting)

Title: Leigh Syndrome Spectrum: Genetic Causes, Natural History and Preparing for Clinical Trials

Date: 25-27 March 2022

Organisers: Pr. Shamima Rahman (UK), Pr. Manuel Schiff (France), Pr. Bruce Cohen (USA) and Pr. Enrico Bertini (Italy)

Participants:
Anna Ardissone (ITALY), Enrico Bertini (ITALY), John Christodoulou (AUSTRALIA), Bruce Cohen (USA), Amy Goldstein (USA), Richard Haas (USA), Hitoshi Osaka (JAPAN), Rita Horvath (UK), Robert McFarland (UK), Kei Murayama (JAPAN), Alessandro Prigione (GERMANY), Holger Prokisch (GERMANY), Shamima Rahman (UK), Agnès Rötig (FRANCE), Manuel Schiff (FRANCE), Markus Schuelke (GERMANY), Anu Suomalainen-Waartiovara (FINLAND), David Thorburn (AUSTRALIA), Jiri Zeman (CZECH REPUBLIC), Zarazuela Zolkipli-Cunningham (USA), Young scientists: Daria Diodato (ITALY), Alessandra Pennisi (FRANCE), and Pieti Pällijeff (FINLAND); Industry: Matthew Klein (USA); Patient representatives: Philip Yeske (USA), Alison Maguire (UK), Katie Waller (UK) and Amanda and Faye Wylie (UK).

Translations of this lay report:
German by Prof. Markus Schuelke

Leigh syndrome is a brain condition that usually affects young children (adult onset is very rare) and is caused by a variety of different genetic problems. Originally described in 1951 by Dr Denis Leigh, this syndrome typically involves symmetrical damage to both sides of the brain in areas known as the basal ganglia, thalamus, brainstem and spinal cord. The overarching aims of this series of virtual ENMC workshops were to discuss the genetic causes, disease course and development of therapies for this severe and progressive disorder.

Following three virtual conferences on the Leigh Syndrome Spectrum (LSS) held on 16th October and 4th December 2020 (https://www.enmc.org/download/258th-enmc-international-workshop-on-leigh-syndrome-spectru/) and 9 July 2021 (https://www.enmc.org/download/genetic-epidemiology-and-clinical-trial-readiness-in-encephalomyopathy-of-leigh-syndrome-spectrum/), a fourth and final hybrid workshop was held in Amsterdam on the weekend of 25-27 March 2022. Six participants (three of the organisers: Bertini, Rahman and Schiff), two scientists (Prigione and Rotig) and an industry representative (Klein) attended the workshop in person, and the other attendees participated online.

The hybrid meeting was opened by Enrico Bertini (Rome, Italy), who welcomed participants and gave an overview of the main objectives of this final hybrid workshop. Day 1 was devoted to a further discussion of the genetics of LSS. Shamima Rahman (London, UK) started the first session with a summary of the NIH-funded ClinGen curation of gene-disease associations of 113 nuclear and mitochondrial DNA-encoded genes and LSS, including the internationally agreed consensus definition of LSS. Next, Holger Prokisch (Munich, Germany) presented an update on GENOMIT, an international collaborative eRARE-funded project, and Daria Diodato (Rome, Italy) provided an overview of published national registries of LSS, including registries from Italy, UK, USA, France, Czech Republic, Australia, and Japan.

The workshop then focussed on issues concerning the disease mechanisms and diagnosis of LSS. Agnes Rötig (Paris, France) discussed the difficulties of variable clinical presentation of genetic variants in the SDHB gene and ongoing transcriptomic (RNA) studies aiming to unravel the underlying mechanisms. Next, Alessandra Pennisi (Paris, France) provided an update on a project aiming to bring together clinical and imaging features of LSS not caused by primary mitochondrial disease. This was an international collaborative project that began after the second virtual workshop of this series. Anna Ardissone (Milan, Italy) then discussed the changing diagnostic approach to LSS, moving from muscle biopsies to genetics as the first line, which was followed by a lively discussion including all members of the consortium. Day 1 concluded with a presentation from Rita Horvath (Cambridge UK) who described Treatabolome, a published meta-analysis of treatments in LSS.

Day 2 commenced with a review of biomarkers for primary mitochondrial diseases including LSS from Anu Suomalainen-Waartiovara (Helsinki, Finland). Alessandro Prigione (Dusseldorf, Germany) then presented his work modelling LSS in patient-derived brain organoids, and Markus Schuelke (Berlin, Germany) discussed the results of pharmacological screening of repurposed drugs – those drugs licensed for a different purpose but now investigated for potential use in mitochondrial disease – in induced pluripotent stem cells (iPSCs) also derived from patients affected by LSS.

The second session of Day 2 concerned natural history studies. Robert McFarland (Newcastle, UK) reported the findings of a retrospective LSS natural history study performed in Newcastle and presented the recently commenced LION (Leigh syndrome: Investigating Outcome measures & Natural history) study, a prospective longitudinal cohort study of LSS. Bruce Cohen (Akron, USA) then introduced the Leigh Syndrome Roadmap Project (LSRP) prospective natural history study of LSS and discussed the outcome measures that have been selected for this study.

The next session was devoted to emerging clinical trials for primary mitochondrial diseases including LSS. Hitoshi Osaka (Tochigi, Japan) provided an update of the Japanese study of apomorphine, a potent inhibitor of ferroptosis-related apoptosis (a form of programmed cell death), in mitochondrial disease. Matthew Klein (New Jersey, USA) presented the PTC Therapeutics MIT-E study of vatiquinone, a drug that targets 15-lipoxygenase, in treatment resistant epilepsy in genetically confirmed primary mitochondrial disease. He also discussed the complexities and challenges of clinical trial development for primary mitochondrial diseases.

The final session of Day 2 considered the patient journey. Zarazuela Zolkipli-Cunningham (Philadelphia, USA) reported on using her Mitochondrial Myopathy Composite Assessment Tool (MM-COAST) to quantify motor deficits in Leigh syndrome and how clinical outcomes are being collected at the Children’s Hospital of Philadelphia for the LSRP natural history study. Faye Wylie (Leigh Network, UK) and her mother Amanda then gave a moving account of the lived experience of Leigh syndrome through childhood into adult life and recited a poem written by Faye. Finally, Phil Yeske (UMDF, USA) discussed patient registries from the Patient Advocacy Group (PAG) viewpoint and introduced MitoSHARE, a global research database with multi stakeholder oversight and discussed the importance of collaboration.

Day 3 began with a presentation from Markus Schuelke about engaging with the European Medicines Agency (EMA) to take forward a compound identified in his iPSc drug repurposing screen into a formal clinical trial for LSS. Alison Maguire and Katie Waller (Lily Foundation, UK) then discussed the role of PAGs in LSS, again emphasising the importance of multidisciplinary collaboration, and described the process by which international care guidelines were developed for Duchenne muscular dystrophy, which could provide useful lessons for LSS. Day 3 concluded with a summary of the workshop by Manuel Schiff (Paris, France) and a roundtable discussion of the next steps.

During this series of workshops, international expert members of the Leigh syndrome consortium met with the objective of collecting genetic and natural history data to inform future clinical trials. These virtual and hybrid meetings have been an excellent opportunity to update and deepen our knowledge of the genetic causes and natural history of Leigh syndrome, promoting international research and collaborative studies, including fruitful discussions about prospective natural history studies and clinical trials. Collaborations arising from these meetings include an international collaborative project collating clinical and imaging features of non-primary mitochondrial disease causes of LSS, the potential use of a shared MRI and MRS protocol across multiple international centres and plans for delivering the LSRP prospective natural history study globally.

A full report is published in Neuromuscular Disorders (pdf).

258^th ENMC International Workshop:

Location: Virtual Meeting

Title: Genetic Epidemiology and Clinical Trial Readiness in Encephalomyopathy of Leigh Syndrome Spectrum

Date: 9 July 2021

Organisers: Pr. Shamima Rahman (UK), Pr. Manuel Schiff (France), Pr. Bruce Cohen (USA) and Pr. Enrico Bertini (Italy)

Participants: Enrico Bertini (ITALY), John Christodoulou (AUSTRALIA), Bruce Cohen (USA), Marni Falk (USA), Amy Goldstein (USA), Richard Haas (USA), Hitochi Osaka (JAPAN), Robert McFarland (UK), Kei Murayama (JAPAN), Holger Prokisch (GERMANY), Shamima Rahman (UK), Agnès Rötig (FRANCE), Manuel Schiff (FRANCE), Markus Schulke (GERMANY), David Thorburn (AUSTRALIA), Jiri Zeman (CZECH REPUBLIC), Zarazuela Zolkipli-Cunningham (USA), Young scientist: Daria Diodato (ITALY), Industry: Matthew Klein (USA) and Jan Smeitink (THE NETHERLANDS), Patient representatives: Philip Yeske (USA), Alison Maguire (UK) and Faye Wylie (UK)

Leigh syndrome, also known as a “subacute necrotizing encephalomyelopathy”, is a genetically heterogeneous disease that primarily affects the central nervous system. Originally described in 1951, this syndrome is characterized by focal and bilaterally symmetrical, necrotic lesions involving the basal ganglia, thalamus, brainstem, and posterior columns of the spinal cord. Leigh syndrome typically affects children; adult onset is rare. The overarching aims of this series of virtual ENMC workshops were to discuss the genetic aetiology, natural history, and development of therapies for this severe and progressive disorder.

Two virtual conferences were held on 16th October and 4th December 2020 (https://www.enmc.org/download/258th-enmc-international-workshop-on-leigh-syndrome-spectru/). International expert members of the Leigh syndrome consortium met with the objective of collecting genetic and natural history data to inform future clinical trials.

The planned face-to-face meeting on 9 July 2021 was ultimately also held virtually because of continued travel restrictions related to the SARS-CoV-2 pandemic. This event was attended by 23 participants from the Czech Republic, France, Germany, Italy, Netherlands, UK, Australia, Japan, and USA. Participants included clinicians, scientists and representatives of patient organisations and industrial collaborators.

The meeting was opened by Shamima Rahman (London, UK), who welcomed participants and gave an overview of the main objectives of this third virtual workshop: to discuss imaging biomarkers, clinical outcome measures and preclinical trials for Leigh syndrome.

Amy Goldstein (Philadelphia, USA) presented a single centre review of the spectrum of neuroimaging abnormalities observed in 53 patients with Leigh syndrome who had a baseline and at least one follow-up MRI brain scan. Her group had observed three broad patterns of imaging changes. The panel discussed that the genetic heterogeneity of Leigh syndrome means that 53 cases are not sufficient to establish definitive corelations between pathogenic genetic aetiology and imaging findings, and that global collaboration may facilitate the identification of such correlations, where they exist. Preliminary plans were discussed regarding the potential use of a shared MRI and MRS protocol across multiple international centres, which would allow such comparisons to be made.

Zarazuela Zolkipli-Cunningham (Philadelphia, USA) then discussed clinical outcome measures for Leigh syndrome, dividing these into central nervous system (CNS) and extra-CNS features. She discussed the importance of tailoring outcome measures to the age of the patient (child or adult) and considering the impact of the disease on patients and caregivers. Dr Zolkipli-Cunningham presented a series of performance outcome measures and patient/caregiver reported outcome measures, before describing the development of a composite assessment tool called MM-COAST.

In the third presentation of the afternoon, Hitoshi Osaka (Tochigi, Japan) reported on a drug repurposing screen, in which fibroblasts from patients with Leigh syndrome were exposed to the Prestwick library of chemical compounds, using a cell viability assay as an outcome measure. This chemical screen identified apomorphine as a modulator of mitochondrial dysfunction, leading to decreased levels of cytokines and chemokines including GDF-15. Dr Hitoshi also discussed a proposed clinical trial of apomorphine in Leigh syndrome in Japan.

Finally, Agnes Rotig (Paris, France) presented an update of the project to collate non primary mitochondrial disease causes of Leigh-like diseases, an international collaborative project that was initiated after the second virtual workshop of this series.

These three virtual meetings have been an excellent opportunity to update and deepen our knowledge of the genetic aetiology and natural history of Leigh syndrome, promoting international research and collaborative studies, including fruitful discussions about prospective natural history studies and clinical trials.

A final face-to-face/hybrid workshop is planned to be held in Amsterdam on 25 to 27 March 2022.

 

258^th ENMC International Workshop on Leigh syndrome spectrum

Location: Virtual Meeting

Title: Genetic Epidemiology and Clinical Trial Readiness in Encephalomyopathy of Leigh Syndrome spectrum

Date: 16 October and 4 December 2020

Organisers: Prof. Shamima Rahman (UK), Prof. Manuel Schiff (France), Prof. Bruce Cohen (USA) and Prof. Enrico Bertini (Italy)

Participants:

Anna Ardissone (ITALY), Enrico Bertini (ITALY), John Christodoulou (AUSTRALIA), Bruce Cohen (USA), Marni Falk (USA), Amy Goldstein (USA), Richard Haas (USA), Rita Horvath (UK), Hitochi Osaka (JAPAN), Robert McFarland (UK), Kei Murayama (JAPAN), Holger Prokisch (GERMANY), Shamima Rahman (UK), Agnès Rötig (FRANCE), Manuel Schiff (FRANCE), Markus Schulke (GERMANY), David Thorburn (AUSTRALIA), Saskia Wortmann (GERMANY), Jiri Zeman (CZECH REPUBLIC), Young scientist: Daria Diodato (ITALY), industry: Matthew Klein (USA) and Jan Smeitink (THE NETHERLANDS), patient representatives: Philip Yeske (USA), Alison Maguire (UK) and Faye Wylie (UK)

Leigh syndrome, also known as a “subacute necrotizing encephalomyopathy”, is a genetically heterogeneous disease that primarily affects the central nervous system. Necrosis means death of cells through disease, especially in a localized area of a tissue or organ Originally described in 1951, this syndrome is characterized by focal and bilaterally symmetrical, necrotic lesions involving a few specific areas in the brain: the thalamus, brainstem, and posterior columns of the spinal cord. Leigh syndrome typically affects children; adult onset is rare. Leigh syndrome is a severe and progressive disorder. During this virtual ENMC workshop, international expert members of the Leigh syndrome consortium met with the objective to collect data on the natural history (or natural cause and development) of the disease in order to develop future trials.

The first (virtual) conference was held during two afternoons on the 16th of October and the 4^th of December 2020. This event gathered 25 participants from Japan, France, Italy, Netherlands, UK, Australia and USA. Participants included clinicians, scientists,  representatives of patient organisations and one patient affected by Leigh syndrome, and two industrial collaborators.

The meeting was opened by Enrico Bertini (Rome, Italy), who welcomed participants and gave an overview of the meeting’s main objectives: to increase knowledge of the natural history of Leigh syndrome, to improve its diagnosis, to collect information on the genetic epidemiology of the syndrome, to facilitate the identification of biomarkers, and to move forward with possible therapeutic strategies.

The first afternoon session was dedicated to addressing several issues concerning the diagnosis, and the clinical and genetic landscape of Leigh syndrome: 1) Based on Anu Suomalainen’s recent publication, we raised the importance of developing biomarkers in order to set outcome measures for future trials; 2) Marni Falk (USA) showed the genetic and clinical spectrum of patients with Leigh syndrome in USA; 3) Shamima Rahman (UK) talked about the importance of an appropriate Leigh syndrome definition, the Leigh syndrome spectrum disorders and the ClinGen international gene curation process, involving 30 experts from all over the world, aimed to define the Leigh syndrome-associated genes and level of evidence for their association with Leigh syndrome; 4) Bruce Cohen (USA) showed the structure of the Leigh Syndrome Roadmap Project that aims to improve diagnosis, and the impact on the lives of patients; 5) Anna Ardissone (Italy) presented data regarding the Leigh syndrome patients included in the Italian Registry of mitochondrial patients; 6) Holger Prokisch (Germany) presented the Genomit project; 7) and Robert Mc Farland (UK) presented data of patients with Leigh syndrome from the UK registry. After these brainstorming sessions, major issues were discussed regarding definition of the Leigh syndrome spectrum, outcome measures, importance of metabolomics (which is the large-scale study of small molecules, commonly known as metabolites, within cells, biofluids, tissues or organisms), and proper functional scales to be used in clinical trials.

In the second afternoon session, other experts presented genetic data from their local Leigh syndrome patient databases: 1) Agnes Rötig (France), David Thorburn (Australia), Kei Murayama (Japan), Jiri Zeman (Czech Republic), and Holger Prokisch showed additional data from the Genomit registry (Germany, Paris, Milan, Tokyo, Newcastle.

This virtual meeting has been an excellent opportunity to update and deepen our knowledge of the genetic cause (aetiology) and natural history of Leigh syndrome, promoting international research and collaborative studies to better characterize and follow our patients.

All participants learnt much about the frequency of each type of genetic cause of Leigh syndrome, and future steps include building a human phenotype ontology* map for Leigh syndrome and defining optimal outcome measures and biomarkers for use in future clinical trials.

The final meeting of this ENMC workshop will be hopefully face-to-face in July 2021.

*The Human Phenotype Ontology (HPO) provides a standardized vocabulary of phenotypic abnormalities (symptoms) encountered in human disease. Each term in the HPO describes a phenotypic abnormality, such as Atrial septal defect. The HPO is currently being developed using the medical literature, Orphanet, DECIPHER, and OMIM.