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

Date 9 July 2021

258th 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 ( 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.