Leigh syndrome spectrum


Number 258
Date 4 December 2020

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 4th 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. A full report will be published after the final meeting in Neuromuscular Disorders.

*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.