Workshop report176th ENMC International Workshop: Diagnosis and treatment of coenzyme Q10 deficiency
Introduction
An ENMC meeting was held in Naarden, the Netherlands (July 9th–11th 2010) with 12 clinical and basic scientists and three industrial representatives from Europe (France, Belgium, Germany, Italy, Spain, Switzerland, the Netherlands and the UK) and the USA, to discuss their collective experience with the molecular underpinnings, diagnosis, and management of patients with deficiency of coenzyme Q10 (CoQ10).
CoQ10, also known as ubiquinone, is a unique electron carrier [1]. It is essential for aerobic organisms because of its role in mitochondrial energy production as a chaperone of electrons from complexes I and II (and also from the electron transfer flavoproteins, ETF) to complex III of the respiratory chain. In addition, this lipophilic molecule has numerous other vital functions in cells that include: serving as antioxidant in both lipoproteins and cell membranes; connecting energy production with important cellular pathways such as the cell cycle and DNA replication and repair through its role in pyrimidine biosynthesis; modulation of apoptosis through its regulation of the transition pore; and maintenance of body temperature via its action on uncoupling proteins.
The aims of this workshop were: to define how to clinically recognise and diagnose patients with CoQ10 deficiency; to optimize strategies to identify the underlying molecular genetic defects; to review basic CoQ10 biology; and to delineate therapeutic options for this group of disorders, which represent the most readily treatable subset of mitochondrial diseases.
Section snippets
Biosynthesis of coenzyme Q
Primary CoQ10 deficiencies are caused by defects of the ubiquinone biosynthesis pathway, which is a complex and incompletely understood metabolic pathway [2]. In humans, the benzoquinone ring is synthesized from tyrosine or phenylalanine, while the polyprenyl side-chain is generated from acetyl-CoA through the mevalonate pathway and the enzymatic activity of decaprenyl diphosphate synthase. After condensation of 4-hydroxybenoate (4HB) with the polyprenyl tail, the ring undergoes
Future prospects
As a result of the workshop, an international consortium was established with the aim of optimising the diagnosis and treatment of patients with CoQ10 deficiency. The prevalence of CoQ10 deficiency remains unknown but, because of its novelty and relative obscurity, the consortium members suspect that this condition is underdiagnosed. The lack of a specific ‘CoQ10 phenotype’ hampers clinical recognition of this disorder, but it is hoped that the diagnostic algorithm presented here will help to
Chairpersons
Shamima Rahman, UCL Institute of Child Health, London, UK.
Michio Hirano, Columbia University, New York, USA.
Workshop participants
Clinicians & Scientists:
Catherine Clarke, UCLA, USA.
Iain Hargreaves, National Hospital, London, UK.
Michio Hirano, Columbia University, New York, USA.
Rita Horvath, Institute of Genetic Medicine, Newcastle, UK.
Luis C López, Universidad de Granada, Spain.
Placido Navas, CABD, Seville, Spain.
Maria del Mar O’Callaghan, Barcelona, Spain.
Hélène Puccio, IGBMC, Strasbourg, France.
Catarina Quinzii, Columbia University, New York, USA.
Shamima Rahman, UCL Institute of Child Health, London, UK.
Agnes Rötig,
Acknowledgements
This Workshop was made possible thanks to the financial support of the European Neuromuscular Centre (ENMC) and ENMC main sponsors: Deutsche Gesellschaft für Muskelkranke (Germany), Muscular Dystrophy Campaign (UK), Muskelsvindfonden (Denmark), Prinses Beatrix Fonds (The Netherlands), Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland), Telethon Foundation (Italy), Vereniging Spierziekten Nederland (The Netherlands) and associated members: Association Française
References (64)
- et al.
Metabolism and function of coenzyme Q
Biochim. Biophys. Acta
(2004) - et al.
Biosynthesis of ubiquinone
Vitam. Horm.
(1983) - et al.
Involvement of mitochondrial ferredoxin and para-aminobenzoic acid in yeast coenzyme Q biosynthesis
Chem. Biol.
(2010) - et al.
Para-Aminobenzoic acid is a precursor in coenzyme Q6 biosynthesis in Saccharomyces cerevisiae
J. Biol. Chem.
(2010) - et al.
CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures
Am. J. Hum. Genet.
(2008) - et al.
Quinone-responsive multiple respiratory-chain dysfunction due to widespread coenzyme Q10 deficiency
Lancet
(2000) - et al.
Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations
Am. J. Hum. Genet.
(2006) - et al.
A Mutation in para-hydroxybenzoate-polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency
Am. J. Hum. Genet.
(2006) - et al.
Neonatal presentation of coenzyme Q10 deficiency
J. Pediatr.
(2001) - et al.
ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency
Am. J. Hum. Genet.
(2008)