Mitochondrial Disease and the Eye

Mitochondrial network morphology in cultured fibroblasts (skin cells) from a healthy control individual. Staining was performed with MitoTrackerTM, a mitochondrion-specific fluorescent dye (green), and Hoechst 33342 for the nucleus (blue).This theme is led by Patrick Yu Wai Man, a clinical ophthalmologist with a subspecialist interest in neuro-ophthalmology and mitochondrial genetics. He is also a principal investigator within the Newcastle Mitochondrial Research Group and his current research has three main areas of focus: (i) to understand why the eye is selectively vulnerable in mitochondrial disease e.g. the preferential involvement of extraocular muscles in patients with chronic progressive external ophthalmoplegia (CPEO); (ii) to dissect the key molecular mechanisms leading to retinal ganglion cell loss in the two most common inherited optic neuropathies in the population, Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA); and (iii) to translate these advances in basic research into effective treatment strategies for these currently untreatable and often blinding mitochondrial disorders.

Funded by the MRC, he has set up a combined neuro-ophthalmology and neurogenetics service with Mr Philip Griffiths, Dr Rita Horvath, and Professor Patrick Chinnery. They also work closely with other key members of the Newcastle Mitochondrial Research Group, including Professor Doug Turnbull, Professor Robert Taylor, and Dr Bobby McFarland. The aim of this combined neuro-ophthalmology and neurogenetics service is to improve patients’ access to specialised genetic investigations and to help them make informed decisions with additional support from trained genetic counsellors. As part of their translational agenda and in collaboration with clinical partners in the UK, Germany and Canada, they recently conducted a multicentre double-blind randomised controlled trial (RCT) to investigate the safety, tolerability, and efficacy of high-dose idebenone in LHON (http://lhon.ncl.ac.uk/). RHODOS (Rescue of Hereditary Optic Disease Outpatient Study) is the first RCT for a primary mitochondrial disorder and the results obtained with high-dose idebenone are encouraging (see recent press release here). After two decades of sustained basic research, they are now at the start of an exciting translational phase not only for LHON, but for other mitochondrial eye disorders, which as a group represent an important cause of chronic visual morbidity in the population.

Selected Publications:

  • Klopstock K, Yu Wai Man P, Dimitriadis K, Rouleau J, Heck S, Atawan A, Chattopadhyay S, Bailie M, Schubert M, Rummey C, Metz G, Leinonen M, Griffiths PG, Meier T, Chinnery PF. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain. 2011; epub ahead of print.
  • Yu Wai Man P, Griffiths PG, Chinnery PF. Inherited optic neuropathies – Disease mechanisms and therapeutic strategies. Progress in Retinal and Eye Research. 2011;30(2):81-114.
  • Yu Wai Man P, Shankar SP, Biousse V, Miller NR, Bean LJH, Coffee B, Hegde M, Newman NJ. Genetic screening for OPA1 and OPA3 mutations in patients with suspected inherited optic neuropathies. Ophthalmology. 2011;118(3):558-63.
  • Yu Wai Man P, Sitarz KS, Samuels DC, Griffiths PG, Reeve AK, Bindoff LA, Horvath R, Chinnery PF. OPA1 mutations cause cytochrome c oxidase deficiency due to loss of wild-type mtDNA molecules. Human Molecular Genetics. 2010;19(15):3043-52.
  • Yu Wai Man P, Griffiths PG, Gorman GS, Lourenco CM, Wright AF, Auer-Grumbach M, Toscano A, Musumeci O, Valentino ML, Caporali L, Lamperti C, Tallaksen CM, Duffey P, Miller J, Whittaker RG, Baker MR, Jackson MJ, Clarke MP, Dhillon B, Czermin B, Stewart JD, Hudson G, Reynier P, Bonneau D, Marques W Jr, Lenaers G, McFarland R, Taylor RW, Turnbull DM, Votruba M, Zeviani M, Carelli V, Bindoff LA, Horvath R, Amati-Bonneau P, Chinnery PF. Multi-system neurological disease is common in patients with OPA1 mutations. Brain. 2010;133(3):771-86.
  • Yu Wai Man P, Lai-Cheong JE, Borthwick GM, He L, Taylor GA, Greaves LC, Taylor RW, Griffiths PG, Turnbull DM. Somatic mitochondrial DNA deletions accumulate to high levels in aging human extraocular muscles. Investigative Ophthalmology and Visual Science. 2010;51(7):3347-53.