Send Comments to IFOND

International Foundation for Optic Nerve Disease

Funding research and disseminating information on causes, prevention and treatment.
Welcome | Impact | Glaucoma | LHON | Toxic | Ischaemic | Projects | Donors | Coping | Glossary | Links | Use | About | Contact | Donate
IFOND Dictionary: Index | A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | NUM

IFOND research | LHON treatment prospects | Mitochondrial Genome Editing | COVID-19 and LHON | LHON talks | Pay it forward | Mitochondrial Regulation | Avoid BAK eye drop preservative, etc. | We experiment with cigarette smoke so you need not. | Viral vector trials | EPI-743 LHON trials | Idebenone LHON trials

Digests: NEI News | Mitochondrial Disease News LHON | ARVO Journals LHON | PubMed LHON | Europe PMC LHON | MRC-MBU news
Project updates: 2022 | 2019 | 2018 | 2017 | 2016 | 2015 | 2013 | 2011 | 2009 | 2008 | 2007 | 2006 | 2005-2001 |

Progress Report: Brazil LHON Project and other Investigations into Mitochondrial Optic Neuropathy

Alfredo A. Sadun, MD, PhD

September 6, 2008 

      I was privileged to lead an international team of investigators to rural Brazil for a field investigation for the seventh time in October 5-9, 2007.  We focused on four main issues during the first three years of our project.  1) Genetics: We found and organized and defined the world's largest pedigree of LHON established to be 11778, homoplasmic, J-haplogroup.  2) Epigenetics and epidemiology:  We investigated whether there was an increased risk of converting from carrier to affected status with diet, toxins and exposure to smoking, drinking and non-tobacco smoke. 3) Clinical characteristics of this giant pedigree with LHON:  We brought to rural Colatina several leading investigators and, with sophisticated equipment performed comprehensive neuro-ophthalmological examinations.  4) Psychophysical testing: We developed novel testing including cutting edge psychophysical evaluation techniques such as multifocal ERGs and include the developers of this technology.  We also investigated a number of new serological measures of oxidative stress. 

      Several conclusions were reached and published.  These included the fact that there were likely both genetic and epigenetic factors:  Genetically, nuclear modifying genes influenced the penetrance rate of those affected.  Environmental factors, including smoking and drinking (ETOH), more than doubled the risk of conversion to affected status.  We also concluded that there were subclinical manifestations of the disease that could be commonly described in carriers.  Further, we could measure chronic progression in non-affected carriers.  For example, we found alterations in mfERG, color vision, and contrast sensitivity testing.  We also noted retinal nerve fiber layer swelling that could be documented photographically by GDx and especially by OCT that reflected itself in subtle visual field changes.  The disease is more chronic and complicated than commonly believed.   

      This led to our theory of pathophysiologic mechanisms.  In short, the mutation of 11778 causes a defect of complex I that not only leads to a blockage of electron transport, but also to the production of reactive oxygen species (ROS).  This changes the membrane potential of the mitochondria and induces an opening of the mitochondrial pores (MPTP) that liberates cytochrome C and this induces apoptotic death of the retinal ganglion cells. 

      Four important new laboratory projects have also helped us understand the role of mitochondrial metabolism in optic neuropathies and helped us anticipate promising new treatment modalities for LHON.   

      1)  We have explored the effects of Linezolid, a new antibiotic which is usually prescribed for 28 days in patients with MRSA infections.  Taken longer, however, it can produce a LHON like optic neuropathy and blindness.  This is because bacteria and mitochondria share similar ribosomes and protein making machinery.  The Linezolid inhibits bacterial and also mitochondrial protein synthesis by binding to the common 50S ribosomal subunit.  We have carefully and published on this Leber's-like optic neuropathy. 

      2)  Melanopsin retinal ganglion cells were discovered about five years ago as a new class of retinal ganglion cells that provide information to the hypothalamus to help entrain circadian rhythms (our lab was indeed the first to suggest this pathway in humans).  Our studies suggest that these cells are the only types of retinal ganglion cells spared in LHON.  If so, then we should be able to stain for them and see them intact in retinas from LHON patients and indeed we have just completed proof of such in three cases.  This would also mean that unlike other cases of blindness, LHON patients should have intact circadian rhythms.  We have just demonstrated that in nine normal patients and nine patients with mitochondrial optic neuropathy (five with LHON), the circadian rhythm and the control of this rhythm by light, remains intact.  Therefore, if we can understand the differences in the metabolism of these special cells, we may also have a means of protecting the larger population of normal retinal ganglion cells in LHON.  This major work will be submitted for publication in late October. 

      3)  One such means might be a compensation by having more mitochondria (or more precisely, more mitochondrial -- mtDNA).  In collaboration with Drs. Valerio Carelli in Bologna, Italy and Carla Giordano in Rome, Italy, we are using laser capture to send the mtDNA from retinal ganglion cells, normal and melanopsin, for analysis. If the mtDNA is more abundant in the latter, we may have our answer.  We are also looking at mtDNA copy number in LHON affected vs. carriers vs. normals.  Preliminary results suggest that in carriers (those with the genetic defect but normal or near normal vision) the mtDNA copy number is significantly elevated.  This may indeed be the basis of a successful compensation that keeps these patients from going blind.  Since mtDNA copy number is higher in women than men (in all categories), it may also explain why men with the mtDNA mutation of LHON are more likely to go blind. This mtDNA work will be submitted for publication at the end of the year. 

      4) On each trip to Brazil we have brought back serum as well as blood cells from the extensive pedigree.  We have used this serum to test two biomarkers.  Our work in the last year has shown one of these biomarkers, phosphorylated heavy chain axonal neurofilament (PAN) to be particularly sensitive as a measure of which LHON patients have subclinical symptoms and which go blind.  We found that affected cases of LHON had higher levels than carriers who in turn had higher levels of PAN than normals.  But more remarkably, the carriers of LHON who had subclinical signs (worked out by our group in the seven years of field investigations in Brazil) had higher levels than those without subclinical signs.  This work has been accepted for publication with revisions pending.   

      We also have new exciting studies planned in anticipation of returning to Brazil with the large international team this October (Oct. 2-8, 2008).  We have planned this as a "practice run" for the anticipated clinical trial described above.  On this trip we will not be using any agent yet.  But we need to establish the mechanics of the study we hope to do next year.  We will be using multiple measures of subclinical findings, blood markers, etc. before and after (sham) drug administration.  The process of measuring, and then re-measuring, with all these instruments, will be complicated and involve about twenty investigators and over one hundred patients from the LHON family.  The patients will have to demonstrate, as they have before, forbearance, compliance and patience.  The investigators will be working sixteen hour days.  We look forward to it. 

Respectively submitted, 

Alfredo A. Sadun, MD, PhD 

Link to Papers IFOND helped sponsor

Here find links to published peer reviewed papers acknowledging IFOND's help. This research helped stimulate a cascade of broad research on mitochondrial and optic nerve disease.

Efficient funding

IFOND is an extremely lean, all volunteer 501(c)(3) tax status registered nonprofit. Our process minimizes costs and maximizes funding for researchers' direct, non administrative expenses. All donations are tax deductible in the United States of America. Our recent tax returns are here or also here. Our scientific board includes many of the prominent world leading published researchers in optic neuropathies. If this big bang for your buck model appeals to you, please donate. If you are a researcher in optic neuropathy, we welcome your funding application.

IFOND welcomes questions and comments
Welcome | Impact | Glaucoma | LHON | Toxic | Ischaemic | Projects | Donors | Coping | Glossary | Links | Use | About | Contact | Donate

Donate to IFOND sponsored research. You can designate which area of current IFOND activities to direct your funds:
>> Donate online <<
donate directly to IFOND at the address below:

The International Foundation for Optic Nerve Disease
P. O. Box 777, Cornwall NY 12518, USA.
Phone/Fax: (845)5348606
Web site:

IFOND is registered service mark of The International Foundation for Optic Nerve Disease, est. October 1995.

Copyright 1999-2023, International Foundation for Optic Nerve Disease.

The information contained on this website should not be considered medical guidance or professional advice. IFOND is not responsible for errors or omissions in information provided on this site or actions resulting from its use. IFOND does not publish all information from all available sources on optic nerve disease. IFOND is not responsible for the validity of the studies or reviews nor is it an advocate of studies or reviews mentioned on or linked from the IFOND web site. IFOND does not endorse or recommend participation in any particular clinical trial or treatment protocol which may be mentioned on this site. Direct any questions concerning your personal health to your appropriate health care professional.