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Progress Report: Brazil LHON Project and other Investigations into Mitochondrial Optic Neuropathy
Alfredo A. Sadun, MD, PhD
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
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
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.
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.
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.
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.
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
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.
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.
Alfredo A. Sadun, MD, PhD
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.>
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