BCH2BMA

Integrated Research Assignment on

Genetically Inherited Metabolic
Disorders
Name: Kai Yeung Lui
Student number: 16081325
Prac.: Tuesday with Phillip

Leber Hereditary Optic Neuropathy

Introduction

Leber Hereditary Optic Neuropathy (LHON) is a mitochondrial genetic disease founded

by Theodor Leber in 1871 (Howell 1997).It has a characteristic of incomplete dominance.
This results in a gender bias which most suffers are young male. Those with LHON may
experience visual failure due to degeneration of the retinal ganglion cell layer and optic
nerve (Man et al., 2002). The primary cause of LHON is three mitochondrial DNA
(mtDNA) point mutation at 11778/ND4, 14484/ND6 and 3460/ND1 respectively (Carelli
et al., 2004). Nuclear genetic factors and environmental factors also affect the onset of
LHON.

Malfunction of Ubiquinone Oxidoreductase, Cell Death and

Optic Nerve Atrophy

Ubiquinone oxidoreductase (complex I) is an enzyme which is embedded in the inner

mitochondria membrane with a head part which is projected into the matrix. Apart from
converting NADH+ from the matrix to NAD+, it is responsible for pumping protons into
the intermembrance space, where to protons enters the electron transport chain generating
ATPs. The three mtDNA point mutations encode subunits which is located at the part
which is embedded in the inner membrane. All three mutations reduces mitochondria
respiration of complex I but only mutation at subunit ND1 results in a significant electron
transport chain activity decrease. Figure 1 show a diagram of complex I. However,
although ATP production by complex I is reduced, cell can compensate by using
alternative pathways or substrates to reach its energy demands (Carelli et al., 2004). So a
lack of energy is not the main reason for atrophy. Another study has shown that ganglion
cell function mainly relies on glycolysis but not mitochondrial respiration for energy.
Only the high energy demanding photoreceptors on the retina rely on mitochondrial ATP
synthesis. It is proposed that decrease in ganglion cell function is due to an increase
NADH+/NAD+ ratio, as one of complex I function is converting NADH+ to NAD+
(Howell 1997). This causes a decrease in pH affecting redox centres of the respiratory
chain, leading to accumulation of reactive oxygen species (ROS) (Carelli et al., 2004).
Also the inability for complex I to regenerate NAD+, has induced the overall flux of
NADH+ substrates in the respiratory chain to decrease by half (Howell 1997).
There are lots of cell death pathways which are triggered by the mitochondria. Below are
several proposed theory on how cell death occurs due to the abnormal complex I. On of
them is the change of configuration of complex I increases the sensitivity to Fas. Fas is an
activator for the Fas ligand death receptor. Another model has been proposed using
LHON cybrids. In a glucose containing medium, cells with LHON can still maintain it
energy requirements via alternative method, but when glucose is switch to galactose, it a
different story. The conversion rate of galactose to glucose is too slow for the cell to
make enough energy by glycolysis, so the cell switches on it’s impair respiratory chain
for ATP production. The lack of energy induces the activation of the cell death pathway.
LHON cybrid models have also shown LHON cells mitochondria release a significant
amount of cytochrome c. Cytochrome c is then involved in a number of reaction steps in
which capase-3 is activated. Capase-3 then releases CAD into the nucleus. CAD causes
DNA fragmentation and chromosome condensation, a process of cell death. The final
mechanism is when ROS concentration increase due to pH decrease, antioxidant defenses
are activated. But under high energy demanding situations, the defense is not able to keep
up with the ROS build up, eventually leading to cell death (Carelli et al., 2004).

The cause of optic nerve degeneration, unlike the ganglion cells, is mainly due to energy
deficiency. Due to its high firing rate of nerve impulse, it requires ATP production for its
respiratory chain (Howell 1997).

Symptoms, Diagnosis and Treatment

Symptoms:

Patients with LHON usually experience vision loss at age 13-28. Vision loss happened
with both eyes separate by a slight lag time. Vision gradually decreases from 1-36 weeks,
most patient will only limited to counting fingers; others may results in perception to
light only or total blindness. LHON is usually painless but pain may occur during eye
movements. Depending on the type of mutation, multiple-sclerosis like symptoms may
occur (Riordan-Eva et al., 1995).

Diagnosis:

The most reliable diagnosis method is genetic counseling, analysis of mtDNA. Diagnosis
by clinical features is often misleading, especially for patient with no affected relatives
(Riordan-Eva et al., 1995). Some patients may show atypical LHON symptoms which is
misled to other optic atrophy. Assessment of visual fields can be done by kinetic
perimetry and fluorescein angiography to check the microvasculature of the retina.
Electrophysiological methods like electroretinograms and visual evoked potentials can
determine optic nerve function (Man et al., 2002).

Treatment:

There is currently no treatment available to improve visual loss. Unaffected LHON

carriers however should stop smoking and lower alcohol consumption; this is for the
benefit of general health (Man et al., 2002). Most patients will not recover from vision
lost, but the lower the age of LHON onset, the greater the chance of recovery. Recovery
mechanism is unknown. Recovery is also dependent to the type of mutation (Riordan-Eva
et al., 1995).

Reference List
Calerlli, V, Rugolo, M, Sgarbi, G, Ghelli, A, Zanna, C, Baracca, A, Lenaz, G, Napoli, E,
Martinuzzi, A & Solaini, G 2004, ‘ Bioenergetics shapes cellular death pathways in
Leber’s hereditary optic neuropathy: a model of mitochondrial neurodegeneration’,
Biochimica ct Biophysica Acta, vol. 1658, pp. 172-179, viewed 2 October 2010,
<http://www.sciencedirect.com/>.

Howell, N 1997, ‘Leber Hereditary Optic Neuropathy: How Do Mitochondrial DNA

Mutations Cause Degeneration of the Optic Nerve’, Journal of Bioenergetics and
Biomembranes, vol. 29, pp. 165-173, viewed 9 October 2010,
<http://www.springerlink.com/content/r00p5235p2l49348/>.
Man, PYM, Turnbull, DM & Chinnery, PF 2002, ‘ Leber hereditary optic neuropathy’,
Journal of Medical Genetics, vol. 39, pp. 162-169, viewed 3 October 2010, <http://0-
find.galegroup.com.alpha2.latrobe.edu.au/gtx/>.

Riodan-Eva, P, Sanders, MD, Govan, GG, Sweeney, MG, Da Costa, J & Harding, AE
1995, ‘The clinical features of Leber’s hereditary optic neuropathy defined by the
presence of a pathogenic mitochondria DNA mutation’, Brain, vol. 118, pp. 319-337,
viewed 6 October 2010, < http://0-proquest.umi.com.alpha2.latrobe.edu.au/>.