Leber's hereditary optic neuropathy
Encyclopedia
Leber’s hereditary optic neuropathy (LHON) or Leber optic atrophy is a mitochondrially inherited
(mother to all offspring) degeneration of retina
l ganglion cell
s (RGCs) and their axon
s that leads to an acute or subacute loss of central vision; this affects predominantly young adult males. However, LHON is only transmitted through the mother as it is primarily due to mutation
s in the mitochondrial (not nuclear) genome
and only the egg
contributes mitochondria to the embryo
. LHON is usually due to one of three pathogenic mitochondrial DNA
(mtDNA) point mutation
s. These mutations are at nucleotide
positions 11778 G
to A
, 3460 G
to A
and 14484 T
to C
, respectively in the ND4, ND1 and ND6 subunit gene
s of complex I of the oxidative phosphorylation
chain in mitochondria. Men cannot pass on the disease to their offspring.
(G) to adenosine (A) mutation at nucleotide position 11778 in nine families. This mutation converts a highly conserved arginine
to histidine
at codon 340 in the NADH dehydrogenase
subunit 4 of complex I of the mitochondrial respiratory chain. The other two mutations known to cause this condition were identified in 1991 (G to A point mutation at nucleotide position 3460) and 1992 (thymidine
(T) to cytosine
(C) mutation at nucleotide 14484). These three mutations account for over 95% of cases: the 11778 mutation accounts for 50-70% of cases, the 14484 mutation for 10-15% and the 3460 mutation for 8-25%.
, and then a few weeks to months later in the other. Onset is usually young adulthood, but age range at onset from 7-60 is reported. The age of onset is slightly higher in females (range 19-55 years: mean 31.3 years) than males (range 15-53 years: mean 24.3). The male to female ratio varies between mutations: 3:1 for 3460 G>A, 6:1 for 11778 G>A and 8:1 for 14484 T>C. No reason for this difference is known.
This typically evolves to very severe optic atrophy and permanent decrease of visual acuity
. Both eyes become affected either simultaneously (25% of cases) or sequentially (75% of cases) with a median inter-eye delay of 8 weeks. Rarely only one eye may be affected. In the acute stage, lasting a few weeks, the affected eye demonstrates an edematous appearance of the nerve fiber layer especially in the arcuate bundles and enlarged or telangectatic and tortuous peripapillary vessels (microangiopathy). The main features are seen on fundus
examination, just before or subsequent to the onset of visual loss. A pupillary defect
may be visible in the acute stage as well. Examination reveals decreased visual acuity, loss of color vision
and a cecocentral scotoma
on visual field examination
.
because of the lack of muscular control.
Leber hereditary optic neuropathy is a condition related to changes in mitochondrial DNA
. Although most DNA is packaged in chromosomes within the nucleus, mitochondria have a distinct mitochondrial genome composed of mtDNA.
Mutations in the MT-ND1
, MT-ND4, MT-ND4L, and MT-ND6 genes cause Leber hereditary optic neuropathy. These genes code for the NADH dehydrogenase
protein involved in the normal mitochondrial function of oxidative phosphorylation
. Oxidative phosphorylation uses a large multienzyme complex to convert oxygen and simple sugars to energy. Mutations in any of the genes disrupt this process to cause a variety of syndromes depending on the type of mutation and other factors. It remains unclear how these genetic changes cause the death of cells in the optic nerve and lead to the specific features of Leber hereditary optic neuropathy.
There is a prevalence
of between 1:30,000 to 1:50,000 in Europe.
The LHON ND4 G11778A mutation dominates as the primary mutation in most of the world
with 70% of European cases and 90% of Asian cases. Due to a Founder effect
, the LHON ND6 T14484C mutation accounts for 86% of LHON cases in Quebec
, Canada
.
More than 50 percent of males with a mutation and more than 85 percent of females with a mutation never experience vision loss or related medical problems. The particular mutation type may predict likelihood of penetrance
, severity of illness and probability of vision recovery in the affected. As a rule of thumb, a woman who harbors a homoplasmic primary LHON mutation has a ~40% risk of having an affected son and a ~10% risk of having an affected daughter.
Additional factors may determine whether a person develops the signs and symptoms of this disorder. Environmental factors such as smoking and alcohol use may be involved, although studies of these factors have produced conflicting results. Researchers are also investigating whether changes in additional genes, particularly genes on the X chromosome,
contribute to the development of signs and symptoms. The degree of heteroplasmy
, the percentage of mitochondria which have mutant alleles, may play a role. Patterns of mitochondrial alleles called haplogroup
may also affect expression of mutations.
. Experimental evidence reveals impaired glutamate transport and increased reactive oxygen species
(ROS) causing apoptosis
of retinal ganglion cells. Also, experiments suggest that normal non LHON affected retinal ganglion cells produce less of the potent superoxide
radical than other normal central nervous system neurons. Viral vector experiments which augment superoxide dismutase
2 in LHON cybrids or LHON animal models or use of exogenous glutathione
in LHON cybrids have been shown to rescue LHON affected retinal ganglion cells from apoptotic death. These experiments may in part explain the death of LHON affected retinal ganglion cells in preference to other central nervous system neurons which also carry LHON affected mitochondria.
and perimetry
checks are advised for follow up of affected individuals. There is beneficial treatment available for some cases of this disease especially for early onset disease. Also, experimental treatment protocols are in progress. Genetic counselling should be offered.
For those who are carriers of a LHON mutation, preclinical markers may be used to monitor progress. For example fundus photography can monitor nerve fiber layer
swelling. Optical coherence tomography
can be used for more detailed study of retinal nerve fiber layer thickness. Red green color vision
testing may detect losses. Contrast sensitivity may be diminished. There could be an abnormal electroretinogram or visual evoked potentials. Neuron-specific enolase and axonal heavy chain neurofilament
blood markers may predict conversion to affected status.
Avoiding optic nerve toxins is generally advised, especially tobacco and alcohol. Certain prescription drugs are known to be a potential risk, so all drugs should be treated with suspicion and checked before use by those at risk.
Ethambutol, in particular, has been implicated as triggering visual loss in carriers of LHON. In fact, toxic and nutritional optic neuropathies
may have overlaps with LHON in symptoms, mitochondrial mechanisms of disease and management. Of note, when a patient carrying or suffering from LHON or toxic/nutritional optic neuropathy
suffers a hypertensive crisis as a possible complication of the disease process, nitroprusside (trade name: Nipride) should not be used due to increased risk of optic nerve ischemia
in response to this anti-hypertensive in particular.
Idebenone
has been shown in a small placebo controlled trial to have modest benefit in about half of patients. People most likely to respond best were those treated early in onset.
α-tocotrienol
-quinone, a Vitamin E metabolite, has had some success in small open label trials in reversing early onset vision loss.
There are various treatment approaches which have had early trials or are proposed, none yet with convincing evidence of usefulness or safety for treatment or prevention including:
Brimonidine
; Minocycline
; Curcumin
;
glutathione
; Near infrared light treatment
; and Viral vector
techniques.
"Three person in vitro fertilisation" is a proof of concept research technique for preventing mitochondrial disease in developing human fetuses. So far, viable macaque monkeys have been produced. But ethical and knowledge hurdles remain before use of the technique in humans is established.
Human mitochondrial genetics
Human mitochondrial genetics is the study of the genetics of the DNA contained in human mitochondria. Mitochondria are small structures in cells that generate energy for the cell to use, and are hence referred to as the "powerhouses" of the cell....
(mother to all offspring) degeneration of retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
l ganglion cell
Ganglion cell
A retinal ganglion cell is a type of neuron located near the inner surface of the retina of the eye. It receives visual information from photoreceptors via two intermediate neuron types: bipolar cells and amacrine cells...
s (RGCs) and their axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
s that leads to an acute or subacute loss of central vision; this affects predominantly young adult males. However, LHON is only transmitted through the mother as it is primarily due to mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in the mitochondrial (not nuclear) genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
and only the egg
Ovum
An ovum is a haploid female reproductive cell or gamete. Both animals and embryophytes have ova. The term ovule is used for the young ovum of an animal, as well as the plant structure that carries the female gametophyte and egg cell and develops into a seed after fertilization...
contributes mitochondria to the embryo
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
. LHON is usually due to one of three pathogenic mitochondrial DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
(mtDNA) point mutation
Point mutation
A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair...
s. These mutations are at nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
positions 11778 G
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
to A
Adenine
Adenine is a nucleobase with a variety of roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate and the cofactors nicotinamide adenine dinucleotide and flavin adenine dinucleotide , and protein synthesis, as a chemical component of DNA...
, 3460 G
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
to A
Adenine
Adenine is a nucleobase with a variety of roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate and the cofactors nicotinamide adenine dinucleotide and flavin adenine dinucleotide , and protein synthesis, as a chemical component of DNA...
and 14484 T
Thymine
Thymine is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nucleobase. As the name suggests, thymine may be derived by methylation of uracil at...
to C
Cytosine
Cytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...
, respectively in the ND4, ND1 and ND6 subunit gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s of complex I of the oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
chain in mitochondria. Men cannot pass on the disease to their offspring.
History
This disease was first described by the German ophthalmologist Theodore Leber (1840-1917) in 1871. In this paper Leber described four families in which a number of young men suffered abrupt loss of vision in both eyes either simultaneously or sequentially. This disease was initially thought to be X linked but was subsequently shown to be mitochondrial. The nature of the causative mutation was first identified in 1988 by Wallace et al who discovered the guanineGuanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
(G) to adenosine (A) mutation at nucleotide position 11778 in nine families. This mutation converts a highly conserved arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
to histidine
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
at codon 340 in the NADH dehydrogenase
NADH dehydrogenase
NADH dehydrogenase is an enzyme located in the inner mitochondrial membrane that catalyzes the transfer of electrons from NADH to coenzyme Q...
subunit 4 of complex I of the mitochondrial respiratory chain. The other two mutations known to cause this condition were identified in 1991 (G to A point mutation at nucleotide position 3460) and 1992 (thymidine
Thymidine
Thymidine is a chemical compound, more precisely a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine in double-stranded DNA...
(T) to cytosine
Cytosine
Cytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...
(C) mutation at nucleotide 14484). These three mutations account for over 95% of cases: the 11778 mutation accounts for 50-70% of cases, the 14484 mutation for 10-15% and the 3460 mutation for 8-25%.
Signs & symptoms
Clinically, there is an acute onset of visual loss, first in one eyeHuman eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
, and then a few weeks to months later in the other. Onset is usually young adulthood, but age range at onset from 7-60 is reported. The age of onset is slightly higher in females (range 19-55 years: mean 31.3 years) than males (range 15-53 years: mean 24.3). The male to female ratio varies between mutations: 3:1 for 3460 G>A, 6:1 for 11778 G>A and 8:1 for 14484 T>C. No reason for this difference is known.
This typically evolves to very severe optic atrophy and permanent decrease of visual acuity
Visual acuity
Visual acuity is acuteness or clearness of vision, which is dependent on the sharpness of the retinal focus within the eye and the sensitivity of the interpretative faculty of the brain....
. Both eyes become affected either simultaneously (25% of cases) or sequentially (75% of cases) with a median inter-eye delay of 8 weeks. Rarely only one eye may be affected. In the acute stage, lasting a few weeks, the affected eye demonstrates an edematous appearance of the nerve fiber layer especially in the arcuate bundles and enlarged or telangectatic and tortuous peripapillary vessels (microangiopathy). The main features are seen on fundus
Fundus (eye)
The fundus of the eye is the interior surface of the eye, opposite the lens, and includes the retina, optic disc, macula and fovea, and posterior pole. The fundus can be viewed with an ophthalmoscope. The term may also be inclusive of Bruch's membrane and the choroid.The color of the fundus varies...
examination, just before or subsequent to the onset of visual loss. A pupillary defect
Marcus Gunn pupil
Marcus Gunn pupil is a medical sign observed during the swinging-flashlight test whereupon the patient's pupils constrict less when a bright light is swung from the unaffected eye to the affected eye...
may be visible in the acute stage as well. Examination reveals decreased visual acuity, loss of color vision
Color vision
Color vision is the capacity of an organism or machine to distinguish objects based on the wavelengths of the light they reflect, emit, or transmit...
and a cecocentral scotoma
Scotoma
A scotoma is an area of partial alteration in one's field of vision consisting of a partially diminished or entirely degenerated visual acuity which is surrounded by a field of normal - or relatively well-preserved - vision.Every normal mammalian eye has a scotoma in its field of vision, usually...
on visual field examination
Perimetry
Perimetry or campimetry is the systematic measurement of differential light sensitivity in the visual field by the detection of the presence of test targets on a defined background. Visual field testing can be performed clinically with confrontational field testing keeping the subject's gaze fixed...
.
LHON Plus
"LHON Plus" is a name given to rare strains of the disorder with eye disease together with other conditions. The symptoms of this higher form of the disease include loss of the brain's ability to control the movement of muscles, tremors, and cardiac arrhythmia. Many cases of LHON plus have been comparable to multiple sclerosisMultiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
because of the lack of muscular control.
Genetics
Mitochondrial DNA
Mitochondrial DNA is the DNA located in organelles called mitochondria, structures within eukaryotic cells that convert the chemical energy from food into a form that cells can use, adenosine triphosphate...
. Although most DNA is packaged in chromosomes within the nucleus, mitochondria have a distinct mitochondrial genome composed of mtDNA.
Mutations in the MT-ND1
MT-ND1
MT-ND1 is a mitochondrial gene. It is associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.-External links:*...
, MT-ND4, MT-ND4L, and MT-ND6 genes cause Leber hereditary optic neuropathy. These genes code for the NADH dehydrogenase
NADH dehydrogenase
NADH dehydrogenase is an enzyme located in the inner mitochondrial membrane that catalyzes the transfer of electrons from NADH to coenzyme Q...
protein involved in the normal mitochondrial function of oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
. Oxidative phosphorylation uses a large multienzyme complex to convert oxygen and simple sugars to energy. Mutations in any of the genes disrupt this process to cause a variety of syndromes depending on the type of mutation and other factors. It remains unclear how these genetic changes cause the death of cells in the optic nerve and lead to the specific features of Leber hereditary optic neuropathy.
Epidemiology
In Northern European populations about one in 9000 people carry one of the three primary LHON mutations.There is a prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
of between 1:30,000 to 1:50,000 in Europe.
The LHON ND4 G11778A mutation dominates as the primary mutation in most of the world
with 70% of European cases and 90% of Asian cases. Due to a Founder effect
Founder effect
In population genetics, the founder effect is the loss of genetic variation that occurs when a new population is established by a very small number of individuals from a larger population. It was first fully outlined by Ernst Mayr in 1942, using existing theoretical work by those such as Sewall...
, the LHON ND6 T14484C mutation accounts for 86% of LHON cases in Quebec
Quebec
Quebec or is a province in east-central Canada. It is the only Canadian province with a predominantly French-speaking population and the only one whose sole official language is French at the provincial level....
, Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...
.
More than 50 percent of males with a mutation and more than 85 percent of females with a mutation never experience vision loss or related medical problems. The particular mutation type may predict likelihood of penetrance
Penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
, severity of illness and probability of vision recovery in the affected. As a rule of thumb, a woman who harbors a homoplasmic primary LHON mutation has a ~40% risk of having an affected son and a ~10% risk of having an affected daughter.
Additional factors may determine whether a person develops the signs and symptoms of this disorder. Environmental factors such as smoking and alcohol use may be involved, although studies of these factors have produced conflicting results. Researchers are also investigating whether changes in additional genes, particularly genes on the X chromosome,
contribute to the development of signs and symptoms. The degree of heteroplasmy
Heteroplasmy
Heteroplasmy is the presence of a mixture of more than one type of an organellar genome within a cell or individual...
, the percentage of mitochondria which have mutant alleles, may play a role. Patterns of mitochondrial alleles called haplogroup
Haplogroup
In the study of molecular evolution, a haplogroup is a group of similar haplotypes that share a common ancestor having the same single nucleotide polymorphism mutation in both haplotypes. Because a haplogroup consists of similar haplotypes, this is what makes it possible to predict a haplogroup...
may also affect expression of mutations.
Pathophysiology
The eye pathology is limited to the retinal ganglion cell layer especially the maculopapillary bundle. Degeneration is evident from the retinal ganglion cell bodies to the axonal pathways leading to the lateral geniculate nucleiiLateral geniculate nucleus
The lateral geniculate nucleus is the primary relay center for visual information received from the retina of the eye. The LGN is found inside the thalamus of the brain....
. Experimental evidence reveals impaired glutamate transport and increased reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
(ROS) causing apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
of retinal ganglion cells. Also, experiments suggest that normal non LHON affected retinal ganglion cells produce less of the potent superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...
radical than other normal central nervous system neurons. Viral vector experiments which augment superoxide dismutase
Superoxide dismutase
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...
2 in LHON cybrids or LHON animal models or use of exogenous glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
in LHON cybrids have been shown to rescue LHON affected retinal ganglion cells from apoptotic death. These experiments may in part explain the death of LHON affected retinal ganglion cells in preference to other central nervous system neurons which also carry LHON affected mitochondria.
Diagnosis & management
Without a known family history of LHON the diagnosis is difficult and usually requires a neuro-ophthalmological evaluation and/or blood testing for DNA assessment that is available only in a few laboratories. Hence the incidence is probably greater than appreciated. The prognosis for those affected left untreated is almost always that of continued very severe visual loss. Regular corrected visual acuityVisual acuity
Visual acuity is acuteness or clearness of vision, which is dependent on the sharpness of the retinal focus within the eye and the sensitivity of the interpretative faculty of the brain....
and perimetry
Perimetry
Perimetry or campimetry is the systematic measurement of differential light sensitivity in the visual field by the detection of the presence of test targets on a defined background. Visual field testing can be performed clinically with confrontational field testing keeping the subject's gaze fixed...
checks are advised for follow up of affected individuals. There is beneficial treatment available for some cases of this disease especially for early onset disease. Also, experimental treatment protocols are in progress. Genetic counselling should be offered.
For those who are carriers of a LHON mutation, preclinical markers may be used to monitor progress. For example fundus photography can monitor nerve fiber layer
Nerve fiber layer
The retinal nerve fiber layer is formed by the expansion of the fibers of the optic nerve; it is thickest near the porus opticus, gradually diminishing toward the ora serrata....
swelling. Optical coherence tomography
Optical coherence tomography
Optical coherence tomography is an optical signal acquisition and processing method. It captures micrometer-resolution, three-dimensional images from within optical scattering media . Optical coherence tomography is an interferometric technique, typically employing near-infrared light...
can be used for more detailed study of retinal nerve fiber layer thickness. Red green color vision
Color vision
Color vision is the capacity of an organism or machine to distinguish objects based on the wavelengths of the light they reflect, emit, or transmit...
testing may detect losses. Contrast sensitivity may be diminished. There could be an abnormal electroretinogram or visual evoked potentials. Neuron-specific enolase and axonal heavy chain neurofilament
Neurofilament
Neurofilaments are the 10 nanometer intermediate filaments found specifically in neurons. They are a major component of the cell's cytoskeleton, and provide support for normal axonal radial growth...
blood markers may predict conversion to affected status.
Avoiding optic nerve toxins is generally advised, especially tobacco and alcohol. Certain prescription drugs are known to be a potential risk, so all drugs should be treated with suspicion and checked before use by those at risk.
Ethambutol, in particular, has been implicated as triggering visual loss in carriers of LHON. In fact, toxic and nutritional optic neuropathies
Toxic and Nutritional Optic Neuropathy
Toxic and Nutritional Optic Neuropathy is a group of medical disorders defined by visual impairment due to optic nerve damage secondary to a toxic substance and/or nutritional deficiency. The causes of these disorders are various, but they are linked by shared signs and symptoms, which this...
may have overlaps with LHON in symptoms, mitochondrial mechanisms of disease and management. Of note, when a patient carrying or suffering from LHON or toxic/nutritional optic neuropathy
Toxic and Nutritional Optic Neuropathy
Toxic and Nutritional Optic Neuropathy is a group of medical disorders defined by visual impairment due to optic nerve damage secondary to a toxic substance and/or nutritional deficiency. The causes of these disorders are various, but they are linked by shared signs and symptoms, which this...
suffers a hypertensive crisis as a possible complication of the disease process, nitroprusside (trade name: Nipride) should not be used due to increased risk of optic nerve ischemia
Ischemic optic neuropathy
Ischemic optic neuropathy is the loss of structure and function of a portion of the optic nerve due to obstruction of blood flow to the nerve...
in response to this anti-hypertensive in particular.
Idebenone
Idebenone
Idebenone is an experimental drug, initially developed by Takeda Pharmaceutical Company for the treatment of Alzheimer's disease and other cognitive defects. This has been met with limited success. The Swiss company Santhera Pharmaceuticals has started to investigate it for the treatment of...
has been shown in a small placebo controlled trial to have modest benefit in about half of patients. People most likely to respond best were those treated early in onset.
α-tocotrienol
Tocotrienol
Tocotrienols are members of the vitamin E family. An essential nutrient for the body, vitamin E is made up of four tocopherols and four tocotrienols . The slight difference between tocotrienols and tocopherols lie in the unsaturated side chain having three double bonds in its farnesyl isoprenoid...
-quinone, a Vitamin E metabolite, has had some success in small open label trials in reversing early onset vision loss.
There are various treatment approaches which have had early trials or are proposed, none yet with convincing evidence of usefulness or safety for treatment or prevention including:
Brimonidine
Brimonidine
Brimonidine is a drug used to treat open-angle glaucoma or ocular hypertension.It acts via decreasing synthesis of aqueous humor, and increasing the amount that drains from the eye through uveoscleral outflow.As a treatment for glaucoma, it is usually given in eyedrop form.Brimonidine is an...
; Minocycline
Minocycline
Minocycline is a broad-spectrum tetracycline antibiotic, and has a broader spectrum than the other members of the group. It is a bacteriostatic antibiotic, classified as a long-acting type...
; Curcumin
Curcumin
Curcumin is the principal curcuminoid of the popular Indian spice turmeric, which is a member of the ginger family . The other two curcuminoids are desmethoxycurcumin and bis-desmethoxycurcumin. The curcuminoids are natural phenols and are responsible for the yellow color of turmeric...
;
glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
; Near infrared light treatment
Light therapy
Light therapy or phototherapy consists of exposure to daylight or to specific wavelengths of light using lasers, light-emitting diodes, fluorescent lamps, dichroic lamps or very bright, full-spectrum light, usually controlled with various devices...
; and Viral vector
Viral vector
Viral vectors are a tool commonly used by molecular biologists to deliver genetic material into cells. This process can be performed inside a living organism or in cell culture . Viruses have evolved specialized molecular mechanisms to efficiently transport their genomes inside the cells they infect...
techniques.
"Three person in vitro fertilisation" is a proof of concept research technique for preventing mitochondrial disease in developing human fetuses. So far, viable macaque monkeys have been produced. But ethical and knowledge hurdles remain before use of the technique in humans is established.
See also
- AmaurosisAmaurosisAmaurosis is vision loss or weakness that occurs without an apparent lesion affecting the eye. It may result from either a medical condition or from excess acceleration, as in flight...
- Dominant optic atrophyDominant optic atrophyDominant optic atrophy, or dominant optic atrophy, Kjer's type, is an autosomally inherited disease that affects the optic nerves, causing reduced visual acuity and blindness beginning in childhood. This condition is due to mitochondrial dysfunction mediating the death of optic nerve fibers...
- GlaucomaGlaucomaGlaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
- Ischemic optic neuropathyIschemic optic neuropathyIschemic optic neuropathy is the loss of structure and function of a portion of the optic nerve due to obstruction of blood flow to the nerve...
- List of eye diseases and disorders
- Optic atrophy
- Toxic and Nutritional Optic NeuropathyToxic and Nutritional Optic NeuropathyToxic and Nutritional Optic Neuropathy is a group of medical disorders defined by visual impairment due to optic nerve damage secondary to a toxic substance and/or nutritional deficiency. The causes of these disorders are various, but they are linked by shared signs and symptoms, which this...
External links
- Yu-Wai-Man P, Chinnery P (2008) Leber Hereditary Optic Neuropathy. GeneReviews