Mitochondrial optic neuropathies

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Mitohondrial optic neuropathies are a heterogenous group of disorders that present with visual disturbances resultant from mitochondrial dysfunction within the anatomy of the Retinal Ganglion Cells (RGC), optic nerve, optic chiasm, and optic tract. These disturbances are multifactorial, their aetiology consisting of metabolic and/or structural damage as a consequence of genetic mutations, environmental stressors, or both. The three most common neuro-ophthalmic abnormalities seen in mitochondrial disorders are bilateral optic neuropathy, ophthalmoplegia with ptosis, and pigmentary retinopathy. [1]

Contents

Signs and Symptoms

The generalized, common presentation for this broad and inclusive group of diseases is painless, bilateral loss of visual acuity and pallor of the optic disc accompanied with varying degrees of dyschromatopsia and central/cecocentral scatomas. On examination the pupillary responses may be sluggish to light. One would not expect to find an afferent pupillary defect because optic neuropathies are often bilateral and symmetric. [2] The optic disc may appear mildly hyperemic with small splinter hemorrhages on or around the disc, or may appear nearly normal. Optic atrophy typically develops later and may appear mild. In later stages the optic atrophy can become severe, which indicates less opportunity for recovery. [3]

The duration of onset can vary between immediate and insidious, owing to the specific etiology. Two key features may be helpful in distinguishing acquired from inherited optic neuropathies: absence of a family history and simultaneous involvement of both eyes; the former more commonly characterized by these two features. [3]

Causes

Because this grouping of diseases is of heterogenic origin, the causes can be singular or additive consequences of genetic, toxic, or nutritional stress.

Mitochondria are maternally inherited, so a genetic defect in mitochondrial DNA (mtDNA) is passed on from mother to child. Mitochondria, however, depend on other proteins that are encoded by nuclear genes, constructed in the cytoplasm and then transported into the mitochondria. So it follows that, while an mtDNA point mutation are inherited through the mother, defects in nuclear DNA, even those affecting the mitochondria, will be transmitted in Mendelian fashion. [1]

Optic neuropathies that are acquired can be the result of several processes. These include prolonged use of certain antibiotics or anti-tuberculosis medications, exposure to certain toxic chemicals, and situations that contribute to poor consumption or decreased absorption of nutrient-dense foods.[ citation needed ]

A possible synergism between genetic and acquired mitochondrial optic neuropathies has been suggested and there are only a few case reports to support this phenomenon, requiring further research and demonstration of evidence to corroborate these findings [4] [5]

Nutritional optic neuropathies

Nutritional deficiency may be the cause of a genuine optic neuropathy, sometimes associated with involvement of the peripheral nervous system, called peripheral neuropathy. Loss of vision is usually bilateral, painless, chronic, insidious and slowly progressive. Most often, they present as a non-specific retrobulbar optic neuropathy. Patients may notice that colors are not as vivid or bright as before and that the color red is washed out. This normally occurs in both eyes at the same time and is not associated with any eye pain. They might initially notice a blur or fog, followed by a drop in vision. While vision loss may be rapid, progression to blindness is unusual. These patients tend to have blind spots in the center of their vision with preserved peripheral vision. In most cases, the pupils continue to respond normally to light.[ citation needed ]

Again, the pathophysiological mechanisms involved in nutritional optic neuropathies is common to all mitochondrial optic neuropathies: it affects biochemical pathways involved in cell energetic production, correction of oxidative stress and quenching of free radicals. [6] Specific deficiencies of cyanocobalamin, thiamine, riboflavin, niacin, and pyridoxine, folic acid, and other proteins with sulfur-containing amino acids may play a role. [7]

Months of depletion are usually necessary to deplete body stores of most nutrients and a nutritional optic neuropathy may be present in a patient with or without obvious evidence of under-nutrition. An individual suffering from starvation could be easily recognized as a person who is undernourished due to their cachectic corporal appearance. However, a not so obvious individual may be the recipient of a gastric bypass surgery, a procedure that may lead to vitamin B12 deficiency from poor absorption. [8] The optic neuropathy associated with pernicious anemia and vitamin B12 deficiency can be seen amongst individuals who obtain adequate caloric input from foods low in nutritional and micronutrient density (see Food desert). [9]

Additionally, nutrient-poor diet may also be low in anti-oxidants, substances critical to preventing the damaging effects of reactive oxygen species (ROS). ROS are a natural bi-product of the mitochondrial production of ATP. [10] As such, if they are allowed to accumulate without being neutralized, they could damage the very mitochondria from which they are being produced.

There is documentation of nutritional optic neuropathy among undernourished Allied prisoners of war of the Japanese during World War II. After four months of food deprivation, some of the prisoners developed sub-acute vision loss in both eyes in addition to experiencing pain in their extremities and hearing loss. Their visual loss did not correlate well with malnutrition and that not all prisoners experienced the loss of vision. [11]

Toxic optic neuropathies (TON)

Toxic optic neuropathy refers to the ingestion of a toxin or an adverse drug reaction that results in vision loss from optic nerve damage. Patients may report either a sudden loss of vision in both eyes, in the setting of an acute intoxication, or an insidious asymmetric loss of vision from an adverse drug reaction. The most important aspect of treatment is recognition and drug withdrawal. [12]

Among the many causes of TON, the top 10 toxins include:

Metabolic disorders may also cause this version of disease. Systemic problems such as diabetes mellitus, kidney failure, and thyroid disease can cause optic neuropathy, which is likely through buildup of toxic substances within the body. In most cases, the cause of the toxic neuropathy impairs the tissue's vascular supply or metabolism. It remains unknown as to why certain agents are toxic to the optic nerve while others are not and why particularly the papillomacular bundle gets affected.[ citation needed ]

Combined Mitochondrial Optic Neuropathies

Tobacco Alcohol Ambylopia (TAA)

TAA is an old term for a constellation of elements that can lead to a mitochondrial optic neuropathy. The classic patient is a man with a history of heavy alcohol and tobacco consumption. Respectively, this combines nutritional mitochondrial impairment, from vitamin deficiencies (folate and B-12) classically seen in alcoholics, with tobacco-derived products, such as cyanide and ROS. It has been suggested that the additive effect of the cyanide toxicity, ROS, and deficiencies of thiamine, riboflavin, pyridoxine, and b12 result in TAA. [14]

Cuban Epidemic of Optic Neuropathy

Between 1992 and 1993, in the Cuban Epidemic of Optic Neuropathy, nearly 50,000 people in Cuba were affected with optic neuropathy, sensory and autonomic peripheral neuropathy, neural deafness, and in a few cases, myelopathy. [15] [16] The most common pattern of symptoms consisted of severe weight loss, fatigue and a subacute loss of vision. On the fundus, an objective sign was noted: a wedge defect of the temporal optic disc and the loss of the corresponding Papillomacular bundle. [17] Most of the patients reported high consumption of alcohol particularly homemade rum and smoking cigarettes. [18] This was associated with severe deficiencies of protein and vitamin intake, in particular of vitamin B12 and folate. This picture of vitamin deficiencies was exacerbated by low levels of methanol present in homemade rum. It was thought that the Cuban epidemic may have been caused by the chronic accumulation of formate from methanol metabolism in a population with severe folic acid depletion and the accumulation of cyanide from cigarette smoke. [17] This conclusion was supported by evidence of improvement in visual acuity on prompt and daily administration of cyanocobalamin (3 mg) and folate (250 mg) along with dietary supplementation. [17] [18] [19]

Hereditary Optic Neuropathies

The inherited optic neuropathies typically manifest as symmetric bilateral central visual loss. Optic nerve damage in most inherited optic neuropathies is permanent and progressive.

Leber's Hereditary Optic Neuropathy (LHON)

LHON, as the name suggests, is an inherited mutation that results in acute or subacute vision loss, displays incomplete penetrance and predominantly affects young males. Onset is usually between the 2nd and 4th decade of life, and usually presents with rapid vision loss in one eye followed by involvement of the second eye (usually within months). Visual acuity often remains stable and poor (below 20/200) with a residual central visual field defect. Patients with the m.14484/ND6 mutation are most likely to have visual recovery. [20]

Autosomal Dominant Optic Atrophy (DOA)

DOA is an autosomal dominant disease caused by a defect in the nuclear gene OPA1. A slowly progressive optic neuropathy, usually presents in the first decade of life and is bilaterally symmetrical. Examination of these patients shows loss of visual acuity, temporal pallor of the optic discs, centrocecal scotomas with peripheral sparing, and subtle impairments in color vision.[ citation needed ]

Behr’s syndrome

This is a rare autosomal recessive disorder characterized by early-onset optic atrophy, ataxia, and spasticity.[ citation needed ]

Charcot Marie Tooth disease (CMT)

This disease is a heterogenous group of inherited neuropathies, stemming from a MFN2 mutation, in which both motor and sensory nerves are affected, resulting in distal limb weakness, sensory loss, decreased deep tendon reflexes, and foot deformities. Affected individuals develop progressive optic nerve dysfunction starting later in childhood. [21]

Hereditary spastic paraplegia (HSP)

HSP is marked by slowly progressive lower limb spasticity and weakness. HSP can be classified into pure and complicated forms, depending on whether additional clinical features are present besides spastic paraplegia, such as optic atrophy, ataxia, peripheral neuropathy, extrapyramidal deficits, and cognitive decline. [22]

Friedreich's ataxia (FA)

FA is an autosomal recessive disorder caused by pathological GAA trinucleotide repeat expansions in the FXN gene. [23] The encoded protein frataxin is directed to the mitochondrial inner membrane and is involved in the assembly of iron-sulphur cluster, which are a critical component of the mitochondrial respiratory chain complexes. [24] [25]

In a recent study of 26 patients with confirmed FA, all patients had evidence of optic nerve dysfunction, although only five were visually symptomatic. [26] The optic neuropathy differed from that of LHON or DOA, displaying a pattern of retinal nerve fiber layer (RNFL) loss and no preferential involvement of papillomacular bundle. [21]

Mitochondrial encephalomyopathies

Includes Mitochondrial Encephalitis Lactic Acidosis Seizures (MELAS), myoclonic epilepsy and ragged red fibers (MERRF), maternally inherited Leigh syndrome (MILS), and mitochondrial neurograstrointestinal encephalomyopathy (MNGIE), all of which can all develop optic neuropathies, although it is usually a secondary feature overshadowed by more prominent neurological features. [27]

Overlapping phenotypes

As our understanding of mitochondrial diseases improves a degree of similarity and overlap are seen within this group of disorders. For example, in some OPA1 carriers, patients will develop neurological features indistinguishable from HSP while others develop a pattern of peripheral neuropathy with a similar disease course to CMT, and still others will develop a prominent cerebellar syndrome consistent with FRDA. [21]

Pathophysiology

Even though dysfunction of the mitochondria can be either congenital or acquired, both causes share a common pathophysiology: an impairment of oxidative phosphorylation within the mitochondria, which leads to a decrease of ATP production and a simultaneous increase in ROS. [28]

These mitochondria are made within the central somata of the retinal ganglion cell, transported down axons, and distributed where they are needed. Efficient transportation of mitochondria depends on multiple factors, including their own energy production, the integrity of the cytoskeleton and its protein components (tubulin, etc.), and adequate myelination of the axons. Any dysfunction of these systems may be of pathological relevance for optic neuropathies with primary or secondary involvement of mitochondria. [29] Genetic mutations, toxic insult, and nutritional depletion can all have a negative impact on the structure and function of mitochondria within the optic system, resulting in this type of neuropathy.

Diagnosis

A thorough history is essential and should cover family history, diet; drug/toxin exposure social history, including tobacco and alcohol use; and occupational background, with details on whether similar cases exist among coworkers. Treatment of any chronic disease such as pernicious anemia should always be elucidated. [2]

In most cases of nutritional/toxic optic neuropathy, the diagnosis may be obtained via detailed medical history and eye examination. Additionally, supplementary neurological imaging studies, such as MRI or enhanced CT, may be performed if the cause remains unclear.

When the details of the examination and history indicate a familial history of similar ocular or systemic disease, whether or not there is evidence of toxic or nutritional causes for disease, certain genetic tests may be required. Because there are several congenital causes of mitochondrial dysfunction, the patients history, examination, and radiological studies must be examined in order to determine the specific genetic tests required. For example, 90% of cases of Leber's Hereditary Optic Neuropathy (LHON) are associated with three common mtDNA point mutations (m.3460G>A/MT-ND1, m.11778G>A/MT-ND4, m.14484T>C/MT-ND6) while a wider range of mtDNA mutations (MT-ND1, MT-ND5, MT-ND6; http://www.mitomap.org/) have been associated with overlapping phenotypes of LHON, MELAS, and Leigh syndrome. [29] [30]

Treatment

Treatment is dependent upon diagnosis and the stage at which the diagnosis is secured. For toxic and nutritional optic neuropathies, the most important course is to remove the offending agent if possible and to replace the missing nutritional elements, orally, intramuscularly, or intravenously. If treatment is delayed, the injury may be irreversible. The course of treatment varies with the congenital forms of these neuropathies. There are some drug treatments that have shown modest success, such as Idebenone used to treat LOHN. Often treatment is relegated to lifestyle alterations and accommodations and supportive measures.[ citation needed ]

Epidemiology

Those diseases understood as congenital in origin could either be specific to the ocular organ system (LHON, DOA) or syndromic (MELAS, multiple sclerosis). It is estimated that these inherited optic neuropathies in the aggregate affect 1 in 10,000 [31] [32] [33] [34]

Of the acquired category, disease falls into further etiological distinction as arising from toxic (drugs or chemicals) or nutritional/metabolic (vitamin deficiency/diabetes) insult. It is worth mentioning that under-nutrition and toxic insult can occur simultaneously, so a third category may be understood as having a combined or mixed etiology. We[ who? ] will refer to this as Toxic/Nutritional Optic Neuropathy, whereby nutritional deficiencies and toxic/metabolic insults are the simultaneous culprits of visual loss associated with damage and disruption of the RGC and optic nerve mitochondria.

Related Research Articles

<span class="mw-page-title-main">Optic nerve</span> Second cranial nerve, which connects the eyes to the brain

In neuroanatomy, the optic nerve, also known as the second cranial nerve, cranial nerve II, or simply CN II, is a paired cranial nerve that transmits visual information from the retina to the brain. In humans, the optic nerve is derived from optic stalks during the seventh week of development and is composed of retinal ganglion cell axons and glial cells; it extends from the optic disc to the optic chiasma and continues as the optic tract to the lateral geniculate nucleus, pretectal nuclei, and superior colliculus.

<span class="mw-page-title-main">Mitochondrial disease</span> Spontaneously occurring or inherited disorder that involves mitochondrial dysfunction

Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy of food molecules into the ATP that powers most cell functions.

<span class="mw-page-title-main">Homoplasmy</span> Identity of organellar DNA sequences in a cell

Homoplasmy is a term used in genetics to describe a eukaryotic cell whose copies of mitochondrial DNA are all identical. In normal and healthy tissues, all cells are homoplasmic. Homoplasmic mitochondrial DNA copies may be normal or mutated; however, most mutations are heteroplasmic. It has been discovered, though, that homoplasmic mitochondrial DNA mutations may be found in human tumors.

<span class="mw-page-title-main">Leber's hereditary optic neuropathy</span> Mitochondrially inherited degeneration of retinal cells in human

Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; it predominantly affects young adult males. LHON is transmitted only through the mother, as it is primarily due to mutations in the mitochondrial genome, and only the egg contributes mitochondria to the embryo. Men cannot pass on the disease to their offspring. LHON is usually due to one of three pathogenic mitochondrial DNA (mtDNA) point mutations. 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 genes of complex I of the oxidative phosphorylation chain in mitochondria.

Anterior ischemic optic neuropathy (AION) is a medical condition involving loss of vision caused by damage to the optic nerve as a result of insufficient blood supply (ischemia). This form of ischemic optic neuropathy is generally categorized as two types: arteritic AION, in which the loss of vision is the result of an inflammatory disease of arteries in the head called temporal arteritis, and non-arteritic AION, which is due to non-inflammatory disease of small blood vessels.

<span class="mw-page-title-main">Neuritis</span> Inflammation of a nerve or generally any part of the nervous system

Neuritis is inflammation of a nerve or the general inflammation of the peripheral nervous system. Inflammation, and frequently concomitant demyelination, cause impaired transmission of neural signals and leads to aberrant nerve function. Neuritis is often conflated with neuropathy, a broad term describing any disease process which affects the peripheral nervous system. However, neuropathies may be due to either inflammatory or non-inflammatory causes, and the term encompasses any form of damage, degeneration, or dysfunction, while neuritis refers specifically to the inflammatory process.

Kearns–Sayre syndrome (KSS), oculocraniosomatic disorder or oculocranionsomatic neuromuscular disorder with ragged red fibers is a mitochondrial myopathy with a typical onset before 20 years of age. KSS is a more severe syndromic variant of chronic progressive external ophthalmoplegia, a syndrome that is characterized by isolated involvement of the muscles controlling movement of the eyelid and eye. This results in ptosis and ophthalmoplegia respectively. KSS involves a combination of the already described CPEO as well as pigmentary retinopathy in both eyes and cardiac conduction abnormalities. Other symptoms may include cerebellar ataxia, proximal muscle weakness, deafness, diabetes mellitus, growth hormone deficiency, hypoparathyroidism, and other endocrinopathies. In both of these diseases, muscle involvement may begin unilaterally but always develops into a bilateral deficit, and the course is progressive. This discussion is limited specifically to the more severe and systemically involved variant.

<span class="mw-page-title-main">MELAS syndrome</span> Medical condition

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the family of mitochondrial diseases, which also include MIDD, MERRF syndrome, and Leber's hereditary optic neuropathy. It was first characterized under this name in 1984. A feature of these diseases is that they are caused by defects in the mitochondrial genome which is inherited purely from the female parent. The most common MELAS mutation is mitochondrial mutation, mtDNA, referred to as m.3243A>G.

Dominant optic atrophy (DOA), or autosomal dominant optic atrophy (ADOA), (Kjer's type) is an autosomally inherited disease that affects the optic nerves, causing reduced visual acuity and blindness beginning in childhood. However, the disease can seem to re-present a second time with further vision loss due to the early onset of presbyopia symptoms (i.e., difficulty in viewing objects up close). DOA is characterized as affecting neurons called retinal ganglion cells (RGCs). This condition is due to mitochondrial dysfunction mediating the death of optic nerve fibers. The RGCs axons form the optic nerve. Therefore, the disease can be considered of the central nervous system. Dominant optic atrophy was first described clinically by Batten in 1896 and named Kjer’s optic neuropathy in 1959 after Danish ophthalmologist Poul Kjer, who studied 19 families with the disease. Although dominant optic atrophy is the most common autosomally inherited optic neuropathy (i.e., disease of the optic nerves), it is often misdiagnosed.

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 article will describe. In several of these disorders, both toxic and nutritional factors play a role, acting synergistically.

Optic neuropathy is damage to the optic nerve from any cause. The optic nerve is a bundle of millions of fibers in the retina that sends visual signals to the brain. [1].

Allotopic expression (AE) refers to expression of genes in the cell nucleus that normally are expressed only from the mitochondrial genome. Biomedically engineered AE has been suggested as a possible future tool in gene therapy of certain mitochondria-related diseases, however this view is controversial. While this type of expression has been successfully carried out in yeast, the results in mammals have been conflicting.

<span class="mw-page-title-main">Mitochondrial neurogastrointestinal encephalopathy syndrome</span> Medical condition

Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) is a rare autosomal recessive mitochondrial disease. It has been previously referred to as polyneuropathy, ophthalmoplegia, leukoencephalopathy, and POLIP syndrome. The disease presents in childhood, but often goes unnoticed for decades. Unlike typical mitochondrial diseases caused by mitochondrial DNA (mtDNA) mutations, MNGIE is caused by mutations in the TYMP gene, which encodes the enzyme thymidine phosphorylase. Mutations in this gene result in impaired mitochondrial function, leading to intestinal symptoms as well as neuro-ophthalmologic abnormalities. A secondary form of MNGIE, called MNGIE without leukoencephalopathy, can be caused by mutations in the POLG gene.

<span class="mw-page-title-main">MT-ND6</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND6 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 6 protein (ND6). The ND6 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variations in the human MT-ND6 gene are associated with Leigh's syndrome, Leber's hereditary optic neuropathy (LHON) and dystonia.

<span class="mw-page-title-main">MT-ND4</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND4 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 4 (ND4) protein. The ND4 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variations in the MT-ND4 gene are associated with age-related macular degeneration (AMD), Leber's hereditary optic neuropathy (LHON), mesial temporal lobe epilepsy (MTLE) and cystic fibrosis.

<span class="mw-page-title-main">MT-ND5</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND5 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 5 protein (ND5). The ND5 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variations in human MT-ND5 are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) as well as some symptoms of Leigh's syndrome and Leber's hereditary optic neuropathy (LHON).

<span class="mw-page-title-main">MT-ND1</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND1 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 1 (ND1) protein. The ND1 protein is a subunit of NADH dehydrogenase, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variants of the human MT-ND1 gene are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh's syndrome (LS), Leber's hereditary optic neuropathy (LHON) and increases in adult BMI.

<span class="mw-page-title-main">Cytochrome c oxidase subunit I</span> Enzyme of the respiratory chain encoded by the mitochondrial genome

Cytochrome c oxidase I (COX1) also known as mitochondrially encoded cytochrome c oxidase I (MT-CO1) is a protein that is encoded by the MT-CO1 gene in eukaryotes. The gene is also called COX1, CO1, or COI. Cytochrome c oxidase I is the main subunit of the cytochrome c oxidase complex. In humans, mutations in MT-CO1 have been associated with Leber's hereditary optic neuropathy (LHON), acquired idiopathic sideroblastic anemia, Complex IV deficiency, colorectal cancer, sensorineural deafness, and recurrent myoglobinuria.

Chronic relapsing inflammatory optic neuropathy (CRION) is a form of recurrent optic neuritis that is steroid responsive and dependent. Patients typically present with pain associated with visual loss. CRION is a clinical diagnosis of exclusion, and other demyelinating, autoimmune, and systemic causes should be ruled out. An accurate antibody test which became available commercially in 2017 has allowed most patients previously diagnosed with CRION to be re-identified as having MOG antibody disease, which is not a diagnosis of exclusion. Early recognition is crucial given risks for severe visual loss and because it is treatable with immunosuppressive treatment such as steroids or B-cell depleting therapy. Relapse that occurs after reducing or stopping steroids is a characteristic feature.

<span class="mw-page-title-main">Alfredo Sadun</span> American ophthalmologist

Alfredo Arrigo Sadun is an American ophthalmologist, academic, author and researcher. He holds the Flora L. Thornton Endowed Chair at Doheny Eye Centers-UCLA and is Vice-Chair of Ophthalmology at UCLA.

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  29. 1 2 Carelli, Valerio; Ross-Cisneros, Fred N.; Sadun, Alfredo A. (2004). "Mitochondrial dysfunction as a cause of optic neuropathies". Progress in Retinal and Eye Research. 23 (1): 53–89. doi:10.1016/j.preteyeres.2003.10.003. PMID   14766317. S2CID   15862778.
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  31. ↑ Man, P.Y.W.; Griffiths, P.G.; Brown, D.T.; Howell, N.; Turnbull, D.M.; Chinnery, P.F. (2003). "The Epidemiology of Leber Hereditary Optic Neuropathy in the North East of England". The American Journal of Human Genetics. 72 (2): 333–9. doi:10.1086/346066. PMC   379226 . PMID   12518276.
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