MITOCHONDRIAL DISEASES

The Human Mitochondrial Genome

Mitochondrial disorders • Mitochondrial diseases are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the mitochondrial respiratory chain. They can be caused by mutations of nuclear or mitochondrial DNA (mtDNA). • Mitochondrial disease can take many forms, depending on the severity of the disease and the location that is affected. The range of symptoms is vast and mitochondrial disorders can present at any age, with any combination of symptoms and with any pattern of inheritance.

What is Mitochondrial Disease? If a child is stricken with a catastrophic disease affecting three or more organ systems, or if a child has been afflicted with a relapsing disease that affects two or more organ systems and leads to slow but measurable deterioration, he or she may have a mitochondrial disease.

What is Mitochondrial Disease? At times, mitochondrial diseases can cause isolated symptoms. These may include unexplained seizures, low blood counts, dystonia (abnormal muscle tone or spasms), blindness, deafness, dementia, ataxia (stumbling or tremors), cerebral palsy, heart failure, or progressive muscle weakness.

What is Mitochondrial Disease? More often, however, several organ systems are affected in sequence, one faltering or failing after another. Good periods are frequently punctuated by abrupt deteriorations that are caused by simple infections. For children with mitochondrial disease these infections can be life threatening, and leave them with deficits that cannot be recovered.

How Common is Childhood Mitochondrial Disease? There are more than 50 inherited diseases of metabolism that are known to affect mitochondria. Taken together, more than 1 in 4,000 children born each year will develop a mitochondrial disease by 10 year of age. This means that 1000 to 4000 children will be born each year with mitochondrial disease in the US . By comparison, about 8000 new cases of childhood cancer are reported each year. Both mitochondrial disease and childhood cancer range in mortality from 1O to 50 percent per year, depending on the specific disease.

How Common is Adult Mitochondrial Disease? Defects in mitochondrial function have now been I inked to many of the most common diseases of aging. These include Type II Diabetes Mellitus, Parkinson Disease, Atherosclerotic Heart Disease, Stroke, Alzheimer Dementia, and Cancer. Over 50 million people in the US suffer from these chronic degenerative disorders. While it cannot yet be said that mitochondria cause these problems, it is clear that mitochondria are involved because their function is measurably disturbed. Even autoimmune diseases such as Multiple Sclerosis, Systemic Lupus Erythematosus, and Rheumatoid Arthritis appear to have mitochondrial components.

What are Mitochondria? • Mitochondria are complex structures, which exist in every cell of the body (except red blood cells). Every nucleated cell in the body contains 5-2000 mitochondria.

What are Mitochondria? • They are the size and shape of long, thread-like bacteria woven through our cells.

What Do Mitochondria Do? Air and food are metabolized by mitochondria.

• Mitochondria consume over 80 % of the oxygen we breathe and make over 90 % of the energy our cells need to function. They use the oxygen in the air we breathe to release energy from food. This process transforms food calories into chemical energy, water, and carbon dioxide.

What Do Mitochondria Do? • The released chemical energy is then stored in the form of ATP. ATP is the universal currency of energy used by all life on earth. It is like an electrical power source that drives the engines of the cell. This process of burning food to make ATP is called oxidative phosphorylation. Only mitochondria can do it. Without it, muscles could not contract and neurons could not fire. Mitochondria literally make it possible for us to move and think.

What are Mitochondria? The mitochondrion has been called the ‘powerhouse’ of the cell, as produce most of the energy. The most energy dependent organs are the brain, heart, skeletal muscle, kidney, endocrine glands and bone marrow and these are the organ systems commonly affected in mitochondrial diseases

What are Mitochondria? In 1963, researchers discovered that mitochondria have their own DNA or "blueprint" (mtDNA), which is different than the nuclear DNA (nDNA) found in the cells' nucleus. Mitochondria have their own DNA consisting of a double-stranded circular molecule. This mitochondrial DNA consists of 16 569 base pairs that constitute 37 genes.

What are Mitochondria?

What are Mitochondria? • Mitochondrial DNA is the only DNA that we inherit exclusively from mothers. Some scientists have called it our 24th chromosome. It codes for just 13 mitochondrial proteins. All the other proteins in mitochondria (>99%) come from genes in the nucleus

What is Mitochondrial Disease? •

Mutations in mitochondrial DNA have been identified in a number of diseases, notably Leber hereditary optic neuropathy (LHON), myoclonic epilepsy with ragged red fibres (MERRF), mitochondrial myopathy with encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and progressive external ophthalmoplegia including Kaerns–Sayre syndrome.

The types of mitochondrial disease inheritance 1. nDNA (DNA contained in the nucleus of the cell) inheritance. Also called autosomal inheritance. • ∙If this gene trait is recessive (one gene from each parent), often no other family members appear to be affected. There is a 25 % chance of the trait occurring in other siblings. • ∙If this gene trait is dominant (a gene from either parent), the disease often occurs in ther family members. There is a 50 % chance of the trait occurring in other siblings.

The types of mitochondrial disease inheritance 2. mtDNA (DNA contained in the mitochondria) inheritance. • ∙There is a 100 % chance of the trait occurring in other siblings, since all mitochondria are inherited from the mother, although symptoms might be either more or less severe. 3. Combination of mtDNA and nDNA defects: • ∙Relationship between nDNA and mtDNA and their correlation in mitochondrial formation is unknown.

The types of mitochondrial disease inheritance 4.Random 4.Random occurrences Diseases specifically from deletions of large parts of the mitochondrial DNA molecule are usually sporadic without affecting other family member •

∙Medicines or other toxic substances can trigger mitochondrial disease

Genetic counselling dilemmas in mitochondrial diseases • • Some disorders of mitochondrial function are due to nuclear gene mutations • • Some disorders caused by mitochondrial mutations are sporadic • • When maternally transmitted, not all offspring are affected • • Severity is very variable and difficult to predict • • Prenatal diagnosis is not feasible

Problems Associated with Mitochondrial Cytopathies

BRAIN

- developmental delays - mental retardation - dementia - seizures - neuro-psychiatric disturbances - atypical cerebral palsy - migraines - strokes

Problems Associated with Mitochondrial Cytopathies

NERVES

- weakness (which may be intermittent) - neuropathic pain - absent reflexes - gastrointestinal problem (gastroesophogeal reflux, delayed gastric emptying, constipation, pseudo-obstruction) - fainting - absent or excessive sweating resulting in temperature regulation problems

Problems Associated with Mitochondrial Cytopathies

MUSCELS KIDNEYS

- weakness - hypotonia - cramping - muscle pain - proximal renal tubular wasting resulting in loss of protein, magnesium, phosphorous, calcium and other electrolytes

Problems Associated with Mitochondrial Cytopathies

HEART

LIVER EYES

- cardiac conduction defects (heart blocks) - cardiomyopathy - hypoglycemia - liver failure - visual loss and blindness

Problems Associated with Mitochondrial Cytopathies

EARS

- hearing loss and deafness

PANCREAS

- diabetes and exocrine pancreatic failure (inability to make digestive enzymes)

SYSTEMIC

- failure to gain weight - short stature - fatigue -respiratory problems including intermittent air hunger

Many combinations of symptoms are possible.

Clinical Syndromes of Mitochrondrial Diseases Disorder

Kearns-Sayre syndrome (KSS)

Primary Features

Additional Features

- PEO onset before age 20 years - Pigmentary retinopathy - One of the following: CSF protein greater than 1g/L, cerebellar ataxia, heart block

- Bilateral deafness - Myopathy - Dysphagia - Diabetes mellitus -Hypoparathyroidism - Dementia

Clinical Syndromes of Mitochrondrial Diseases Disorder

Pearson syndrome

Primary Features

Additional Features

- Sideroblastic anemia of childhood - Renal tubular - Pancytopenia defects - Exocrine pancreatic failure

Clinical Syndromes of Mitochrondrial Diseases Disorder

Primary Features

Additional Features

Mitochondrial encephalomyo pathy with lactic acidosis and stroke-like episodes ( MELAS)

- Stroke-like episodes before age 40 years - Seizures and/or dementia - Ragged-red fibers and/or lactic acidosis

- Diabetes mellitus -Cardiomyopathy (initially hypertrophic; later dilated) - Bilateral deafness - Pigmentary retinopathy - Cerebellar ataxia

Clinical Syndromes of Mitochrondrial Diseases Disorder

Primary Features

Additional Features

Myoclonic epilepsy with ragged-red fibers (MERRF )

- Myoclonus - Seizures - Cerebellar ataxia - Myopathy

-Dementia -Optic atrophy -Bilateral deafness -Peripheral neuropathy -Spasticity -Multiple lipomata

Clinical Syndromes of Mitochrondrial Diseases Disorder

Primary Features

Additional Features

Leber hereditary optic neuropathy (LHON)

-Subacute painless bilateral visual failure -Males:females ~4:1 -Median age of onset 24 years

-Dystonia -Cardiac pre-excitation syndromes

Kearns-Sayre Syndrome (KSS) Genetis • KSS is the result of deletions in mitochondrial DNA (mtDNA) that cause a particular phenotype. mtDNA is transmitted exclusively from the mother's ovum. Etiology • Kearns–Sayre syndrome occurs spontaneously in the majority of cases. In some cases it has been shown to be inherited through mitochondrial, autosomal dominant, or autosomal recessive inheritance. There is no predilection for race or sex, and there are no known risk factors.

Kearns-Sayre Syndrome (KSS) • KSS is a slowly progressive multi-system mitochondrial disease that often begins with drooping of the eyelids (ptosis). Other eye muscles eventually become involved, resulting in paralysis of eye movement. Degeneration of the retina usually causes difficulty seeing in dimly lit environments.

Signs and Symptoms There are three main features of Kearns -Sayre syndrome: •

It starts before age 20

•

Paralysis of certain eye muscles (external ophthalmoplegia) that gets worse over time

•

Degeneration of the retina, the part of the eye responsible for sight

Kearns-Sayre Syndrome • The first symptom of KSS is a unilateral ptosis, or difficulty opening the eyelids, that gradually progresses to a bilateral ptosis. As the ptosis worsens, the individual commonly extends their neck, elevating their chin in an attempt to prevent the eyelids from occluding the visual axis. Along with the insidious development of ptosis, eye movements eventually become limited causing a person to rely more on turning the head side to side or up and down to view objects in the peripheral visual field.

Kearns-Sayre Syndrome

Signs and Symptoms of KSS The second symptom of KSS is degeneration of the retina Pigmentary retinopathy: KSS results in a pigmentation of the retina, primarily in the posterior fundus. The appearance is described as a "salt-and-pepper" appearance.

Signs and Symptoms of KSS There is diffuse depigmentation of the retinal pigment epithelium with the greatest effect occurring at the macula. Modest night-blindness can be seen in patients with KSS. Visual acuity loss is usually mild and only occurs in 40-50% of patients.

Signs and Symptoms of KSS OD

OD

• OS

FUNDUS PHOTOS

OS

There is a faint speckled pigmentary retinopathy evident in the periphery – a light “ salt & pepper change”

Symptoms of KSS may include: Because mitochondria are found in cells hroughout the body, Kearns Sayre syndrome may affect many different organs and body systems.

• • • • • • •

Muscle weakness Difficulty walking or moving Dementia, brain damage, or both Deafness Heart disease Short stature (38% of individuals) Small sex organs (20% of individuals)

Symptoms of KSS may include: Cardiac conduction abnormalities: most often occurs years after the development of ptosis and ophthalmoplegia. Atrioventricular("AV") block is the most common cardiac conduction deficit. This often progresses to a Third-degree AV block, which is a complete blockage of the electrical conduction from the atrium to the ventrical. Symptoms of heart block include syncope, exercise intolerance and bradycardia.

KSS is a rare disorder One online eMedicine article found only 226 cases worldwide in the literature by (Kearns-Sayre Syndrome by Ewa Posner, MD). It is usually caused by a single large deletion (loss) of genetic material within the DNA of the mitochondria (mtDNA), rther than in the DNA of the cell nucleus. These deletions, of which there are over 150 species, typically arise spontaneously. Less frequently, the mutation is transmitted by the mother.

Kearns-Sayre Syndrome Diagnosis If a diagnosis of Kearns Sayre syndrome is suspected, two tests can be done. One is to check the protein and lactate levels in the cerebrospinal fluid; if the syndrome is present, the levels are elevated. Blood lactate and pyruvate levels usually are elevated as a result of increased anaerobic metabolism and a decreased ratio of ATP:ADP. CSF analysis shows an elevated protein level, usually >100 mg/dl, as well as an elevated lactate level.

Kearns-Sayre Syndrome Diagnosis The other test would be to examine a muscle sample (biopsy), looking to see if the DNA in the mitochondria is abnormal. Biopsy findings: The orbicularis oculi muscle is chosen because of its high concentration of mitochondria, and the preferential distribution of mutated mitochondria in these cells. Cross-section of muscle fibers stained with Gömöri trichrome stain is viewed using light microscopy.

Kearns-Sayre Syndrome In muscle fibers containing high ratios of the mutated mitochondria, there is a higher concentration of mitochondria in an attempt to compensate for the decreased efficiency of energy production. This gives these fibers a darker red color, causing the overall appearance of the biopsy to be described as " ragged red fibers ."

An example of ragged red fibers

Kearns-Sayre Syndrome TREATMENT As with all mitochondrial diseases, there is no cure for KSS. Treatments are based on the types of symptoms and organs involved, and may include: Coenzyme Q10, insulin for diabetes, cardiac drugs, and a cardiac pacemaker which may be life-saving. Surgical intervention for drooping eyelids may be considered but should be undertaken by specialists in ophthalmic surgical centers.

KSS is slowly progressive and the prognosis varies depending on severity. Death is common in the third or fourth decade and may be due to organ system failures.

Pearson syndrome Frequency - Pearson syndrome is rare. Approximately 80 cases have been reported worldwide. Mortality/Morbidity - Pearson syndrome is often fatal in infancy or early childhood. The usual causes of death are bacterial sepsis due to neutropenia, metabolic crisis, and hepatic failure. Race - all races can be affected. Sex - Pearson syndrome has no sex predilection.

Pearson syndrome Patients with Pearson Syndrome may have poor food absorption (malabsorption) and low white blood cell counts (neutropenia). Low red cell counts (anemia) can be a major problem, and low platelet counts ( thrombocytopenia ) can also occur. Symptoms are often present in infancy. Liver and kidney disease usually develop. Examination of the bone marrow under the microscope reveals characteristic holes ("vacuoles") in many cells. The disease is caused by a loss, or deletion , of large pieces of DNA from tiny structures in the substance of cells, which are called mitochondria . Mitochondria are responsible for producing much of the energy that cells need in order to function normally.

Pearson syndrome • –

• – –

• –

– –

•

What are the major findings on physical examination? Short stature.

What is the age at diagnosis? Patients have been diagnosed from birth to 7 years of age The diagnosis is usually made in the first year of life.

What is the pattern of bone marrow failure? The bone marrow fails to produce a specific type of white blood cell called "neutrophils." When these cells are present in lower than normal numbers in the bloodstream, the condition is called "neutropenia." Low red cell count (anemia) Low platelet count (platelets are the cells which help the blood to clot)

Patients may develop aplastic anemia when all 3 types of cells (red cells, white cells and platelets) are abnormally low because the bone marrow is not producing them.

Pearson syndrome Differentials • Anemia, Fanconi • Bone Marrow Failure • Failure to Thrive • Kearns-Sayre Synd rome • MELAS Syndrome • Shwachman-Diamon d Syndrome

Pearson syndrome Laboratory Studies CBC count with differential and reticulocyte count • Patients with Pearson syndrome have macrocytic anemia. • The reticulocyte count is inappropriately low for the degree of anemia. • Some patients also have leukopenia, neutropenia, or thrombocytopenia. Test of pancreatic exocrine function • Document evidence of pancreatic exocrine dysfunction. • Various direct and indirect tests are available, including the following: - Measurement of secretory capacity induced by exogenous hormones, a test meal, or a duodenal stimulant - Stool microscopy and analysis of fecal fat and nitrogen - Measurement of serum pancreatic isoamylase, trypsinogen, and lipase concentrations

Pearson syndrome Laboratory Studies Measurement of serum lactic acid • Patients may have lactic acidemia, most commonly seen during intercurrent illnesses. • The ratio of lactate to pyruvate may be increased at baseline. Urinalysis • Complex organic aciduria, including 3-methylglutaconic aciduria, has been reported. • Some patients have proximal renal tubular dysfunction that causes urinary wasting of amino acids, glucose, bicarbonate, phosphate, citrate, and urate. Hepatic study • Hepatic transaminase values may be increased in patients with hepatic involvement. • Bilirubin levels may be increased, and albumin concentrations and coagulation values (eg, prothrombin time) may reflect a defect in synthetic function. Endocrinologic study • Some patients have evidence of having deficiencies of thyroid, parathyroid, or growth hormones.

Pearson syndrome Laboratory Studies Analysis of mitochondrial DNA • The causative deletions of mitochondrial DNA can be demonstrated with molecular genetic analysis. Because of heteroplasmy, not all tissues contain abundant amounts of mutant mitochondrial DNA. • Bone marrow cells and peripheral blood cells are appropriate for analysis. However, because of heteroplasmy, mutant DNA may not always be found. If Pearson syndrome is suspected despite normal findings in other tissues, analysis of bone marrow should be performed. • No specific imaging studies are needed to diagnose Pearson syndrome.

Pearson syndrome Medical Care •

No specific therapy is available for individuals with Pearson syndrome or other mitochondrial cytopathies. Awareness of possible complications and early intervention may prevent death and minimize morbidity. • Red blood cell transfusions are often needed to manage the macrocytic anemia, and patients may be dependent on transfusions. Erythropoietin has been tried to decrease the frequency of transfusions. • Pancreatic enzyme replacement is needed for patients with malabsorption due to exocrine pancreatic insufficiency. Supplementation with fat-soluble vitamins may also be needed. • In neutropenic patients, fever higher than 101.5 º F should be evaluated promptly. Parenteral antibiotics should be administered after blood is obtained. Splenic atrophy may also increase the risk of bacteremia due to encapsulated organism. Granulocyte colony-stimulating factor (G-CSF) has been used in some patients to ameliorate severe neutropenia.

Pearson syndrome Medical Care •

Manage intermittent metabolic crises with hydration, correction of electrolyte abnormalities, correction of acidosis, and a search for underlying causes (eg, infection). Seek evidence of concomitant hepatic failure. Chronic bicarbonate supplementation and dichloroacetic acid have been used to treat persistent metabolic acidosis. • Patients may have hypothyroidism, hypoparathyroidism, diabetes mellitus, or growth hormone deficiency. These conditions should be screened for and treated, if present. • Stem cell transplantation has been reported in only one individual with Pearson syndrome.[4] Pearson syndrome is a multisystem disorder, thus, transplantation can only correct the hematologic manifestations of the disorder and cannot correct the dysfunction of other systems. Transplantation may be associated with unique or greater than expected toxicities as well.

MELAS

SYNDROME

neurodegenerative disorder

• MELAS syndrome is caused by problems with the genetic material in body cells. Specifically, it is due to defects in the genetic material in mitochondria, the parts of cells that generate energy for the body to do its work. • It is not yet known how many individuals have developed MELAS throughout the world. The syndrome affects all ethnic groups and both males and females. It is known, however, that the genetic defect most often involved in MELAS is passed down through the mother’s side of the family.

MELAS

SYNDROME

neurodegenerative disorder MELAS is a condition that affects many of the body's systems, particularly the brain and nervous system (encephalo-) and muscles (myopathy). In most cases, the signs and symptoms of this disorder appear in childhood following a period of normal development. Early symptoms may include muscle weakness and pain, recurrent headaches, loss of appetite, vomiting, and seizures. Most affected individuals experience stroke-like episodes beginning before age 40. These episodes often involve temporary muscle weakness on one side of the body (hemiparesis), altered consciousness, vision abnormalities, seizures, and severe headaches resembling migraines. Repeated stroke-like episodes can progressively damage the brain, leading to vision loss, problems with movement, and a loss of intellectual function (dementia).

MELAS

SYNDROME

symptoms MELAS stands for: • Mitochondrial myopathy – weakness of muscles throughout the body • Encephalopathy – disease of the central nervous system • Lactic Acidosis – abnormal build-up of lactic acid, normally a waste product, in the body • Stroke – occurs when the blood supply to part of the brain is cut off by disease, and brain cells die.

MELAS

SYNDROME Diagnosis

In many individuals with MELAS syndrome, a stroke, or similar symptoms such as headache, vomiting, or seizures, is the first clue that something is wrong. The first stroke episode usually occurs in childhood between the ages of 4 and 15 years, but it may occur in infants or in young adults. Prior to the first stroke, the child may be slow to grow and develop, have learning disabilities or attention deficit disorder.

MELAS

SYNDROME Diagnosis

Tests can check the level of lactic acid in the blood and cerebrospinal fluid. Blood tests can check for an enzyme (creatine kinase) present in muscle disease. A muscle sample (biopsy) can be tested for the most common genetic defect present in MELAS. Brain imaging studies, such as computed tomography (CT scan) or magnetic resonance imaging (MRI), can look for signs of brain damage from stroke.

A-several ragged red fibers (arrowhead)

C-succinate dehydrogenase staining showing a few ragged blue fibers and intense staining in the mitochondria of the blood vessels (arrow).

B-cytochrome c oxidase stain showing Type-1 lightly stained and Type II fibers, darker fibers, and a few fibers with abnormal collections of mitochondria (arrowhead) D- electron microscopy showing abnormal collection of mitochondria with paracrystalline inclusions (arrowhead), osmiophilic inclusions (large arrowhead) and mitochondrial vacuoles (small arrowhead)

MELAS

SYNDROME

computed tomography (CT scan) or magnetic resonance imaging (MRI)

MELAS

SYNDROME

Treatment Unfortunately there is as yet no treatment to stop the damage done by MELAS syndrome, and the outcome for individuals with the syndrome is usually poor. Moderate treadmill training can help improve the endurance of individuals with myopathy. Metabolic therapies, including dietary supplements, have shown benefits for some individuals. These treatments include coenzyme Q10, phylloquinone, menadione, ascorbate, riboflavin, nicotinamide, creatine monohydrate, idebenone, succinate, and dichloroacetate. Whether these supplements will help all individuals with MELAS syndrome is still being studied.

Myoclonic epilepsy with ragged-red fibers (MERRF) Symptoms: Myoclonus, epilepsy, progressive ataxia, muscle weakness and degeneration, deafness, and dementia. Cause: Mitochondrial DNA point mutations: A8344G, T8356C MERRF is a progressive multi-system syndrome usually beginning in childhood, but onset may occur in adulthood. The rate of progression varies widely. Onset and extent of symptoms can differ among affected siblings.

MERRF symptoms The classic features of MERRF include: • Myoclonus (brief, sudden, twitching muscle spasms) – the most characteristic symptom • Epileptic seizures • Ataxia (impaired coordination) • Ragged-red fibers (a characteristic microscopic abnormality observed in muscle biopsy of patients with MERRF and other mitochondrial disorders). • Additional symptoms may include: hearing loss, lactic acidosis, short stature, exercise intolerance, dementia, cardiac defects, eye abnormalities, and speech impairment.

MERRF Although a few cases of MERRF are sporadic, most cases are maternally inherited due to a mutation within the mitochondria. The most common MERRF mutation is A8344G, which accounted for over 80% of the cases. Four other mitochondrial DNA mutations have been reported to cause MERRF. While a mother will transmit her MERRF mutation to all of her offspring, some may never display symptoms.

MERRF As with all mitochondrial disorders, there is no cure for MERRF. Therapies may include coenzyme Q10, L-carnitine, and various vitamins, often in a “cocktail” combination. Management of seizures usually requires anticonvulsant drugs. Medications for control of other symptoms may also be necessary. The prognosis for MERRF varies widely depending on age of onset, type and severity of symptoms, organs involved, and other factors.

Leber hereditary optic neuropathy (LHON) •

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.[5] 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.

LHON Epidemiology • 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. • LHON mutations are prevalent in ~1 in 8,500 individuals in the general population • More than 50 % of males with a mutation and more than 85 % of females with a mutation never experience vision loss or related medical problems.

LHON 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 nucleii. Experimental evidence reveals impaired glutamate transport and increased reactive oxygen species (ROS) causing apoptosis of retinal ganglion cells.

LHON Signs & symptoms Clinically, there is an acute onset of visual loss, first in one eye, 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. This typically evolves to very severe optic atrophy and permanent decrease of visual acuity. 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). These 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.

LHON Signs & symptoms

Primarily blindness in young men. Less common symptoms: mild dementia, ataxia, spasticity, peripheral neuropathy, and heart conduction defects.

LHON Diagnosis The discovery that LHON is a mitochondrial disease has led to a diagnostic molecular genetic blood test. Testing for mutations using polymerase chain reaction techniques is available in a few centers around the world. The test is 100% accurate for LHON when visual loss has already occurred. Family members of someone with LHON who test positive may be at risk for LHON. It is important for family members to be tested because changes in lifestyle and diet may help prevent the onset of LHON.

LHON

Leber hereditary optic neuropathy

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.[16] Hence the incidence is probably greater than appreciated. The prognosis for those affected is almost always that of continued very severe visual loss. Regular corrected visual acuity and perimetry checks are advised for follow up of affected individuals. There is no accepted treatment for this disease. Genetic counselling should be offered.

Good luck!