These most often occur years after the development of ptosis and ophthalmoplegia. Atrioventricular(abbreviated "AV") block is the most common cardiac conduction deficit. This often progresses to a Third-degree atrioventricular block, which is a complete blockage of the electrical conduction from the atrium to the ventricle. Symptoms of heart block include syncope, exercise intolerance, and bradycardia

As characterized in Kearns' original publication in 1965 and in later publications, inconsistent features of KSS that may occur are weakness of facial, pharyngeal, trunk, and extremity muscles, hearing loss, small stature, electroencephalographic changes, cerebellar ataxia and elevated levels of cerebrospinal fluid protein.

Learning disabilities and developmental delays are often seen in children with NARP, and older individuals with this condition may experience a loss of intellectual function (dementia). Other features of NARP include seizures, hearing loss, and abnormalities of the electrical signals that control the heartbeat (cardiac conduction defects). These signs and symptoms vary among affected individuals.

Neuropathy, ataxia, and retinitis pigmentosa, also known as NARP syndrome, is a rare disease with mitochondrial inheritance that causes a variety of signs and symptoms chiefly affecting the nervous system Beginning in childhood or early adulthood, most people with NARP experience numbness, tingling, or pain in the arms and legs (sensory neuropathy); muscle weakness; and problems with balance and coordination (ataxia). Many affected individuals also have vision loss caused by changes in the light-sensitive tissue that lines the back of the eye (the retina). In some cases, the vision loss results from a condition called retinitis pigmentosa. This eye disease causes the light-sensing cells of the retina gradually to deteriorate.

Onset : Early childhood

Progression: Chronic progressive

Clinical: Cerebellar ataxia plus syndrome / Optic Atrophy Plus Syndrome

Ocular: Optic atrophy, nystagmus, scotoma, and bilateral retrobulbar neuritis.

Other: Mental retardation, myoclonic epilepsy, spasticity, and posterior column sensory loss. Tremor in some cases.

Musculoskeletal

Contractures, lower limbs, Achilles tendon contractures, Hamstring contractures, Adductor longus contractures

Systemic

Hypogonadotrophic hypogonadism.

Signs and symptoms include (for each of the following causes):

- Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome (MELAS)

- Varying degrees of cognitive impairment and dementia

- Lactic acidosis

- Strokes

- Transient ischemic attacks

- Hearing loss

- Weight loss

- Myoclonic epilepsy and ragged-red fibers (MERRF)

- Progressive myoclonic epilepsy

- Clumps of diseased mitochondria accumulate in muscle fibers and appear as "ragged-red fibers" when muscle is stained with modified Gömöri trichrome stain

- Short stature

- Kearns-Sayre syndrome (KSS)

- External ophthalmoplegia

- Cardiac conduction defects

- Sensorineural hearing loss

- Chronic progressive external ophthalmoplegia (CPEO)

- Progressive ophthalmoparesis

- Symptomatic overlap with other mitochondrial myopathies

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). The stroke-like episodes can be mis-diagnosed as epilepsy by a doctor not aware of the MELAS condition.

Most people with MELAS have a buildup of lactic acid in their bodies, a condition called lactic acidosis. Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, loss of bowel control, and difficulty breathing. Less commonly, people with MELAS may experience involuntary muscle spasms (myoclonus), impaired muscle coordination (ataxia), hearing loss, heart and kidney problems, diabetes, epilepsy, and hormonal imbalances.

The presentation of some cases is similar to that of Kearns-Sayre syndrome.

All forms of MDDS are very rare. MDDS causes a wide range of symptoms, which can appear in newborns, infants, children, or adults, depending on the class of MDDS; within each class symptoms are also diverse.

In MDDS associated with mutations in "TK2", infants generally develop normally, but by around two years of age, symptoms of general muscle weakness (called "hypotonia"), tiredness, lack of stamina, and difficulty feeding begin to appear. Some toddlers start to lose control of the muscles in their face, mouth, and throat, and may have difficulty swallowing. Motor skills that had been learned may be lost, but generally the functioning of the brain and ability to think are not affected.

In MDDS associated with mutations in "SUCLA2" or "SUCLG1" that primarily affect the brain and muscle, hypotonia generally arises in infants before they are 6 months old, their muscles begin wasting away, and there is delay in psychomotor learning (learning basic skills like walking, talking, and intentional, coordinated movement). The spine often begins to curve (scoliosis or kyphosis), and the child often has abnormal movements (dystonia, athetosis or chorea), difficulty feeding, acid reflux, hearing loss, stunted growth, and difficulty breathing that can lead to frequent lung infections. Sometime epilepsy develops.

In MDDS associated with mutations in "RRM2B" that primarily affect the brain and muscle, there is again hypotonia in the first months, symptoms of lactic acidosis like nausea, vomiting, and rapid deep breathing, failure to thrive including the head remaining small, delay or regression in moving, and hearing loss. Many body systems are affected.

In MDDS associated with mutations in "DGUOK" that primarily affect the brain and the liver, there are two forms. There is an early-onset form in which symptoms arise from problems in many organs in the first week of life, especially symptoms of lactic acidosis as well as low blood sugar. Within weeks of birth they can develop liver failure and the associated jaundice and abdominal swelling, and many neurological problems including developmental delays and regression, and uncontrolled eye movement. Rarely within class of already rare diseases, symptoms only relating to liver disease emerge later in infancy or in childhood.

In MDDS associated with mutations in "MPV17" that primarily affect the brain and the liver, the symptoms are similar to those caused by DGUOK and also emerge shortly after birth, generally with fewer and less severe neurological problems. There is a subset of people of Navajo descent who develop Navajo neurohepatopathy, who in addition to these symptoms also have easily broken bones that do not cause pain, deformed hands or feet, and problems with their corneas.

In MDDS associated with mutations in "POLG" that primarily affect the brain and the liver, the symptoms are very diverse and can emerge anytime from shortly after birth to old age. The first signs of the disease, which include intractable seizures and failure to meet meaningful developmental milestones, usually occur in infancy, after the first year of life, but sometimes as late as the fifth year. Primary symptoms of the disease are developmental delay, progressive intellectual disability, hypotonia (low muscle tone), spasticity (stiffness of the limbs) possibly leading to quadriplegia, and progressive dementia. Seizures may include epilepsia partialis continua, a type of seizure that consists of repeated myoclonic (muscle) jerks. Optic atrophy may also occur, often leading to blindness. Hearing loss may also occur. Additionally, although physical signs of chronic liver dysfunction may not be present, many people suffer liver impairment leading to liver failure.

In MDDS associated with mutations in "PEO1"/"C10orf2" that primarily affect the brain and the liver, symptoms emerge shortly after birth or in early infancy, with hypotonia, symptoms of lactic acidosis, enlarged liver, feeding problems, lack of growth, and delay of psychomotor skills. Neurologically, development is slowed or stopped, and epilepsy emerges, as do sensory problems like loss of eye control and deafness, and neuromuscular problems like a lack of reflexes, muscular atrophy, and twitching, and epilepsy.

In MDDS associated with mutations in the genes associated with mutations in "ECGF1"/"TYMP" that primarily affects the brain and the gastrointestinal tract, symptoms can emerge any time in the first fifty years of life; most often they emerge before the person turns 20. Weight loss is common as is a lack of the ability of the stomach and intestines to automatically expand and contract and thus move through it (called gastrointestinal motility) – this leads to feeling full after eating only small amounts of food, nausea, acid reflux, All affected individuals develop weight loss and progressive gastrointestinal dysmotility manifesting as early satiety, nausea, diarrhea, vomiting, and stomach pain and swelling. People also develop neuropathy, with weakness and tingling. There are often eye problems, and intellectual disability.

Behr syndrome is characterized by the association of early-onset optic atrophy with spinocerebellar degeneration resulting in ataxia, pyramidal signs, peripheral neuropathy and developmental delay.

Although it is an autosomal recessive disorder, heterozygotes may still manifest much attenuated symptoms. Autosomal dominant inheritance also being reported in a family. Recently a variant of OPA1 mutation with phenotypic presentation like Behr syndrome is also described. Some reported cases have been found to carry mutations in the OPA1, OPA3 or C12ORF65 genes which are known causes of pure optic atrophy or optic atrophy complicated by movement disorder.

The syndrome causes cerebellar ataxia (balance and coordination problems), mental retardation, congenital cataracts in early childhood, muscle weakness, inability to chew food, thin brittle fingernails, and sparse hair.

Small stature, mild to severe mental retardation and dysarthria (slow, imprecise speech) are usually present.

Various skeletal abnormalities (e.g., curvature of the spine) and hypergonadotropic hypogonadism often occur.

Muscle weakness is progressive, but life expectancy is near normal.

Symptoms include poor growth, loss of muscle coordination, muscle weakness, visual problems, hearing problems, learning disabilities, heart disease, liver disease, kidney disease, gastrointestinal disorders, respiratory disorders, neurological problems, autonomic dysfunction and dementia. Acquired conditions in which mitochondrial dysfunction has been involved are: diabetes, Huntington's disease, cancer, Alzheimer's disease, Parkinson's disease, bipolar disorder, schizophrenia, aging and senescence, anxiety disorders, cardiovascular disease, sarcopenia, chronic fatigue syndrome.

The body, and each mutation, is modulated by other genome variants; the mutation that in one individual may cause liver disease might in another person cause a brain disorder. The severity of the specific defect may also be great or small. Some minor defects cause only "exercise intolerance", with no serious illness or disability. Defects often affect the operation of the mitochondria and multiple tissues more severely, leading to multi-system diseases.

As a rule, mitochondrial diseases are worse when the defective mitochondria are present in the muscles, cerebrum, or nerves, because these cells use more energy than most other cells in the body.

Although mitochondrial diseases vary greatly in presentation from person to person, several major clinical categories of these conditions have been defined, based on the most common phenotypic features, symptoms, and signs associated with the particular mutations that tend to cause them.

An outstanding question and area of research is whether ATP depletion or reactive oxygen species are in fact responsible for the observed phenotypic consequences.

Cerebellar atrophy or hypoplasia has sometimes been reported to be associated.

Like other mitochrondrial diseases, "MNGIE is a multisystem disorder". MNGIE primarily affects the gastrointestinal and neurological systems. Gastrointestinal symptoms may include gastrointestinal dysmotility, due to inefficient peristalsis, which may result in pseudo-obstruction and cause malabsorption of nutrients. Additionally, gastrointestinal symptoms such as borborygmi, early satiety, diarrhea, constipation, gastroparesis, nausea, vomiting, weight loss, and diverticulitis may be present in MNGIE patients. Neurological symptoms may include diffuse leukoencephalopathy, peripheral neuropathy, and myopathy. Ocular symptoms may include retinal degeneration, ophthalmoplegia, and ptosis. Those with MNGIE are often thin and experience continuous weight loss. The characteristic thinness of MNGIE patients is caused by multiple factors including inadequate caloric intake due to gastrointestinal symptoms and discomfort, malabsorption of food from bacterial overgrowth due to decreased motility, as well as an increased metabolic demand due to inefficient production of ATP by the mitochondria.

Mitochondrial myopathies are types of myopathies associated with mitochondrial disease. On biopsy, the muscle tissue of patients with these diseases usually demonstrate "ragged red" muscle fibers. These ragged-red fibers contain mild accumulations of glycogen and neutral lipids, and may show an increased reactivity for succinate dehydrogenase and a decreased reactivity for cytochrome c oxidase. Inheritance was believed to be maternal (non-Mendelian extranuclear). It is now known that certain nuclear DNA deletions can also cause mitochondrial myopathy such as the OPA1 gene deletion. There are several subcategories of mitochondrial myopathies.

The symptoms of Leigh syndrome are classically described as beginning in infancy and leading to death within a span of several years; however, as more cases are recognized, it is apparent that symptoms can emerge at any age—including adolescence or adulthood—and patients can survive for many years following diagnosis. Symptoms are often first seen after a triggering event that taxes the body's energy production, such as an infection or surgery. The general course of Leigh syndrome is one of episodic developmental regression during times of metabolic stress. Some patients have long periods without disease progression while others develop progressive decline.

Infants with the syndrome have symptoms that include diarrhea, vomiting, and dysphagia (trouble swallowing or sucking), leading to a failure to thrive. Children with early Leigh disease also may appear irritable and cry much more than usual. Seizures are often seen. Excess lactate may be seen in the urine, cerebrospinal fluid, and blood of a person with Leigh syndrome.

As the disease progresses, the muscular system is debilitated throughout the body, as the brain cannot control the contraction of muscles. Hypotonia (low muscle tone and strength), dystonia (involuntary, sustained muscle contraction), and ataxia (lack of control over movement) are often seen in people with Leigh disease. The eyes are particularly affected; the muscles that control the eyes become weak, paralyzed, or uncontrollable in conditions called ophthalmoparesis (weakness or paralysis) and nystagmus (involuntary eye movements). Slow saccades are also sometimes seen. The heart and lungs can also fail as a result of Leigh disease. Hypertrophic cardiomyopathy (thickening of part of the heart muscle) is also sometimes found and can cause death; asymmetric septal hypertrophy has also been associated with Leigh syndrome. In children with Leigh-syndrome associated ventricular septal defects, caused by pyruvate dehydrogenase deficiency, high forehead and large ears are seen; facial abnormalities are not typical of Leigh syndrome.

However, respiratory failure is the most common cause of death in people with Leigh syndrome. Other neurological symptoms include peripheral neuropathy, loss of sensation in extremities caused by damage to the peripheral nervous system.

Hypertrichosis is seen in Leigh syndrome caused by mutations in the nuclear gene SURF1.

Weakness of extraocular muscle groups including, the orbicularis oculi muscle as well as facial and limb muscles may be present in up to 25% of patients with CPEO. As a result of the orbicularis oculi weakness, patients may suffer from exposure keratopathy (damage to cornea) from the inability to close the eyes tightly. Frontalis muscle weakness may exacerbate the ptotic lids with the inability to compensate for the ptosis. Facial muscles may be involved which lead to atrophy of facial muscle groups producing a thin, expressionless face with some having difficulty with chewing. Neck, shoulder and extremity weakness with atrophy may affect some patients and can be mild or severe.

Mild visual impairment was seen in 95% of patients that were evaluated using the Visual Function Index (VF-14).

The ciliary muscles that control the lens shape and the iris muscles are often unaffected by CPEO.

Additional symptoms are variable, and may include exercise intolerance, cataracts, hearing loss, sensory axonal neuropathy, ataxia, clinical depression, hypogonadism, and parkinsonism.

Kearns–Sayre syndrome is characterized by onset before 15 years of age of CPEO, heart block and pigmentary retinopathy.

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 7-75 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.

This typically evolves to very severe optic atrophy and a 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 telangiectatic 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.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the family of mitochondrial cytopathies, which also include MERRF, 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. However, it is important to know that some of the proteins essential to normal mitochondrial function are produced by the nuclear genome, and are subsequently transported to the mitochondria for use. As such, mutations in these proteins can result in mitochondrial disorders, but can be inherited from both male and female parent in the typical fashion. The disease can manifest in both sexes.

Mitochondrial diseases are a group of disorders caused by dysfunctional mitochondria, the organelles that generate energy for the cell. Mitochondria are found in every cell of the human body except red blood cells, and convert the energy of food molecules into the ATP that powers most cell functions.

Mitochondrial diseases are sometimes (about 15% of the time) caused by mutations in the mitochondrial DNA that affect mitochondrial function. Other mitochondrial diseases are caused by mutations in genes of the nuclear DNA, whose gene products are imported into the mitochondria (mitochondrial proteins) as well as acquired mitochondrial conditions. Mitochondrial diseases take on unique characteristics both because of the way the diseases are often inherited and because mitochondria are so critical to cell function. The subclass of these diseases that have neuromuscular disease symptoms are often called a mitochondrial myopathy.

CPEO is a slowly progressing disease. It may begin at any age and progresses over a period of 5–15 years. The first presenting symptom of ptosis is often unnoticed by the patient until the lids droop to the point of producing a visual field defect. Often, patients will tilt the head backwards to adjust for the slowly progressing ptosis of the lids. In addition, as the ptosis becomes complete, the patients will use the frontalis (forehead) muscle to help elevate the lids. The ptosis is typically bilateral, but may be unilateral for a period of months to years before the fellow lid becomes involved.

Ophthalmoplegia or the inability or difficulty to move the eye is usually symmetrical. As such, double vision is sometimes a complaint of these patients. The progressive ophthalmoplegia is often unnoticed till decreased ocular motility limits peripheral vision. Often someone else will point out the ocular disturbance to the patient. Patients will move their heads to adjust for the loss of peripheral vision caused by inability to abduct or adduct the eye. All directions of gaze are affected; however, downward gaze appears to be best spared. This is in contrast to progressive supranuclear palsy (PSP), which typically affects vertical gaze and spares horizontal gaze.

MDDS are a group of genetic disorders that share a common pathology — a lack of functioning DNA in mitochondria. There are generally four classes of MDDS:

- a form that primarily affects muscle associated with mutations in the "TK2" gene;

- a form that primarily affects the brain and muscle associated with mutations in the genes "SUCLA2", "SUCLG1", or "RRM2B";

- a form that primarily affects the brain and the liver associated with mutations in "DGUOK", "MPV17", "POLG", or "PEO1" (also called "C10orf2"); and

- a form that primarily affects the brain and the gastrointestinal tract associated with mutations in "ECGF1" (also called "TYMP").

Diagnosis of MSS is based on clinical symptoms, magnetic resonance imaging (MRI) of the brain (cerebellar atrophy particularly involving the cerebellar vermis), and muscle biopsy.

It can be associated with mutations of the SIL1 gene, and a mutation can be found in about 50% of cases.

Differential diagnosis includes Congenital Cataracts Facial Dysmorphism Neuropathy (CCFDN), Marinesco–Sjögren like syndrome with chylomicronemia, carbohydrate deficient glycoprotein syndromes, Lowe syndrome, and mitochondrial disease.

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".

MERRF syndrome (or myoclonic epilepsy with ragged red fibers) is a mitochondrial disease. It is extremely rare, with an estimated prevalence of 1/4,000 in Northern Europe, and has varying degrees of expressivity owing to heteroplasmy. MERRF syndrome affects different parts of the body, particularly the muscles and nervous system. The signs and symptoms of this disorder appear at an early age, generally childhood or adolescence. The causes of MERRF syndrome is difficult to determine, however since its a mitochondrial disorder it can be caused by the mutation of nuclear DNA or mitochondrial DNA. The classification of this disease varies from patient to patient, since many individuals do not fall into one specific disease category.The primary features displayed on a person with MERRF include myoclonus, seizures, cerebellar ataxia, myopathy and ragged ref fibers (RRF) on muscle biopsy, leading to the diseases name. Secondary features include dementia, optic atrophy, bilateral deafness, peripheral neuropathy, spasticity or multiple lipomata. Mitochondrial disorders may present at any age, and this holds truth for MERRFS, since it forms part of them.

An individual displaying MERRFs syndrome will manifest not only a single symptom, but regularly patients display more than one affected body part at a time. It has been observed that patients with MERRF syndrome will primarily display Myoclonus as a first symptom, along with it they can also manifest seizures, cerebellar ataxia and myopathy. Secondary features include dementia, optic atrophy, bilateral deafness, peripheral neuropathy, spasticity or multiple lipomata. Additional symptoms include dementia, optic atrophy, bilateral deafness and peripheral neuropathy, spasticity, lipomatosis, and/or cardiomyopathy with wolff parkinson-white syndrome. Most patients will not exhibit all of these symptoms, however more than one of these symptoms will be present in a patient who has been diagnosed with MERRFS disease. Due to the multi-symptoms presented by the individual, the severity of the syndrome is very difficult to evaluate. Mitochondrial disorders may present at any age, and this holds truth for MERRS, since it forms part of them. Therefore, if a patient is presenting some of these symptoms, the doctor is able to narrow it down to MEERF mitochondrial disorder.

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