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.

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.

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.

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.

Individuals with KSS present initially in a similar way to those with typical CPEO. Onset is in the first and second decades of life.

The first symptom of this disease 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.

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.

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").

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.

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.

Common symptoms of the disease are weakness and atrophy in the distal muscles of the lower limbs which progresses to the hands and arms, then to the trunk, neck and face. Respiratory impairment often follows.

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".

Symptomatic presentation usually occurs between 6 and 24 months of age, but the majority of cases have been documented in children less than 1 year of age. The infantile form involves multiple organ systems and is primarily characterized by hypoketotic hypoglycemia (recurring attacks of abnormally low levels of fat breakdown products and blood sugar) that often results in loss of consciousness and seizure activity. Acute liver failure, liver enlargement, and cardiomyopathy are also associated with the infantile presentation of this disorder. Episodes are triggered by febrile illness, infection, or fasting. Some cases of sudden infant death syndrome are attributed to infantile CPT II deficiency at autopsy.

This exclusively myopathic form is the most prevalent and least severe phenotypic presentation of this disorder. Characteristic signs and symptoms include rhabdomyolysis (breakdown of muscle fibers and subsequent release of myoglobin), myoglobinuria, recurrent muscle pain, and weakness. It is important to note that muscle weakness and pain typically resolves within hours to days, and patients appear clinically normal in the intervening periods between attacks. Symptoms are most often exercise-induced, but fasting, a high-fat diet, exposure to cold temperature, or infection (especially febrile illness) can also provoke this metabolic myopathy. In a minority of cases, disease severity can be exacerbated by three life-threatening complications resulting from persistent rhabdomyolysis: acute kidney failure, respiratory insufficiency, and episodic abnormal heart rhythms. Severe forms may have continual pain from general life activity. The adult form has a variable age of onset. The first appearance of symptoms usually occurs between 6 and 20 years of age but has been documented in patients as young as 8 months as well as in adults over the age of 50. Roughly 80% cases reported to date have been male.

Generally, the majority of individuals with creatine transporter defect express the following symptoms with varying levels of severity: developmental delay and regression, mental retardation, and abnormalities in expressive and cognitive speech. However, several studies have shown a wider variety of symptoms including, but not limited to attention deficit and hyperactivity with impulsivity, myopathy, hypotonia, semantic-pragmatic language disorder, oral dyspraxia, extrapyramidal movement disorder, constipation, absent speech development, seizures, and epilepsy. Furthermore, symptoms can significantly vary between hemizygous males and heterozygous females, although, symptoms are generally more severe in hemizygous males. Hemizygous males more commonly express seizures, growth deficiency, severe mental retardation, and severe expressive language impairment. Heterozygous females more commonly express mild retardation, impairments to confrontational naming and verbal memory, and learning and behavior problems.

Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an under-recognized inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who first described the condition in 1951.

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.

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.

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

There are three major types of inheritance for this disease: Autosomal dominant, autosomal recessive and de novo.

- The most severe form is autosomal recessive and it also has the earliest onset. It usually involves all three muscle tissues and leads to cardiac and respiratory failure as well as intestinal obstruction.

- Autosomal Dominant inheritance shows a later onset and slower progression. It usually involves only one or two of the muscle tissues.

- De novo diseases occur when a new mutation arises in the person that was not inherited through either parent. This form has a wide range of symptoms and varies depending on the mutation made.

Severe cases of CLA manifest in the neonatal period; milder cases caused by mtDNA mutations may not manifest until as late as early adulthood. Symptoms may be constant or brought on by an event causing stress, such as an asthma attack, seizure, or infection. Symptoms in the neonatal period include hypotonia, lethargy, vomiting, and tachypnea. As the disease progresses, it causes developmental delay, cognitive disabilities, abnormal development of the face and head, and organ failure.

The low incidence of this syndrome is often related to aldolase A's essential glycolytic role along with its exclusive expression in blood and skeletal muscle. Early developmental reliance and constitutive function prevents severe mutation in successful embryos. Infrequent documentation thus prevents clear generalisation of symptoms and causes. However five cases have been well described. ALDOA deficiency is diagnosed through reduced aldoA enzymatic activity, however, both physiological response and fundamental causes vary.

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.

Creatine transporter defect (CTD) is an inborn error of creatine metabolism in which creatine is not properly transported to the brain and muscles due to defective creatine transporters. CTD is an X-linked disorder caused by mutations in the SLC6A8 gene. The SLC6A8 gene is located on the short arm of the sex chromosome, Xq28. Hemizygous males with CTD express speech and behavior abnormalities, intellectual disabilities, development delay, seizures, and autistic behavior. Heterozygous females with CTD generally express fewer, less severe symptoms. CTD is one of three different types of cerebral creatine deficiency (CCD). The other two types of CCD are guanidinoacetate methyltransferase (GAMT) deficiency and deficiency. Clinical presentation of CTD is similar to that of GAMT and AGAT deficiency. CTD was first identified in 2001 with the presence of a hemizygous nonsense mutation in the SLC6A8 gene in a male patient.

Zaspopathy, also called ZASP-related myofibril myopathy, is a novel autosomal dominant form of progressive muscular dystrophy, first described in 2005.

The disease encompasses multiple forms of both distal and proximal myopathies, and is caused by mutations in the gene referred to as ZASP.

Congenital lactic acidosis (CLA) is a rare disease caused by mutations in mitochondrial DNA (mtDNA) that affect the ability of cells to use energy and cause too much lactic acid to build up in the body, a condition called lactic acidosis.