Different genetic causes and types of Leigh syndrome have different prognoses, though all are poor. The most severe forms of the disease, caused by a full deficiency in one of the affected proteins, cause death at a few years of age. If the deficiency is not complete, the prognosis is somewhat better and an affected child is expected to survive 6–7 years, and in rare cases, to their teenage years.

SUCLA2 and RRM2B related forms result in deformities to the brain. A 2007 study based on 12 cases from the Faroe Islands (where there is a relatively high incidence due to a founder effect) suggested that the outcome is often poor with early lethality. More recent studies (2015) with 50 people with SUCLA2 mutations, with range of 16 different mutations, show a high variability in outcomes with a number of people surviving into adulthood (median survival was 20 years. There is significant evidence (p = 0.020) that people with missense mutations have longer survival rates, which might mean that some of the resulting protein has some residual enzyme activity.

RRM2B mutations have been reported in 16 infants with severe encephalomyopathic MDS that is associated with early-onset (neonatal or infantile), multi-organ presentation, and mortality during infancy.

Leigh disease occurs in at least 1 of 40,000 live births, though certain populations have much higher rates. In the Saguenay-Lac-Saint-Jean region of central Quebec, Leigh syndrome occurs at a rate of 1 in 2000 newborns.

The TK2 related myopathic form results in muscle weakness, rapidly progresses, leading to respiratory failure and death within a few years of onset. The most common cause of death is pulmonary infection. Only a few people have survived to late childhood and adolescence.

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".

The exact incidence of MELAS is unknown. It is one of the more common conditions in a group known as mitochondrial diseases. Together, mitochondrial diseases occur in about 1 in 4,000 people.

A variety of mutations in the TYMP gene have been discovered that lead to the onset of mitochondrial neurogastrointestinal encephalopathy syndrome. The TYMP gene is a nuclear gene, however, mutations in the TYMP gene affect mitochrondrial DNA and function. Mutations in this gene result in a loss of thymidine phosphorylase activity. Thymidine phosphorylase is the enzymatic product of the TYMP gene and is responsible for breaking down thymidine nucleosides into thymine and 2-deoxyribose 1-phosphate. Without normal thymidine phosphorylase activity, thymidine nucleosides begin to build up in cells. High nucleoside levels are toxic to mitochondrial DNA and cause mutations that lead to dysfunction of the respiratory chain, and thus, inadequate energy production in the cells. These mitochondrial effects are responsible for the symptomatology associated with the disease.

Bloom syndrome is an extremely rare disorder in most populations and the frequency of the disease has not been measured in most populations. However, the disorder is relatively more common amongst people of Central and Eastern European (Ashkenazi) Jewish background. Approximately 1 in 48,000 Ashkenazi Jews are affected by Bloom syndrome, who account for about one-third of affected individuals worldwide.

About 1 in 4,000 children in the United States will develop mitochondrial disease by the age of 10 years. Up to 4,000 children per year in the US are born with a type of mitochondrial disease. Because mitochondrial disorders contain many variations and subsets, some particular mitochondrial disorders are very rare.

The average number of births per year among women at risk for transmitting mtDNA disease is estimated to approximately 150 in the United Kingdom and 800 in the United States.

The severity and prognosis vary with the type of mutation involved.

The journal of child neurology published a paper in 2012, Buccal swab analysis of mitochondrial enzyme deficiency and DNA defects in a child with suspected myoclonic epilepsy and ragged red fibers (MERRF), discusses possible new methods to test for MERRF and other mitochondrial diseases, through a simple swabbing technique. This is a less invasive techniques which allows for an analysis of buccal mitochondrial DNA, and showed significant amounts of the common 5 kb and 7.4 kb mitochondrial DNA deletions, also detectable in blood. This study suggests that a buccal swab approach can be used to informatively examine mitochondrial dysfunction in children with seizures and may be applicable to screening mitochondrial disease with other clinical presentations.

Proceedings of the National Academy of Science of the United States of America published an article in 2007 which investigate the human mitochondrial tRNA (hmt-tRNA) mutations which are associated with mitochondrial myopathies. Since the current understanding of the precise molecular mechanisms of these mutations is limited, there is no efficient method to treat their associated mitochondrial diseases. All pathogenic mutants displayed pleiotropic phenotypes, with the exception of the G34A anticodon mutation, which solely affected aminoacylation.

Some of the genes (MT-ND1, MT-ND5) affected in MELAS encode proteins that are part of NADH dehydrogenase (also called complex I) in mitochondria, that helps convert oxygen and simple sugars to energy.

Bloom syndrome has no specific treatment; however, avoiding sun exposure and using sunscreens can help prevent some of the cutaneous changes associated with photo-sensitivity. Efforts to minimize exposure to other known environmental mutagens are also advisable.

The cause of MERRF disorder is due to the mitochondrial genomes mutation. This means that its a pathogenic variants in mtDNA and is transmitted by maternal inheritance. A four points mutations in the genome can be identified which are associated with MERRF: A8344G, T8356C, G8361A, and G8363A. The point mutation A8344G is mostly associated with MERRF, in a study published by Paul Jose Lorenzoni from the Department of neurology at University of Panama stated that 80% of the patients with MERRF disease exhibited this point mutation.This point mutation disrupts the mitochondrial gene for tRNA-Lys and so disrupts synthesis of proteins essential for oxidative phosphorylation.The remaining mutations only account for 10% of cases, and the remaining 10% of he patients with MERRF did not have an identifiable mutation in the mitochondrial DNA.

Many genes are involved. These genes include:

- MT-TK

- MT-TL1

- MT-TH

- MT-TS1

- MT-TS2

- MT-TF

It involves the following characteristics:

- progressive myoclonic epilepsy

- ""Ragged Red Fibers"" - clumps of diseased mitochondria accumulate in the subsarcolemmal region of the muscle fiber and appear as "Ragged Red Fibers" when muscle is stained with modified Gömöri trichrome stain .

There is currently no cure for MERRF.

Chemotherapy medication, for example, fludarabine can cause a

permanent severe global encephalopathy. Ifosfamide can cause

a severe encephalopathy (but it can be reversible with stop using the drug and the use of methylene blue). Bevacizumab and other anti–vascular endothelial growth factor medication can cause posterior reversible encephalopathy syndrome.

Infant mortality is high for patients diagnosed with early onset; mortality can occur within less than 2 months, while children diagnosed with late-onset syndrome seem to have higher rates of survival. Patients suffering from a complete lesion of mut0 have not only the poorest outcome of those suffering from methylaonyl-CoA mutase deficiency, but also of all individuals suffering from any form of methylmalonic acidemia.

Though lactic acidosis can be a complication of other congenital diseases, when it occurs in isolation it is typically caused by a mutation in the pyruvate dehydrogenase complex genes. It has either an autosomal recessive or X-linked mode of inheritance. Congenital lactic acidosis can be caused by mutations on the X chromosome or in mitochondrial DNA.

Life expectancy is only moderately affected by NE because the rate of disease progression is slow. Patients usually survive past 40-50 years of age.

Imaging studies reveal widespread absence of the myelin sheaths of the neurons in the white matter of the brain, and general atrophy of the cortex. Calcifications have also been found in the putamen, an area of the forebrain that regulates movements and aids in some forms of learning, along with in the cortex. Additionally, atrophy of the central area of the cerebellum found in patients with Cockayne syndrome could also result in the lack of muscle control, particularly involuntary, and poor posture typically seen.

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.

There is no permanent cure for this syndrome, although patients can be treated according to their specific symptoms. The prognosis for those with Cockayne syndrome is poor, as death typically occurs by the age of 12. Treatment usually involves physical therapy and minor surgeries to the affected organs, like cataract removal. Also wearing high-factor sunscreen and protective clothing is recommended as patients with Cockayne syndrome are very sensitive to UV radiation. Optimal nutrition can also help. Genetic counseling for the parents is recommended, as the disorder has a 25% chance of being passed to any future children, and prenatal testing is also a possibility. Another important aspect is prevention of recurrence of CS in other sibling. Identification of gene defects involved makes it possible to offer genetic counseling and antenatal

diagnostic testing to the parents who already have one affected child.

NARP syndrome is not curable. Symptomatic relief is targeted. Antioxidants play a role in improving the oxidative phosphorylation that is otherwise impaired.

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. As of 1992 there were only 226 cases reported in published literature.

Progeroid syndromes (PS) are a group of rare genetic disorders which mimic physiological aging, making affected individuals appear to be older than they are. The term "progeroid syndrome" does not necessarily imply progeria (Hutchinson–Gilford progeria syndrome), which is a specific type of progeroid syndrome.

"Progeroid" means "resembling premature aging", a definition that can apply to a broad range of diseases. Familial Alzheimer's disease and familial Parkinson's disease are two well-known accelerated-aging diseases that are more frequent in older individuals. They affect only one tissue and can be classified as unimodal progeroid syndromes. Segmental progeria, which is more frequently associated with the term "progeroid syndrome", tends to affect multiple or all tissues while causing affected individuals to exhibit only some of the features associated with aging.

All disorders within this group are thought to be monogenic, meaning they arise from mutations of a single gene. Most known PS are due to genetic mutations that lead to either defects in the DNA repair mechanism or defects in lamin A/C.

Examples of PS include Werner syndrome (WS), Bloom syndrome (BS), Rothmund–Thomson syndrome (RTS), Cockayne syndrome (CS), xeroderma pigmentosum (XP), trichothiodystrophy (TTD), combined xeroderma pigmentosum-Cockayne syndrome (XP-CS), restrictive dermopathy (RD), and Hutchinson–Gilford progeria syndrome (HGPS). Individuals with these disorders tend to have a reduced lifespan. Progeroid syndromes have been widely studied in the fields of aging, regeneration, stem cells, and cancer. The most widely studied of the progeroid syndromes are Werner syndrome and Hutchinson–Gilford progeria, as they are seen to most resemble natural aging.

There are many types of encephalopathy. Some examples include:

- Mitochondrial encephalopathy: Metabolic disorder caused by dysfunction of mitochondrial DNA. Can affect many body systems, particularly the brain and nervous system.

- Glycine encephalopathy: A genetic metabolic disorder involving excess production of glycine.

- Hepatic encephalopathy: Arising from advanced cirrhosis of the liver.

- Hypoxic ischemic encephalopathy: Permanent or transitory encephalopathy arising from severely reduced oxygen delivery to the brain.

- Static encephalopathy: Unchanging, or permanent, brain damage.

- Uremic encephalopathy: Arising from high levels of toxins normally cleared by the kidneys—rare where dialysis is readily available.

- Wernicke's encephalopathy: Arising from thiamine (B) deficiency, usually in the setting of alcoholism.

- Hashimoto's encephalopathy: Arising from an auto-immune disorder.

- Hypertensive encephalopathy: Arising from acutely increased blood pressure.

- Chronic traumatic encephalopathy: Progressive degenerative disease associated with multiple concussions and other forms of brain injury.

- Lyme encephalopathy: Arising from Lyme disease bacteria, including "Borrelia burgdorferi".

- Toxic encephalopathy: A form of encephalopathy caused by chemicals, often resulting in permanent brain damage.

- Toxic-Metabolic encephalopathy: A catch-all for brain dysfunction caused by infection, organ failure, or intoxication.

- Transmissible spongiform encephalopathy: A collection of diseases all caused by prions, and characterized by "spongy" brain tissue (riddled with holes), impaired locomotion or coordination, and a 100% mortality rate. Includes bovine spongiform encephalopathy (mad cow disease), scrapie, and kuru among others.

- Neonatal encephalopathy (hypoxic-ischemic encephalopathy): An obstetric form, often occurring due to lack of oxygen in bloodflow to brain-tissue of the fetus during labour or delivery.

- Salmonella encephalopathy: A form of encephalopathy caused by food poisoning (especially out of peanuts and rotten meat) often resulting in permanent brain damage and nervous system disorders.

- Encephalomyopathy: A combination of encephalopathy and myopathy. Causes may include mitochondrial disease (particularly MELAS) or chronic hypophosphatemia, as may occur in cystinosis.

- Creutzfeldt–Jakob disease (CJD; transmissible spongiform encephalopathy).

- HIV encephalopathy (encephalopathy associated with HIV infection and AIDS, characterized by atrophy and ill-defined white matter hyperintensity).

- Sepsis-associated encephalopathy (this type can occur in the setting of apparent sepsis, trauma, severe burns, or trauma, even without clear identification of an infection).

- Epileptic encephalopathies:

- Early infantile epileptic encephalopathy (acquired or congenital abnormal cortical development).

- Early myoclonic epileptic encephalopathy (possibly due to metabolic disorders).