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.

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.

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.

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.

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.

The incidence of metachromatic leukodystrophy is estimated to occur in 1 in 40,000 to 1 in 160,000 individuals worldwide. There is a much higher incidence in certain genetically isolated populations, such as 1 in 75 in Habbanites (a small group of Jews who immigrated to Israel from southern Arabia), 1 in 2,500 in the western portion of the Navajo Nation, and 1 in 8,000 among Arab groups in Israel.

As an autosomal recessive disease, 1 in 40,000 equates to a 1 in 100 carrier frequency in the general population.

There are an estimated 3,600 MLD births per year, with 1,900 alive in the US, 3,100 in Europe, and 49,000 alive worldwide with MLD.

MLD is considered a rare disease in the US and other countries.

X-linked intellectual disability (previously known as X-linked mental retardation) refers to forms of intellectual disability which are specifically associated with X-linked recessive inheritance.

As with most X-linked disorders, males are more heavily affected than females. Females with one affected X chromosome and one normal X chromosome tend to have milder symptoms.

Unlike many other types of intellectual disability, the genetics of these conditions are relatively well understood. It has been estimated there are ~200 genes involved in this syndrome; of these ~100 have been identified.

X-linked intellectual disability accounts for ~16% of all cases of intellectual disability in males.

Currently there is no curative treatment for KSS. Because it is a rare condition, there are only case reports of treatments with very little data to support their effectiveness. Several promising discoveries have been reported which may support the discovery of new treatments with further research. Satellite cells are responsible for muscle fiber regeneration. It has been noted that mutant mtDNA is rare or undetectable in satellite cells cultured from patients with KSS. Shoubridge et al. (1997) asked the question whether wildtype mtDNA could be restored to muscle tissue by encouraging muscle regeneration. In the forementioned study, regenerating muscle fibers were sampled at the original biopsy site, and it was found that they were essentially homoplasmic for wildtype mtDNA. Perhaps with future techniques of promoting muscle cell regeneration and satellite cell proliferation, functional status in KSS patients could be greatly improved.

One study described a patient with KSS who had reduced serum levels of coenzyme Q10. Administration of 60–120 mg of Coenzyme Q10 for 3 months resulted in normalization of lactate and pyruvate levels, improvement of previously diagnosed first degree AV block, and improvement of ocular movements.

A screening ECG is recommended in all patients presenting with CPEO. In KSS, implantation of pacemaker is advised following the development of significant conduction disease, even in asymptomatic patients.

Screening for endocrinologic disorders should be performed, including measuring serum glucose levels, thyroid function tests, calcium and magnesium levels, and serum electrolyte levels. Hyperaldosteronism is seen in 3% of KSS patients.

MLD has an autosomal recessive inheritance pattern. The inheritance probabilities "per birth" are as follows:

- If both parents are carriers:

- 25% (1 in 4) children will have the disease

- 50% (2 in 4) children will be carriers, but unaffected

- 25% (1 in 4) children will be free of MLD – unaffected child that is not a carrier

- If one parent is affected and one is free of MLD:

- 0% (0) children will have the disorder – only one parent is affected, other parent always gives normal gene

- 100% (4 in 4) children will be carriers (but unaffected)

- If one parent is a carrier and the other is free of MLD:

- 50% (2 in 4) children will be carriers (but unaffected)

- 50% (2 in 4) children will be free of MLD – unaffected child that is not a carrier

In addition to these frequencies there is a 'pseudo'-deficiency that affects 7–15% of the population. People with the pseudo deficiency do not have any MLD problems unless they also have affected status. With the current diagnostic tests, Pseudo-deficiency reports as low enzyme levels but sulfatide is processed normally so MLD symptoms do not exist. This phenomenon wreaks havoc with traditional approaches to Newborn Screening so new screening methods are being developed.

"For further information, see recessive gene and dominance relationship. Also, consult the MLD genetics page at MLD Foundation."

This disorder, epidemiologically speaking, is thought to affect approximately 1 in 50,000 newborns according to Jethva, et al. While in the U.S. state of California there seems to be a ratio of 1 in 35,000.

Several X-linked syndromes include intellectual disability as part of the presentation. These include:

- Coffin–Lowry syndrome

- MASA syndrome

- MECP2 duplication syndrome

- X-linked alpha thalassemia mental retardation syndrome

- mental retardation and microcephaly with pontine and cerebellar hypoplasia

Examples of mitochondrial diseases include:

- Mitochondrial myopathy

- Diabetes mellitus and deafness (DAD)

- this combination at an early age can be due to mitochondrial disease

- Diabetes mellitus and deafness can be found together for other reasons

- Leber's hereditary optic neuropathy (LHON)

- visual loss beginning in young adulthood

- eye disorder characterized by progressive loss of central vision due to degeneration of the optic nerves and retina

- affects 1 in 50,000 people in Finland

- Leigh syndrome, subacute sclerosing encephalopathy

- after normal development the disease usually begins late in the first year of life, although onset may occur in adulthood

- a rapid decline in function occurs and is marked by seizures, altered states of consciousness, dementia, ventilatory failure

- Neuropathy, ataxia, retinitis pigmentosa, and ptosis (NARP)

- progressive symptoms as described in the acronym

- dementia

- Myoneurogenic gastrointestinal encephalopathy (MNGIE)

- gastrointestinal pseudo-obstruction

- neuropathy

- Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

- progressive myoclonic epilepsy

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

- short stature

- hearing loss

- lactic acidosis

- exercise intolerance

- Mitochondrial myopathy, encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS)

- mtDNA depletion

- mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

"Conditions such as Friedreich's ataxia can affect the mitochondria but are not associated with mitochondrial proteins."

Succinic semialdehyde dehydrogenase deficiency (SSADHD), also known as 4-hydroxybutyric aciduria or gamma-hydroxybutyric aciduria, is a rare autosomal recessive disorder of the degradation pathway of the inhibitory neurotransmitter γ-aminobutyric acid, or GABA. The disorder has been identified in approximately 350 families, with a significant proportion being consanguineous families. The first case was identified in 1981 and published in a Dutch clinical chemistry journal that highlighted a person with a number of neurological conditions such as delayed intellectual, motor, speech, and language as the most common manifestations. Later cases reported in the early 1990s began to show that hypotonia, hyporeflexia, seizures, and a nonprogressive ataxia were frequent clinical features as well.

SSADH deficiency is caused by an enzyme deficiency in GABA degradation. Under normal conditions, SSADH works with the enzyme GABA transaminase to convert GABA to succinic acid. Succinic acid can then be utilized for energy production via the Krebs cycle. However, because of the deficiency, the final intermediate of the GABA degradation pathway, succinic semialdehyde, accumulates and cannot be oxidized to succinic acid and is therefore reduced to gamma-hydroxybutyric acid (GHB) by gamma-hydroxybutyric dehydrogenase. This causes elevations in GHB and is believed to be the trademark of this disorder and cause for the neurological manifestations seen.

Several scientists have developed murine models of SSADH (Aldh5a1-/-) by typical gene methodology to create a uniform absence of the SSADH enzyme activity as well as accumulations of GHB and GABA in tissues and physiological fluids. The mice are born at the expected Mendelian frequencies for an autosomal recessive disorder. Most of the models include distinctive neurological phenotypes and exhibit hypotonia, truncal ataxia, generalized tonic-clonic seizures associated with 100% mortality. The mice uniformly die at 3-4 postnatal weeks. While this model is considered to be more severe than the phenotypes seen in humans, currently, it is the most highly regarded, valid, metabolic model to study potential therapeutic interventions for the disorder.

Studies have shown that alterations of both the GABA receptor and the GABA receptor early in the life of the Aldh5a1-/- mice can increase levels of GHB and enhance GABA release. Besides these effects, it has also been shown that "...a developmental down-regulation of GABA receptor mediated neurotransmission in Aldh5a1-/- mice likely contributes to the progression of generalized convulsive seizures seen in mutant animals." Other studies have confirmed the relationship between elevated levels of GHB and MAP kinase in mutant animals contribute to profound myelin abnormalities.

That MMA can have disastrous effects on the nervous system has been long reported; however, the mechanism by which this occurs has never been determined. Published on June 15th 2015, research performed on the effects of methylmalonic acid on neurons isolated from fetal rats in an in vitro setting using a control group of neurons treated with an alternate acid of similar pH. These tests have suggested that methylmalonic acid causes decreases in cellular size and increase in the rate of cellular apoptosis in a concentration dependent manner with more extreme effects being seen at higher concentrations. Furthermore, micro-array analysis of these treated neurons have also suggested that on a epigenetic-level methylmalonic acid alters the transcription rate of 564 genes, notably including those involved in the apoptosis, p53, and MAPK signaling pathways.

Multiple sulfatase deficiency (also known as "Austin disease", and "mucosulfatidosis") is a very rare autosomal recessive lysosomal storage disease caused by a deficiency in multiple sulfatase enzymes, or in formylglycine-generating enzyme, which activates sulfatases. It is similar to mucopolysaccharidosis.

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.

MSD has an autosomal recessive inheritance pattern.

The inheritance probabilities "per birth" are as follows:

- If both parents are carriers:

- 25% (1 in 4) children will have the disorder

- 50% (2 in 4) children will be carriers (but unaffected)

- 25% (1 in 4) children will be free of MSD - unaffected child that is not a carrier

- If one parent is affected and one is free of MSD:

- 0% (0) children will have the disorder - only one parent is affected, other parent always gives normal gene

- 100% (4 in 4) children will be carriers (but unaffected)

- If one parent is a carrier and the other is free of MSD:

- 50% (2 in 4) children will be carriers (but unaffected)

- 50% (2 in 4) children will be free of MSD - unaffected child that is not a carrier

Neuroferritinopathy or adult-onset basal ganglia disease is a genetic neurodegenerative disorder characterized by the accumulation of iron in the basal ganglia, cerebellum, and motor cortex of the human brain. Symptoms, which are extrapyramidal in nature, progress slowly and generally do not become apparent until adulthood. These symptoms include chorea, dystonia, and cognitive deficits which worsen with age.

This disorder is autosomal dominant and is caused by mutations in the gene encoding the light chain subunit of the ferritin protein. Wild type ferritin functions as a buffer for iron, sequestering it and controlling its release. Thus, mutations in the light chain of ferritin result in the accumulation of iron in the brain which can be imaged using MRI. Currently, neuroferritinopathy is the only neurodegenerative disease with an iron accumulation in the brain classified as an autosomal dominant syndrome.

Treatment of neuroferritinopathy is focused on managing symptoms associated with chorea and dystonia using standard medications for each. The disorder is progressive and symptoms become worse with age. Fewer than 100 cases of neuroferritinopathy have been reported since its identification in 2001. Its incidence has been largely localized to Northeast England suggesting a founder effect. Due to its genetic nature, current research is focused on therapeutic management of the symptoms caused by the disorder.

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.

All brain iron disorders were previously labeled Hallervorden-Spatz syndrome, after the scientists who first discovered individuals with abnormal iron levels in 1922. Brain iron disorders are now divided into three categories: genetic neurodegeneration with brain iron accumulation, genetic systemic iron accumulation with neurologic features, and acquired diseases associated with iron excess or iron deficiency. Neuroferritinopathy is classified under the first category, genetic neurodegeneration with brain iron accumulation. Neuroferritinopathy is classified as a late-onset basal ganglia disease and is a dominantly inherited neurodegenerative disease. Four different alleles are responsible for neuroferritinopathy. Three arise from nucleotide insertions in the ferritin light chain (FTL) polypeptide gene while the fourth arises from a missense mutation in the FTL gene.

A 2001 study followed up on 50 patients. Of these 38% died in childhood while the rest suffered from problems with morbidity.

Babies with this disorder are usually healthy at birth. The signs and symptoms may not appear until later in infancy or childhood and can include poor feeding and growth (failure to thrive), a weakened and enlarged heart (dilated cardiomyopathy), seizures, and low numbers of red blood cells (anemia). Another feature of this disorder may be very low blood levels of carnitine (a natural substance that helps convert certain foods into energy).

Isobutyryl-CoA dehydrogenase deficiency may be worsened by long periods without food (fasting) or infections that increase the body's demand for energy. Some individuals with gene mutations that can cause isobutyryl-CoA dehydrogenase deficiency may never experience any signs and symptoms of the disorder.

Recent case studies in several patients presenting nonresponsive mut0 MMA with a specific mutation designated p.P86L have suggest the possibility of further subdivision in mut type MMA might exist. Though currently unclear if this is due to the specific mutation or early detection and treatment, despite complete nonresponse to cobalamin supplements, these individuals appeared to develop a largely benign and near completely asymptomatic version of MMA. Despite consistently showing elevated methylmalonic acid in the blood and urine, these individuals appeared for the large part developmentally normal.

Short-chain acyl-coenzyme A dehydrogenase deficiency (SCADD), also called ACADS deficiency and SCAD deficiency, is an autosomal recessive fatty acid oxidation disorder which affects enzymes required to break down a certain group of fats called short chain fatty acids.