Clinical Diagnosis

Mitochondrial DNA-associated (mtDNA-associated) Leigh syndrome and NARP are part of a continuum of progressive neurodegenerative disorders observed in members of the same family caused by abnormalities of mitochondrial energy generation.

Leigh syndrome. Stringent diagnostic criteria for Leigh syndrome were defined by Rahman et al [1996]*:

• Progressive neurologic disease with motor and intellectual developmental delay
• Signs and symptoms of brain stem and/or basal ganglia disease
• Raised lactate concentration in blood and/or cerebrospinal fluid (CSF)
• One or more of the following:
  • Characteristic features of Leigh syndrome on neuroradioimaging (see Testing)
  • Typical neuropathologic changes: multiple focal symmetric necrotic lesions in the basal ganglia, thalamus, brain stem, dentate nuclei, and optic nerves. Histologically, lesions have a spongiform appearance and are characterized by demyelination, gliosis, and vascular proliferation. Neuronal loss can occur, but typically the neurons are relatively spared.
  • Typical neuropathology in a similarly affected sibling

*Note: Prior to the development of modern imaging techniques, definitive diagnosis of Leigh syndrome was based on characteristic neuropathologic features and thus could only be made post mortem.

Leigh-like syndrome. The term "Leigh-like syndrome" is often used for individuals with clinical and other features that are strongly suggestive of Leigh syndrome but who do not fulfill the stringent diagnostic criteria because of atypical neuropathology (variation in the distribution or character of lesions or with the additional presence of unusual features such as extensive cortical destruction), atypical or normal neuroimaging, normal blood and CSF lactate levels, or incomplete evaluation.

NARP. Strict diagnostic criteria for NARP have not yet been established. Diagnosis of NARP is based on the following clinical features:

• Neurogenic muscle weakness. Electromyography (EMG) and nerve conduction studies may demonstrate peripheral neuropathy (which may be a sensory or sensorimotor axonal polyneuropathy).
• Ataxia. Cerebral and cerebellar atrophy may be noted on MRI.
• Retinitis pigmentosa. The ocular manifestations of NARP are extremely variable and range from a mild salt and pepper retinopathy to bull's eye maculopathy and classic retinitis pigmentosa with bone spicule formation [Ortiz et al 1993]. Ophthalmologic examination may reveal pigmentary retinopathy or optic atrophy. Electroretinogram (ERG) may reveal abnormalities (including small-amplitude waveform) or may be normal. ERG may demonstrate predominantly cone dysfunction in some pedigrees and mainly rod dysfunction in others [Chowers et al 1999].

In addition, neuropathy, seizures, and learning difficulties are usually present.

Testing

Blood and CSF lactate levels

• Lactate is usually elevated in blood, but this is not an invariant feature and tends to be more marked in post-prandial samples.
• Testing multiple blood samples to obtain a daily profile is more sensitive than testing a single random sample.
• Lactate elevation is more consistent in CSF samples than blood samples.
• Plasma amino acids may show elevated alanine concentration (formed from the transamination of pyruvate), reflecting persistent elevation of plasma lactate concentration.
• Low plasma citrulline concentration has been reported in individuals with the m.8993T>G mutation [Rabier et al 1998].
• Urine organic acid analysis often detects lactic aciduria and is useful in excluding other organic acidurias (see Organic Acidemias Overview).
• Proton magnetic resonance spectroscopy (MRS) can also be useful in detecting regional elevations in brain lactate levels.

Brain imaging

• Characteristic features of Leigh syndrome are bilateral symmetric hypodensities in the basal ganglia on computed tomography (CT) or bilateral symmetrical hyperintense signal abnormality in the brain stem and/or basal ganglia on T₂-weighted magnetic resonance imaging (MRI) [Arii & Tanabe 2000, Rossi et al 2003].
• Specific tracts have not been reported to be affected in mtDNA-associated Leigh syndrome; however, specific brain lesions (affecting the mamillothalamic tracts, substantia nigra, medial lemniscus, medial longitudinal fasciculus, spinothalamic tracts, and cerebellum) appear to be characteristic of Leigh syndrome caused by mutations in the nuclear gene NDUFAF2, encoding an assembly factor for respiratory chain complex I [Ogilvie et al 2005, Barghuti et al 2008, Hoefs et al 2009, Herzer et al 2010].
• In NARP, cerebral and cerebellar atrophy may be noted on MRI.

Muscle biopsy. Usually, histologic examination shows only minimal if any changes, such as accumulation of intracytoplasmic neutral lipid droplets. Ragged red fibers (a hallmark of adult-onset mitochondrial diseases) are rarely, if ever, seen. Cytochrome c oxidase-negative fibers are occasionally found in individuals with Leigh syndrome caused by certain mtDNA and nuclear gene mutations.

Note: (1) Although muscle biopsy is only occasionally abnormal, when it is abnormal it can be as much of a contributor to diagnostic certainty as respiratory chain enzymes or molecular testing. (2) If an affected individual is having a muscle biopsy for enzyme testing, histologic examination should also be performed.

Respiratory chain enzyme studies. Biochemical analysis of tissue biopsies or cultured cells often detects deficient activity of one or more of the respiratory chain enzyme complexes. Isolated defects of complex I or complex IV are the most common enzyme abnormalities observed and can help guide subsequent molecular genetic testing of mtDNA or nuclear genes. Biochemical results can also be normal, usually in individuals with mtDNA mutations affecting complex V subunits such as the mutations at mitochondrial nucleotides 8993 and 9176 (Table 5).

• Skeletal muscle is usually the tissue of choice for enzyme studies.
• Skin fibroblasts can be used, but only about 50% of respiratory chain enzyme defects identified in skeletal muscle are also identified in skin fibroblasts.
• Approximately 10%-20% of individuals with normal skeletal muscle respiratory chain enzymes may have an enzyme defect detected in liver or cardiac muscle, particularly if those tissues are involved clinically [Thorburn et al 2004].

Testing Strategy

To confirm/establish the diagnosis in a proband

• Clinical testing, including brain imaging and measurement of lactic acid concentration in body fluids
• Molecular genetic testing of blood (or other samples obtained in relatively non-invasive manner) for targeted mutation analysis of common mtDNA mutations
• If targeted mutation analysis in blood does not identify a disease-causing mtDNA mutation, muscle biopsy for histology, biochemistry (respiratory chain enzyme assays), and complete mitochondrial DNA sequence analysis
• Enzyme studies of other tissues including skin fibroblasts, white blood cells, liver, or cardiac muscle may be performed in some centers.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family; however, the use of molecular genetic test results to predict long-term outcome is difficult.

Genetically Related (Allelic) Disorders

Mitochondrial DNA mutations can also be associated with a variety of disorders including MELAS, MERRF, Leber hereditary optic neuropathy (LHON), infantile bilateral striatal necrosis, progressive external ophthalmoplegia, diabetes mellitus, cardiomyopathy, deafness, or sudden (unexplained) death in infancy, childhood, or adulthood (see Mitochondrial Disorders Overview).

Natural History

Mitochondrial DNA-associated Leigh syndrome (subacute necrotizing encephalomyelopathy). Onset of symptoms can be from the neonatal period through adulthood but is typically between age three to 12 months, often following a viral infection. Later onset (i.e., after age one year, including presentation in adulthood) and slower progression occur in up to 25% of individuals [Goldenberg et al 2003, Huntsman et al 2005].

Leigh syndrome is a progressive neurodegenerative disorder. Initial features may be nonspecific, such as failure to thrive and persistent vomiting. Decompensation (often with raised blood and/or CSF lactate concentrations) during an intercurrent illness is typically associated with psychomotor retardation or regression. A period of recovery may follow the initial decompensation, but the individual rarely returns to the developmental status achieved prior to the presenting illness.

Neurologic features include hypotonia, spasticity, dystonia, muscle weakness, hypo- or hyperreflexia, seizures (myoclonic or generalized tonic-clonic), infantile spasms, movement disorders (including chorea), cerebellar ataxia, and peripheral neuropathy. Brain stem lesions may cause respiratory difficulty (apnea, hyperventilation, or irregular respiration), swallowing difficulty, persistent vomiting, and abnormalities of thermoregulation (hypo- and hyperthermia). Ophthalmologic findings include optic atrophy, retinitis pigmentosa, and eye movement disorders [Morris et al 1996, Rahman et al 1996, Tsuji et al 2003].

Extraneurologic manifestations can be cardiac (hypertrophic cardiomyopathy [Agapitos et al 1997]), hepatic (hepatomegaly or liver failure [Leshinsky-Silver et al 2003a]), or renal (renal tubulopathy or diffuse glomerulocystic kidney damage [Yamakawa et al 2001, Tay et al 2005]).

Table 2 lists the frequency of various clinical features in individuals with Leigh syndrome and Leigh-like syndrome, with and without mtDNA mutations. The data have been updated from those reported by Rahman et al [1996] by allowing for six of the original individuals in whom mtDNA mutations have subsequently been identified. Some features appear to be more common in individuals with mtDNA mutations, for example, bulbar problems and (although not specifically studied by Rahman et al [1996]) pigmentary retinopathy in up to 40% of individuals with mtDNA 8993 mutations [Santorelli et al 1993]. Not surprisingly, consanguinity is more common in individuals without mtDNA mutations; most of whom are likely to have an autosomal recessive disorder (see Differential Diagnosis). However, for most individuals with Leigh syndrome, the profile of clinical features in a particular individual is not strongly indicative of the likely genetic origin (mtDNA vs. nuclear gene mutation) of the disorder.

Most affected individuals have episodic deterioration interspersed with "plateaus" during which development may be quite stable or even show some progress. The duration of these plateaus is variable and on occasion may be ten years or more. Death typically occurs by age two to three years, most often from respiratory or cardiac failure. In undiagnosed cases, death may appear to be sudden and unexpected.

NARP. Onset of symptoms, particularly ataxia and learning difficulties, is often in early childhood.

First described by Holt et al [1990], NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) is characterized by proximal neurogenic muscle weakness with sensory neuropathy, ataxia, pigmentary retinopathy, seizures, learning difficulties, and dementia. Other clinical features include short stature, sensorineural hearing loss, progressive external ophthalmoplegia, cardiac conduction defects (heart block) and a mild anxiety disorder [Santorelli et al 1997a, Sembrano et al 1997]. Visual symptoms may be the only clinical feature. One individual had obstructive sleep apnea requiring tracheostomy and nocturnal mechanical ventilation [Sembrano et al 1997].

Individuals with NARP can be relatively stable for many years, but may suffer episodic deterioration, often in association with viral illnesses.

Intermediate phenotypes in the continuum. Maternal relatives of individuals with Leigh syndrome or NARP can have any one or a combination of the individual symptoms associated with Leigh syndrome, NARP, or other mitochondrial disorders. These include mild learning difficulties, muscle weakness, night blindness, deafness, diabetes mellitus, migraine, or sudden unexpected death.

Genotype-Phenotype Correlations

For most mtDNA mutations, it is difficult to distinguish a simple correlation between genotype and phenotype because clinical expression of a mtDNA mutation is influenced not only by the pathogenicity of the mutation itself but also by the relative amount of mutant and wildtype mtDNA (the heteroplasmic mutant load), the variation in mutant load among different tissues, and the energy requirements of brain and other tissues, which may vary with age.

The m.8993T>G and m.8993T>C mutations probably show the strongest genotype-phenotype correlation of any mtDNA mutations. A notable feature is that they show very little tissue-dependent or age-dependent variation in mutant load [White et al 1999c] and have a strong correlation between mutant load and disease severity. These features allowed White et al [1999a] to generate logistic regression models that gave curves predicting the probability of a severe outcome in an individual based on their measured mutant load of m.8993T>G and m.8993T>C (Figure 1). However, it should be noted that in such retrospective studies it is not possible to completely avoid ascertainment bias, and the data should be regarded as broadly indicative rather than precise.

Figure

Figure 1. Estimated probability of a severe outcome (with 95% confidence intervals) for an individual with the mtDNA m.8993T>G or m.8993T>C mutation, based on the mutant load of the individual. A severe outcome is defined as severe symptoms (more...)

• m.8993T>G. Individuals with m.8993T>G mutant loads below 60% are usually asymptomatic, or have only mild pigmentary retinopathy or migraine headaches; however, asymptomatic adults with mutant loads of up to 75% have been reported [Tatuch et al 1992, Ciafaloni et al 1993]. As a generalization, individuals with moderate levels (~70%-90%) of the m.8993T>G mutation present with the NARP phenotype, while those with mutant loads above 90% have maternally inherited Leigh syndrome.
  
  Note: Overlap in mutant loads is observed between some asymptomatic individuals and others with NARP, and between some individuals with NARP and others with Leigh syndrome.
• m.8993T>C. m.8993T>C is a less severe mutation than m.8993T>G, and virtually all symptomatic individuals have m.8993T>C mutant loads of more than 90%.

Genotype-phenotype correlations are much weaker for other mtDNA mutations detected in multiple unrelated cases of Leigh syndrome (e.g., m.3243A>G in MT-TL1, m.8344A>G in MT-TK, m.9176T>C in MT-ATP6, m.14459G>A and m.14487T>C in MT-ND6, m.10158T>C and m.10191T>C in MT-ND3, and m.13513G>A in MT-ND5). The presence of any of these mutations in individuals with symptoms of Leigh syndrome identifies the genetic cause of the disorder. However, unlike the m.8993T>G and m.8993T>C mutations, it is usually not possible to interpret the heteroplasmic mutant load to predict outcome (e.g., in asymptomatic family members or in prenatal diagnosis) unless the value is near 0% or near 100%. This situation should improve in the future, at least for some mtDNA mutations, as more data become available.

Penetrance

See Genotype-Phenotype Correlations.

Nomenclature

In 1951, Leigh reported the neuropathology of a seven-month-old infant who died following a progressive neurologic illness of six weeks' duration, with somnolence, blindness, deafness, and generalized limb spasticity [Leigh 1951]. Leigh's findings were focal bilaterally symmetric subacute necrotic lesions in the thalamus, extending to the pons and the inferior olives and spinal cord. Histologic characteristics of these lesions were intense capillary proliferation, gliosis, demyelination, and vacuolation with relative preservation of neurons.

Since Leigh's original description of "subacute necrotizing encephalomyelopathy," several hundred more individuals with Leigh syndrome have been reported in the literature. Many of them had defects of mitochondrial energy production, including deficiencies of mitochondrial respiratory chain complex I or IV and pyruvate dehydrogenase deficiency.

Individuals with Leigh syndrome caused by a mtDNA mutation are often referred to as having “maternally inherited Leigh syndrome” (MILS) [Ciafaloni et al 1993].

Prevalence

The following prevalence data are for all Leigh syndrome; it is reasonable to assume that approximately 30% of all Leigh syndrome is mtDNA-associated Leigh syndrome.

In southeastern Australia, Leigh syndrome developed in 1:77,000 live births, and the combined birth prevalence of Leigh syndrome plus Leigh-like disease was 1:40,000 births [Rahman et al 1996]. In western Sweden, the prevalence of Leigh syndrome in preschool children was 1:34,000 live births [Darin et al 2001]. Thus, the typical birth prevalence of Leigh syndrome is likely to be 1:30,000 to 1:40,000 live births, and the birth prevalence of mtDNA-associated Leigh syndrome is likely to be 1:100,000 to 1:140,000 births.

No data exist on the prevalence of NARP; which is substantially less common than Leigh syndrome.

Evaluation Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with mtDNA-associated Leigh syndrome or NARP, the following evaluations are recommended:

• Developmental assessment
• Neurologic evaluation, MRI, MRS [Takahashi et al 1999], EEG (if seizures are suspected) ,and nerve conduction studies (if neuropathy is suspected)
• Metabolic evaluation, plasma and cerebrospinal fluid lactate and pyruvate concentrations, urine organic acids
• Ophthalmologic evaluation
• Cardiac evaluation

Treatment of Manifestations

No specific treatment for mtDNA-associated Leigh syndrome and NARP exists. Supportive management includes treatment of the following:

• Acidosis. Sodium bicarbonate or sodium citrate for acute exacerbations of acidosis
• Seizures. Appropriate antiepileptic drugs tailored to the type of seizure under the supervision of a neurologist. Sodium valproate and barbiturates should be avoided because of their inhibitory effects on the mitochondrial respiratory chain [Melegh & Trombitas 1997, Anderson et al 2002].
• Dystonia
  • Benzhexol, baclofen, tetrabenezine, and gabapentin may be useful, alone or in various combinations; an initial low dose should be started and gradually increased until symptom control is achieved or intolerable side effects occur.
  • Botulinum toxin injection has also been used in individuals with Leigh syndrome and severe intractable dystonia.
• Cardiomyopathy. Anticongestive therapy may be required and should be supervised by a cardiologist.

Regular assessment of daily caloric intake and adequacy of dietary structure including micronutrients and feeding management is indicated.

Psychological support for the affected individual and family is essential.

Prevention of Primary Manifestations

No specific preventative treatment for primary manifestations of mtDNA-associated Leigh syndrome and NARP exists.

Surveillance

Affected individuals should be followed at regular intervals (typically every 6-12 months) to monitor progression and the appearance of new symptoms. Neurologic, ophthalmologic, and cardiologic evaluations are recommended.

Agents/Circumstances to Avoid

Sodium valproate and barbiturates should be avoided because of their inhibitory effect on the mitochondrial respiratory chain [Melegh & Trombitas 1997, Anderson et al 2002].

Anesthesia can potentially aggravate respiratory symptoms and precipitate respiratory failure, so careful consideration should be given to its use and to monitoring of the individual prior to, during, and after anesthetic procedures [Shear & Tobias 2004].

Dichloroacetate (DCA) reduces blood lactate by activating the pyruvate dehydrogenase complex.

• Anecdotal reports have suggested that DCA may cause some short-term clinical improvement in mtDNA-associated Leigh syndrome [Takanashi et al 1997, Fujii et al 2002].
• A double-blind, placebo-controlled trial of DCA in a different mitochondrial disease, MELAS, found no benefit and in fact documented a toxic effect of DCA on peripheral nerves [Kaufmann et al 2006].
• A more recent report described the results of long-term administration of DCA to 36 children with congenital lactic acidosis (randomized control trial followed by an open label extension) [Stacpoole et al 2008]. This study concluded that oral DCA is well tolerated in young children with congenital lactic acidosis and that it was not possible to determine whether the peripheral neuropathy associated with long-term DCA administration is attributable to the drug or to the underlying disease process. It therefore appears prudent for individuals with mtDNA-associated Leigh syndrome or NARP to avoid DCA, in view of the underlying risk of peripheral neuropathy caused by the disease itself in these conditions.

Evaluation of Relatives at Risk

Molecular genetic testing of at-risk maternal relatives may reveal individuals who have high mutation loads and are thus at risk of developing symptoms. However, no proven disease-modifying intervention exists at present.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Antioxidants, including coenzyme Q and analogs such as idebenone, can enhance the function and viability of cultured cells from individuals with the m.8993T>G mutation [Geromel et al 2001, Mattiazzi et al 2004], but have no proven efficacy in treatment of Leigh syndrome. Newer mitochondrial-targeted antioxidants (such as mitoQ) that show much greater protection against oxidative stress in cultured cell and animal models [Jauslin et al 2003, Adlam et al 2005] are being investigated as potential therapies for a range of oxidative stress-related disorders.

Gene therapy provides a potential approach to decreasing the proportion of mutant mtDNA in the cells of an individual. Studies in cultured cells have shown that a mitochondrially targeted restriction endonuclease can recognize and degrade mtDNA containing the m.8993T>G mutation found in NARP and mtDNA-associated Leigh syndrome, while leaving wild-type mtDNA intact [Tanaka et al 2002]. A more recent study used an adenoviral vector to deliver the restriction endonuclease to the mitochondrion and showed that there was no evidence of nuclear DNA damage in treated cells [Alexeyev et al 2008]. However, such approaches are clearly still a long way from clinical applicability.

Promising results have been obtained using a similar proof-of-principle approach in a mouse model of mtDNA heteroplasmy to shift the mtDNA heteroplasmy in muscle and brain transduced with recombinant viruses [Bayona-Bafaluy et al 2005]. This strategy could potentially prevent disease onset or reverse clinical symptoms in individuals harboring certain heteroplasmic mutations in mtDNA.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

A range of vitamins and other compounds are often used in the hope of improving mitochondrial function. Most commonly these include riboflavin, thiamine, and coenzyme Q₁₀ (each at 50-100 mg/3x/day) [Panetta et al 2004].

A high-fat diet, providing 50%-60% of daily caloric intake from fat, may be prescribed to individuals with Leigh syndrome resulting from complex I deficiency, although currently there is no evidence supporting this therapeutic rationale in this particular disorder.

Biotin, creatine, succinate, and idebenone have also been used. Some of these agents may show partial efficacy in some individuals with milder mitochondrial disorders, but sustained therapeutic response in NARP or Leigh syndrome has not been described.

Several recent studies have investigated whether upregulation of mitochondrial biogenesis may provide an effective therapeutic approach for mitochondrial respiratory chain diseases. This approach involves using agonists such as bezafibrate or resveratrol to stimulate the peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator alpha (PGC-1alpha) pathway.

• Bezafibrate treatment of a mouse model of muscle-specific complex IV deficiency resulted in increased complex IV activity and improved survival [Wenz et al 2008].
• A second study showed promising results in fibroblasts from patients with a range of respiratory chain enzyme defects; nine of 14 patient cell lines tested exhibited a significant increase in the activity of the deficient respiratory chain enzyme after bezafibrate treatment [Bastin et al 2008]. These data are likely to prompt clinical trials but no data have yet been reported to show that such approaches will be effective in persons with mitochondrial disorders.

A recent study explored the use of alpha-ketoglutarate and aspartate in transmitochondrial cybrids heteroplasmic for the m.8993T>G mutation [Sgarbi et al 2009]. The rationale was that these substrates would increase flux through the citric acid cycle, thereby increasing ATP production independently of oxidative phosphorylation (so-called ‘substrate level phosphorylation’). Initial results were promising, but further studies are needed before clinical applications can be considered.

Mode of Inheritance

Mitochondrial DNA-associated Leigh syndrome and NARP are transmitted by maternal inheritance.

Risk to Family Members

Parents of a proband

• The father of a proband is not at risk of having the disease-causing mtDNA mutation.
• The mother of a proband usually has the mtDNA mutation and may have symptoms.
  • In most cases, the mother has a much lower mutant load of the mutation than the proband and usually remains asymptomatic or develops only mild symptoms.
  • Occasionally the mother has a substantial mutant load and develops severe symptoms in adulthood, as described in de Vries et al [1993].
  • With the exception of the m.8993T>G and m.8993T>C mutations, low mutant loads of the mtDNA mutation in maternal blood do not exclude higher mutant loads in tissues such as brain or muscle.
• Alternatively, the proband may have a de novo mitochondrial mutation.

Sibs of a proband

• The risk to the sibs depends on the genetic status of the mother.
• If the mother of the proband has the disease-causing mtDNA mutation, all sibs are at risk of inheriting it.
• For the m.8993T>G and m.8993T>C mutations, if the mother of the proband has undetectable mutant mtDNA in blood, sibs of the proband are at very low risk (substantially less than 10%) of having inherited sufficient mutant mtDNA to cause symptoms. White et al [1999a] generated logistic regression models that gave predictive curves for m.8993T>G and m.8993T>C predicting the recurrence risks for sibs of a proband based on the mother's blood mutant load (Figure 2). A strong positive relationship exists between the mother's mutant load and the predicted recurrence risk. However, the 95% confidence interval of the risk estimate was wide and these data are of limited use for genetic counseling.
• For mutations other than m.8993T>G and m.8993T>C, the mutant load may be undetectable in blood from the mother but may be detectable in other tissues including oocytes. Thus, sibs of a proband have a risk of developing symptoms, depending on the tissue distribution and mutant load of the disease-causing mtDNA mutation.

Figure

Figure 2. Predicted recurrence risks (with 95% confidence intervals) for NARP or Leigh syndrome caused by the mtDNA m.8993T>G or m.8993T>C mutations based on the mother's measured mutant load in blood [White et al 1999a].

Offspring of a proband

• Offspring of males with a mtDNA mutation are not at risk. Paternal transmission of mtDNA, reported by Schwartz & Vissing [2002] appears to be an extremely rare event [Filosto et al 2003, Taylor et al 2003].
• All offspring of females with a mtDNA mutation are at risk of inheriting the mutation. The risk to offspring of a female proband of developing symptoms depends on the tissue distribution and mutant load of the disease-causing mtDNA mutation. Retrospective studies for some of the most common mtDNA mutations can be used to indicate an approximate (empirical) recurrence risk for women who have or are at risk of having these mutations. See White et al [1999a] for m.8993T>G and m.8993T>C; see Chinnery et al [1998] for m.3243A>G and m.8344A>G.

Other family members. The risk to other family members depends on the genetic status of the proband's mother. If the mother has a mtDNA mutation, her sibs and mother are also at risk.

Related Genetic Counseling Issues

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Genetic counseling and prenatal diagnosis of disorders caused by mitochondrial mutations present considerable challenges. A Consensus Workshop on this topic was held in 1999, sponsored by the European Neuromuscular Disease Centre and involving representatives from 14 major international centers specializing in mtDNA diseases. The major findings of the workshop [Poulton & Turnbull 2000] relating to Leigh syndrome and NARP are summarized here (see also ; registration or institutional access required). The important issues for both counseling and prenatal diagnosis depend on the following:

• Does a close relationship exist between the mtDNA mutant load and disease severity?
• Is mutant mtDNA uniformly distributed in all tissues?
• Does mutant load change with time?

Four conclusions were reached:

• Genetic counseling and prenatal diagnosis for women known to have or suspected of having a mtDNA mutation require the involvement of professionals with up-to-date experience in this area to ensure that prospective parents are counseled regarding all potential outcomes of prenatal diagnosis or assisted reproduction technologies (ART) and that possible limitations of interpretation are explained.
• Practice is limited by lack of available information. Collection and analysis of more information on the outcome of pregnancies is warranted.
• No general rules allow for precise prediction of the inheritance risks for heteroplasmic mtDNA mutations. Each mutation must therefore be assessed separately.
• Despite the difficulties currently associated with counseling for mtDNA mutations, affected families are seeking advice and help. Furthermore, extensive investigation has shown that the transmission of a heteroplasmic mtDNA mutation can be predicted within some broad range of possibilities. Thus, a consensus was reached on recommendations for prenatal testing of some mtDNA mutations. See Prenatal Testing.

Prenatal Testing

If the disease-causing mutation in an affected family member has been identified, prenatal diagnosis for pregnancies at increased risk is possible by analysis of mtDNA extracted from non-cultured fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

• Available evidence suggests that the mutant load in all extra-embryonic and embryonic tissues is similar and does not change substantially during pregnancy [Thorburn & Dahl 2001].
• Analysis should be done on the biopsy, not on cultured cells.
• The major limitation of this approach is potential difficulty in interpreting the results to predict outcome.
  • Intermediate mutant loads would represent a "gray zone" in which interpretation is difficult or impossible.
  • For the m.8993T>G and m.8993T>C mutations, Poulton & Turnbull [2000] recommend that it is reasonable to offer this form of prenatal testing to asymptomatic women with less than 50% levels of mutant mtDNA.
  • CVS and amniocentesis can also potentially be offered to women with low blood mutant loads of other mutations including m.3243A>G, m.8344A>G, and rare mtDNA point mutations, but the weaker correlation between mutant load and disease severity means that couples would require careful counseling before embarking on these procedures. Prenatal testing for the m.8993T>G [Harding et al 1992, Bartley et al 1996, Ferlin et al 1997, White et al 1999b], m.8993T>C [Leshinsky-Silver et al 2003b], and m.9176T>C [Jacobs et al 2005] mutations has been reported.

Published Guidelines/Consensus Statements

1. A Consensus Workshop on genetic counseling and prenatal diagnosis of mtDNA disorders was held in Naarden, The Netherlands, in 1999, sponsored by the European Neuromuscular Disease Centre and involving representatives from 14 major international centers specializing in mtDNA diseases. The conclusions of this workshop have been reported in Poulton & Turnbull [2000]. Full text available online (registration or institutional access required). 2000. Accessed 2-3-11.

Literature Cited

1. Adlam VJ, Harrison JC, Porteous CM, James AM, Smith RA, Murphy MP, Sammut IA. Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury. FASEB J. 2005;19:1088–95. [PubMed: 15985532]
2. Agapitos E, Pavlopoulos PM, Patsouris E, Davaris P. Subacute necrotizing encephalomyelopathy (Leigh's disease): a clinicopathologic study of ten cases. Gen Diagn Pathol. 1997;142:335–41. [PubMed: 9228257]
3. Alexeyev MF, Venediktova N, Pastukh V, Shokolenko I, Bonilla G, Wilson GL. Selective elimination of mutant mitochondrial genomes as therapeutic strategy for the treatment of NARP and MILS syndromes. Gene Ther. 2008;15:516–23. [PubMed: 18256697]
4. Anderson CM, Norquist BA, Vesce S, Nicholls DG, Soine WH, Duan S, Swanson RA. Barbiturates induce mitochondrial depolarization and potentiate excitotoxic neuronal death. J Neurosci. 2002;22:9203–9. [PubMed: 12417645]
5. Antonicka H, Leary SC, Guercin GH, Agar JN, Horvath R, Kennaway NG, Harding CO, Jaksch M, Shoubridge EA. Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early onset clinical phenotypes associated with isolated COX deficiency. Hum Mol Genet. 2003;12:2693–702. [PubMed: 12928484]
6. Antonicka H, Ostergaard E, Sasarman F, Weraarpachai W, Wibrand F, Pedersen AM, Rodenburg RJ, van der Knaap MS, Smeitink JA, Chrzanowska-Lightowlers ZM, Shoubridge EA. Mutations in C12orf65 in patients with encephalomyopathy and a mitochondrial translation defect. Am J Hum Genet. 2010;87:115–22. [PMC free article: PMC2896764] [PubMed: 20598281]
7. Arii J, Tanabe Y. Leigh syndrome: serial MR imaging and clinical follow-up. AJNR Am J Neuroradiol. 2000;21:1502–9. [PubMed: 11003287]
8. Barghuti F, Elian K, Gomori JM, Shaag A, Edvardson S, Saada A, Elpeleg O. The unique neuroradiology of complex I deficiency due to NDUFA12L defect. Mol Genet Metab. 2008;94:78–82. [PubMed: 18180188]
9. Bartley J, Senadheera D, Park P, Brar H, Abad D, Wong LJ. Prenatal diagnosis of T8993G mitochondrial DNA point mutation in amniocytes by heteroplasmy detection. Am J Hum Genet. 1996;59:A316.
10. Basel-Vanagaite L, Muncher L, Straussberg R, Pasmanik-Chor M, Yahav M, Rainshtein L, Walsh CA, Magal N, Taub E, Drasinover V, Shalev H, Attia R, Rechavi G, Simon AJ, Shohat M. Mutated nup62 causes autosomal recessive infantile bilateral striatal necrosis. Ann Neurol. 2006;60:214–22. [PubMed: 16786527]
11. Bastin J, Aubey F, Rötig A, Munnich A, Djouadi F. Activation of peroxisome proliferator-activated receptor pathway stimulates the mitochondrial respiratory chain and can correct deficiencies in patients' cells lacking its components. J Clin Endocrinol Metab. 2008;93(4):1433–41. [PubMed: 18211970]
12. Bayona-Bafaluy MP, Blits B, Battersby BJ, Shoubridge EA, Moraes CT. Rapid directional shift of mitochondrial DNA heteroplasmy in animal tissues by a mitochondrially targeted restriction endonuclease. Proc Natl Acad Sci U S A. 2005;102:14392–7. [PMC free article: PMC1242285] [PubMed: 16179392]
13. Benit P, Chretien D, Kadhom N, de Lonlay-Debeney P, Cormier-Daire V, Cabral A, Peudenier S, Rustin P, Munnich A, Rotig A. Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency. Am J Hum Genet. 2001;68:1344–52. [PMC free article: PMC1226121] [PubMed: 11349233]
14. Benit P, Slama A, Cartault F, Giurgea I, Chretien D, Lebon S, Marsac C, Munnich A, Rotig A, Rustin P. Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome. J Med Genet. 2004;41:14–7. [PMC free article: PMC1757256] [PubMed: 14729820]
15. Bourgeron T, Rustin P, Chretien D, Birch-Machin M, Bourgeois M, Viegas-Pequignot E, Munnich A, Rotig A. Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency. Nat Genet. 1995;11:144–9. [PubMed: 7550341]
16. Calvo SE, Tucker EJ, Compton AG, Kirby DM, Crawford G, Burtt NP, Rivas M, Guiducci C, Bruno DL, Goldberger OA, Redman MC, Wiltshire E, Wilson CJ, Altshuler D, Gabriel SB, Daly MJ, Thorburn DR, Mootha VK. High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. Nat Genet. 2010;42:851–8. [PMC free article: PMC2977978] [PubMed: 20818383]
17. Chinnery PF, Howell N, Lightowlers RN, Turnbull DM. MELAS and MERRF. The relationship between maternal mutation load and the frequency of clinically affected offspring. Brain. 1998;121(Pt 10):1889–94. [PubMed: 9798744]
18. Chowers I, Lerman-Sagie T, Elpeleg ON, Shaag A, Merin S. Cone and rod dysfunction in the NARP syndrome. Br J Ophthalmol. 1999;83:190–3. [PMC free article: PMC1722923] [PubMed: 10396197]
19. Ciafaloni E, Santorelli FM, Shanske S, Deonna T, Roulet E, Janzer C, Pescia G, DiMauro S. Maternally inherited Leigh syndrome. J Pediatr. 1993;122:419–22. [PubMed: 8095070]
20. Craven L, Tuppen HA, Greggains GD, Harbottle SJ, Murphy JL, Cree LM, Murdoch AP, Chinnery PF, Taylor RW, Lightowlers RN, Herbert M, Turnbull DM. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature. 2010;465:82–5. [PMC free article: PMC2875160] [PubMed: 20393463]
21. Curtis AR, Fey C, Morris CM, Bindoff LA, Ince PG, Chinnery PF, Coulthard A, Jackson MJ, Jackson AP, McHale DP, Hay D, Barker WA, Markham AF, Bates D, Curtis A, Burn J. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet. 2001;28:350–4. [PubMed: 11438811]
22. Darin N, Oldfors A, Moslemi AR, Holme E, Tulinius M. The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA anbormalities. Ann Neurol. 2001;49:377–83. [PubMed: 11261513]
23. De Meirleir L, Seneca S, Lissens W, Schoentjes E, Desprechins B. Bilateral striatal necrosis with a novel point mutation in the mitochondrial ATPase 6 gene. Pediatr Neurol. 1995;13:242–6. [PubMed: 8554662]
24. de Vries DD, van Engelen BG, Gabreels FJ, Ruitenbeek W, van Oost BA. A second missense mutation in the mitochondrial ATPase 6 gene in Leigh's syndrome. Ann Neurol. 1993;34:410–2. [PubMed: 8395787]
25. Dean NL, Battersby BJ, Ao A, Gosden RG, Tan SL, Shoubridge EA. Prospect of preimplantation genetic diagnosis for heritable mitochondrial DNA diseases. Mol Hum Reprod. 2003;9:631–8. [PubMed: 12970401]
26. Ferlin T, Landrieu P, Rambaud C, Fernandez H, Dumoulin R, Rustin P, Mousson B. Segregation of the G8993 mutant mitochondrial DNA through generations and embryonic tissues in a family at risk of Leigh syndrome. J Pediatr. 1997;131:447–9. [PubMed: 9329425]
27. Fernandez-Moreira D, Ugalde C, Smeets R, Rodenburg RJ, Lopez-Laso E, Ruiz-Falco ML, Briones P, Martin MA, Smeitink JA, Arenas J. X-linked NDUFA1 gene mutations associated with mitochondrial encephalomyopathy. Ann Neurol. 2007;61:73–83. [PubMed: 17262856]
28. Filosto M, Mancuso M, Vives-Bauza C, Vila MR, Shanske S, Hirano M, Andreu AL, DiMauro S. Lack of paternal inheritance of muscle mitochondrial DNA in sporadic mitochondrial myopathies. Ann Neurol. 2003;54:524–6. [PubMed: 14520667]
29. Fujii T, Ito M, Miyajima T, Okuno T. Dichloroacetate therapy in Leigh syndrome with a mitochondrial T8993C mutation. Pediatr Neurol. 2002;27:58–61. [PubMed: 12160976]
30. Garcia JJ, Ogilvie I, Robinson BH, Capaldi RA. Structure, functioning, and assembly of the ATP synthase in cells from patients with the T8993G mitochondrial DNA mutation. Comparison with the enzyme in Rho(0) cells completely lacking mtdna. J Biol Chem. 2000;275:11075–81. [PubMed: 10753912]
31. Gerards M, Sluiter W, van den Bosch BJ, de Wit LE, Calis CM, Frentzen M, Akbari H, Schoonderwoerd K, Scholte HR, Jongbloed RJ, Hendrickx AT, de Coo IF, Smeets HJ. Defective complex I assembly due to C20orf7 mutations as a new cause of Leigh syndrome. J Med Genet. 2010;47:507–12. [PMC free article: PMC2921275] [PubMed: 19542079]
32. Geromel V, Kadhom N, Cebalos-Picot I, Ouari O, Polidori A, Munnich A, Rotig A, Rustin P. Superoxide-induced massive apoptosis in cultured skin fibroblasts harboring the neurogenic ataxia retinitis pigmentosa (NARP) mutation in the ATPase-6 gene of the mitochondrial DNA. Hum Mol Genet. 2001;10:1221–8. [PubMed: 11371515]
33. Goldenberg PC, Steiner RD, Merkens LS, Dunaway T, Egan RA, Zimmerman EA, Nesbit G, Robinson B, Kennaway NG. Remarkable improvement in adult Leigh syndrome with partial cytochrome c oxidase deficiency. Neurology. 2003;60:865–8. [PubMed: 12629249]
34. Grafakou O, Oexle K, van den Heuvel L, Smeets R, Trijbels F, Goebel HH, Bosshard N, Superti-Furga A, Steinmann B, Smeitink J. Leigh syndrome due to compound heterozygosity of dihydrolipoamide dehydrogenase gene mutations. Description of the first E3 splice site mutation. Eur J Pediatr. 2003;162:714–8. [PubMed: 12925875]
35. Harding AE, Holt IJ, Sweeney MG, Brockington M, Davis MB. Prenatal diagnosis of mitochondrial DNA8993 T----G disease. Am J Hum Genet. 1992;50:629–33. [PMC free article: PMC1684296] [PubMed: 1539598]
36. Herzer M, Koch J, Prokisch H, Rodenburg R, Rauscher C, Radauer W, Forstner R, Pilz P, Rolinski B, Freisinger P, Mayr JA, Sperl W. Leigh disease with brainstem involvement in complex I deficiency due to assembly factor NDUFAF2 defect. Neuropediatrics. 2010;41:30–4. [PubMed: 20571988]
37. Hoefs SJ, Dieteren CE, Distelmaier F, Janssen RJ, Epplen A, Swarts HG, Forkink M, Rodenburg RJ, Nijtmans LG, Willems PH, Smeitink JA, van den Heuvel LP. NDUFA2 complex I mutation leads to Leigh disease. Am J Hum Genet. 2008;82:1306–15. [PMC free article: PMC2427319] [PubMed: 18513682]
38. Hoefs SJ, Dieteren CE, Rodenburg RJ, Naess K, Bruhn H, Wibom R, Wagena E, Willems PH, Smeitink JA, Nijtmans LG, van den Heuvel LP. Baculovirus complementation restores a novel NDUFAF2 mutation causing complex I deficiency. Hum Mutat. 2009;30:E728–36. [PubMed: 19384974]
39. Hoefs SJ, van Spronsen FJ, Lenssen EW, Nijtmans LG, Rodenburg RJ, Smeitink JA, van den Heuvel LP. NDUFA10 mutations cause complex I deficiency in a patient with Leigh disease. Eur J Hum Genet. 2011;19:270–4. [PMC free article: PMC3061993] [PubMed: 21150889]
40. Holt IJ, Harding AE, Petty RK, Morgan-Hughes JA. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet. 1990;46:428–33. [PMC free article: PMC1683641] [PubMed: 2137962]
41. Huntsman RJ, Sinclair DB, Bhargava R, Chan A. Atypical presentations of leigh syndrome: a case series and review. Pediatr Neurol. 2005;32:334–40. [PubMed: 15866434]
42. Jacobs LJ, de Coo IF, Nijland JG, Galjaard RJ, Los FJ, Schoonderwoerd K, Niermeijer MF, Geraedts JP, Scholte HR, Smeets HJ. Transmission and prenatal diagnosis of the T9176C mitochondrial DNA mutation. Mol Hum Reprod. 2005;11:223–8. [PubMed: 15709156]
43. Jacobs LJ, de Wert G, Geraedts JP, de Coo IF, Smeets HJ. The transmission of OXPHOS disease and methods to prevent this. Hum Reprod Update. 2006;12:119–36. [PubMed: 16199488]
44. Jauslin ML, Meier T, Smith RA, Murphy MP. Mitochondria-targeted antioxidants protect Friedreich Ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants. FASEB J. 2003;17:1972–4. [PubMed: 12923074]
45. Johns DR, Neufeld MJ. Pitfalls in the molecular genetic diagnosis of Leber hereditary optic neuropathy (LHON). Am J Hum Genet. 1993;53:916–20. [PMC free article: PMC1682383] [PubMed: 8213820]
46. Kaufmann P, Engelstad K, Wei Y, Jhung S, Sano MC, Shungu DC, Millar WS, Hong X, Gooch CL, Mao X, Pascual JM, Hirano M, Stacpoole PW, DiMauro S, De Vivo DC. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology. 2006;66(3):324–30. [PubMed: 16476929]
47. Kirby DM, Boneh A, Chow CW, Ohtake A, Ryan MT, Thyagarajan D, Thorburn DR. Low mutant load of mitochondrial DNA G13513A mutation can cause Leigh's disease. Ann Neurol. 2003;54:473–8. [PubMed: 14520659]
48. Kirby DM, Kahler SG, Freckmann ML, Reddihough D, Thorburn DR. Leigh disease caused by the mitochondrial DNA G14459A mutation in unrelated families. Ann Neurol. 2000;48:102–4. [PubMed: 10894222]
49. Kirby DM, Milovac T, Thorburn DR. A false-positive diagnosis for the common MELAS (A3243G) mutation caused by a novel variant (A3426G) in the ND1 gene of mitochondria DNA. Mol Diagn. 1998;3:211–215. [PubMed: 10089279]
50. Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry. 1951;14(3):216–21. [PMC free article: PMC499520] [PubMed: 14874135]
51. Leshinsky-Silver E, Levine A, Nissenkorn A, Barash V, Perach M, Buzhaker E, Shahmurov M, Polak-Charcon S, Lev D, Lerman-Sagie T. Neonatal liver failure and Leigh syndrome possibly due to CoQ-responsive OXPHOS deficiency. Mol Genet Metab. 2003a;79:288–93. [PubMed: 12948744]
52. Leshinsky-Silver E, Perach M, Basilevsky E, Hershkovitz E, Yanoov-Sharav M, Lerman-Sagie T, Lev D. Prenatal exclusion of Leigh syndrome due to T8993C mutation in the mitochondrial DNA. Prenat Diagn. 2003b;23:31–3. [PubMed: 12533809]
53. Lissens W, De Meirleir L, Seneca S, Liebaers I, Brown GK, Brown RM, Ito M, Naito E, Kuroda Y, Kerr DS, Wexler ID, Patel MS, Robinson BH, Seyda A. Mutations in the X-linked pyruvate dehydrogenase (E1) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Hum Mutat. 2000;15:209–19. [PubMed: 10679936]
54. Loeffen JL, Smeitink JA, Trijbels JM, Janssen AJ, Triepels RH, Sengers RC, van den Heuvel LP. Isolated complex I deficiency in children: clinical, biochemical and genetic aspects. Hum Mutat. 2000;15:123–34. [PubMed: 10649489]
55. López LC, Schuelke M, Quinzii CM, Kanki T, Rodenburg RJ, Naini A, Dimauro S, Hirano M. Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations. Am J Hum Genet. 2006;79(6):1125–9. [PMC free article: PMC1698707] [PubMed: 17186472]
56. Makino M, Horai S, Goto Y, Nonaka I. Confirmation that a T-to-C mutation at 9176 in mitochondrial DNA is an additional candidate mutation for Leigh's syndrome. Neuromuscul Disord. 1998;8:149–51. [PubMed: 9631394]
57. Mattiazzi M, Vijayvergiya C, Gajewski CD, DeVivo DC, Lenaz G, Wiedmann M, Manfredi G. The mtDNA T8993G (NARP) mutation results in an impairment of oxidative phosphorylation that can be improved by antioxidants. Hum Mol Genet. 2004;13:869–79. [PubMed: 14998933]
58. McDonnell MT, Schaefer AM, Blakely EL, McFarland R, Chinnery PF, Turnbull DM, Taylor RW. Noninvasive diagnosis of the 3243A > G mitochondrial DNA mutation using urinary epithelial cells. Eur J Hum Genet. 2004;12:778–81. [PubMed: 15199381]
59. Melegh B, Trombitas K. Valproate treatment induces lipid globule accumulation with ultrastructural abnormalities of mitochondria in skeletal muscle. Neuropediatrics. 1997;28:257–61. [PubMed: 9413004]
60. Mitchell G, Ogier H, Munnich A, Saudubray JM, Shirrer J, Charpentier C, Rocchiccioli F. Neurological deterioration and lactic acidemia in biotinidase deficiency. A treatable condition mimicking Leigh's disease. Neuropediatrics. 1986;17:129–31. [PubMed: 3762868]
61. Mootha VK, Lepage P, Miller K, Bunkenborg J, Reich M, Hjerrild M, Delmonte T, Villeneuve A, Sladek R, Xu F, Mitchell GA, Morin C, Mann M, Hudson TJ, Robinson B, Rioux JD, Lander ES. Identification of a gene causing human cytochrome c oxidase deficiency by integrative genomics. Proc Natl Acad Sci U S A. 2003;100:605–10. [PMC free article: PMC141043] [PubMed: 12529507]
62. Morris AA, Leonard JV, Brown GK, Bidouki SK, Bindoff LA, Woodward CE, Harding AE, Lake BD, Harding BN, Farrell MA, Bell JE, Mirakhur M, Turnbull DM. Deficiency of respiratory chain complex I is a common cause of Leigh disease. Ann Neurol. 1996;40:25–30. [PubMed: 8687187]
63. Neilson DE, Adams MD, Orr CM, Schelling DK, Eiben RM, Kerr DS, Anderson J, Bassuk AG, Bye AM, Childs AM, Clarke A, Crow YJ, Di Rocco M, Dohna-Schwake C, Dueckers G, Fasano AE, Gika AD, Gionnis D, Gorman MP, Grattan-Smith PJ, Hackenberg A, Kuster A, Lentschig MG, Lopez-Laso E, Marco EJ, Mastroyianni S, Perrier J, Schmitt-Mechelke T, Servidei S, Skardoutsou A, Uldall P, van der Knaap MS, Goglin KC, Tefft DL, Aubin C, de Jager P, Hafler D, Warman ML. Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2. Am J Hum Genet. 2009;84:44–51. [PMC free article: PMC2668029] [PubMed: 19118815]
64. Nijtmans LG, Henderson NS, Attardi G, Holt IJ. Impaired ATP synthase assembly associated with a mutation in the human ATP synthase subunit 6 gene. J Biol Chem. 2001;276:6755–62. [PubMed: 11076946]
65. Ogilvie I, Kennaway NG, Shoubridge EA. A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy. J Clin Invest. 2005;115(10):2784–92. [PMC free article: PMC1236688] [PubMed: 16200211]
66. Oquendo CE, Antonicka H, Shoubridge EA, Reardon W, Brown GK. Functional and genetic studies demonstrate that mutation in the COX15 gene can cause Leigh syndrome. J Med Genet. 2004;41:540–4. [PMC free article: PMC1735852] [PubMed: 15235026]
67. Ortiz RG, Newman NJ, Shoffner JM, Kaufman AE, Koontz DA, Wallace DC. Variable retinal and neurologic manifestations in patients harboring the mitochondrial DNA 8993 mutation. Arch Ophthalmol. 1993;111:1525–30. [PubMed: 8240109]
68. Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB, Ong SE, Walford GA, Sugiana C, Boneh A, Chen WK, Hill DE, Vidal M, Evans JG, Thorburn DR, Carr SA, Mootha VK. A mitochondrial protein compendium elucidates complex I disease biology. Cell. 2008;134:112–23. [PMC free article: PMC2778844] [PubMed: 18614015]
69. Pagnamenta AT, Hargreaves IP, Duncan AJ, Taanman JW, Heales SJ, Land JM, Bitner-Glindzicz M, Leonard JV, Rahman S. Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II. Mol Genet Metab. 2006;89:214–21. [PubMed: 16798039]
70. Panetta J, Smith LJ, Boneh A. Effect of high-dose vitamins, coenzyme Q and high-fat diet in paediatric patients with mitochondrial diseases. J Inherit Metab Dis. 2004;27:487–98. [PubMed: 15303006]
71. Pequignot MO, Dey R, Zeviani M, Tiranti V, Godinot C, Poyau A, Sue C, Di Mauro S, Abitbol M, Marsac C. Mutations in the SURF1 gene associated with Leigh syndrome and cytochrome C oxidase deficiency. Hum Mutat. 2001;17:374–81. [PubMed: 11317352]
72. Poulton J, Bredenoord AL. 174th ENMC international workshop: Applying pre-implantation genetic diagnosis to mtDNA diseases: implications of scientific advances 19-21 March 2010, Naarden, The Netherlands. Neuromuscul Disord. 2010;20:559–63. [PubMed: 20627569]
73. Poulton J, Turnbull DM. 74th ENMC international workshop: mitochondrial diseases 19-20 November 1999, Naarden, The Netherlands. Neuromuscul Disord. 2000;10:460–2. [PubMed: 10899455]
74. Quintana E, Mayr JA, García Silva MT, Font A, Tortoledo MA, Moliner S, Ozaez L, Lluch M, Cabello A, Ricoy JR, Koch J, Ribes A, Sperl W, Briones P. PDH E(1)beta deficiency with novel mutations in two patients with Leigh syndrome. J Inherit Metab Dis. 2009;32 Suppl 1:S339–43. [PubMed: 19924563]
75. Rabier D, Diry C, Rotig A, Rustin P, Heron B, Bardet J, Parvy P, Ponsot G, Marsac C, Saudubray JM, Munnich A, Kamoun P. Persistent hypocitrullinaemia as a marker for mtDNA NARP T 8993 G mutation? J Inherit Metab Dis. 1998;21:216–9. [PubMed: 9686360]
76. Rahman S, Blok RB, Dahl HH, Danks DM, Kirby DM, Chow CW, Christodoulou J, Thorburn DR. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol. 1996;39:343–51. [PubMed: 8602753]
77. Rahman S, Poulton J, Marchington D, Suomalainen A. Decrease of 3243 A—>G mtDNA mutation from blood in MELAS syndrome: a longitudinal study. Am J Hum Genet. 2001;68:238–40. [PMC free article: PMC1234919] [PubMed: 11085913]
78. Rantamaki MT, Soini HK, Finnila SM, Majamaa K, Udd B. Adult-onset ataxia and polyneuropathy caused by mitochondrial 8993T-->C mutation. Ann Neurol. 2005;58:337–40. [PubMed: 16049925]
79. Rossi A, Biancheri R, Bruno C, Di Rocco M, Calvi A, Pessagno A, Tortori-Donati P. Leigh Syndrome with COX deficiency and SURF1 gene mutations: MR imaging findings. AJNR Am J Neuroradiol. 2003;24:1188–91. [PubMed: 12812953]
80. Santorelli FM, Mak SC, Vazquez-Memije E, Shanske S, Kranz-Eble P, Jain KD, Bluestone DL, De Vivo DC, DiMauro S. Clinical heterogeneity associated with the mitochondrial DNA T8993C point mutation. Pediatr Res. 1996;39:914–7. [PubMed: 8726250]
81. Santorelli FM, Shanske S, Macaya A, DeVivo DC, DiMauro S. The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh's syndrome. Ann Neurol. 1993;34:827–34. [PubMed: 8250532]
82. Santorelli FM, Tanji K, Sano M, Shanske S, El-Shahawi M, Kranz-Eble P, DiMauro S, De Vivo DC. Maternally inherited encephalopathy associated with a single-base insertion in the mitochondrial tRNATrp gene. Ann Neurol. 1997a;42:256–60. [PubMed: 9266739]
83. Santorelli FM, Tanji K, Shanske S, DiMauro S. Heterogeneous clinical presentation of the mtDNA NARP/T8993G mutation. Neurology. 1997b;49:270–3. [PubMed: 9222207]
84. Sato A, Kono T, Nakada K, Ishikawa K, Inoue S, Yonekawa H, Hayashi J. Gene therapy for progeny of mito-mice carrying pathogenic mtDNA by nuclear transplantation. Proc Natl Acad Sci U S A. 2005;102:16765–70. [PMC free article: PMC1283814] [PubMed: 16275929]
85. Schiff M, Miné M, Brivet M, Marsac C, Elmaleh-Bergés M, Evrard P, Ogier de Baulny H. Leigh's disease due to a new mutation in the PDHX gene. Ann Neurol. 2006;59:709–14. [PubMed: 16566017]
86. Schwartz M, Vissing J. Paternal inheritance of mitochondrial DNA. N Engl J Med. 2002;347:576–80. [PubMed: 12192017]
87. Sembrano E, Barthlen GM, Wallace S, Lamm C. Polysomnographic findings in a patient with the mitochondrial encephalomyopathy NARP. Neurology. 1997;49:1714–7. [PubMed: 9409376]
88. Sgarbi G, Casalena GA, Baracca A, Lenaz G, DiMauro S, Solaini G. Human NARP mitochondrial mutation metabolism corrected with alpha-ketoglutarate/aspartate: a potential new therapy. Arch Neurol. 2009;66:951–7. [PubMed: 19667215]
89. Shanske S, Pancrudo J, Kaufmann P, Engelstad K, Jhung S, Lu J, Naini A, DiMauro S, De Vivo DC. Varying loads of the mitochondrial DNA A3243G mutation in different tissues: implications for diagnosis. Am J Med Genet A. 2004;130A:134–7. [PubMed: 15372523]
90. Shear T, Tobias JD. Anesthetic implications of Leigh's syndrome. Paediatr Anaesth. 2004;14:792–7. [PubMed: 15330965]
91. Stacpoole PW, Gilbert LR, Neiberger RE, Carney PR, Valenstein E, Theriaque DW, Shuster JJ. Evaluation of long-term treatment of children with congenital lactic acidosis with dichloroacetate. Pediatrics. 2008;121:e1223–8. [PubMed: 18411236]
92. Steffann J, Frydman N, Gigarel N, Burlet P, Ray PF, Fanchin R, Feyereisen E, Kerbrat V, Tachdjian G, Bonnefont JP, Frydman R, Munnich A. Analysis of mtDNA variant segregation during early human embryonic development: a tool for successful NARP preimplantation diagnosis. J Med Genet. 2006;43:244–7. [PMC free article: PMC2563237] [PubMed: 16155197]
93. Suwa K, Yamagata T, Momoi MY, Kawakami A, Kikuchi Y, Miyao M, Hirokawa H, Oikawa T. Acute relapsing encephalopathy mimicking acute necrotizing encephalopathy in a 4-year-old boy. Brain Dev. 1999;21:554–8. [PubMed: 10598058]
94. Taanman JW, Rahman S, Pagnamenta AT, Morris AA, Bitner-Glindzicz M, Wolf NI, Leonard JV, Clayton PT, Schapira AH. Analysis of mutant DNA polymerase gamma in patients with mitochondrial DNA depletion. Hum Mutat. 2009;30:248–54. [PubMed: 18828154]
95. Tachibana M, Sparman M, Sritanaudomchai H, Ma H, Clepper L, Woodward J, Li Y, Ramsey C, Kolotushkina O, Mitalipov S. Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature. 2009;461:367–72. [PMC free article: PMC2774772] [PubMed: 19710649]
96. Takahashi S, Oki J, Miyamoto A, Okuno A. Proton magnetic resonance spectroscopy to study the metabolic changes in the brain of a patient with Leigh syndrome. Brain Dev. 1999;21:200–4. [PubMed: 10372907]
97. Takanashi J, Sugita K, Tanabe Y, Maemoto T, Niimi H. Dichloroacetate treatment in Leigh syndrome caused by mitochondrial DNA mutation. J Neurol Sci. 1997;145:83–6. [PubMed: 9073033]
98. Tanaka M, Borgeld HJ, Zhang J, Muramatsu S, Gong JS, Yoneda M, Maruyama W, Naoi M, Ibi T, Sahashi K, Shamoto M, Fuku N, Kurata M, Yamada Y, Nishizawa K, Akao Y, Ohishi N, Miyabayashi S, Umemoto H, Muramatsu T, Furukawa K, Kikuchi A, Nakano I, Ozawa K, Yagi K. Gene therapy for mitochondrial disease by delivering restriction endonuclease SmaI into mitochondria. J Biomed Sci. 2002;9:534–41. [PubMed: 12372991]
99. Tatuch Y, Christodoulou J, Feigenbaum A, Clarke JT, Wherret J, Smith C, Rudd N, Petrova-Benedict R, Robinson BH. Heteroplasmic mtDNA mutation (T----G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am J Hum Genet. 1992;50:852–8. [PMC free article: PMC1682643] [PubMed: 1550128]
100. Tatuch Y, Robinson BH. The mitochondrial DNA mutation at 8993 associated with NARP slows the rate of ATP synthesis in isolated lymphoblast mitochondria. Biochem Biophys Res Commun. 1993;192:124–8. [PubMed: 8476414]
101. Tay SK, Sacconi S, Akman HO, Morales JF, Morales A, De Vivo DC, Shanske S, Bonilla E, Dimauro S. Unusual clinical presentations in four cases of Leigh disease, cytochrome C oxidase deficiency, and SURF1 gene mutations. J Child Neurol. 2005;20:670–4. [PubMed: 16225813]
102. Taylor RW, McDonnell MT, Blakely EL, Chinnery PF, Taylor GA, Howell N, Zeviani M, Briem E, Carrara F, Turnbull DM. Genotypes from patients indicate no paternal mitochondrial DNA contribution. Ann Neurol. 2003;54:521–4. [PubMed: 14520666]
103. Thorburn DR, Chow CW, Kirby DM. Respiratory chain enzyme analysis in muscle and liver. Mitochondrion. 2004;4:363–75. [PubMed: 16120398]
104. Thorburn DR, Dahl HH. Mitochondrial disorders: genetics, counseling, prenatal diagnosis and reproductive options. Am J Med Genet. 2001;106:102–14. [PubMed: 11579429]
105. Thyagarajan D, Shanske S, Vazquez-Memije M, De Vivo D, DiMauro S. A novel mitochondrial ATPase 6 point mutation in familial bilateral striatal necrosis. Ann Neurol. 1995;38:468–72. [PubMed: 7668837]
106. Tsuji M, Kuroki S, Maeda H, Yoshioka M, Maihara T, Fujii T, Ito M. Leigh syndrome associated with West syndrome. Brain Dev. 2003;25:245–50. [PubMed: 12767455]
107. Tuppen HA, Hogan VE, He L, Blakely EL, Worgan L, Al-Dosary M, Saretzki G, Alston CL, Morris AA, Clarke M, Jones S, Devlin AM, Mansour S, Chrzanowska-Lightowlers ZM, Thorburn DR, McFarland R, Taylor RW. The p.M292T NDUFS2 mutation causes complex I-deficient Leigh syndrome in multiple families. Brain. 2010;133:2952–63. [PMC free article: PMC2947428] [PubMed: 20819849]
108. Ugalde C, Triepels RH, Coenen MJ, van den Heuvel LP, Smeets R, Uusimaa J, Briones P, Campistol J, Majamaa K, Smeitink JA, Nijtmans LG. Impaired complex I assembly in a Leigh syndrome patient with a novel missense mutation in the ND6 gene. Ann Neurol. 2003;54:665–9. [PubMed: 14595656]
109. Van Hove JL, Saenz MS, Thomas JA, Gallagher RC, Lovell MA, Fenton LZ, Shanske S, Myers SM, Wanders RJ, Ruiter J, Turkenburg M, Waterham HR. Succinyl-CoA ligase deficiency: a mitochondrial hepatoencephalomyopathy. Pediatr Res. 2010;68:159–64. [PMC free article: PMC2928220] [PubMed: 20453710]
110. Van Maldergem L, Trijbels F, DiMauro S, Sindelar PJ, Musumeci O, Janssen A, Delberghe X, Martin JJ, Gillerot Y. Coenzyme Q-responsive Leigh's encephalopathy in two sisters. Ann Neurol. 2002;52:750–4. [PubMed: 12447928]
111. Wenz T, Diaz F, Spiegelman BM, Moraes CT. Activation of the PPAR/PGC-1alpha pathway prevents a bioenergetic deficit and effectively improves a mitochondrial myopathy phenotype. Cell Metab. 2008;8:249–56. [PMC free article: PMC2613643] [PubMed: 18762025]
112. White SL, Collins VR, Wolfe R, Cleary MA, Shanske S, DiMauro S, Dahl HH, Thorburn DR. Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993. Am J Hum Genet. 1999a;65:474–82. [PMC free article: PMC1377946] [PubMed: 10417290]
113. White SL, Shanske S, Biros I, Warwick L, Dahl HM, Thorburn DR, Di Mauro S. Two cases of prenatal analysis for the pathogenic T to G substitution at nucleotide 8993 in mitochondrial DNA. Prenat Diagn. 1999b;19:1165–8. [PubMed: 10590437]
114. White SL, Shanske S, McGill JJ, Mountain H, Geraghty MT, DiMauro S, Dahl HH, Thorburn DR. Mitochondrial DNA mutations at nucleotide 8993 show a lack of tissue or age-related variation. J Inherit Metab Dis. 1999c;22:899–914. [PubMed: 10604142]
115. White SL, Thorburn DR, Christodoulou J, Dahl HH. Novel mitochondrial DNA variant that may give a false positive diagnosis for the T8993C mutation. Mol Diagn. 1998;3:113–7. [PubMed: 10029662]
116. Yamakawa T, Yoshida F, Kumagai T, Watanabe H, Takano A, Mizuno M, Ikeguchi H, Morita Y, Sobue G, Matsuo S. Glomerulocystic kidney associated with subacute necrotizing-encephalomyelopathy. Am J Kidney Dis. 2001;37:E14. [PubMed: 11157400]

Revision History

• 3 May 2011 (cd) Revision: MT-ND2 added as gene in which mutation is causative
• 8 February 2011 (me) Comprehensive update posted live
• 3 February 2006 (me) Comprehensive update posted to live Web site
• 30 October 2003 (me) Review posted to live Web site
• 3 July 2003 (dt) Original submission