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].

Molecular Genetic Testing

Genes

• Mitochondrial DNA-associated Leigh syndrome. Mutations in the mitochondrial genes MT-ATP6, MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6, and MT-CO3 are associated with mtDNA-associated Leigh syndrome.

• NARP. MT-ATP6 is the only gene in which mutation is known to cause NARP.

Clinical testing

• Targeted mutation analysis. Targeted mutation analysis can be performed in DNA extracted from leukocytes, since the following mutations are always present at high load in leukocytes from persons with maternally inherited Leigh syndrome or NARP.
  
  Mitochondrial DNA-associated Leigh syndrome. Approximately 10%-20% of individuals with Leigh syndrome have either the m.8993T>G or the m.8993T>C mutation in MT-ATP6 [Santorelli et al 1993, Rahman et al 1996, Makino et al 1998]. Approximately 10%-20% have mutations in other mitochondrial genes.
  
  NARP. The proportion of individuals with NARP who have a detectable mutation at MT-ATP6 nucleotide 8993 is not known but is likely to be greater than 50%, at least in individuals with elevated blood lactate concentration. m.8993T>G is most common; m.8993T>C has also been described [Rantamaki et al 2005]. However, in one study, only two of ten individuals with neuropathy, ataxia, and retinitis pigmentosa (the 'cardinal' features of NARP) had a MT-ATP6 nucleotide 8993 mutation [Santorelli et al 1997b]; detailed clinical features were not described for the other eight individuals in that study.
  
  Note: Most mtDNA mutations are 'heteroplasmic' (i.e., mutant mtDNA coexists with wild type mtDNA) and for some mutations, the mutation load may vary among different tissues and may increase or decrease with age.
  
  The m.8993T>G and m.8993T>C mutations do not appear to show any significant variation in mutation load among tissues [White et al 1999c], so white blood cells or any other tissue type can be used to test for these two mutations.
  
  Some mtDNA mutations tend to disappear from white blood cells with increasing age [Rahman et al 2001]. Thus, for individuals with milder symptoms and for asymptomatic maternal relatives, the pathogenic mutation may be undetectable in leukocytes and may only be detected in other tissues such as hair follicles, urine sediment cells, or skeletal muscle. Skeletal muscle is the most reliable tissue for detection of mtDNA mutations and recent studies indicate that urine sediment sediment cells are preferable to blood [McDonnell et al 2004, Shanske et al 2004].

• Sequence analysis of all/part of the mitochondrial genome

Table 1. Summary of Molecular Genetic Testing Used in Mitochondrial DNA-Associated Leigh Syndrome and NARP

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1		Test Availability
			Mitochondrial DNA-Associated Leigh Syndrome	NARP
MT-ATP6 2	Targeted mutation analysis in leukocyte DNA	m.8993T>G and m.8993T>C mutations of MT-ATP6	10%-20%	50%	Clinical
Any or all of the genes: MT-ATP6, MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6, MT-CO3	Sequence analysis of complete mtDNA in muscle	Many different mtDNA mutations	10%-20%	0%

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Panel varies by laboratory and may include testing for mutations associated with MT-ATP6, MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6, and/or MT-CO3 (see Mitochondrial Disorders Overview).

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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

Mitochondrial Disease Registry and Tissue Bank
Phone: 617-726-5718
Fax: 617-724-9620
Email: nslate@partners.org

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.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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. See for a list of laboratories offering DNA banking.

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

Prenatal diagnosis for pregnancies at increased risk may be possible by analysis of mtDNA extracted from non-cultured fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

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 at www.sciencedirect.com (registration or institutional access required). 2000. Accessed 2-3-11.

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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