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Mitochondrial DNA-Associated Leigh Syndrome and NARP

Synonym: mtDNA-Associated Leigh Syndrome and NARP

, PhD and , FRCP, FRCPCH, PhD.

Author Information
, PhD
NHMRC Principal Research Fellow
Murdoch Children's Research Institute and Genetic Health Services Victoria
Royal Children's Hospital
Department of Paediatrics
University of Melbourne
Melbourne, Australia
, FRCP, FRCPCH, PhD
Reader in Paediatric Metabolic Medicine
Genetics and Genomic Medicine
UCL Institute of Child Health
London, United Kingdom

Initial Posting: ; Last Update: April 17, 2014.

Summary

Disease characteristics. Mitochondrial (mt) DNA-associated Leigh syndrome and NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) are part of a continuum of progressive neurodegenerative disorders caused by abnormalities of mitochondrial energy generation.

  • Leigh syndrome (or subacute necrotizing encephalomyelopathy) is characterized by onset of symptoms typically between age three and 12 months, often following a viral infection. Decompensation (often with elevated lactate levels in blood and/or CSF) during an intercurrent illness is typically associated with psychomotor retardation or regression. Neurologic features include hypotonia, spasticity, movement disorders (including chorea), cerebellar ataxia, and peripheral neuropathy. Extraneurologic manifestations may include hypertrophic cardiomyopathy. About 50% of affected individuals die by age three years, most often as a result of respiratory or cardiac failure.
  • NARP is characterized by proximal neurogenic muscle weakness with sensory neuropathy, ataxia, and pigmentary retinopathy. Onset of symptoms, particularly ataxia and learning difficulties, is often in early childhood. Individuals with NARP can be relatively stable for many years, but may suffer episodic deterioration, often in association with viral illnesses.

Diagnosis/testing. The diagnosis of NARP and mtDNA-associated Leigh syndrome is established using clinical criteria and molecular genetic testing. 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 the mitochondrial genes in which pathogenic variants are known to cause mtDNA-associated Leigh syndrome. MT-ATP6 is the only gene in which pathogenic variants are known to cause NARP. Approximately 10% of individuals with Leigh syndrome have either the m.8993T>G or m.8993T>C MT-ATP6 pathogenic variant; approximately 10%-20% have pathogenic variants in other mitochondrial genes. The proportion of individuals with NARP who have a detectable pathogenic variant at MT-ATP6 nucleotide 8993 is unknown but likely greater than 50%; a T-to-G transversion (m.8993T>G) is most common; a T-to-C transition (m.8993T>C) has also been described.

Management. Treatment of manifestations: Supportive treatment includes use of sodium bicarbonate or sodium citrate for acidosis and antiepileptic drugs for seizures. Dystonia is treated with benzhexol, baclofen, tetrabenezine, and gabapentin alone or in combination, or by injections of botulinum toxin. Anticongestive therapy may be required for cardiomyopathy. Regular nutritional assessment of daily caloric intake and adequacy of diet and psychological support for the affected individual and family are essential.

Surveillance: Neurologic, ophthalmologic, and cardiologic evaluations at regular intervals to monitor progression and appearance of new symptoms.

Agents/circumstances to avoid: Sodium valproate and barbiturates, anesthesia, and dichloroacetate (DCA).

Genetic counseling. Mitochondrial DNA-associated Leigh syndrome and NARP are transmitted by maternal inheritance. The father of a proband is not at risk of having the mtDNA pathogenic variant. The mother of a proband usually has the mtDNA pathogenic variant and may or may not have symptoms. In most cases, the mother has a much lower mutant load 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. Offspring of males with a mtDNA pathogenic variant are not at risk; all offspring of females with a mtDNA pathogenic variant are at risk of inheriting the pathogenic variant. The risk to offspring of a female proband of developing symptoms depends on the tissue distribution and mutant load of the mtDNA pathogenic variant. Prenatal diagnosis and preimplantation genetic diagnosis for couples at increased risk of having children with mitochondrial DNA-associated Leigh syndrome and NARP is possible by analysis of mtDNA extracted from non-cultured fetal cells or from single blastomeres, respectively; however, the use of molecular genetic test results to predict long-term outcome is difficult.

GeneReview Scope

Mitochondrial DNA-Associated Leigh Syndrome and NARP: Included Disorders
  • Leigh syndrome (mtDNA mutation)
  • Leigh-like syndrome
  • NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa)

For synonyms and outdated names see Nomenclature.

Diagnosis

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.

More recently, Baertling et al [2014] described similar diagnostic criteria that allow for the diagnosis of Leigh syndrome in the absence of raised lactate levels. Their criteria include the following:

  • Neurodegenerative disease with variable symptoms resulting from mitochondrial dysfunction
  • Mitochondrial dysfunction caused by a hereditary genetic defect
  • Bilateral CNS lesions that can be associated with further abnormalities in diagnostic imaging

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 (but not always) elevated in blood; the elevation tends to be more marked in post-prandial samples.
  • Testing several blood samples is more sensitive than testing a single random sample.
  • Lactate elevation is more consistent in CSF samples than blood samples, but is not an invariant finding.
  • 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 pathogenic variant [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 symmetric hyperintense signal abnormality in the brain stem and/or basal ganglia on T2-weighted magnetic resonance imaging (MRI) [Rahman et al 1996, Arii & Tanabe 2000, Rossi et al 2003, Baertling et al 2014].
  • 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 pathogenic variants 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 variants.

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 pathogenic variants affecting complex V subunits such as the pathogenic variants 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

Mitochondrial DNA-associated Leigh syndrome. 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 the mitochondrial genes in which mutations are known to cause mtDNA-associated Leigh syndrome.

NARP. MT-ATP6 is the only mitochondrial gene in which mutations are known to cause NARP.

Testing strategy

  • One strategy for molecular diagnosis of a proband suspected of having mtDNA-associated Leigh syndrome or NARP is to start with targeted mutation analysis of leukocyte DNA for the two common MT-ATP6 mutations (Table 1). If a disease-causing MT-ATP6 mutation is not detected, whole mitochondrial genome sequence analysis is performed. Note that muscle tissue is often the preferred source of DNA.
    Note: Deletions/duplications of mtDNA are an extremely rare cause of Leigh syndrome.
    • In children deletion/duplication analysis is usually performed in leukocyte DNA at the same time as screening for the two common MT-ATP6 mutations.
    • Deletions are not usually detectable in leukocyte DNA from adults; in this age group, muscle (or urinary epithelial cells) is the tissue of choice for analysis.
  • Another strategy for molecular diagnosis of a proband suspected of having mtDNA-associated Leigh syndrome or NARP is to start with whole mitochondrial genome sequence analysis (Table 1). Note that muscle tissue is often the preferred source of DNA.

Interpretation of test results

  • 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.
  • 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 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 cells are preferable to blood [McDonnell et al 2004, Shanske et al 2004].

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

Test Method
(Tissue Type)
Mutations Detected Mutation Detection Frequency by Test Method
Mitochondrial DNA-Associated Leigh Syndrome NARP
MT-ATP6 targeted mutation analysis
(leukocyte DNA1
m.8993T>G and m.8993T>C ~10% 250% 3
Sequence analysis of whole mt genome (preferably muscle) Sequence variants in select genes 4, 5 ~10%-20% 6, 7, 80%
Deletion/duplication analysis of whole mt genome 9
(children: leukocyte DNA; adults: muscle or urinary epithelial cells)
Variable deletions; most common is 4.977-kb deletion Rare0%

1. Molecular testing can be performed in DNA extracted from leukocytes because 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]; these mutations always present at high load in leukocytes from persons with maternally inherited Leigh syndrome or NARP.

2. Approximately 10% of individuals with Leigh syndrome have either the MT-ATP6 m.8993T>G or m.8993T>C mutation [Santorelli et al 1993, Rahman et al 1996, Makino et al 1998].

3. The proportion of individuals with NARP who have a detectable mutation at MT-ATP6 nucleotide 8993 is unknown but likely >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 2 of 10 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 8 individuals in that study.

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. MT-ATP6, MT-TL1, MT-TK, MT-TW, MT-TV, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MT-ND6, MT-CO3

6. Approximately 10%-20% of individuals with Leigh syndrome have mutations in mitochondrial genes other than MT-ATP6.

7. Detection rate depends on gene(s) tested.

8. For MT-ATP6 this detection rate refers to mutations other than m.8993T>G and m.8993T>C.

9. Testing that identifies deletions/duplications not readily detectable by Sanger sequence analysis of the coding and flanking intronic regions of genomic DNA. The variety of methods used may be: quantitative PCR, long-range PCR and next-generation DNA sequence analysis that targets mtDNA.

Clinical Description

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 and 12 months, often following a viral infection. Later onset (i.e., age >1 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 pathogenic variants. (Data have been updated from those reported by Rahman et al [1996] to reflect the subsequent identification of mtDNA pathogenic variants in six of the originally reported individuals.) Some features appear to be more common in individuals with mtDNA pathogenic variants, 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 pathogenic variants [Santorelli et al 1993]. Not surprisingly, consanguinity is more common in individuals without mtDNA pathogenic variants; 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 pathogenic variant) 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 in rare cases may be ten years or more. More typically, death 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.

Table 2. Prevalence of Clinical Features in Leigh Syndrome and Leigh-Like Syndrome

Leigh SyndromeLeigh-Like Syndrome
# of individuals13 1 22 2 27
Pathogenic mtDNA variant identifiedYesNoYesNo
Median age in months at onset (range in months)6 (3-120)6 (1-42)9 (0-118)7 (0-102)
Clinical Feature% of Individuals in whom Feature was Present
  • Consanguinity
018030
  • Family history
46452056
  • Male
62556070
  • Developmental delay
10010010089
  • Hypotonia
92824070
  • Spasticity
62502052
  • Reflexes increased
69646052
  • Reflexes decreased
823022
  • Weakness
62556044
  • Ataxia
38368037
  • Involuntary movements
15362033
  • Dystonia
15272019
  • Seizures
3145067
  • Nystagmus
46452037
  • Ophthalmoplegia/ squint
54234056
  • Optic atrophy
3832015
  • Ptosis
15184015
  • Cranial nerve palsies
155015
  • Bulbar problems
693610044
  • Peripheral neuropathy
0907
  • Respiratory disturbance
85646056
  • Poor feeding
31556030
  • Unexplained vomiting
31364037
  • Failure to thrive
38556056
  • Cardiac problems
8507

Adapted from Rahman et al [1996]

1. These 13 individuals include four with the m.8993T>G pathogenic variant, two with the m.8993T>C pathogenic variant, one with the m.8344G>A pathogenic variant, and six in whom mtDNA pathogenic variants have been identified subsequently: namely, two brothers with the m.14459G>A pathogenic variant [Kirby et al 2000], two unrelated individuals with the m.14487T>C pathogenic variant [unpublished data], and single individuals with the m.13513G>A pathogenic variant [Kirby et al 2003] and the m.12706T>C pathogenic variant [Swalwell et al 2011].

2. These five individuals include two with the m.8993T>G pathogenic variant, two with m.8993T>C, and one with a mtDNA deletion.

Table 3. Investigation Results in Leigh Syndrome and Leigh-Like Syndrome

Leigh SyndromeLeigh-Like Syndrome
# of individuals13 1 222 27
Pathogenic mtDNA variant identifiedYesNoYesNo
Median age in months at onset (range in months)6 (3-120)6 (1-42)9 (0-118)7 (0-102)
Investigation% of Individuals in whom Feature was Present
  • Lactate
Not done05204
Normal05033
Raised100868063
  • CT/MRI
Not done094015
Normal814033
Atypical006037
Typical9277015
  • Postmortem diagnosis
3841022

Adapted from Rahman et al [1996]

1. These 13 individuals include four with the m.8993T>G pathogenic variant, two with the m.8993T>C pathogenic variant, one with the m.8344G>A pathogenic variant, and six in whom mtDNA pathogenic variants have been identified subsequently: namely, two brothers with the m.14459G>A pathogenic variant [Kirby et al 2000], two unrelated individuals with the m.14487T>C pathogenic variant [unpublished data], and single individuals with the m.13513G>A pathogenic variant [Kirby et al 2003] and the m.12706T>C pathogenic variant [Swalwell et al 2011].

2. These five individuals include two with the m.8993T>G pathogenic variant, two with m.8993T>C, and one with a mtDNA deletion.

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 experience 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 pathogenic variants, it is difficult to distinguish a simple correlation between genotype and phenotype because clinical expression of a mtDNA pathogenic variant is influenced not only by the pathogenicity of the variant itself but also by the relative amount of mutant and wild type 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 pathogenic variants probably show the strongest genotype-phenotype correlation of any mtDNA pathogenic variants. Notably, they show very little tissue-dependent or age-dependent variation in mutant load [White et al 1999c] as well as a strong correlation between mutant load and disease severity, allowing White et al [1999a] to generate logistic regression models that predict the probability of a severe outcome in an individual based on the measured mutant load of m.8993T>G and m.8993T>C (Figure 1). Note, however, 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 1

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 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 pathogenic variants, as more data become available.

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 pathogenic variant 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.

Differential Diagnosis

NARP

Leigh syndrome. In most individuals with Leigh syndrome, the disease is not caused by a mtDNA mutation but by an autosomal recessive or X-linked disorder of mitochondrial energy generation. It was previously thought that mtDNA mutations caused only a very small proportion of Leigh syndrome [Morris et al 1996]. However, in most reports on large series of individuals with Leigh syndrome, the proportion caused by mutation of mtDNA is found to be 10%-30% [Santorelli et al 1993, Rahman et al 1996, Makino et al 1998]. Further analyses of a large series of 67 individuals with Leigh or Leigh-like syndrome reported by Rahman et al [1996] have now identified mtDNA pathogenic variants in 27% of the entire group and 37% of the individuals with a stringent diagnosis of Leigh syndrome (Table 2) [Author, personal communication].

Pathogenic variants in nuclear genes that result in respiratory chain complex deficiencies and Leigh syndrome are summarized in Table 4.

Table 4. Leigh Syndrome Caused By Nuclear Gene Mutations Resulting in Respiratory Chain Complex Deficiencies

Respiratory Chain Complex DeficiencyNameGenesReferences
I
(NADH-coenzyme Q reductase)
Complex I-deficient Leigh syndromeNDUFV1, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFA1, NDUFA2, NDUFA10, NDUFA9, NDUFA12, NDUFAF2, , NDUFAF5, NDUFAF6, FOXRED1 Loeffen et al [2000], Benit et al [2001], Benit et al [2004], Fernandez-Moreira et al [2007], Hoefs et al [2008], Pagliarini et al [2008], Hoefs et al [2009], Calvo et al [2010], Gerards et al [2010], Tuppen et al [2010], Hoefs et al [2011], Ostergaard et al [2011], Van den Bosch et al [2012]
Other unknown genes
II
(succinate-ubiquinone reductase)
Complex II-deficient Leigh syndromeSDHA, SDHAF1Bourgeron et al [1995], Pagnamenta et al [2006], Ohlenbusch et al [2012]
III
(ubiquinone-cytochrome c reductase)
Complex III-deficient Leigh syndromeBCS1L, UQCRQ, TTC19de Lonlay-Debeney et al [1999], Barel et al [2008], Atwal [2013]
IV
(cytochrome c oxidase)
Cytochrome c oxidase-deficient Leigh syndromeSURF1, COX10, COX15, SCO2, NDUFA4, PET100 Pequignot et al [2001], Antonicka et al [2003], Oquendo et al [2004], Joost et al [2010], Pitceathly et al [2013], Lim et al [2014]
French-Canadian or Saguenay-Lac Saint Jean typeLRPPRC Mootha et al [2003]
Other unknown genes
II+III
(succinate cytochrome c reductase)
Coenzyme Q10 deficiencyPDSS2, other unknown genesVan Maldergem et al [2002] , López et al [2006]
I, III + IV
(multiple respiratory chain enzyme deficiencies)
Mitochondrial DNA depletion syndromePOLG, SUCLG1, SUCLA2, other unknown genesOstergaard et al [2007], Taanman et al [2009], Van Hove et al [2010]
I, III + IV
(multiple respiratory chain enzyme deficiencies)
Mitochondrial translation defectC12orf65, GFM1, TACO1, MTFMT, FARS2, EARS2, other unknown genesValente et al [2007], Weraarpachai et al [2009], Antonicka et al [2010], Tucker et al [2011], Martinelli et al [2012], Shamseldin et al [2012]
Variable enzyme deficienciesMitochondrial membrane phospholipid remodelingSERAC1Wortmann et al [2012]

Other disorders that cause or resemble Leigh syndrome include:

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluation Following Initial Diagnosis

To establish the extent of disease and needs 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
  • Medical genetics consultation

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.

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, Niezgoda & Morgan 2013].

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 subsequent 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 Q10 and analogs such as idebenone, can enhance the function and viability of cultured cells from individuals with the m.8993T>G pathogenic variant [Geromel et al 2001, Mattiazzi et al 2004], but have no proven efficacy in the 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.

EPI-743 is a structurally modified variant of CoQ10 (bis-methyl instead of bis-methoxy groups on the quinone ring, and chain length of 3 instead of 10 prenyl units) and was identified in a drug screen to have 1000-fold increased antioxidant properties compared to native CoQ10 [Enns et al 2012]. Open-label trials in end-of-life settings appeared to slow disease progression compared to historical natural history data [Enns et al 2012, Martinelli et al 2012], but the extremely unpredictable natural history of Leigh syndrome causes difficulty in interpretation of open-label studies. A randomized double blind crossover clinical trial of EPI-743 in children with Leigh syndrome is ongoing [Klein 2012].

Gene therapy provides a potential approach to decreasing the proportion of mutant mtDNA in the cells of an individual. However, all of the approaches discussed below are still a long way from clinical applicability.

Studies in cultured cells have shown that a mitochondrially targeted restriction endonuclease can recognize and degrade mtDNA containing the m.8993T>G pathogenic variant found in NARP and mtDNA-associated Leigh syndrome, while leaving wild-type mtDNA intact [Tanaka et al 2002].

Another 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].

Recently a new approach used transcription activator-like effector nucleases (TALENs) engineered to localize to mitochondria, to eliminate mutant mtDNA from cybrids containing the m.14459G>A pathogenic variant, a maternally inherited variant that can cause Leigh syndrome [Bacman et al 2013]. In allotopic gene expression, mtDNA genes are recoded so that they can be inserted into and expressed from the nucleus. This technique was used successfully to transfer recoded mitochondrial MTATP6 and thereby rescue the ATP synthesis defect in cybrids containing the m.8993T>G pathogenic variant associated with maternally inherited Leigh syndrome and NARP [Manfredi et al 2002].

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 pathogenic variants 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 approach in Leigh syndrome.

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 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 findings are likely to prompt clinical trials; however, no data have yet been reported to show that such approaches will be effective in persons with mitochondrial disorders.

Another study explored the use of alpha-ketoglutarate and aspartate in transmitochondrial cybrids heteroplasmic for the m.8993T>G pathogenic variant [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.

Finally, another promising approach is suggested by a recent study, which reported that rapamycin markedly delayed the onset and progression of symptoms in the Ndufs4-/- mouse model of Leigh syndrome [Johnson et al 2013]. The mechanism of action was unclear, as it did not appear to be acting via known mechanisms such as immune suppression, stimulating macroautophagy or induction of the mitochondrial unfolded protein response. However, the Ndufs4-/- mouse brains showed activation of the rapamycin target mTOR, which is a central coordinator of nutrient sensing and growth. Rapamycin suppressed mTOR activation, indicating that restoration of cellular signaling pathways may be a key to the beneficial effect. Rapamycin has a number of side effects (e.g., immunosuppression, hyperlipidemia, decreased wound healing) that may limit its clinical utility; however, this report identifies a potential new pathway to target for treatment of Leigh syndrome and other mitochondrial disorders.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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 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 mtDNA pathogenic variant, 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 are at risk of developing symptoms, depending on the tissue distribution and mutant load of the disease-causing mtDNA mutation.
Figure 2

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

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

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Phenotypic variability. The phenotype of an individual with an mtDNA mutation results from a combination of factors including the severity of the pathogenic variant, the percentage of mutant mitochondria (mtDNA heteroplasmy) and the organs and tissues in which they are found (tissue distribution). Different family members often inherit different percentages of mutant mtDNA and therefore can have a wide range of clinical symptoms.

Interpretation of testing results of asymptomatic at-risk family members is extremely difficult. Prediction of phenotype based on test results is not possible. Furthermore, absence of the mtDNA mutation in one tissue (e.g., blood) does not guarantee that the pathogenic variant is absent in other tissues.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
  • It is appropriate to offer genetic counseling (including general discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk; however, it is not possible to make specific predictions about the potential severity of disease in individuals or their offspring.

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, allelic variants, 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 DNA mutation 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 (full text)] relating to Leigh syndrome and NARP are summarized here. The important issues for both counseling and prenatal diagnosis depend on the following:

  • Does a close relationship between the mtDNA mutant load and disease severity exist?
  • 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 pathogenic variants, 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 pathogenic variants. See Prenatal Testing.

Prenatal Testing

If the mtDNA mutation has been identified in an affected family member, prenatal testing for pregnancies at increased risk is possible either through a clinical laboratory or a laboratory offering custom prenatal testing.

  • 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.

Other Reproductive Options

Oocyte donation accompanied by IVF using the partner's sperm. Use of a maternal relative as the oocyte donor should be avoided since the relative may have oocytes with a high mutant load even though her leukocytes may lack detectable mutant mtDNA.

The two major limitations of oocyte donation are:

  • Limited availability of donor oocytes;
  • Personal or cultural views regarding the use of donor gametes or the desire for a child who is genetically related to both parents.

Preimplantation genetic diagnosis (PGD) may be an option for some families with mtDNA pathogenic variants [Thorburn & Dahl 2001, Dean et al 2003, Jacobs et al 2006]. Successful use of preimplantation genetic diagnosis has been reported for the m.8993T>G mutation [Steffann et al 2006, Sallevelt et al 2013]. Embryos should only be regarded as suitable for implantation if they have very low, preferably zero, mutant mtDNA loads.

The high copy number of mtDNA (>104 copies per cell in an 8-cell embryo) means that mtDNA mutation analysis should be less prone to artifacts (e.g., amplification failure, allele dropout) that can complicate mutation analysis of nuclear gene defects in single cells.

In some women, a large proportion of oocytes may have a substantial mutant load, in which case even multiple cycles of ovarian stimulation may not result in an unaffected embryo.

Preimplantation genetic diagnosis for mtDNA mutations may provide valuable information even if a successful unaffected conception is not achieved.

  • If most of the embryos tested have a substantial mtDNA mutant load, oocyte donation is likely to be the only current option for ensuring an unaffected embryo.
  • In contrast, if most of the embryos tested have undetectable mutant mtDNA, the parents may opt for CVS analysis in subsequent unassisted (natural) pregnancies.

A workshop on preimplantation genetic diagnosis for mtDNA mutations was held in 2010, sponsored by the European Neuromuscular Centre (ENMC) and involving representatives from 15 international centers specializing in mtDNA diseases. Attendees described data on PGD studies in a total of nine families; a summary of the workshop discussions has been published [Poulton & Bredenoord 2010].

Nuclear transfer. Transfer of nuclear material (the pronucleus or the maternal spindle) from an unfertilized oocyte or single-cell embryo into an enucleated donor cell could potentially avoid transmission of mutant mtDNA into the developing embryo. This approach may be suitable even for women with a high proportion of mutant mtDNA, in whom preimplantation genetic diagnosis is unlikely to be an effective reproductive option. Studies in mice and macaque have shown that nuclear transfer approaches can prevent transmission of substantial amounts of mutant mtDNA to offspring [Sato et al 2005, Tachibana et al 2009]. Proof-of-principle studies with abnormally fertilized human zygotes also demonstrated minimal carry-over of donor zygote mtDNA and allowed onward development to the blastocyst stage in vitro [Craven et al 2010]. Although promising, several scientific, ethical, and legal issues remain to be solved before nuclear transfer could be regarded as a safe and appropriate reproductive option. After extensive scientific, ethical, and public consultation, recently the UK Government has given permission for further human research using these techniques to take place [House of Commons 2013].

Thorburn & Dahl [2001], Jacobs et al [2006] and Poulton & Bredenoord [2010] provide more detailed discussions of reproductive options for women with mtDNA mutations.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Children's European Mitochondrial Disease Network
    Mayfield House
    30 Heber Walk
    Northwich CW9 5JB
    United Kingdom
    Phone: +44(0) 01606 43946 (Helpline)
    Email: info@cmdn.org.uk
  • National Library of Medicine Genetics Home Reference
  • National Library of Medicine Genetics Home Reference
  • United Mitochondrial Disease Foundation (UMDF)
    8085 Saltsburg Road
    Suite 201
    Pittsburg PA 15239
    Phone: 888-317-8633 (toll-free); 412-793-8077
    Fax: 412-793-6477
    Email: info@umdf.org
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Retina International
    Retina Suisse
    Ausstellungsstrasse 36
    Zurich CH-8005
    Switzerland
    Phone: +41 (0) 44 444 1077
    Fax: +41 (0) 44 444 1070
    Email: christina.fasser@retina-international.org
  • eyeGENE® - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032
    Email: eyeGENEinfo@nei.nih.gov
  • Mitochondrial Disease Registry and Tissue Bank
    Massachusetts General Hospital
    185 Cambridge Street
    Simches Research Building 5-238
    Boston MA 02114
    Phone: 617-726-5718
    Fax: 617-724-9620
    Email: nslate@partners.org
  • RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Mitochondrial DNA-Associated Leigh Syndrome and NARP: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Mitochondrial DNA-Associated Leigh Syndrome and NARP (View All in OMIM)

161700NECROTIZING ENCEPHALOMYELOPATHY, SUBACUTE, OF LEIGH, ADULT
256000LEIGH SYNDROME; LS
516000COMPLEX I, SUBUNIT ND1; MTND1
516001COMPLEX I, SUBUNIT ND2; MTND2
516002COMPLEX I, SUBUNIT ND3; MTND3
516003COMPLEX I, SUBUNIT ND4; MTND4
516005COMPLEX I, SUBUNIT ND5; MTND5
516006COMPLEX I, SUBUNIT ND6; MTND6
516050CYTOCHROME c OXIDASE III; MTCO3
516060ATP SYNTHASE 6; MTATP6
551500NEUROPATHY, ATAXIA, AND RETINITIS PIGMENTOSA
590050TRANSFER RNA, MITOCHONDRIAL, LEUCINE, 1; MTTL1
590060TRANSFER RNA, MITOCHONDRIAL, LYSINE; MTTK
590095TRANSFER RNA, MITOCHONDRIAL, TRYPTOPHAN; MTTW
590105TRANSFER RNA, MITOCHONDRIAL, VALINE; MTTV

All mtDNA genes lack introns and are transcribed as large polycistronic transcripts that are processed into monocistronic mRNAs. Protein-coding genes are then translated by the mitochondrial-specific translational machinery.

Benign allelic variants. Mitochondrial DNA is highly polymorphic and information on known polymorphisms can be obtained at MITOMAP: A Human Mitochondrial Genome Database, which provides a compendium of benign variants and pathogenic variants of the human mtDNA

The highly polymorphic nature of mtDNA means that special care must be taken in molecular genetic testing to distinguish pathogenic variants from benign variants, particularly when using common PCR-RFLP assays. For example, several benign variants introduce or abolish a restriction site such that fragments produced by restriction digest viewed on a Southern blot may suggest a false positive or false negative result [Johns & Neufeld 1993, Kirby et al 1998, White et al 1998]. Positive results generated by such methods should always be confirmed by an independent method such as sequencing.

Pathogenic allelic variants. Mitochondrial DNA pathogenic variants that have been shown to cause Leigh syndrome, Leigh-like syndrome, or NARP are listed in Table 5.

Table 5. Selected Pathogenic Variants in Mitochondrial DNA-Associated Leigh Syndrome, Leigh-Like Syndrome, and NARP

Mitochondrial DNA Nucleotide ChangeGene Protein Amino Acid Change Reference
Sequences
m.3243A>G MT-TL1Not applicable NC_012920​.1
m.3460G>AMT-ND1p.Ala52Thr
m.3481G>Ap.Glu59Lys
m.3890G>Ap.Arg195Gln
m.5523T>GMT-TWNot applicable
m.5537insTNot applicable
m.5559A>GNot applicable
m.8344A>GMT-TKNot applicable
m.8363G>ANot applicable
m.8851T>CMT-ATPp.Trp109Arg
m.8993T>Gp.Leu156Arg
m.8993T>Cp.Leu156Pro
m.9176T>Cp.Leu217Pro
m.9176T>Gp.Leu271Arg
m.9185T>Cp.Leu220Pro
m.9191T>Cp.Leu222Pro
m.9478T>CMT-CO3p.Val91Ala
m.9537insCFrameshift
m.10158T>CMT-ND3p.Ser34Pro
m.10191T>Cp.Ser45Pro
m.10197G>Ap.Ala47Thr
m.10254G>Ap.Asp66Asn
m.11777C>AMT-ND4p.Arg340Ser
m.11984T>Cp.Tyr409His
m.12706T>CMT-ND5p.Phe124Leu
m.13513G>Ap.Asp393Asn
m.13514A>Gp.Asp393Gly
m.14484T>CMT-ND6p.Met64Val
m.14459G>Ap.Ala72Val
m.14487T>Cp.Met63Val
m.1624C>TMT-TVNot applicable
m.1644G>TNot applicable
m.4681T>CMT-ND2p.Leu71Pro

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

See MITOMAP for details of mitochondrial genome and allelic variants. See Table 2 and Table 3 for phenotype information.

Note: See Table 6 (pdf) for pathogenic variants and percentages associated with Leigh syndrome only.

Normal gene product. Human mtDNA encodes 37 genes, including 13 genes encoding protein subunits of the mitochondrial respiratory chain and oxidative phosphorylation, 22 tRNA genes, and two rRNA genes. The mitochondrial-specific translational machinery is required because translation of mtDNA-encoded genes is physically separated from the cytosolic translational machinery and because the mtDNA genetic code differs from the universal genetic code in several codons.

Abnormal gene product. For mtDNA pathogenic variants associated with the NARP and Leigh syndrome (mtDNA pathogenic variants) continuum, there is at best a partial understanding of the molecular genetic pathogenic mechanism. In most cases, a strong correlation exists between heteroplasmic mutant load and severity of the biochemical phenotype in cultured cells. In some cases, such as m.8993T>G and m.8993T>C, a strong correlation also exists between heteroplasmic mutant load and severity of the clinical phenotype in affected individuals. However, it cannot yet be explained why some mtDNA pathogenic variants cause a phenotype such as Leigh syndrome, while others cause myopathy, deafness, or diabetes mellitus.

Molecular genetic pathogenic mechanisms for mtDNA variants causing the NARP and Leigh syndrome (mtDNA pathogenic variants) continuum fall into two major classes, namely tRNA genes and protein-coding genes.

  • Not surprisingly, tRNA pathogenic variants cause decreased mitochondrial protein synthesis by mechanisms that appear to involve abnormalities in both base modification and aminoacylation of the mutant tRNA and in some cases processing of the polycistronic mtRNA transcript, as discussed elsewhere (see MELAS and MERRF).
  • Pathogenic variants in protein-coding mtDNA genes typically cause decreased activity of the respiratory chain complex of which that subunit is a part.

    The pathogenic variant for which the molecular pathogenesis is best understood is the most common mtDNA pathogenic variant in the NARP and Leigh syndrome (mtDNA pathogenic variants) continuum, the MT-ATP6 m.8993T>G pathogenic variant. The m.8993T>G pathogenic variant changes a conserved leucine to an arginine (p.Leu156Arg) in subunit 6 of the mitochondrial F1F0 ATP synthase. ATP synthase (or complex V) uses the proton gradient generated by respiratory chain complexes I to IV to drive ATP synthesis. Subunit 6 forms part of the F0 proton channel of the ATP synthase and the p.Leu156Arg amino acid substitution appears to block proton translocation and inhibit ATP synthesis [Tatuch & Robinson 1993]. The mutation may also interfere with assembly or stability of the ATP synthase [Garcia et al 2000, Nijtmans et al 2001]. Inhibition of ATP synthesis by the m.8993T>G mutation is expected to increase mitochondrial membrane potential and lead to increased production of superoxide, perhaps triggering increased cell death [Geromel et al 2001, Mattiazzi et al 2004]. These pathogenic mechanisms must contribute to the specific pattern of tissue involvement and cell loss seen in the NARP and Leigh syndrome (mtDNA pathogenic variants) continuum.

    The MT-ATP6 m.8993T>C pathogenic variant changes p.Leu156Pro rather than an arginine, and presumably results in less severe interference with proton translocation and a milder clinical phenotype than the m.8993T>G pathogenic variant [Santorelli et al 1996].

    The MT-ND6 m.14459G>A and m.14487T>C pathogenic variants result in a dramatic decrease in the steady-state amounts of fully assembled complex I [Kirby et al 2003, Ugalde et al 2003].

There are few data on the molecular genetic pathogenesis of other mtDNA subunit pathogenic variants associated with the NARP and Leigh syndrome (mtDNA pathogenic variants) continuum, but most presumably cause either (1) a catalytic defect or (2) instability of the subunit and complex in which it is incorporated, or both.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Published Guidelines/Consensus Statements

Poulton J, Turnbull DM. 74th European Neuromuscular Centre International Consensus Workshop on genetic counseling and prenatal diagnosis of mitochondrial DNA disorders. 19-20 November 1999, Naarden, The Netherlands. Available online. 2000. Accessed 3-13-14.

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Chapter Notes

Revision History

  • 17 April 2014 (me) Comprehensive update posted live
  • 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
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