Mitochondrial Dna-Associated Leigh Syndrome And Narp

Clinical characteristics.

Mitochondrial DNA (mtDNA)-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 ages 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 mtDNA-associated Leigh syndrome is established clinically in a proband with 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, and any one of the following:

• Characteristic features on brain imaging
• Typical neuropathologic changes
• Typical neuropathology in a similarly affected sib

Identification of a pathogenic variant in one of the 14 mitochondrial genes known to be involved in mtDNA-associated Leigh syndrome confirms the diagnosis.

The diagnosis of NARP is established in a proband with suggestive clinical features and identification of a heteroplasmic pathogenic variant in one of the three mitochondrial genes known to be involved in NARP.

Management.

Treatment of manifestations: Supportive treatment includes use of sodium bicarbonate or sodium citrate for acute exacerbations of acidosis and antiepileptic drugs for seizures. Dystonia is treated with benzhexol, baclofen, tetrabenazine, 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. Care is frequently coordinated by a biochemical geneticist in North America, and by a metabolic physician/pediatrician elsewhere in the world.

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

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 proportion of abnormal mtDNA than the proband and usually remains asymptomatic or develops only mild symptoms. Occasionally the mother has a substantial proportion of abnormal mtDNA 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 proportion of abnormal mtDNA. Prenatal testing and preimplantation genetic testing for couples at increased risk of having children with mtDNA-associated Leigh syndrome or NARP are possible by analysis of mtDNA extracted from non-cultured fetal cells or from single blastomeres, respectively. However, long-term outcome cannot be reliably predicted on the basis of molecular genetic test results.

Suggestive Findings

Establishing the Diagnosis

Leigh syndrome. The diagnosis of mtDNA-associated Leigh syndrome is established in a proband fulfilling the criteria for Leigh syndrome (see following) in whom a heteroplasmic or homoplasmic pathogenic variant in one of the genes listed in Table 1a or Table 1b has been identified.

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 Suggestive Findings)
  • 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 sib

* 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 postmortem.

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

Lake et al [2016] revised the diagnostic criteria to include "abnormal energy metabolism indicated by a severe defect in oxidative phosphorylation (OXPHOS) or pyruvate dehydrogenase complex (PDHc) activity, a molecular diagnosis in a gene related to mitochondrial energy generation, or elevated serum or CSF lactate."

NARP. Strict diagnostic criteria for NARP have not yet been established. The diagnosis of NARP is established in a proband with the above suggestive clinical features and identification of a mtDNA pathogenic variant on molecular genetic testing.

Molecular genetic testing approaches for Leigh syndrome and NARP can include targeted single-gene testing, mitochondrial genome sequencing, and more comprehensive genomic testing.

Option 1 (preferred in children)*

1.

Targeted analysis for the two common MT-ATP6 pathogenic variants (see Table 1) is performed concurrently with deletion/duplication analysis on leukocyte DNA.

2.

Mitochondrial genome sequencing is performed next if an MT-ATP6 pathogenic variant or deletion/duplication is not detected.

Option 2 (preferred in adults)*

1.

Targeted sequence analysis of leukocyte DNA for the two common MT-ATP6 pathogenic variants can be performed first (see Table 1).

2.

Mitochondrial genome sequencing is performed next if an MT-ATP6 pathogenic variant is not detected by targeted analysis.

Option 3. Mitochondrial genome sequencing is performed first (see Table 1).

* Note: (1) Most mtDNA pathogenic variants are "heteroplasmic" (i.e., mutated mtDNA coexists with wild type mtDNA) and for some pathogenic variants, the mutation load may vary among different tissues and may increase or decrease with age. (2) Mitochondrial DNA pathogenic variants may be lost from the leukocyte population with increasing age [Rahman et al 2001]; therefore, in adults with milder symptoms and for asymptomatic older maternal relatives, the pathogenic variant may only be detected in tissues such as hair follicles, urine sediment cells, or skeletal muscle, which is the most reliable source of mtDNA for analysis [McDonnell et al 2004, Shanske et al 2004]. (3) Leukocyte (vs skeletal muscle) testing is acceptable in children, particularly when using next-generation sequencing methods, which allow detection of very low heteroplasmy levels. (4) 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. (5) Deletions/duplications of mtDNA are an extremely rare cause of Leigh syndrome in adults. The authors are not aware of any published reports of children with Leigh syndrome, Leigh-like syndrome, or NARP where a pathogenic mtDNA variant was not detected in blood.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

See Table 1a for the most common genetic causes (i.e., pathogenic variants of any one of the mtDNA-encoded genes included in this table account for >1% of mtDNA-associated Leigh syndrome and NARP) and Table 1b for less common genetic causes (i.e., pathogenic variants of any one of the mitochondrial genes included in this table are reported in only a few families).

Clinical Description

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 [Sofou et al 2014].

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), bulbar problems such as abnormal swallowing and speech, persistent vomiting, and abnormalities of thermoregulation (hypo- and hyperthermia).

Ophthalmologic findings include optic atrophy, retinitis pigmentosa, and eye movement disorders. Pigmentary retinopathy occurs in up to 40% of individuals with a mtDNA 8993 pathogenic variant [Santorelli et al 1993].

Other. Individuals with Leigh syndrome may present with extraneurologic multisystem manifestations. These can include cardiac (hypertrophic or dilated cardiomyopathy [Wang et al 2008, Hadzsiev et al 2010]), hepatic (hepatomegaly or liver failure [Van Hove et al 2010, Duff et al 2015]), or renal (renal tubulopathy or diffuse glomerulocystic kidney damage [López et al 2006, Naess et al 2009] manifestations. Leigh syndrome as a whole is the most phenotypically heterogeneous mitochondrial disease, with more than 200 associated phenotypes [Rahman et al 2017].

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 individuals, death may appear to be sudden and unexpected.

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. The heterogeneous clinical presentation that occurs in Leigh syndrome is also present in Leigh-like syndromes.

NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa). Onset of symptoms, particularly ataxia and learning difficulties, is often in early childhood.

NARP 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 1997, Sembrano et al 1997, Rawle & Larner 2013]. 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 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 mutated and wild type mtDNA (the heteroplasmic mutant load), the variation in the proportion of abnormal mtDNA 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 the proportion of abnormal mtDNA [White et al 1999c] as well as a strong correlation between the proportion of abnormal mtDNA 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 proportion of abnormal mtDNA 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.

Estimated probability of a severe outcome (95% CI) for an individual with the mtDNA m.8993T>G or m.8993T>C variant, based on the proportion of abnormal mtDNA (mutant load) in the individual. A severe outcome is defined as severe symptoms (more...)

• m.8993T>G. Individuals in whom the proportion of abnormal mtDNA is below 60% are usually asymptomatic, or have only mild pigmentary retinopathy or migraine headaches; however, asymptomatic adults with levels of abnormal mtDNA as high as 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 pathogenic variant present with the NARP phenotype, while those with more than 90% abnormal mtDNA have maternally inherited Leigh syndrome [Claeys et al 2016].
  Note: Overlap in the proportion of abnormal mtDNA 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 variant than m.8993T>G, and virtually all symptomatic individuals with m.8993T>C ve more than 90% abnormal mtDNA.

Genotype-phenotype correlations are much weaker for other mtDNA pathogenic variants detected in multiple unrelated individuals with 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 variants in individuals with symptoms of Leigh syndrome identifies the genetic cause of the disorder. However, unlike the m.8993T>G and m.8993T>C variants, 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%.

Penetrance

See Genotype-Phenotype Correlations.

Nomenclature

Leigh syndrome was originally described by Leigh [1951] as "subacute necrotizing encephalomyelopathy" in an infant age seven months.

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. In southeastern Australia, Leigh syndrome occurs in 1:77,000 infants, and the combined birth prevalence of Leigh syndrome plus Leigh-like syndrome was 1:40,000 [Rahman et al 1996]. In western Sweden, the prevalence of Leigh syndrome in preschool children was 1:34,000 [Darin et al 2001]. Thus, the prevalence of Leigh syndrome is likely to be 1:30,000 to 1:40,000.

Analyses of a large series of 67 individuals with Leigh or Leigh-like syndrome reported by Rahman et al [1996] have identified mtDNA pathogenic variants in 34% [Author, personal communication]. The prevalence of mtDNA-associated Leigh syndrome is likely to be 1:100,000 to 1:140,000.

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