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Mitochondrial DNA-Associated Leigh Syndrome and NARP

Authors: Thorburn, David R  Rahman, Shamima 
Citation: PubMed Book Article
Pubmed: (View Article at PubMed) PMID:20301352

CLINICAL 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.


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RGD Object Information
RGD ID: 5148009
Created: 2011-09-01
Species: All species
Last Modified: 2017-01-04
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.