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 a heteroplasmic pathogenic variant in one of the three mitochondrial genes known to be involved in NARP identified by molecular genetic testing.
Management: Treatment of manifestations: Supportive treatment includes use of sodium bicarbonate or sodium citrate for acute exacerbations of acidosis and anti-seizure medication 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.
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