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A clinically heterogeneous progressive condition characterized by a combination of proximal neurogenic muscle weakness, sensory-motor neuropathy, ataxia, and pigmentary retinopathy.
ORPHA:644Classification level: Disorder
Wordwide prevalence is unknown but may be estimated at 0.8-1/100,000.
NARP (Neuropathy, Ataxia, and Retinitis Pigmentosa) syndrome is characterized by a great phenotypic variability and habitually clearly manifests in young adulthood. Early childhood manifestations often describe learning difficulties, developmental delay and ataxia, whereas ocular signs, proximal neurogenic muscle weakness with sensory neuropathy usually develop in the second decade of life. Ocular manifestations are variable and range from early salt and pepper retinopathy to retinitis pigmentosa, sluggish pupils, nystagmus, ophthalmoplegia, night blindness and loss of visual field. Other features may include short stature, seizures, corticospinal tract atrophy, depression, dementia, sleep apnea, hearing loss or cardiac arrhythmias.
NARP syndrome is caused in the large majority of patients by a m.8993T>C/G in the subunit 6 of mitochondrial H(+)-ATPase gene (MTATP6). Most NARP patients have 70-90% mutated mitochondrial DNA. The m.8993T>G mutation is also present in 8-10% of patients with Leigh syndrome when mutated mitochondrial DNA is > 90%. Less common ATP6 heteroplasmic mutations include m.8839G>C, m.8989G>C, m.8618-8619insT, m.9032T>C, and m.9127-9128 delAT microdeletion, all identified in single families.
Diagnosis is based on clinical manifestations, electroretinogram, and genetic testing. Peripheral neuropathy may be demonstrated by electromyography, whereas an MRI may pick up cerebral and cerebellar atrophy in later stages. Serum lactate may be normal or elevated. At muscle biopsy, histochemical or biochemical signs of oxidative phosphorylation may be absent.
Differential diagnosis includes maternally inherited Leigh syndrome (MILS, like NARP syndrome part of the same group of disorders of mitochondrial oxidative phosphorylation), Refsum disease, Cockayne syndrome, abetalipoproteinemia, Usher syndrome (see these terms), neurological complication of lipidosis or rare cases of spinocerebellar disorder/ataxia.
Prenatal diagnosis by amniocentesis or chorionic villus sampling and cytogenetic analysis if the mutation has been identified in an affected family member. Preimplantation genetic diagnosis is available for affected couples in few centers.
NARP syndrome is a maternally inherited syndrome and women can transmit to all their offspring. Clinical severity usually depends on the mutation load. There must be extreme caution in predictive counseling because of the genetic shift between mother and offspring.
Management and treatment
Management and treatment is only supportive and may include sodium bicarbonate or sodium citrate for acute aggravation of acidosis; antioxidant treatment, treatment of epileptic seizures by appropriate anticonvulsants; treatment of dystonia (e.g., benzhexol, baclofen, tetrabenazine, and gabapentin); and anticongestive therapy in case of cardiomyopathy. Patients require psychological support and should be followed up periodically by neurologists, ophthalmologists and cardiologists to monitor disease progression. Agents to avoid include Sodium Valproate, barbiturates and anesthesia (in general) as well as dichloroacetate.
As NARP syndrome is progressive, patients may become increasingly dependent of others. The quality of life is severely reduced. Patients may go blind and deaf and may experience depression and dementia. Due to the progressive neurogenic muscle weakness patients may become wheelchair bound.
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