Neuropathy, ataxia, and retinitis pigmentosa (NARP) is a clinically heterogeneous progressive condition characterized by a combination of proximal neurogenic muscle weakness, sensory-motor neuropathy, ataxia, and pigmentary retinopathy.
The prevalence of NARP is unknown. This disorder is probably less common than a similar but more severe condition, Leigh syndrome, which affects about 1 in 40,000 people.
Beginning in childhood or early adulthood, most people with NARP experience numbness, tingling, or pain in the arms and legs (sensory neuropathy); muscle weakness; and problems with balance and coordination (ataxia). Many affected individuals also have vision loss caused by changes in the light-sensitive tissue that lines the back of the eye (the retina). In some cases, the vision loss results from a condition called retinitis pigmentosa. This eye disease causes the light-sensing cells of the retina gradually to deteriorate.
Learning disabilities and developmental delays are often seen in children with NARP, and older individuals with this condition may experience a loss of intellectual function (dementia). Other features of NARP include seizures, hearing loss, and abnormalities of the electrical signals that control the heartbeat (cardiac conduction defects). These signs and symptoms vary among affected individuals.
NARP results from mutations in the MT-ATP6 gene. This gene is contained in mitochondrial DNA, also known as mtDNA. The MT-ATP6 gene provides instructions for making a protein that is essential for normal mitochondrial function. The MT-ATP6 protein forms one part (subunit) of an enzyme called ATP synthase, which is responsible for the last step in ATP production. Mutations in the MT-ATP6 gene alter the structure or function of ATP synthase, reducing the ability of mitochondria to make ATP. It remains unclear how this disruption in mitochondrial energy production leads to muscle weakness, vision loss, and the other specific features of NARP.
Most individuals with NARP have the specific MT-ATP6 mutation in 70 percent to 90 percent of their mitochondria. When this mutation is present in a higher percentage of a person's mitochondria—greater than 90 percent to 95 percent—it causes a more severe condition known as maternally inherited Leigh syndrome. Because these two conditions result from the same genetic changes and can occur in different members of a single family, researchers believe that they may represent a spectrum of overlapping features instead of two distinct syndromes.
This condition is inherited in a mitochondrial pattern, which is also known as maternal inheritance. This pattern of inheritance applies to genes contained in mtDNA, hence, children can only inherit this disorder from their mother. The disorder can appear in every generation of a family and can affect both males and females.
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. Mitochondrial studies or NARP mtDNA evaluation plays a role in genetic diagnosis. Prenatal diagnosis can be done 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.
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.
NARP syndrome is not curable. 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.
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