Neuropathy, Ataxia, Retinitis Pigmentosa (NARP) Syndrome

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Article initiated by:

Andrew Go Lee, MD, Peter W. Mortensen, MD, Sami Younes, Subahari Raviskanthan, MBBS

All contributors:

Nagham Al-Zubidi, MD, Subahari Raviskanthan, MBBS, Danah Albreiki, MBBS FRCSC

Assigned editor:

Danah Albreiki, MBBS FRCSC

Review:

Assigned status Up to Date

 by Danah Albreiki, MBBS FRCSC on October 26, 2024.

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Disease Entity

Disease

Neuropathy, ataxia, retinitis pigmentosa syndrome (NARP) is a rare progressive neurodegenerative disease that classically presents with the features in its name as well as other neurological findings, including cognitive impairments and seizures. Holt et al. described the first case of NARP in 1990.

Epidemiology

NARP classically manifests in childhood and is estimated to have an incidence rate of approximately 1 to 9 per 100,000. NARP affects males and females in equal numbers.

Etiology

NARP is a mitochondrial disorder that is primarily caused by a thymine to guanine point mutation at nucleotide 8993 of the MT-ATP6 gene (m.8993T>G). Other less common variants of NARP have been described, including a thymine to cytosine substitution at the same site (m.8993T>C) and a guanine to adenine substitution at nucleotide 14459 of the MT-ND6 gene (m.14459G>A).

Pathophysiology

A significant correlation seems to exist between the proportion of pathologic to wild-type mtDNA and clinical outcomes, with mutant gene heteroplasmy levels that are generally around 70-90%. The m.8993T>G variant substitutes a conserved leucine with an arginine in subunit 6 of the mitochondrial F1F0 ATP synthase. Subunit 6 forms part of the F0 proton channel of the ATP synthase and the leucine to arginine amino acid substitution appears to block proton translocation and inhibit ATP synthesis. The pathogenic variant may also interfere with the structure and stability of the ATP synthase. Inhibition of ATP synthesis by the m.8993T>G variant can increase mitochondrial membrane potential and lead to increased production of superoxide, potentially triggering increased cell death. The m.8993T>C pathogenic variant changes the leucine to a proline at the same position, which results in decreased severity of interference with proton translocation and an overall milder clinical phenotype than the m.8993T>G variant. The MT-ND6 m.14459G>A pathogenic variant causes a significant decrease in the steady-state amounts of fully assembled complex I.

Diagnosis

History

Generally, individuals with NARP become symptomatic in early childhood. The classical symptoms are neuropathy (proximal neurogenic muscle weakness along with sensory neuropathy), cerebellar ataxia, and retinitis pigmentosa but other accompanying symptoms and signs may occur in NARP (see below). Often symptoms of learning difficulty and ataxia start in early childhood. NARP is progressive but with periods of stability which may last for years but episodes of deterioration can occur. Some NARP exacerbations may be triggered by illness (e.g., viral infection).

Symptoms & Signs

Common additional symptoms in NARP include seizures, migraines, learning disabilities, developmental delays, sensory neuropathies, and muscle weakness. Typical ocular findings in NARP are the “salt-and-pepper” retinopathy appearing early in the disease course that eventually progresses to retinitis pigmentosa. Other ocular findings include nystagmus and sluggish pupils. Juaristi et al. report on a NARP patient with macular atrophy on OCT. Less common findings seen with NARP include hearing loss, ophthalmoplegia, cardiac conduction defects, anxiety, dementia, sleep apnea, and short stature. NARP does not typically cause lactic acidosis, which contrasts with other mitochondrial disorders

Diagnostic Workup

Though difficult to diagnose, NARP is generally worked-up by identifying key signs and symptoms through a detailed patient history and comprehensive clinical evaluation. While there are no clear diagnostic criteria, genetic testing can be used to confirm the diagnosis of NARP through detection of the common mutated variants.

Other potentially helpful tests that can help delineate NARP from other disorders include a complete blood count, urinalysis, and lumbar puncture. Magnetic resonance imaging (MRI) and computerized tomography (CT) of the brain may demonstrate cerebral and cerebellar atrophy along with basal ganglia abnormalities. An electrocardiogram and echocardiogram can be used to detect arrhythmias and cardiomyopathies, while electromyography and nerve conduction studies can be used to assess for peripheral neuropathy. An electroencephalogram can be helpful because of the association between seizures and NARP. Keränen and Kuusisto report on a patient with NARP that had generalized spike and wave discharges on EEG that preceded the development of adult-onset seizures.

Differential Diagnosis

NARP must be differentiated from other mitochondrial disorders, which share many common features (particularly Leigh syndrome). Leigh syndrome is an autosomal recessive disorder that presents during infancy and results in many of the same neurologic features as NARP in a progressively degenerative fashion. Classic symptoms include motor regression, loss of appetite, vomiting, seizures, generalized weakness, hypotonia, and episodes of lactic acidosis.

Other disorders that should be considered include various ataxia disorders, Charcot-Marie-Tooth hereditary neuropathy, retinitis pigmentosa, pyruvate dehydrogenase deficiency, and biotinidase deficiency.

Management

Medical Therapy

There is no cure for NARP and the treatment is largely supportive including treatments for acute acidosis (e.g., sodium bicarbonate or sodium citrate), anticonvulsants, dystonia (e.g., baclofen, gabapentin), and cardiomyopathy. Regular surveillance (every 6-12 months) and psychological support may be helpful. Some medications to consider avoiding that may worsen NARP include sodium valproate, barbiturates, dichloroacetate, and anesthetics.

Prognosis

Whilst NARP can have periods of stability, generally there is disease progression over time. Patients can experience cognitive decline, with vision, hearing and mobility impairments. It can be exacerbated by viral illness.

Genetic Counseling

NARP is a mitochondrial disease, and therefore transmitted by mothers to all offspring. Mutation load becomes an important factor in determining the clinical severity of the disease in potential progeny. Women should be counseled on the potential variable expressivity of NARP due to the genetic shift from mother to offspring.

If there is a family history of NARP, prenatal use of chorionic villus sampling with cytogenetic analysis and amniocentesis can be used to identify mutations in the fetus. Preimplantation genetic diagnosis is another method to detect mutations.

In summary, NARP is a mitochondrial disorder that is characterized by neuropathy, ataxia, and retinitis pigmentosa. Although there is no cure, genetic counseling and supportive treatments should be considered and appropriate multi-disciplinary management (e.g., neurology, ophthalmology, cardiology) is recommended.