Neuropathy ataxia retinitis pigmentosa syndrome

Alternate names

NARP syndrome; NARP

Definition

Neuropathy ataxia retinitis pigmentosa (NARP) syndrome is characterized by a variety of signs and symptoms that mainly affect the nervous system.

Onset

The condition typically begins in childhood or early adulthood, and the signs and symptoms usually worsen over time.

Epidemiology

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.

Cause

NARP results from mutations in the MT-ATP6 gene. This gene is contained in mitochondrial DNA, also known as mtDNA. Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA, known as mitochondrial DNA or mtDNA. The MT-ATP6 gene provides instructions for making a protein that is essential for normal mitochondrial function. Through a series of chemical reactions, mitochondria use oxygen and simple sugars to create adenosine triphosphate (ATP), the cell's main energy source. The MT-ATP6 protein forms one part (subunit) of an enzyme called ATP synthase, which is responsible for the last step in ATP production.

Gene mutations

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.

Inheritance

Mitochondrial inheritance patterns

• 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.
• Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, children can inherit disorders resulting from mtDNA mutations only from their mother. These disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass traits associated with changes in mtDNA to their children.
• Most of the body's cells contain thousands of mitochondria, each with one or more copies of mtDNA. The severity of some mitochondrial disorders is associated with the percentage of mitochondria in each cell that has a particular genetic change. Most individuals with NARP have a 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—more than 90 percent to 95 percent—it usually 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, and because some individuals with MT-ATP6 gene mutations have related signs and symptoms that do not follow the specific patterns of these conditions, researchers believe that the conditions may be part of a spectrum of overlapping features rather than two distinct syndromes.

Signs and symptoms

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). Affected individuals may also have vision loss caused by a condition called retinitis pigmentosa. Other features of NARP include learning disabilities, developmental delay, seizures, dementia, hearing loss, and cardiac conduction defects.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 30%-79% of people have these symptoms

• Abnormal basal ganglia MRI signal intensity
• Abnormal visual field test
• Babinski sign
• Blindness
• Cerebral cortical atrophy(Decrease in size of the outer layer of the brain due to loss of brain cells)
• Constriction of peripheral visual field(Limited peripheral vision)
• Corticospinal tract atrophy
• Dementia(Dementia, progressive)
• Global developmental delay
• Headache(Headaches)
• Hearing impairment(Deafness)
• Intellectual disability, severe(Early and severe mental retardation)
• Irritability(Irritable)
• Muscle spasm
• Myoclonic spasms
• Nystagmus
• Involuntary, rapid, rhythmic eye movements
• Optic disc pallor
• Progressive gait ataxia
• Proximal muscle weakness(Weakness in muscles of upper arms and upper legs)
• Retinal arteriolar tortuosity
• Retinal pigment epithelial mottling
• Rod-cone dystrophy
• Seizure
• Sensory neuropathy(Damage to nerves that sense feeling)
• Short stature(Decreased body height)
• Ventriculomegaly

Diagnosis

NARP should be suspected in individuals with the clinical, electrophysiologic, and radiographic features listed below. However, not all features may be present, at least initially, and the diagnosis should be suspected in individuals with several of the following features:

• Muscle weakness
• Neuropathy
• Ataxia
• Seizures
• Retinitis pigmentosa or optic atrophy
• Learning difficulties

Other:

• Electromyography and nerve conduction studies may demonstrate peripheral neuropathy (which may be a sensory or sensorimotor axonal polyneuropathy).
• Cerebral and cerebellar atrophy may be noted on brain MRI.
• Electroretinogram may reveal abnormalities (including small-amplitude waveform) or may be normal.
• Strict diagnostic criteria for NARP have not yet been established. The diagnosis of NARP is established in a proband with the above suggestive clinical features and identification of a mtDNA pathogenic variant on molecular genetic testing.

Treatment

• Supportive treatment includes use of sodium bicarbonate or sodium citrate for acute exacerbations of acidosis and antiepileptic drugs 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.

Agents/circumstances to avoid: Sodium valproate and barbiturates, anesthesia, and dichloroacetate.[1].

NIH genetic and rare disease info

• NIH info on Neuropathy ataxia retinitis pigmentosa syndrome

Neuropathy ataxia retinitis pigmentosa syndrome is a rare disease.

Neuropathy ataxia retinitis pigmentosa syndrome Resources
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