Neuropathy, Ataxia, and Retinitis Pigmentosa Syndrome

Abstract

Objectives: 

To provide an overview about the phenotype, genotype, treatment, and outcome of neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome.

Methods: 

Systematic review by application of appropriate search terms.

Results: 

NARP syndrome is a syndromic mitochondrial disorder due to pathogenic variants in MT-ATP6. The canonical phenotypic features of NARP syndrome include proximal muscle weakness, axonal neuropathy, cerebellar ataxia, and retinitis pigmentosa. Noncanonical phenotypic features in NARP include epilepsy, cerebral or cerebellar atrophy, optic atrophy, cognitive impairment, dementia, sleep apnea syndrome, hearing impairment, renal insufficiency, and diabetes. So far, 10 pathogenic variants in MT-ATP6 have been associated with NARP, NARP-like syndrome, or NARP/maternally inherited Leigh overlap syndrome. Most pathogenic MT-ATP6 variants are missense, but a few truncating pathogenic variants have been reported. The most common variant responsible for NARP is the transversion m.8993T>G. Only symptomatic treatment for NARP syndrome is available. In most of the cases, patients die prematurely. Patients with late-onset NARP survive longer.

Conclusions: 

NARP is a rare, syndromic, monogenic mitochondrial disorder due to pathogenic variants in MT-ATP6. The nervous system and the eyes are most commonly affected. Although only symptomatic treatment is available, the outcome is usually fair.

INTRODUCTION

Neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome is a syndromic mitochondrial disorder (MID) due to pathogenic variants in the MT-ATP6 gene. The gene encodes the alpha-subunit of complex-V of the respiratory chain.¹ Pathogenic variants in this gene usually reduce the amount of complex-V and impair function of complex-V.² Among MIDs, complex-V deficiency is generally a rare cause of respiratory chain dysfunction.³ The phenotype of carriers with pathogenic variants strongly depends on the heteroplasmy rate (ratio between wild-type and mutated mtDNA) and tissu distribution of the MT-ATP6 variants in this gene.

METHODS

A literature search in the databases PubMed and Google Scholar was conducted using the search terms “NARP”, “neuropathy ataxia retinitis pigmentosa”, in combination with “ATP6”, “mitochondrial DNA”, “respiratory chain”, and “complex-V”. In addition, reference lists were checked for further articles meeting the search criteria. Included were only original articles detailing individual patients' data published since 1966 until the end of January 2022. Excluded from the data analysis were reviews, abstracts, proceedings, and editorials. Cohort studies which did not provide sufficient individual data were also excluded. Altogether 46 articles were included in the review.

RESULTS

Phenotype

Patients with NARP syndrome usually present with a uniform phenotype which can be relatively stable for many years, but episodic deterioration can occur most frequently in association with viral illness.⁴ Onset is more frequently in infancy (early-onset form) than in adolescence/adulthood (late-onset form).^5,6 Canonical features of NARP syndrome include proximal muscle weakness, axonal neuropathy, cerebellar ataxia, and retinitis pigmentosa. Neuropathy in patients with NARP affects lower more than upper limbs, motor and sensory fibers equally, and is usually of the axonal type.⁷ Ataxia is of the cerebellar type.⁸ Retinitis pigmentosa usually manifests as “salt and pepper retinopathy” and with night blindness.⁸ In addition to retinitis pigmentosa, some patients may present with sluggish pupils, nystagmus, ophthalmoplegia, or visual field defects.⁸ Learning difficulties are frequently observed, but other cognitive functions are usually intact at onset. Some patients develop depression which can culminate in suicidal ideation.⁷

Occasionally, the phenotypic spectrum of NARP exceeds the key features. Noncanonical phenotypic features in NARP particularly include short stature,⁸ epilepsy (more frequent in early than in late-onset NARP),⁵ including myoclonic epilepsy,⁹ renal insufficiency,¹⁰ cardiac arrhythmias,⁸ and sleep apnea syndrome.¹¹ Cerebral imaging may show cerebral or cerebellar atrophy⁴ or optic atrophy.¹² With progression of the disease, patients with NARP may develop hearing impairment,¹³ diabetes,¹³ dystonia,⁸ spasticity, or cognitive impairment or even dementia.^4,13 Some patients with NARP/maternally inherited Leigh syndrome (MILS) overlap syndrome manifest with epilepsy and other features of Leigh syndrome.¹⁴

Evolution of clinical manifestations in early-onset NARP usually begins with short stature, developmental delay, learning difficulties, and cerebellar ataxia in the first decade of life. Ocular manifestations usually develop in the second decade followed by proximal muscle weakness and neuropathy. Seizures, spasticity, dementia, sleep apnea syndrome, hearing impairment, and cardiac involvement follow or accompany the initial features.⁴

Genotype

NARP syndrome is due to pathogenic variants in the MT-ATP6 gene.¹⁵MT-ATP6 encodes the alpha-subunit of complex-V of the respiratory chain (F₁F₀—ATP synthetase).¹⁶ Among the >500 patients with complex-V deficiency so far reported, 26 pathogenic variants in the MT-ATP6 gene, 2 pathogenic variants in the MT-ATP6/MT-ATP8 overlap region, and 1 pathogenic variant in the MT-ATP8 gene have been reported.¹⁷ These variants manifest phenotypically not only as NARP or NARP/MILS overlap syndrome but also as MILS; spinocerebellar ataxia; familial bilateral striatal necrosis; or mitochondrial myopathy, lactic acidosis, and sideroblastic anomie.¹⁷ The most common phenotype of MT-ATP6/MT-ATP8 variants is MILS.¹⁷ Extremely rarely, pathogenic variants in either gene occur, which predominantly manifest with cardiomyopathy.³

So far, 10 pathogenic variants in the MT-ATP6 gene were associated with NARP or NARP/MILS overlap syndrome (Table 1). Most pathogenic MT-ATP6 variants are missense, but a few truncating pathogenic variants have been reported.^18–22 No pathogenic variants in the MT-ATP8 gene, which partially overlaps with MT-ATP6 in mammalian mtDNA, have been associated with the NARP phenotype. Pathogenic variants in the same mtDNA nucleotide position can generate a different spectrum of phenotypes (phenotypic heterogeneity).⁷

TABLE 1. - Pathogenic Variants Causing NARP or NARP/MILS Overlap Syndrome

Mutation	Gene	HPR (%)	Phenotype	Reference
m.9185T>C	MT-ATP6	35–100	NARP, MILS, SCA	33,36,49
m.9127delAT	MT-ATP6	10–82	NARP	21
m.9032T>C	MT-ATP6	42–96	NARP	37
m.8993T>G	MT-ATP6	80–100	NARP, MILS, FBSN	14,24
m.8993T>C	MT-ATP6	34–99	NARP, MILS, NARP/MILS, migraine	14,24,28
m.8989G>C	MT-ATP6	het	NARP	37,38
m.8858G>A	MT-ATP6	34	NARP/MILS	14
m.8839G>C	MT-ATP6	1–88	NARP	15,20
m.8729G>A	MT-ATP6	het	NARP	50
m.8618insT	MT-ATP6	85	NARP	20

het, heteroplasmic; HPR, heteroplasmy rate for NARP; LHON, Leber hereditary optic neuropathy; MLASA; mitochondrial myopathy, lactic acidosis, and sideroblastic anemia; SCA, spinocerebellar ataxia.

The most common of the pathogenic MT-ATP6 variants associated with NARP is the m.8993T>G variant.¹⁵ The variant m.8993T>G has been described in patients with NARP, NARP-MILS, and incomplete NARP¹⁴ but also in patients with nonsyndromic phenotypes.²³ Rarely, the variant manifests phenotypically with renal failure or lactic acidosis.¹⁰ Heteroplasmy rates range between low levels and 100% (Table 1).^14,24 Metroplasty rates are significantly higher in patients with NARP with epilepsy than without epilepsy.¹⁴ A single patient carrying the m.8993T>G with a heteroplasmy rate of 94% in urine epithelial cells presented with NARP and not with the expected more severe MILS phenotype.²⁵ The pathogenic variant causes an exchange of the evolutionary highly conserved leucine at position 156 by arginine (L156R). The m.8993T>G variant causes a reduction or loss of F1F0-ATPase.²⁶

The variant m.8993T>C (p.Leu156Pro) is the second most frequently responsible for NARP. The variant is phenotypically heterogeneous and manifests as NARP, NARP/MILS overlap, MILS, or migraine.^14,24,27,28 Concerning NARP, the m.8993T>C variant results in a clinical picture similar to that of m.8993T>G but is generally milder.²⁹ Heteroplasmy rates range between 34% and 99% (Table 1).^14,24,27,28 A 74-year-old man, carrying the m.8993T>C variant with a heteroplasmy of 95%, presented with ataxia, myoclonus aggravated by movement and photic stimulation in the absence of epilepsy and axonal neuropathy with muscle weakness but without retinopathy.⁶ The variant m.8993T>C may also manifest with episodic ataxia and transient hemiparesis.³⁰

More rarely reported are the variants m.9185T>C, m.9127delAT, m.9032T>C, m.8989G>C, m.8839G>C, n.8618insT, and m.8858G>A (Table 1). The variant m.9185T>C may not only manifest as NARP but also as Charcot–Marie–Tooth neuropathy, MILS, or spinocerebellar ataxia (Table 1).³¹ Some patients may manifest with episodic weakness and neuropathy.^32,33 The phenotype of these variants is usually milder as compared with that of the variant m.8993T>G. and m.9176T>G.^34,35 Most of these variants have been described in only a single family or a single patient. Heteroplasmy rates of these rarer variants are also highly variable and range between 10% and 96% (Table 1).^{15,21,22,33,36–38}

Generally, heteroplasmy rates in patients with NARP show a broad range but are usually high (70%–90%) in affected patients but low (10%–15%) in asymptomatic carriers, such as mothers or other asymptomatic or mildly symptomatic relatives of patients with NARP.^25,39,40 Patients with a metroplasty rate >90% usually manifest with MILS and do not survive beyond infancy.^6,39 Heteroiplasmy rates can increase between subsequent generations.³⁹

Pathophysiology

Pathogenic variants in the MT-ATP6 gene result in reduced ATP production and increased oxidative stress because they inhibit oxidative phosphorylation and enhance the production of free radicals.²⁶ Because the increase in free radicals also inhibits the oxidative phosphorylation, it most likely contributes to the reduction of the ATP production.²⁶ Physiologically, subunit-a of the MT-ATP6 gene together with a ring of identical subunits-c moves protons across the mitochondrial inner membrane coupled to rotation of the subunit c-ring and ATP synthesis.¹⁶ Pathophysiologically, MT-ATP6 variants reduce complex-V activity because of impaired assembling of its components. MT-ATP6 variants, such as the pathogenic variant m.8993T>G, may not only impair the assembly of the ATPase but may also reduce proton flow through F0.²⁶ The variant m.8839G>C lowers the efficiency between proton translocation within F0 and F1 rotation, required for ATP synthesis.¹⁵ Fibroblasts from patients with NARP show a tendency of increased apoptosis presumably triggered by increased oxidative stress.²⁶

Frequency

The prevalence of NARP syndrome is unknown but estimated as 0.8–1.0/100,000 or as 1–9/100,000.⁸ The prevalence is generally regarded as lower as that of MILS. The incidence of NARP is also unknown, but it is estimated that NARP occurs in 1/12,000 live births.

Diagnosis

No uniform criteria for diagnosing NARP have been established yet. NARP is diagnosed on the clinical presentation, neurologic examination, nerve conduction studies, ophthalmologic investigations, cerebral MRI, and genetic studies (mtDNA sequencing). Depending on the stage of the disease, patients report visual problems, impaired hearing, muscle weakness, fatigue, tiredness, sensory disturbances, and gait problems. Neurologic examination may show visual impairment, hypoacusis, cerebellar ataxia, proximal and distal muscle weakness, sensory disturbances, and gait disturbance. Nerve conduction studies (NCSs) may reveal an axonal lesion of motor and sensory fibers of nerves supplying limb muscles.⁷ Electroretinography may show low-amplitude waveforms or may be normal.⁴ Cerebral MRI can show cerebral or cerebellar atrophy, cystic lesions of the putamina,⁷ or optic atrophy. Serum lactate may be elevated, particularly postprandial or during subthreshold exercise. Some of the plasma amino acids may be elevated. In patients carrying the m.8993T>G variant, plasma citrulline levels have been found decreased.⁴¹ Analysis of urine organic acids may reveal elevated Krebs cycle intermediates. Biochemical investigations of the muscle are frequently normal in patients with complex-V defects but may occasionally show complex-I or complex-IV deficiency.⁴ Generally, only about half of the respiratory chain defects on biochemical investigations of the muscle can also be identified in skin fibroblasts.⁴

Treatment

Currently, only symptomatic treatment for NARP syndrome is available. A causative approach has been tried in cell cultures but is not yet applicable to humans.⁴² In case of acute exacerbations of lactic acidosis, infusion of sodium bicarbonate or sodium citrate may be temporarily beneficial.⁴ Epilepsy requires appropriate treatment with antiseizure drugs. In case of dystonia, patients may benefit from benzhexol, baclofen, tetrabenazine, or gabapentin.⁸ In case neuropathy is manifesting with neuropathic pain, sodium-channel blockers can be beneficial, if given in an appropriate dosage and if tolerated. Patients require psychological support and should be followed up periodically by neurologists, ophthalmologists, otorhinolaryngologists, and cardiologists to monitor disease progression. Agents to avoid include valproic acid, barbiturates, phenytoin, certain anesthetics, and dichloroacetate.

Cells heteroplasmic for the variant m.8993T>G and infected with an adenovirus encoding the mitochondrially targeted R.Xmal restriction endonuclease which selectively destructs mutated mtDNA, resulted in improved ability to use galactose, in an increased rate of oxygen consumption and ATP production, and in reduced lactic acid production.⁴² Translational studies in humans using this approach have not been conducted yet. Although antioxidants (eg, melatonin and selenium) have been shown to reduce oxidative stress in cell cultures or cybrids,^43,44 the therapeutic effect in affected patients is entirely absent or minimal. It has been shown that the variant m.8993T>G itself activates antioxidant defense systems.⁴⁵ Experimental approaches have shown that overexpression of the mitochondrial zinc-finger nuclease, which degrades mutant tDNA, can improve the metabolic signature in cells carrying the variant m.8993T>G.⁴⁶ In human fibroblasts carrying the m.8993T>G variant, supplementation of alpha-ketoglutarate and alpha-aspartate has been shown beneficial regarding ATP production and cell survival.⁴⁷

Genetic Counseling

Because NARP is due to mtDNA variants, they can be transmitted from the previous generation only through the maternal line. The father of an affected proband is not at risk of transmitting the pathogenic variant. If the mother of an affected individual carries the pathogenic variant, her heteroplasmy rates are usually lower than those of the affected proband why she remains asymptomatic or develops only mild symptoms. If heteroplasmy rates are high in the mother, she can develop severe manifestations in adulthood. In <25% of the cases, pathogenic MT-ATP6 variants occur sporadically.⁴⁸ Only female offspring of a maternal carrier are at risk of inheriting the pathogenic variant. Their risk of developing symptoms depends on the tissue distribution of the variant and its heteroplasmy rates. Prenatal testing and preimplantation genetic testing for female carriers of the pathogenic variant are feasible from mtDNA extracted from noncultured fetal cells or single blastomeres, but the long-tern outcome of an offspring carrying a pathogenic variant cannot be reliably predicted.

Outcome

The outcome of patients with NARP depends on the type of pathogenic variant, on heteroplasmy rates, tissue distribution, on the severity of the phenotype, the presence of comorbidities, and the effect of the applied treatment. With progression of the disease, patients become increasingly dependent of others and the quality of life becomes severely reduced. Patients may go blind and deaf and may experience depression and dementia. Owing to the progressive neurogenic muscle weakness, patients may become wheelchair-bound. In most of the cases, patients with NARP syndrome die prematurely. Some patients may even die from sudden death.³⁹ Patients with late-onset NARP may survive longer than those with early-onset NARP.

CONCLUSIONS

NARP is a rare, syndromic, monogenic MID due to pathogenic variants in MT-ATP6. The nervous system and the eyes are most commonly affected. More rarely affected are the ears, endocrine organs, and the heart. NARP is diagnosed upon the clinical presentation, instrumental investigations, and genetic studies. Although only symptomatic treatment is available, the outcome is usually fair.