RARE DISEASE
NARP syndrome
NARP syndrome
NARP syndrome
Synonyms: Neurogenic muscle weakness-ataxia-retinitis pigmentosa syndrome, Neuropathy-ataxia-retinitis pigmentosa syndrome
Synonyms: Neurogenic muscle weakness-ataxia-retinitis pigmentosa syndrome, Neuropathy-ataxia-retinitis pigmentosa syndrome
Synonyms: Neurogenic muscle weakness-ataxia-retinitis pigmentosa syndrome, Neuropathy-ataxia-retinitis pigmentosa syndrome
Drug discovery
0
drugs
With orphan designations
Overview
Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) Syndrome is a rare, progressive mitochondrial disorder caused by heteroplasmic mutations in the MT-ATP6 gene, disrupting ATP synthase function [1][6][10]. It presents with proximal neurogenic muscle weakness, sensory neuropathy, cerebellar ataxia, and retinitis pigmentosa, alongside variable neurological features like seizures, cognitive decline, and hearing loss [1][6][10]. Diagnosis relies on clinical evaluation, genetic testing, and imaging (MRI/CT showing cerebral/cerebellar atrophy) [1][3][10]. Management is symptomatic, with multidisciplinary supportive care [7][15][18].
Therapies
No disease-modifying treatments exist. Focus includes:
- Symptomatic management (anticonvulsants, hearing aids, low-vision aids) [7][15][18].
- Avoidance of metabolic stressors (infections, mitochondrial toxins) [10][13].
- Investigational approaches (coenzyme Q10, mTOR inhibitors in clinical trials) [5][8].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders
Research Papers
60 drug discovery papers about NARP syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
60 drug discovery papers about NARP syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-04-29 | Specific elimination of m.8993T>G mitochondrial haplotype in NARP cybrid cells by CRISPR-Cas9 system.
Mutations in mitochondrial DNA can cause a wide range of neuromuscular and neurodegenerative diseases in humans. The heteroplasmy level, coexistence of both wild-type and mutant mtDNA within a cell, determines the manifestation and severity of disease symptoms. Therefore, the development of strategies to shift heteroplasmy toward wild-type mtDNA is critical for advancing therapies for mitochondrial disorders. Mitochondrial localization of the modified CRISPR-Cas9 system components was analyzed using western blotting, immunocytochemical staining, confocal microscopy, and immunoelectron microscopy. To assess the heteroplasmy shift, cybrid cell lines carrying the clinically relevant m.8993T>G variant associated with Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) syndrome were used. The heteroplasmy level was evaluated by RFLP analysis of PCR-amplified mtDNA fragments encompassing the mutation site. We adapted the widely used CRISPR-Cas9 system, originally designed for editing nuclear DNA, to induce a heteroplasmy shift of the pathogenic m.8993T>G point mutation in human cybrid cells. We demonstrated that the modified components of the CRISPR-Cas9 system – the mitoCas9 nuclease fused to the mitochondrial targeting sequence from COX8A, and a single guide RNA containing a mitochondrial import determinant within the tetraloop – are effectively imported into the mitochondrial matrix. Transient transfection of the modified sgRNA into cybrid cells stably expressing mitoCas9 resulted in a detectable shift in heteroplasmy. Mitochondria-targeted CRISPR-SpCas9 system can selectively reduce the mutant m.8993T>G mtDNA load in human cybrid cells, achieving a reproducible shift in heteroplasmy. The online version contains supplementary material available at 10.1038/s41598-026-49007-y.
2026-01-26 | Targeting mitochondrial deubiquitinase USP30 to induce mitophagy in heteroplasmic mitochondrial diseases.
BACKGROUND: Mitochondrial DNA (mtDNA) diseases are heterogeneous and lack effective treatments. Their severity correlates with mutant mtDNA load. Mitophagy degrades dysfunctional mitochondria, contributing to a healthy mitochondrial pool. USP30, a mitochondrial deubiquitinase, limits mitophagy by removing the ubiquitin tagging mitochondria for degradation. We investigated whether inhibiting USP30 could enhance mitophagy and reduce mutant mtDNA load in a heteroplasmic mitochondrial disease. METHODS: Cybrids cells harboring mutant m.8993T > G mtDNA - common cause of NARP syndrome and maternally inherited Leigh syndrome (MILS) - were treated with USP30 inhibitor MF-094 under glycolytic and oxidative phosphorylation conditions. On-target activity of MF-094 was assessed by mitochondrial ubiquitination (western-blot) and mitolysosome formation (microscopy). The mutation’s effects were investigated on cell proliferation and metabolism (respirometry and ATP levels). The impact of MF-094 on mutant mtDNA load and mtDNA copy number was quantified by PCR. RESULTS: Comparing with control cells (0% mutant mtDNA), cells with mutant mtDNA exhibited reduced proliferation and ATP levels under oxidative phosphorylation conditions; and reduced oxygen consumption, increased extracellular acidification, and sustained resazurin metabolism after mitochondrial inhibition under glycolytic conditions. MF-094 induced mitophagy via increased mitolysosome formation. Mechanistically, MF-094 showed on-target effects, increasing mitochondrial ubiquitination. However, chronic treatment (3–6 weeks) evoked only a small (5%) non-significant reduction in mutant mtDNA load. CONCLUSIONS: Despite inducing mitophagy, the USP30 inhibitor MF-094 showed little potential to manage m.8993T > G related diseases, as it did not significantly reduce the load of this NARP/MILS causing mtDNA mutation. These results highlight the complexity of mutant mtDNA management and the need for innovative strategies for these disorders.
2025-05-01 | Mitochondrial DNA point mutations and large-scale deletions in maternally inherited metabolic disorders: Genotype-phenotype correlations
Mitochondrial diseases are not rare. They affect roughly 1 in 5,000 individuals, yet their genetic heterogeneity continues to challenge clinical diagnosis and prognosis. This research analyzed genotype-phenotype correlations in 128 patients diagnosed with maternally inherited metabolic disorders carrying mitochondrial DNA (mtDNA) point mutations or large-scale deletions. The patient cohort presented with six primary clinical phenotypes: MELAS, MERRF, NARP/Leigh syndrome, chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, and maternally inherited diabetes with deafness. Heteroplasmy levels ranged from 18% to 97% across different tissues, with blood showing consistently lower values than muscle. A positive correlation (r² = 0.73) was identified between heteroplasmy level and clinical severity score. Patients harboring the m.8993T>G mutation displayed the highest median severity, while those with single large-scale deletions showed the most variable clinical presentations. These findings reinforce that heteroplasmy thresholds differ substantially among mutation types and affected tissues.
2024-12-02 | Expanded-Access Use of Elamipretide Improves Quality of Life in Patients With Rare Mitochondrial Disorders Characterized by Ophthalmic Symptoms: A Case Series.
This case series presents the use of elamipretide in two patients with different progressive mitochondrial disorders (chronic progressive external ophthalmoplegia [CPEO] plus and neuropathy, ataxia, and retinitis pigmentosa [NARP] syndrome) characterized by ophthalmic traits. Elamipretide was well tolerated and both patients demonstrated improvement in symptoms while on therapy.
2024-08-28 | Pathological Role of High Sugar in Mitochondrial Respiratory Chain Defect-Augmented Mitochondrial Stress.
According to many research groups, high glucose induces the overproduction of superoxide anions, with reactive oxygen species (ROS) generally being considered the link between high glucose levels and the toxicity seen at cellular levels. Respiratory complex anomalies can lead to the production of ROS. Calcium [Ca2+] at physiological levels serves as a second messenger in many physiological functions. Accordingly, mitochondrial calcium [Ca2+]m overload leads to ROS production, which can be lethal to the mitochondria through various mechanisms. F1F0-ATPase (ATP synthase or complex V) is the enzyme responsible for catalyzing the final step of oxidative phosphorylation. This is achieved by F1F0-ATPase coupling the translocation of protons in the mitochondrial intermembrane space and shuttling them to the mitochondrial matrix for ATP synthesis to take place. Mitochondrial complex V T8993G mutation specifically blocks the translocation of protons across the intermembrane space, thereby blocking ATP synthesis and, in turn, leading to Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) syndrome. This study seeks to explore the possibility of [Ca2+]m overload mediating the pathological roles of high glucose in defective respiratory chain-mediated mitochondrial stress. NARP cybrids are the in vitro experimental models of cells with F1FO-ATPase defects, with these cells harboring 98% of mtDNA T8993G mutations. Their counterparts, 143B osteosarcoma cell lines, are the parental cell lines used for comparison. We observed that NARP cells mediated and enhanced the death of cells (apoptosis) when incubated with hydrogen peroxide (H2O2) and high glucose, as depicted using the MTT assay of cell viability. Furthermore, using fluorescence probe-coupled laser scanning confocal imaging microscopy, NARP cells were found to significantly enable mitochondrial reactive oxygen species (mROS) formation and enhance the depolarization of the mitochondrial membrane potential (ΔΨm). Elucidating the mechanisms of sugar-enhanced toxicity on the mitochondria may, in the future, help to alleviate the symptoms of patients with NARP syndromes and other neurodegenerative diseases.
2026-04-29 | Specific elimination of m.8993T>G mitochondrial haplotype in NARP cybrid cells by CRISPR-Cas9 system.
Mutations in mitochondrial DNA can cause a wide range of neuromuscular and neurodegenerative diseases in humans. The heteroplasmy level, coexistence of both wild-type and mutant mtDNA within a cell, determines the manifestation and severity of disease symptoms. Therefore, the development of strategies to shift heteroplasmy toward wild-type mtDNA is critical for advancing therapies for mitochondrial disorders. Mitochondrial localization of the modified CRISPR-Cas9 system components was analyzed using western blotting, immunocytochemical staining, confocal microscopy, and immunoelectron microscopy. To assess the heteroplasmy shift, cybrid cell lines carrying the clinically relevant m.8993T>G variant associated with Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) syndrome were used. The heteroplasmy level was evaluated by RFLP analysis of PCR-amplified mtDNA fragments encompassing the mutation site. We adapted the widely used CRISPR-Cas9 system, originally designed for editing nuclear DNA, to induce a heteroplasmy shift of the pathogenic m.8993T>G point mutation in human cybrid cells. We demonstrated that the modified components of the CRISPR-Cas9 system – the mitoCas9 nuclease fused to the mitochondrial targeting sequence from COX8A, and a single guide RNA containing a mitochondrial import determinant within the tetraloop – are effectively imported into the mitochondrial matrix. Transient transfection of the modified sgRNA into cybrid cells stably expressing mitoCas9 resulted in a detectable shift in heteroplasmy. Mitochondria-targeted CRISPR-SpCas9 system can selectively reduce the mutant m.8993T>G mtDNA load in human cybrid cells, achieving a reproducible shift in heteroplasmy. The online version contains supplementary material available at 10.1038/s41598-026-49007-y.
2026-01-26 | Targeting mitochondrial deubiquitinase USP30 to induce mitophagy in heteroplasmic mitochondrial diseases.
BACKGROUND: Mitochondrial DNA (mtDNA) diseases are heterogeneous and lack effective treatments. Their severity correlates with mutant mtDNA load. Mitophagy degrades dysfunctional mitochondria, contributing to a healthy mitochondrial pool. USP30, a mitochondrial deubiquitinase, limits mitophagy by removing the ubiquitin tagging mitochondria for degradation. We investigated whether inhibiting USP30 could enhance mitophagy and reduce mutant mtDNA load in a heteroplasmic mitochondrial disease. METHODS: Cybrids cells harboring mutant m.8993T > G mtDNA - common cause of NARP syndrome and maternally inherited Leigh syndrome (MILS) - were treated with USP30 inhibitor MF-094 under glycolytic and oxidative phosphorylation conditions. On-target activity of MF-094 was assessed by mitochondrial ubiquitination (western-blot) and mitolysosome formation (microscopy). The mutation’s effects were investigated on cell proliferation and metabolism (respirometry and ATP levels). The impact of MF-094 on mutant mtDNA load and mtDNA copy number was quantified by PCR. RESULTS: Comparing with control cells (0% mutant mtDNA), cells with mutant mtDNA exhibited reduced proliferation and ATP levels under oxidative phosphorylation conditions; and reduced oxygen consumption, increased extracellular acidification, and sustained resazurin metabolism after mitochondrial inhibition under glycolytic conditions. MF-094 induced mitophagy via increased mitolysosome formation. Mechanistically, MF-094 showed on-target effects, increasing mitochondrial ubiquitination. However, chronic treatment (3–6 weeks) evoked only a small (5%) non-significant reduction in mutant mtDNA load. CONCLUSIONS: Despite inducing mitophagy, the USP30 inhibitor MF-094 showed little potential to manage m.8993T > G related diseases, as it did not significantly reduce the load of this NARP/MILS causing mtDNA mutation. These results highlight the complexity of mutant mtDNA management and the need for innovative strategies for these disorders.
2025-05-01 | Mitochondrial DNA point mutations and large-scale deletions in maternally inherited metabolic disorders: Genotype-phenotype correlations
Mitochondrial diseases are not rare. They affect roughly 1 in 5,000 individuals, yet their genetic heterogeneity continues to challenge clinical diagnosis and prognosis. This research analyzed genotype-phenotype correlations in 128 patients diagnosed with maternally inherited metabolic disorders carrying mitochondrial DNA (mtDNA) point mutations or large-scale deletions. The patient cohort presented with six primary clinical phenotypes: MELAS, MERRF, NARP/Leigh syndrome, chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, and maternally inherited diabetes with deafness. Heteroplasmy levels ranged from 18% to 97% across different tissues, with blood showing consistently lower values than muscle. A positive correlation (r² = 0.73) was identified between heteroplasmy level and clinical severity score. Patients harboring the m.8993T>G mutation displayed the highest median severity, while those with single large-scale deletions showed the most variable clinical presentations. These findings reinforce that heteroplasmy thresholds differ substantially among mutation types and affected tissues.
2024-12-02 | Expanded-Access Use of Elamipretide Improves Quality of Life in Patients With Rare Mitochondrial Disorders Characterized by Ophthalmic Symptoms: A Case Series.
This case series presents the use of elamipretide in two patients with different progressive mitochondrial disorders (chronic progressive external ophthalmoplegia [CPEO] plus and neuropathy, ataxia, and retinitis pigmentosa [NARP] syndrome) characterized by ophthalmic traits. Elamipretide was well tolerated and both patients demonstrated improvement in symptoms while on therapy.
2024-08-28 | Pathological Role of High Sugar in Mitochondrial Respiratory Chain Defect-Augmented Mitochondrial Stress.
According to many research groups, high glucose induces the overproduction of superoxide anions, with reactive oxygen species (ROS) generally being considered the link between high glucose levels and the toxicity seen at cellular levels. Respiratory complex anomalies can lead to the production of ROS. Calcium [Ca2+] at physiological levels serves as a second messenger in many physiological functions. Accordingly, mitochondrial calcium [Ca2+]m overload leads to ROS production, which can be lethal to the mitochondria through various mechanisms. F1F0-ATPase (ATP synthase or complex V) is the enzyme responsible for catalyzing the final step of oxidative phosphorylation. This is achieved by F1F0-ATPase coupling the translocation of protons in the mitochondrial intermembrane space and shuttling them to the mitochondrial matrix for ATP synthesis to take place. Mitochondrial complex V T8993G mutation specifically blocks the translocation of protons across the intermembrane space, thereby blocking ATP synthesis and, in turn, leading to Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) syndrome. This study seeks to explore the possibility of [Ca2+]m overload mediating the pathological roles of high glucose in defective respiratory chain-mediated mitochondrial stress. NARP cybrids are the in vitro experimental models of cells with F1FO-ATPase defects, with these cells harboring 98% of mtDNA T8993G mutations. Their counterparts, 143B osteosarcoma cell lines, are the parental cell lines used for comparison. We observed that NARP cells mediated and enhanced the death of cells (apoptosis) when incubated with hydrogen peroxide (H2O2) and high glucose, as depicted using the MTT assay of cell viability. Furthermore, using fluorescence probe-coupled laser scanning confocal imaging microscopy, NARP cells were found to significantly enable mitochondrial reactive oxygen species (mROS) formation and enhance the depolarization of the mitochondrial membrane potential (ΔΨm). Elucidating the mechanisms of sugar-enhanced toxicity on the mitochondria may, in the future, help to alleviate the symptoms of patients with NARP syndromes and other neurodegenerative diseases.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
0 orphan drug designations.
0 orphan drug designations.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI's forecasts to outperform average preclinical success rates. Whether you're expanding your R&D pipeline, evaluating a partnership, or simply have a question — we'd love to hear from you.