RARE DISEASE
Leigh syndrome
Leigh syndrome
Leigh syndrome
Synonyms: Infantile subacute necrotizing encephalopathy, Leigh disease
Synonyms: Infantile subacute necrotizing encephalopathy, Leigh disease
Synonyms: Infantile subacute necrotizing encephalopathy, Leigh disease
Drug discovery
10
drugs
With orphan designations
Overview
Leigh syndrome is a genetically heterogeneous mitochondrial disorder characterized by neuroregression, symmetric brainstem/basal ganglia lesions, and impaired oxidative phosphorylation. Typically presenting in infancy with feeding difficulties, ataxia, and hypotonia, it progresses to respiratory failure, with most patients surviving <3 years [1][6][9]. Diagnosis requires clinical features plus biochemical/genetic evidence of mitochondrial dysfunction [1][9].
Therapies
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders
Research Papers
484 drug discovery papers about Leigh syndrome, with 2 first-in-class and 21 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
484 drug discovery papers about Leigh syndrome, with 2 first-in-class and 21 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-21 | Riboflavin therapy in complex I deficiency: Two new cases of leukoencephalopathy and a systematic literature review.
Complex I (CI) deficiency, the most common biochemical defect in pediatric mitochondrial diseases, presents with diverse phenotypes, including cardiomyopathy, myopathy, Leigh syndrome, and mitochondrial leukoencephalopathy (ML). No curative therapies exist. Riboflavin, a precursor of CI cofactors FMN and FAD, is a potential treatment, but evidence is heterogeneous and formal guidelines are lacking. We retrospectively analyzed two patients with genetically confirmed CI deficiency due to NDUFS1 and NDUFV2 variants, treated with high-dose riboflavin with long-term clinical, biochemical, neurophysiological and MRI follow-up (>16 years). A systematic literature review of riboflavin-responsive CI deficiency was also performed. Both patients presented with early acute psychomotor regression and extensive cavitating white matter lesions. Riboflavin (up to 10 mg/kg/day) was associated with rapid, near-complete neurological recovery, normalization of lactate and evoked potentials, and MRI improvement, stable in time. Our review identified 43 additional riboflavin-responsive CI cases, including cardiomyopathy (n = 16, largely due to ACAD9 variants), myopathy (n = 12, all ACAD9 variants), ML (n = 8, predominantly NDUFV1/NDUFV2 variants), Leigh syndrome (n = 5), MELAS-like presentations (n = 1), and optic atrophy (n = 1). Riboflavin may provide durable benefit across several CI-deficiency phenotypes. Beyond established efficacy in ACAD9-related cardiomyopathy, available evidence supports consideration of therapeutic trials in other phenotypes. Our two cases, supported by long-term follow-up and consistent instrumental data, provide further evidence supporting a potential benefit of riboflavin in ML, complementing eight earlier reports limited by short follow-up and sparse imaging. Variants affecting N-module subunits (NDUFV1, NDUFV2, NDUFS1), depending directly on FMN/FAD, may represent particularly suitable candidates for treatment. Prospective studies are warranted.
2026-07-17 | A phase III double-blind, placebo-controlled, randomized withdrawal trial of 5‑aminolevulinic acid hydrochloride with sodium ferrous citrate for efficacy and safety in patients diagnosed as Leigh syndrome.
A phase III, double-blind, placebo-controlled, randomized withdrawal trial of SPP‑004 (5‑aminolevulinic acid hydrochloride and sodium ferrous citrate) was conducted to confirm the efficacy and safety of SPP-004 for maintenance of clinical response in patients diagnosed with Leigh syndrome (LS) showing central nervous system disorders. Fifty-four patients entered a 24-week open-label period of SPP-004 administration. Among them, 28 patients who showed improvement on the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) for cranial nervous symptoms and myopathy symptoms proceeded to a 48-week double-blind (DB) period, where they were randomized (1:1) to receive SPP‑004 or placebo (n = 14 each). Efficacy was evaluated using NPMDS for the full analysis set (FAS) during the DB‑period (SPP-004 n = 13, Placebo n = 14) and the entire study period (n = 54). Safety evaluation focused on adverse events (AEs) in all 54 patients administered SPP-004. The primary endpoint, the proportion of patients who discontinued due to inadequate efficacy at 48 weeks, was lower in the SPP-004 group (15.4% [95% CI: 1.9-45.4%]) compared to the placebo group (50.0% [23.0-77.0%]). Over 80% of the SPP-004 group showed maintained efficacy (p = 0.0486). All adverse drug reactions were mild, with no notable differences in AEs between groups. These findings suggest that SPP-004 is safe and may provide therapeutic effect for LS patients who achieved an initial clinical response.
2026-07-13 | Navigating the Mitochondrial Maze: A Case Report of Emergent Cesarean Delivery After Labor Induction in a Patient With Leigh Syndrome.
Leigh syndrome is a rare mitochondrial disorder characterized by progressive psychomotor regression. Due to high childhood mortality and rare adult-onset cases, there are no guidelines for the obstetric management of this population. In these patients, physiological stress from labor may precipitate acute decompensation, manifesting with metabolic acidosis and multiorgan failure. We report the obstetric anesthetic management of a patient with adult-onset Leigh syndrome who required an emergent intrapartum cesarean delivery after labor induction. This case highlights the necessity of tailored anesthetic strategies to mitigate mitochondrial dysfunction and supports the potential safety of essential peripartum medications previously undocumented in this population.
2026-07-10 | An optimized "hypoxia in a pill" regimen reverses neurodegenerative disease phenotypes in multiple preclinical models.
A growing body of pre-clinical research has demonstrated the therapeutic potential of chronic, continuous hypoxia (11% FIO2) for treating both rare and common forms of neurodegeneration (1). However, the chronic delivery of hypoxic gas poses both practical challenges and long-term safety concerns. We previously introduced a small molecule, "hypoxia-in-a-pill" regimen that combines the hemoglobin affinity enhancer (GBT440) -- which limits oxygen delivery to tissues -- with a HIF-2α inhibitor (PT2399) to prevent compensatory erythropoiesis that can be detrimental. While this regimen extended the lifespan of the Ndufs4 KO mouse model of Leigh syndrome, its efficacy still did not match that of chronic 11% FIO2. Here we report an optimized combination that now utilizes GBT601, a second-generation hemoglobin affinity enhancer with longer half-life and greater hemoglobin occupancy, again with PT2399. Here we report that the GBT601/PT2399 combination achieved therapeutic hypoxia and demonstrated strong efficacy comparable to continuous breathing of 11% FIO2 by halting neurodegeneration and even reversing neurological symptoms in three different mouse models: Leigh syndrome, Friedreich's ataxia, and Parkinson's disease. The dual targeting regimen led to a striking extension in median lifespan in the Leigh syndrome model, from a median of ∼62 day to 158 days, when initiated after onset of advanced disease. Importantly, body weight was stable with the combination and it did not induce any signs of pulmonary hypertension, likely due to attenuation of HIF-2α. Our findings motivate additional pre-clinical and even clinical studies to evaluate the safety and efficacy of the GBT601/PT2399 combination.
2026-07-07 | When LHON Mimics Demyelination: Area Postrema Syndrome in Biallelic DNAJC30 Variants
Introduction: Biallelic pathogenic variants in DNAJC30 cause an autosomal recessive form of Leber hereditary optic neuropathy (LHONAR1), traditionally considered a mitochondrially transmitted disorder. The phenotypic spectrum of diseases linked to DNAJC30 includes isolated optic neuropathy, Leigh syndrome spectrum (LSS), and atypical LHON-plus. Case description: Here, we report a 13-year-old boy presenting symptoms of area postrema syndrome (APS), with recurrent vomiting, vertigo, nystagmus, and subacute visual deterioration with central scotoma. Ophthalmological examination revealed bilateral papilledema with telangiectatic vessels, while visual evoked potentials demonstrated severe bilateral optic pathway dysfunction. Brain magnetic resonance imaging (MRI) showed T2/FLAIR hyperintense lesions involving the area postrema and enhancement of the optic nerves, strongly suggesting seronegative neuromyelitis optica spectrum disorder (NMOSD). Extensive immunological and cerebrospinal fluid studies, including anti-aquaporin-4 (AQP4) and anti-MOG antibodies, were negative. High-dose corticosteroids and intravenous immunoglobulins resulted in only transient and incomplete improvement, followed by further visual decline. Additionally, laboratory tests detected elevated lactate plasma levels. Hence, whole-exome sequencing was performed, which identified a homozygous pathogenic DNAJC30 c.152A>G, p.(Tyr51Cys) variant, associated with LHONAR1. After initiation of idebenone therapy, the patient showed significant improvement in visual function, normalization of lactate levels, and complete resolution of the brainstem lesions on follow-up MRI. Conclusions: This case further expands the neuro-ophthalmic spectrum associated with DNAJC30 variants and suggests that DNAJC30-related disease may closely mimic seronegative NMOSD. We highlight that early genetic diagnosis is essential, as recognition of this mitochondrial etiology enables targeted therapy and may substantially improve clinical outcomes.
2026-07-21 | Riboflavin therapy in complex I deficiency: Two new cases of leukoencephalopathy and a systematic literature review.
Complex I (CI) deficiency, the most common biochemical defect in pediatric mitochondrial diseases, presents with diverse phenotypes, including cardiomyopathy, myopathy, Leigh syndrome, and mitochondrial leukoencephalopathy (ML). No curative therapies exist. Riboflavin, a precursor of CI cofactors FMN and FAD, is a potential treatment, but evidence is heterogeneous and formal guidelines are lacking. We retrospectively analyzed two patients with genetically confirmed CI deficiency due to NDUFS1 and NDUFV2 variants, treated with high-dose riboflavin with long-term clinical, biochemical, neurophysiological and MRI follow-up (>16 years). A systematic literature review of riboflavin-responsive CI deficiency was also performed. Both patients presented with early acute psychomotor regression and extensive cavitating white matter lesions. Riboflavin (up to 10 mg/kg/day) was associated with rapid, near-complete neurological recovery, normalization of lactate and evoked potentials, and MRI improvement, stable in time. Our review identified 43 additional riboflavin-responsive CI cases, including cardiomyopathy (n = 16, largely due to ACAD9 variants), myopathy (n = 12, all ACAD9 variants), ML (n = 8, predominantly NDUFV1/NDUFV2 variants), Leigh syndrome (n = 5), MELAS-like presentations (n = 1), and optic atrophy (n = 1). Riboflavin may provide durable benefit across several CI-deficiency phenotypes. Beyond established efficacy in ACAD9-related cardiomyopathy, available evidence supports consideration of therapeutic trials in other phenotypes. Our two cases, supported by long-term follow-up and consistent instrumental data, provide further evidence supporting a potential benefit of riboflavin in ML, complementing eight earlier reports limited by short follow-up and sparse imaging. Variants affecting N-module subunits (NDUFV1, NDUFV2, NDUFS1), depending directly on FMN/FAD, may represent particularly suitable candidates for treatment. Prospective studies are warranted.
2026-07-17 | A phase III double-blind, placebo-controlled, randomized withdrawal trial of 5‑aminolevulinic acid hydrochloride with sodium ferrous citrate for efficacy and safety in patients diagnosed as Leigh syndrome.
A phase III, double-blind, placebo-controlled, randomized withdrawal trial of SPP‑004 (5‑aminolevulinic acid hydrochloride and sodium ferrous citrate) was conducted to confirm the efficacy and safety of SPP-004 for maintenance of clinical response in patients diagnosed with Leigh syndrome (LS) showing central nervous system disorders. Fifty-four patients entered a 24-week open-label period of SPP-004 administration. Among them, 28 patients who showed improvement on the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) for cranial nervous symptoms and myopathy symptoms proceeded to a 48-week double-blind (DB) period, where they were randomized (1:1) to receive SPP‑004 or placebo (n = 14 each). Efficacy was evaluated using NPMDS for the full analysis set (FAS) during the DB‑period (SPP-004 n = 13, Placebo n = 14) and the entire study period (n = 54). Safety evaluation focused on adverse events (AEs) in all 54 patients administered SPP-004. The primary endpoint, the proportion of patients who discontinued due to inadequate efficacy at 48 weeks, was lower in the SPP-004 group (15.4% [95% CI: 1.9-45.4%]) compared to the placebo group (50.0% [23.0-77.0%]). Over 80% of the SPP-004 group showed maintained efficacy (p = 0.0486). All adverse drug reactions were mild, with no notable differences in AEs between groups. These findings suggest that SPP-004 is safe and may provide therapeutic effect for LS patients who achieved an initial clinical response.
2026-07-13 | Navigating the Mitochondrial Maze: A Case Report of Emergent Cesarean Delivery After Labor Induction in a Patient With Leigh Syndrome.
Leigh syndrome is a rare mitochondrial disorder characterized by progressive psychomotor regression. Due to high childhood mortality and rare adult-onset cases, there are no guidelines for the obstetric management of this population. In these patients, physiological stress from labor may precipitate acute decompensation, manifesting with metabolic acidosis and multiorgan failure. We report the obstetric anesthetic management of a patient with adult-onset Leigh syndrome who required an emergent intrapartum cesarean delivery after labor induction. This case highlights the necessity of tailored anesthetic strategies to mitigate mitochondrial dysfunction and supports the potential safety of essential peripartum medications previously undocumented in this population.
2026-07-10 | An optimized "hypoxia in a pill" regimen reverses neurodegenerative disease phenotypes in multiple preclinical models.
A growing body of pre-clinical research has demonstrated the therapeutic potential of chronic, continuous hypoxia (11% FIO2) for treating both rare and common forms of neurodegeneration (1). However, the chronic delivery of hypoxic gas poses both practical challenges and long-term safety concerns. We previously introduced a small molecule, "hypoxia-in-a-pill" regimen that combines the hemoglobin affinity enhancer (GBT440) -- which limits oxygen delivery to tissues -- with a HIF-2α inhibitor (PT2399) to prevent compensatory erythropoiesis that can be detrimental. While this regimen extended the lifespan of the Ndufs4 KO mouse model of Leigh syndrome, its efficacy still did not match that of chronic 11% FIO2. Here we report an optimized combination that now utilizes GBT601, a second-generation hemoglobin affinity enhancer with longer half-life and greater hemoglobin occupancy, again with PT2399. Here we report that the GBT601/PT2399 combination achieved therapeutic hypoxia and demonstrated strong efficacy comparable to continuous breathing of 11% FIO2 by halting neurodegeneration and even reversing neurological symptoms in three different mouse models: Leigh syndrome, Friedreich's ataxia, and Parkinson's disease. The dual targeting regimen led to a striking extension in median lifespan in the Leigh syndrome model, from a median of ∼62 day to 158 days, when initiated after onset of advanced disease. Importantly, body weight was stable with the combination and it did not induce any signs of pulmonary hypertension, likely due to attenuation of HIF-2α. Our findings motivate additional pre-clinical and even clinical studies to evaluate the safety and efficacy of the GBT601/PT2399 combination.
2026-07-07 | When LHON Mimics Demyelination: Area Postrema Syndrome in Biallelic DNAJC30 Variants
Introduction: Biallelic pathogenic variants in DNAJC30 cause an autosomal recessive form of Leber hereditary optic neuropathy (LHONAR1), traditionally considered a mitochondrially transmitted disorder. The phenotypic spectrum of diseases linked to DNAJC30 includes isolated optic neuropathy, Leigh syndrome spectrum (LSS), and atypical LHON-plus. Case description: Here, we report a 13-year-old boy presenting symptoms of area postrema syndrome (APS), with recurrent vomiting, vertigo, nystagmus, and subacute visual deterioration with central scotoma. Ophthalmological examination revealed bilateral papilledema with telangiectatic vessels, while visual evoked potentials demonstrated severe bilateral optic pathway dysfunction. Brain magnetic resonance imaging (MRI) showed T2/FLAIR hyperintense lesions involving the area postrema and enhancement of the optic nerves, strongly suggesting seronegative neuromyelitis optica spectrum disorder (NMOSD). Extensive immunological and cerebrospinal fluid studies, including anti-aquaporin-4 (AQP4) and anti-MOG antibodies, were negative. High-dose corticosteroids and intravenous immunoglobulins resulted in only transient and incomplete improvement, followed by further visual decline. Additionally, laboratory tests detected elevated lactate plasma levels. Hence, whole-exome sequencing was performed, which identified a homozygous pathogenic DNAJC30 c.152A>G, p.(Tyr51Cys) variant, associated with LHONAR1. After initiation of idebenone therapy, the patient showed significant improvement in visual function, normalization of lactate levels, and complete resolution of the brainstem lesions on follow-up MRI. Conclusions: This case further expands the neuro-ophthalmic spectrum associated with DNAJC30 variants and suggests that DNAJC30-related disease may closely mimic seronegative NMOSD. We highlight that early genetic diagnosis is essential, as recognition of this mitochondrial etiology enables targeted therapy and may substantially improve clinical outcomes.
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
10 orphan drug designations for Leigh syndrome.
10 orphan drug designations for Leigh syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
adeno-associated virus 9 human NADH:ubiquinone oxidoreductase subunit S4 | gene therapies | FDA | 2024-10-22 | — | National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH) |
2-((hydroxy((R)-2-(((5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoyl)oxy)-3-(((E)-octadec-2-en-1-yl)oxy)propoxy)phosphoryl)oxy)ethan-1-ammonium | small molecules | FDA | 2024-09-26 | — | Institute of Rheological Functions of Food |
Methyl 4-(2-acetamidoethylsulfanyl)-4-oxobutanoate | small molecules | EMA | 2023-12-13 | — | Pharming Technologies B.V. |
Sildenafil citrate | small molecules | EMA | 2023-10-13 | — | Charite Universitaetsmedizin Berlin KöR |
Cannabidiol | small molecules | EMA | 2023-07-25 | — | Universitat Autònoma De Barcelona |
Adeno-associated viral vector serotype 9 containing the human SURF1 gene | gene therapies | EMA | 2021-11-12 | — | Raremoon Consulting Esp S.L. |
TGTX-102, an adeno-associated virus serotype 9 (AAV9) vector with engineered transgene encoding the human SURF1 protein. | gene therapies | FDA | 2020-10-20 | — | University of Texas Southwestern Medical Center |
Sonlicromanol hydrochloride [KH-176] | small molecules | EMA | 2014-10-15 | — | Khondrion B.V. |
vatiquinone | small molecules | FDA | 2014-06-04 | — | PTC Therapeutics, Inc. |
Vatiquinone | small molecules | EMA | 2011-12-09 | — | PTC Therapeutics International Limited |
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