RARE DISEASE
MELAS
MELAS
MELAS
Synonyms: Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes, Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes
Synonyms: Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes, Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes
Synonyms: Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes, Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes
Drug discovery
7
drugs
With orphan designations
Overview
MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes) is a maternally inherited mitochondrial disorder characterized by progressive encephalomyopathy, stroke-like episodes (e.g., hemiparesis, cortical blindness), lactic acidosis, and multiorgan involvement. It arises from mitochondrial DNA mutations, most commonly MT-TL1 (80% of cases). Diagnosis relies on clinical features, neuroimaging showing non-vascular infarcts, elevated lactate, and genetic testing. Management is supportive, focusing on symptom control and preventing metabolic crises [1][5][7].
Burden
Progressive neurologic decline, with 40–90% developing dementia and 71–96% epilepsy [2][5].
Median survival ~17 years post-symptom onset; mortality linked to stroke-like events or multisystem failure [7][12].
High healthcare utilization due to recurrent hospitalizations and lifelong multidisciplinary care needs [5][12].
Therapies
Acute care: IV L-arginine for stroke-like episodes; seizure management avoiding valproate [3][7].
Chronic management: Coenzyme Q10, antioxidants, and cochlear implants for hearing loss [7][12].
Multidisciplinary support: Diabetes management, cardiac surveillance, and neurologic rehabilitation [3][7].
Categories: rare cardiac diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare otorhinolaryngological diseases, rare transplant-related disorders
Research Papers
517 drug discovery papers about MELAS, with 4 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
517 drug discovery papers about MELAS, with 4 first-in-class and 8 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-13 | The Role of Autophagy in the Pathogenesis of Mitochondrial Diseases.
Mitochondrial diseases are a heterogeneous group of inherited disorders caused by defects in the mitochondrial genome or nuclear genes encoding proteins essential for mitochondrial function. These conditions are characterised by progressive dysfunction of tissues with high energy demands, particularly the nervous and muscular systems. In recent years, increasing consideration has been paid to the role of autophagy-the cellular mechanism for the degradation and recycling of intracellular components in the pathogenesis of mitochondrial diseases. This review synthesizes current knowledge on molecular mechanisms of macroautophagy and selective forms of au-tophagy targeting specific organelles and structures: mitophagy, pexophagy, ribophagy, ER-phagy, aggrephagy, lipophagy, lisophagy, and nucleophagy. Using classic mitochondrial syndromes-Kearns-Sayre syndrome (KSS), MERRF, and MELAS, as well as various mitochondrial myopathies-as examples, we discuss experimental evidence indicating both compensatory activation of autophagy and its insufficiency or blockade at different stages. Furthermore, we examine the link between deficiencies of key fatty acid β-oxidation enzymes (VLCAD, MCAD, CPT2) and impaired autophagic flux, including secondary defects of mitophagy mediated by energy deficiency. The review systematises current understanding of how dysregulation of selective autophagy promotes the accumulation of damaged mitochondria, oxidative stress, inflammation, and cell death in mitochondrial diseases. Prospects for therapeutic modulation of autophagy as a potential approach to treating these disorders are discussed.
2026-08-10 | Pulmonary Hypertension with a High-Output Hemodynamic Profile in a Child with MELAS: A Case Report.
Pulmonary hypertension (PH) is uncommon in myopathy, encephalopathy, lactic acidosis, and stroke-like (MELAS) and its hemodynamics are poorly described. A 2-year-old Japanese girl was referred to our hospital with PH diagnosed during pneumonia treatment. Cardiac catheterization revealed PH with a high cardiac output. The patient was diagnosed with MELAS based on multiorgan involvement and the detection of an m.3243A>G mutation. PH therapy was partially effective, and oxygen supplementation may help improve PH without worsening the high cardiac output.
2026-08-06 | Lamotrigine-induced Stevens-Johnson syndrome in the setting of mitochondrial encephalomyopathy: A case report.
A 67-year-old male with Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-Like Episodes (MELAS) who developed life-threatening Stevens-Johnson Syndrome (SJS) more than one month after initiating lamotrigine (LTG) for epilepsy management. Despite prompt LTG discontinuation and aggressive immunomodulatory therapy, the patient succumbed to severe infection and multiple organ failure. LTG-induced SJS is associated with multiple risk factors. The immune-activating microenvironment resulting from mitochondrial dysfunction may potentiate the risk of LTG-induced SJS. Lamotrigine should be used cautiously for epilepsy in high-risk patients, particularly those with mitochondrial encephalomyopathy (ME), and comprehensive evaluation is required to minimize severe hypersensitivity reactions.
2026-07-28 | Long-term donor and graft safety despite subclinical mitochondrial abnormalities: mechanistic insights from a 22-year follow-up of a carrier-to-MELAS kidney transplant
Ideally, deceased donor kidney transplantation is preferred for patients with mitochondrial nephropathy caused by the m.3243 A > G mutation to avoid genetic risks. However, in regions where deceased donation is limited and living donation predominates, such as Japan, family members are often the only available donors. The safety of using maternal relatives, who are obligate carriers of the mutation, remains highly controversial due to the risk of unmasking renal failure in both the donor and the allograft. We report a 22-year follow-up of an inadvertent living kidney transplant from a 55-year-old mother to her 26-year-old daughter. The recipient presented with MELAS (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) and end-stage kidney disease due to focal segmental glomerulosclerosis (FSGS), with the m.3243 A > G mutation confirmed prior to transplantation. Conversely, the donor mother was phenotypically normal regarding renal function without diabetes, and conventional genetic testing at the time failed to detect the mutation. Consequently, the recipient’s mutation was presumed to be de novo, allowing the donation to proceed. Notably, the donor’s zero-hour allograft biopsy revealed ultrastructural mitochondrial abnormalities but no overt light microscopic damage (i.e., no FSGS). At 22 years post-transplant, both the recipient’s graft function (serum creatinine 1.16 mg/dL, albuminuria 5.0 mg/gCr) and the donor’s remaining kidney function (serum creatinine 0.98 mg/dL, albuminuria 10.4 mg/gCr) remain excellent. Current highly sensitive genetic analysis revealed an extremely low blood heteroplasmy in the donor (0.1%) compared to 20% in the recipient, demonstrating a severe “genetic bottleneck” effect. Furthermore, the recipient’s older sister was found to have a 4% mutational load, definitively confirming maternal inheritance rather than a de novo mutation. This case represents the longest reported follow-up of a living kidney transplant from an m.3243 A > G carrier. It demonstrates that maternal carriers with extremely low heteroplasmy and no light microscopic evidence of overt renal damage on biopsy can be safe donors and provide excellent long-term graft outcomes. Precise risk stratification based on genotype and biopsy findings, rather than uniform exclusion, may expand transplant options.
2026-07-28 | L-citrulline treatment of nitric oxide deficiency in MELAS a phase I dose-finding and safety study.
There is evidence that nitric oxide deficiency occurs in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and may result in impaired blood perfusion in small blood vessels, contributing to stroke-like episodes (SLEs). The primary aim of this phase one study was to estimate the maximum tolerated dose (MTD) of L-citrulline in adults with MELAS. The primary safety outcome was the occurrence of a dose limiting toxicity (DLT) in the first eight weeks after treatment initiation. Secondary outcomes included changes in cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and plasma citrulline, arginine, and ornithine levels from baseline to end of treatment (week four). Plasma guanidino compounds were assessed from baseline to week one for potential arginine toxicity and plasma lactate and alanine from baseline to end of treatment as pharmacodynamic biomarkers. Ten consecutive patients were screened, enrolled and assigned to the following doses: 10 g (n = 1), 20 g (n = 1), 30 g (n = 2), and 40 g (n = 6). There were no DLTs observed with any of the doses. However, analysis of plasma guanidino compounds demonstrated analyte outliers (Z-scores >2) with higher doses of L-citrulline (30 and 40 g). CBF increased from baseline in seven study participants, six of whom were on the highest dose. The highest CBF increase was observed in the occipital region. With the highest dose of L-citrulline, substantial increases in plasma arginine and citrulline were observed at week four when compared to baseline. While no DLTs were observed, the increase of guanidino compounds with 30 g and 40 g of L-citrulline needs to be further interrogated with serial measurements in a future study to ensure safety of these doses and determine whether the increase is sustained long term. A randomized placebo-controlled trial will be required to evaluate the efficacy of L-citrulline in individuals with MELAS.
2026-08-13 | The Role of Autophagy in the Pathogenesis of Mitochondrial Diseases.
Mitochondrial diseases are a heterogeneous group of inherited disorders caused by defects in the mitochondrial genome or nuclear genes encoding proteins essential for mitochondrial function. These conditions are characterised by progressive dysfunction of tissues with high energy demands, particularly the nervous and muscular systems. In recent years, increasing consideration has been paid to the role of autophagy-the cellular mechanism for the degradation and recycling of intracellular components in the pathogenesis of mitochondrial diseases. This review synthesizes current knowledge on molecular mechanisms of macroautophagy and selective forms of au-tophagy targeting specific organelles and structures: mitophagy, pexophagy, ribophagy, ER-phagy, aggrephagy, lipophagy, lisophagy, and nucleophagy. Using classic mitochondrial syndromes-Kearns-Sayre syndrome (KSS), MERRF, and MELAS, as well as various mitochondrial myopathies-as examples, we discuss experimental evidence indicating both compensatory activation of autophagy and its insufficiency or blockade at different stages. Furthermore, we examine the link between deficiencies of key fatty acid β-oxidation enzymes (VLCAD, MCAD, CPT2) and impaired autophagic flux, including secondary defects of mitophagy mediated by energy deficiency. The review systematises current understanding of how dysregulation of selective autophagy promotes the accumulation of damaged mitochondria, oxidative stress, inflammation, and cell death in mitochondrial diseases. Prospects for therapeutic modulation of autophagy as a potential approach to treating these disorders are discussed.
2026-08-10 | Pulmonary Hypertension with a High-Output Hemodynamic Profile in a Child with MELAS: A Case Report.
Pulmonary hypertension (PH) is uncommon in myopathy, encephalopathy, lactic acidosis, and stroke-like (MELAS) and its hemodynamics are poorly described. A 2-year-old Japanese girl was referred to our hospital with PH diagnosed during pneumonia treatment. Cardiac catheterization revealed PH with a high cardiac output. The patient was diagnosed with MELAS based on multiorgan involvement and the detection of an m.3243A>G mutation. PH therapy was partially effective, and oxygen supplementation may help improve PH without worsening the high cardiac output.
2026-08-06 | Lamotrigine-induced Stevens-Johnson syndrome in the setting of mitochondrial encephalomyopathy: A case report.
A 67-year-old male with Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-Like Episodes (MELAS) who developed life-threatening Stevens-Johnson Syndrome (SJS) more than one month after initiating lamotrigine (LTG) for epilepsy management. Despite prompt LTG discontinuation and aggressive immunomodulatory therapy, the patient succumbed to severe infection and multiple organ failure. LTG-induced SJS is associated with multiple risk factors. The immune-activating microenvironment resulting from mitochondrial dysfunction may potentiate the risk of LTG-induced SJS. Lamotrigine should be used cautiously for epilepsy in high-risk patients, particularly those with mitochondrial encephalomyopathy (ME), and comprehensive evaluation is required to minimize severe hypersensitivity reactions.
2026-07-28 | Long-term donor and graft safety despite subclinical mitochondrial abnormalities: mechanistic insights from a 22-year follow-up of a carrier-to-MELAS kidney transplant
Ideally, deceased donor kidney transplantation is preferred for patients with mitochondrial nephropathy caused by the m.3243 A > G mutation to avoid genetic risks. However, in regions where deceased donation is limited and living donation predominates, such as Japan, family members are often the only available donors. The safety of using maternal relatives, who are obligate carriers of the mutation, remains highly controversial due to the risk of unmasking renal failure in both the donor and the allograft. We report a 22-year follow-up of an inadvertent living kidney transplant from a 55-year-old mother to her 26-year-old daughter. The recipient presented with MELAS (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) and end-stage kidney disease due to focal segmental glomerulosclerosis (FSGS), with the m.3243 A > G mutation confirmed prior to transplantation. Conversely, the donor mother was phenotypically normal regarding renal function without diabetes, and conventional genetic testing at the time failed to detect the mutation. Consequently, the recipient’s mutation was presumed to be de novo, allowing the donation to proceed. Notably, the donor’s zero-hour allograft biopsy revealed ultrastructural mitochondrial abnormalities but no overt light microscopic damage (i.e., no FSGS). At 22 years post-transplant, both the recipient’s graft function (serum creatinine 1.16 mg/dL, albuminuria 5.0 mg/gCr) and the donor’s remaining kidney function (serum creatinine 0.98 mg/dL, albuminuria 10.4 mg/gCr) remain excellent. Current highly sensitive genetic analysis revealed an extremely low blood heteroplasmy in the donor (0.1%) compared to 20% in the recipient, demonstrating a severe “genetic bottleneck” effect. Furthermore, the recipient’s older sister was found to have a 4% mutational load, definitively confirming maternal inheritance rather than a de novo mutation. This case represents the longest reported follow-up of a living kidney transplant from an m.3243 A > G carrier. It demonstrates that maternal carriers with extremely low heteroplasmy and no light microscopic evidence of overt renal damage on biopsy can be safe donors and provide excellent long-term graft outcomes. Precise risk stratification based on genotype and biopsy findings, rather than uniform exclusion, may expand transplant options.
2026-07-28 | L-citrulline treatment of nitric oxide deficiency in MELAS a phase I dose-finding and safety study.
There is evidence that nitric oxide deficiency occurs in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and may result in impaired blood perfusion in small blood vessels, contributing to stroke-like episodes (SLEs). The primary aim of this phase one study was to estimate the maximum tolerated dose (MTD) of L-citrulline in adults with MELAS. The primary safety outcome was the occurrence of a dose limiting toxicity (DLT) in the first eight weeks after treatment initiation. Secondary outcomes included changes in cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and plasma citrulline, arginine, and ornithine levels from baseline to end of treatment (week four). Plasma guanidino compounds were assessed from baseline to week one for potential arginine toxicity and plasma lactate and alanine from baseline to end of treatment as pharmacodynamic biomarkers. Ten consecutive patients were screened, enrolled and assigned to the following doses: 10 g (n = 1), 20 g (n = 1), 30 g (n = 2), and 40 g (n = 6). There were no DLTs observed with any of the doses. However, analysis of plasma guanidino compounds demonstrated analyte outliers (Z-scores >2) with higher doses of L-citrulline (30 and 40 g). CBF increased from baseline in seven study participants, six of whom were on the highest dose. The highest CBF increase was observed in the occipital region. With the highest dose of L-citrulline, substantial increases in plasma arginine and citrulline were observed at week four when compared to baseline. While no DLTs were observed, the increase of guanidino compounds with 30 g and 40 g of L-citrulline needs to be further interrogated with serial measurements in a future study to ensure safety of these doses and determine whether the increase is sustained long term. A randomized placebo-controlled trial will be required to evaluate the efficacy of L-citrulline in individuals with MELAS.
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
7 orphan drug designations for MELAS.
7 orphan drug designations for MELAS.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Vatiquinone | small molecules | EMA | 2022-02-24 | — | PTC Therapeutics International Limited |
Mavodelpar sodium | small molecules | EMA | 2020-08-21 | — | Scendea (NL) B.V. |
2-isopropyl-3H-naphtho[1,2-d]imidazole-4,5-dione | small molecules | EMA | 2017-12-12 | — | Pharming Technologies B.V. |
nicotinamide riboside | small molecules | FDA | 2017-01-25 | — | Rejuvenation Therapeutics |
Sonlicromanol hydrochloride [KH176] | small molecules | EMA | 2015-08-10 | — | Khondrion B.V. |
idebenone | small molecules | FDA | 2009-05-22 | — | Santhera Pharmaceuticals (Switzerland) Ltd. |
5-[(E)-2-(4-hydroxyphenyl)-ethenyl] benzene-1,3 diol | small molecules | FDA | 2008-03-13 | — | Sirtris Pharmaceuticals, Inc. |
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