MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) is a mitochondrial disease first reported in 1984. Its three typical features are: (1) encephalopathy with seizures and dementia, (2) lactic acidosis and ragged red fibers on muscle biopsy, and (3) stroke-like episodes (SLE) before age 40.
MELAS is one of the most common mitochondrial disorders. The global prevalence is estimated at 11.5 per 100,000, while in Japan it is reported as 0.2 per 100,000. Inheritance is almost exclusively maternal.
More than 50% of patients have ophthalmic manifestations, which often prompt an ophthalmology consultation.
The global prevalence is estimated at 11.5 per 100,000 people. In Japan, it is reported at 0.2 per 100,000, making it a relatively rare disease. The prevalence of the most common causative mutation, m.3243A>G, varies by region: 16–18 per 100,000 in Finland and 236 per 100,000 in Australia.
Ophthalmologic findings in MELAS are diverse, ranging from the anterior segment to the posterior segment and neuro-ophthalmology.
Fundus and Retinal Findings
Pigmentary retinopathy: Reported in 15–20% of patients. Includes chorioretinal atrophy and RPE mottling. Some reports indicate that 86% of m.3243A>G carriers have some form of retinal dystrophy. 4)
Optic atrophy: Reported in approximately 20% of cases.
Macular degeneration/macular dystrophy: Includes fovea-sparing retinal dystrophy.
Vitelliform maculopathy: Rare but reported in pediatric cases. 1)
Neuro-ophthalmologic findings
Progressive external ophthalmoplegia (PEO): Reported in 10–15% of cases. Ocular movement impairment in all directions progresses slowly.
Ptosis: Gradually progresses from one eye to both eyes.
Homonymous hemianopia and cortical blindness: Occur as sequelae of stroke-like episodes.
Nystagmus: Reported.
Other Findings
Cataract: May be associated.
Refractive error: Reported.
Neovascular glaucoma (NVG): Extremely rare. Reported in cases with m.3243A>G mutation. 4)
Corneal endothelial cell abnormalities: Polymegethism and mild guttae have been reported in carriers of the m.3243A>G mutation, which may serve as biomarkers.
Multiple mechanisms are involved. These include cortical blindness or homonymous hemianopia due to stroke-like episodes, retinal disorders such as pigmentary retinopathy and macular dystrophy, optic atrophy, and cataracts. The cause differs depending on whether vision loss is acute or slowly progressive.
MELAS is caused by mutations in mitochondrial DNA (mtDNA) and follows a maternal inheritance pattern.
Heteroplasmy and threshold effect: The tissue distribution of mutant mtDNA and the threshold in each tissue determine the phenotype. Not all carriers of the mutation develop symptoms.
Not everyone develops symptoms. Because heteroplasmy (proportion of mutant mtDNA) and the threshold in each tissue determine the phenotype, not all carriers of the mutation develop the disease. It may also manifest as a milder phenotype (e.g., MIDD: mitochondrial diabetes and deafness syndrome).
Two main diagnostic criteria are used for MELAS.
1992 Hirano diagnostic criteria: (1) encephalopathy (dementia and/or seizures), (2) stroke-like episodes at a young age, (3) evidence of mitochondrial dysfunction (lactic acidosis or ragged red fibers). All three items are required.
2012 Japanese MELAS diagnostic criteria (Yatsuga et al.): At least 2 items from Category A (headache + vomiting, seizures, hemiparesis, cortical blindness, acute cortical lesion) and at least 2 items from Category B (elevated plasma/CSF lactate, abnormal muscle biopsy, MELAS-related gene mutation). 2)7)
In the differential diagnosis from hereditary retinal dystrophy, it is important to use a gene panel including mitochondrial genome testing. Note that the initial IRD panel may not include mitochondrial genes. 4)
Symptomatic treatment is the mainstay; no curative treatment has been established.
Mitochondrial cocktail therapy includes the following agents.
Intravenous L-arginine is recommended for acute treatment of stroke-like episodes. Initiation within 5 hours of onset is desirable, switching to oral administration after 2 days of acute intravenous therapy. 5) After the first MELAS episode, oral arginine is continued to prevent recurrence.
Seizure management with antiepileptic drugs is also important. Levetiracetam, oxcarbazepine, lamotrigine, etc. are used. Valproic acid is contraindicated due to mitochondrial toxicity. 5)7)
Hearing loss management may involve cochlear implants.
Diabetes management: Metformin is contraindicated due to risk of lactic acidosis. Incretin-based therapies (GLP-1 receptor agonists, DPP-4 inhibitors) have been reported as optimal choices. 3)
Annual ophthalmic follow-up is recommended. Treatment is primarily symptomatic, tailored to ocular complaints.
Pregnancy is a high-energy-demand state and may trigger the onset or exacerbation of MELAS. 6) Monitoring of diabetes, respiratory failure, and cardiac function is necessary. Genetic counseling is recommended, but the sensitivity of prenatal screening is not 100%.
For delivery management, avoidance of prolonged labor, early epidural anesthesia, limiting the second stage to within 60 minutes, and lactate monitoring are recommended. Multidisciplinary management based on the Newcastle Mitochondrial Disease Guidelines is fundamental. 6)
As symptomatic treatments, eyelid crutches (support devices attached to eyeglass frames), blepharoplasty, and frontalis sling are used. Since the extraocular muscles are affected, frontalis sling is often chosen when levator palpebrae superioris function is insufficient.
The fundamental pathology of MELAS is dysfunction of the mitochondrial electron transport chain. mtDNA mutations reduce protein translation, leading to ATP production failure due to impaired oxidative phosphorylation. Tissues with high energy demands (brain, muscle, retinal pigment epithelium, corneal endothelium, extraocular muscles) are selectively affected.
Pathogenesis of stroke-like episodes: Relative deficiency of NO (nitric oxide) plays an important role.
Ocular pathology: The retinal pigment epithelium (RPE) has high mitochondrial content and metabolic activity. RPE damage causes pigmentary retinopathy and macular dystrophy. 1)
Continuous spectrum with MIDD: The m.3243A>G mutation can cause both MIDD (mitochondrial diabetes and deafness syndrome) and MELAS. MIDD is a milder phenotype, and progression to MELAS has been hypothesized. 4)
Ghosh et al. (2022) reported MELAS in a 33-year-old man with the m.13513G>A (MT-ND5) mutation (heteroplasmy rate 11%, lymphocytes). 7) The m.13513G>A mutation is located in the MT-ND5 gene encoding respiratory chain complex I subunit, and the D393N amino acid change causes loss of the quinone reaction site and reduced oxidative phosphorylation activity. This mutation caused recurrent stroke-like episodes starting at age 23, demonstrating high pathogenicity even at low heteroplasmy rates.
Alves et al. (2023) classified MELAS into two phenotypic patterns, “Classic” and “Atypical”, in a retrospective study of 35 cases. 2) The Classic type is characterized by sensorineural hearing loss (SNHL), visual loss at SLE onset, first SLE episode after age 10, and large cortical stroke-like lesions (≥30 mm), with a predominance of mt-tRNA mutations. The Atypical type is characterized by developmental delay, overlap with Leigh syndrome, first SLE episode at or before age 10, small lesions, and anterior/cerebellar distribution, with a predominance of respiratory chain subunit gene mutations. The Atypical group had a significantly higher risk of respiratory failure and medullary dysfunction, indicating a poor prognosis. Application to clinical trial design using homogeneous subgroups is expected.
Jahrig et al. (2023) reported bilateral vitelliform macular lesions in an 11-year-old female MELAS patient (m.3243A>G 72% heteroplasmy). 1) Best-corrected visual acuity was 20/30 and 20/25, asymptomatic. OCT showed subretinal dome-shaped hyperreflective lesions, and EOG was normal. Large-scale NGS panel did not detect disease-causing variants in IRD genes such as BEST1, PRPH2, IMPG1, and IMPG2. As it may be overlooked due to being asymptomatic, the importance of screening for vitelliform maculopathy in MELAS was suggested.
Khanna et al. (2024) reported the onset of NVG in a 48-year-old woman (m.3243A>G 39.7%, with diabetes and hearing loss). 4) Iris neovascularization, macular atrophy, and neovascularization of the optic disc (NVD) were observed in both eyes, and PRP and aflibercept were administered. A glaucoma tube shunt was required in the right eye. The importance of genetic testing including a mitochondrial gene panel is emphasized.
Sen et al. (2021) reported a case of SLE exacerbation due to COVID-19 infection. 5) Infection worsens lactic acidosis as a catabolic stress. A proposal was made for temporal separation of intravenous L-arginine and anticoagulant administration (avoiding simultaneous use).
Finsterer et al. (2022) reported a case of MELAS/Leigh overlap syndrome due to the m.13513G>A mutation. 8) Respiratory failure and dysphagia due to brainstem involvement are the main causes of death, and cases showing overlap between MELAS and Leigh syndrome are accumulating.
Jahrig C, Ku CA, Marra M, Pennesi ME, Yang P. Vitelliform maculopathy in MELAS syndrome. Am J Ophthalmol Case Rep. 2023.
Alves CAPF, Zandifar A, Peterson JT, et al. MELAS Phenotype Classification into Classic-versus-Atypical Presentations. AJNR Am J Neuroradiol. 2023.
Baszynska-Wilk M, Moszczynska E, Szarras-Czapnik M, et al. Endocrine disorders in a patient with a suspicion of a mitochondrial disease, MELAS syndrome. Pediatr Endocrinol Diabetes Metab. 2021.
Khanna S, Smith BT. Neovascular Glaucoma in MELAS syndrome. Am J Ophthalmol Case Rep. 2024.
Sen K, Harrar D, Hahn A, Wells EM, Gropman AL. Management considerations for stroke-like episodes in MELAS with concurrent COVID-19 infection. J Neurol. 2021.
Balachandran Nair D, Bloomfield M, Parasuraman R, Howe DT. MELAS syndrome in pregnancy. BMJ Case Rep. 2021.
Ghosh R, Dubey S, Bhuin S, Lahiri D, Ray BK, Finsterer J. MELAS with multiple stroke-like episodes due to the variant m.13513G>A in MT-ND5. Clin Case Rep. 2022.
Finsterer J, Hayman J. MELAS/Leigh Overlap Syndrome Due to Variant m.13513G>A in MT-ND5. Cureus. 2022.
