What is Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome?

What is MELAS Syndrome?

MELAS syndrome is a maternally inherited mitochondrial disorder characterized by Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes, caused most commonly (80% of cases) by the A3243G mutation in mitochondrial DNA that impairs cellular energy production, resulting in multi-organ dysfunction with stroke-like episodes that don't follow typical arterial territories, seizures, exercise intolerance, and onset typically before age 40. 1, 2

Genetic Basis and Pathophysiology

• The A3243G mutation occurs in the tRNA leucine gene (MT-TL1), disrupting mitochondrial protein synthesis and electron transport chain function, leading to impaired ATP production 1, 3
• The proportion of mutant versus normal mitochondrial DNA (heteroplasmy level) inherited from the mother determines disease severity, with high-energy organs (brain, heart, muscles) being most vulnerable 1
• Clinical manifestations emerge when mutant mtDNA exceeds a critical threshold percentage, explaining the variable presentation among affected individuals 1

Cardinal Clinical Features

Neurological Manifestations

• Stroke-like episodes that preferentially involve posterior cerebral hemispheres and do not conform to specific arterial territories—this is the hallmark feature 1, 2
• Seizures occurring at any age, often with elevated serum and CSF lactic acid levels 1, 4
• Encephalopathy with progressive neurological decline and dementia 3, 5
• Migraine-like headaches 2, 3
• Bilateral sudden sensorineural hearing loss 1, 5

Metabolic and Systemic Features

• Lactic acidosis—a diagnostic hallmark with elevated serum and CSF lactate 1, 4
• Exercise intolerance and myopathy with "ragged-red" muscle fibers on biopsy 1, 2
• Diabetes mellitus 1, 6
• Short stature 1, 6
• Cardiac conduction defects and pulmonary hypertension 1, 6
• Gastrointestinal disorders 1, 6

Age and Onset Pattern

• Onset typically occurs before age 40 years 1, 2
• Clinical features are not necessarily uniform in early disease stages 4

Pathophysiologic Mechanisms

• Altered cellular metabolism affects small cerebral vessels, impeding blood flow to affected cortex and causing dysfunction of autoregulatory mechanisms 2
• Angiopathy develops from mitochondrial proliferation in smooth muscle and endothelial cells of small blood vessels, leading to impaired microvascular perfusion 3, 7
• Nitric oxide deficiency contributes to vascular complications and stroke-like episodes 3, 7

Diagnostic Approach

Key Diagnostic Features to Identify

• Stroke-like episodes in a patient under 40 with symptoms not matching typical arterial distributions 1, 2
• Elevated serum and CSF lactic acid levels—measure immediately when MELAS is suspected 1, 4
• Muscle biopsy showing ragged-red fibers and vessels with strong succinate dehydrogenase reaction 1, 4
• Genetic testing for A3243G mutation in MT-TL1 gene 1, 2

Differential Diagnoses to Consider

• Transient cerebral arteriopathy 1
• Central nervous system vasculitis 1
• Fabry disease 1
• Other mitochondrial disorders and metabolic diseases 1

Treatment Algorithm

Acute Stroke-Like Episode Management

• Administer intravenous L-arginine hydrochloride immediately: weight <20 kg: 600 mg/kg; weight >20 kg: 12 g/m², given over 90 minutes as bolus, then as maintenance over 24 hours 8
• L-arginine improves acute symptoms including headache, nausea/vomiting, impaired consciousness, and visual disturbances 1, 8
• Monitor for potential hypotension during IV administration 8
• Aggressive antiepileptic drug intervention if seizures occur 1
• Provide adequate oxygen therapy—the mechanism of CO2 retention differs fundamentally from COPD, so do not withhold oxygen 1
• Consider IV sodium bicarbonate for severe acidosis 1

Maintenance Therapy for Prevention

• Oral L-arginine for long-term prevention: same weight-based dosing as acute treatment (weight <20 kg: 600 mg/kg/day; weight >20 kg: 12 g/m²/day) 8
• L-arginine extends the interictal phase between stroke-like episodes by improving endothelial function through nitric oxide-mediated vasodilation 1, 2

Supportive Mitochondrial Therapies

• Idebenone (synthetic coenzyme Q10 analog) to support mitochondrial function 1, 2
• Vitamin C as an antioxidant supporting mitochondrial function 1, 2
• Riboflavins to support the electron transport chain 2
• Dichloroacetate may reduce lactic acid levels 1, 2

Critical Pitfalls to Avoid

• Do not assume elevated CO2 is simply a ventilation problem—in MELAS, it typically reflects the body's inability to compensate for severe metabolic acidosis from mitochondrial dysfunction 1
• Do not withhold oxygen in hypoxemic MELAS patients—unlike COPD, these patients require adequate oxygenation as their CO2 retention mechanism is fundamentally different 1
• Adjust L-arginine dosage in patients with renal impairment 8
• Monitor hemoglobin levels during IV L-arginine therapy, as it may result in lower hemoglobin and fevers 1

Reproductive Counseling Considerations

• Women with MELAS mutations face significant reproductive counseling challenges due to maternal inheritance pattern 1
• Mitochondrial replacement techniques (MRTs) involving transfer of nuclear genetic material into donor oocytes with healthy mitochondria are being developed, though currently only permitted in the UK 1