What is MELAS Syndrome?
MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) is a maternally inherited mitochondrial disorder caused most commonly by the A3243G mutation in mitochondrial DNA, characterized by metabolic strokes before age 40, seizures, exercise intolerance, and multisystem organ dysfunction. 1, 2
Genetic Basis and Pathophysiology
The A3243G mutation in the MT-TL1 gene (encoding mitochondrial tRNA leucine) accounts for approximately 80% of MELAS cases and impairs mitochondrial protein synthesis, leading to defective oxidative phosphorylation and cellular energy failure 2, 3, 4
The disease follows maternal inheritance patterns, with heteroplasmy levels (the proportion of mutant versus normal mitochondrial DNA) determining disease severity—high-energy organs like the brain, heart, and muscles are most vulnerable 2
Energy deficiency triggers mitochondrial proliferation in smooth muscle and endothelial cells of small blood vessels, causing angiopathy and impaired microvascular perfusion, which contributes to stroke-like episodes 4
Nitric oxide deficiency occurs in MELAS and contributes to vascular complications 4
Clinical Manifestations
Neurological Features
- Stroke-like episodes that do not conform to specific arterial territories and preferentially involve the posterior cerebral hemispheres 3
- Seizures (often generalized tonic-clonic) and encephalopathy 1, 2
- Migraine-like headaches with or without aura 2, 3
- Progressive dementia and cognitive decline 2, 4
- Pseudobulbar affect may occur 1
Systemic Manifestations
- Bilateral sudden sensorineural hearing loss (a key diagnostic clue when combined with elevated lactate) 2, 5
- Diabetes mellitus secondary to mitochondrial dysfunction 2, 6
- Cardiac conduction defects and cardiomyopathy 2, 6
- Short stature and growth failure 2, 4
- Myopathy with exercise intolerance and "ragged-red" muscle fibers on biopsy 2, 3
- Gastrointestinal disturbances including nausea and vomiting 2, 6
- Pulmonary hypertension may develop 2
Laboratory Findings
- Elevated serum and CSF lactic acid levels (lactic acidosis) 2, 4
- Onset typically before 40 years of age, though late-onset cases (even in the 60s) have been reported 1, 7
Diagnostic Considerations
When evaluating suspected MELAS, look for the triad of bilateral sudden hearing loss, confusion with elevated serum lactate, and stroke-like episodes in a patient under 40 years old. 2
Differential Diagnosis
The American Heart Association recommends differentiating MELAS from:
- Transient cerebral arteriopathy 2
- Central nervous system vasculitis 2
- Fabry disease 2
- Other mitochondrial disorders and metabolic diseases 2
- CADASIL (presents later, typically 6th decade, with different inheritance pattern) 1
Imaging Characteristics
- MRI shows cortical lesions that don't respect vascular territories 3, 8
- Crossed cerebellar diaschisis (hypoperfusion in cerebellar hemisphere contralateral to cerebral lesion) can occur 8
- Lesions may show complete regression on follow-up imaging 8
Treatment Approach
Primary Therapy: L-Arginine
L-arginine is the primary management approach for MELAS, as it may extend the interictal phase between stroke-like episodes and improve acute symptoms. 2
Acute Stroke-Like Episodes
- Administer L-arginine hydrochloride intravenously:
- Improves headache, nausea/vomiting, impaired consciousness, and visual disturbances 2
- Monitor for potential hypotension and fevers; may cause lower hemoglobin 2, 5
Maintenance Therapy
- Oral L-arginine using the same weight-based dosing for long-term prevention 5
- Extends the interictal phase between stroke-like episodes 2
- Mechanism: L-arginine is a nitric oxide precursor that improves endothelial function through flow-mediated vasodilation 2, 3
Adjunctive Therapies
The American College of Cardiology and American Academy of Neurology recommend considering the following supportive agents: 2
- Idebenone (synthetic coenzyme Q10 analog) to support mitochondrial function 2, 3
- Vitamin C as an antioxidant supporting mitochondrial function 2, 3
- Riboflavins to support the electron transport chain 3
- Dichloroacetate may reduce lactic acid levels 2, 3
- Coenzyme Q10 and levocarnitine are commonly used despite lack of proven efficacy 4, 6
- High-dose taurine is emerging as a potential therapy 9
Symptomatic Management
- Anti-seizure medications for epilepsy control 9
- Diabetes management as needed 2
- Multidisciplinary team approach involving neurology, cardiology, endocrinology, and genetics 4
Important Caveats and Pitfalls
Avoid assuming all young stroke patients have typical vascular etiologies—MELAS prevalence is estimated at 1:5,500-6,000 for the 3243A>G mutation, though estimates vary widely from 1:400 to 1:550,000 depending on population and ascertainment methods 1
Dosage adjustments for L-arginine may be needed in renal impairment 5
The threshold effect means clinical manifestations emerge only when mutant mtDNA exceeds a critical percentage, so family members with the same mutation may have vastly different presentations 2
Optimal dosing, timing, and duration of L-arginine therapy remain to be established through randomized controlled trials, as the rarity of MELAS makes generating high-quality evidence challenging 2
L-citrulline may raise nitric oxide production more effectively than L-arginine but has not been systematically studied in humans with MELAS 2
Reproductive Counseling
Women with MELAS mutations face significant reproductive challenges, as the disease follows maternal inheritance 2. 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 2.