MELAS Syndrome
MELAS Syndrome
MELAS syndrome, which stands for Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes, is a rare, multisystem disorder classified as a mitochondrial disease. It primarily affects the brain and nervous system, as well as muscles.
Key Points:
- Mitochondrial inheritance (maternal)
- Caused by mutations in mitochondrial DNA, most commonly in the MT-TL1 gene
- Prevalence: Estimated at 1 in 4,000 individuals
- Onset typically in childhood or early adulthood
- Characterized by stroke-like episodes, seizures, and progressive neurological dysfunction
- Affects multiple organ systems: nervous, muscular, cardiovascular, and endocrine
Clinical Features
Neurological Manifestations:
- Stroke-like episodes (hallmark feature)
- Seizures (focal or generalized)
- Recurrent headaches (often migraine-like)
- Progressive cognitive decline
- Ataxia and motor dysfunction
- Hearing loss (sensorineural)
Muscular Involvement:
- Exercise intolerance
- Proximal muscle weakness
- Lactic acidosis (elevated lactate levels in blood and cerebrospinal fluid)
Gastrointestinal Symptoms:
- Recurrent vomiting
- Abdominal pain
- Pseudo-obstruction
Cardiac Manifestations:
- Cardiomyopathy (hypertrophic or dilated)
- Conduction defects
Endocrine Abnormalities:
- Diabetes mellitus
- Short stature
- Hypoparathyroidism
Ophthalmologic Findings:
- Pigmentary retinopathy
- Ophthalmoplegia
- Optic atrophy
Diagnosis
Diagnosis of MELAS syndrome is based on clinical presentation, biochemical findings, neuroimaging, and genetic testing.
Clinical Criteria:
- Stroke-like episodes before age 40
- Encephalopathy with seizures and/or dementia
- Lactic acidosis and/or ragged-red fibers in muscle biopsy
Biochemical Testing:
- Elevated lactate and pyruvate levels in blood and CSF
- Abnormal respiratory chain enzyme activities in muscle biopsy
Neuroimaging:
- MRI: Stroke-like lesions not confined to vascular territories
- MR spectroscopy: Elevated lactate peak in affected brain regions
- SPECT or PET: Hyperperfusion in acute lesions
Genetic Testing:
- Mitochondrial DNA sequencing (focusing on MT-TL1 gene)
- Quantification of heteroplasmy levels
Muscle Biopsy:
- Ragged-red fibers on Gomori trichrome stain
- COX-negative fibers
- Ultrastructural analysis showing abnormal mitochondria
Management
Management of MELAS syndrome is largely supportive and aimed at treating symptoms and preventing complications.
Acute Management:
- Prompt treatment of stroke-like episodes
- Seizure control with anti-epileptic drugs
- Management of metabolic acidosis
Chronic Management:
- L-arginine supplementation (to improve nitric oxide production)
- Coenzyme Q10 and other antioxidants
- Carnitine supplementation
- Creatine monohydrate for muscle symptoms
Symptomatic Treatment:
- Diabetes management
- Cardiac monitoring and treatment
- Hearing aids for sensorineural hearing loss
- Physical and occupational therapy
Preventive Measures:
- Avoiding triggers (e.g., certain medications, infections)
- Regular screening for associated complications
- Genetic counseling for family members
Emerging Therapies:
- Mitochondrial replacement therapy (in research phase)
- Gene therapy approaches (experimental)
Genetics
Inheritance Pattern:
- Mitochondrial (maternal) inheritance
- All offspring of an affected mother are at risk
Genetic Basis:
- Mutations in mitochondrial DNA (mtDNA)
- Most common mutation: m.3243A>G in MT-TL1 gene (80% of cases)
- Other less common mutations in MT-ND5, MT-CO3, and MT-TF genes
Heteroplasmy:
- Mixture of mutant and wild-type mtDNA in cells
- Higher levels of heteroplasmy generally correlate with more severe symptoms
- Threshold effect: symptoms appear when mutant mtDNA reaches a critical level
Genotype-Phenotype Correlations:
- Variable expressivity due to heteroplasmy and mitotic segregation
- Same mutation can cause different phenotypes (e.g., MELAS, MIDD, CPEO)
Genetic Testing Considerations:
- Blood testing may miss mutations due to mitotic segregation
- Urine sediment or muscle biopsy often preferred for higher detection rates
- Importance of quantifying heteroplasmy levels
