MELAS syndrome

Overview

MELAS syndrome, which stands for Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes, is a rare and progressive mitochondrial disorder that affects multiple systems, especially the brain and muscles. It typically begins in childhood or adolescence but can occasionally present later in life. MELAS syndrome is caused by mutations in mitochondrial DNA, which impair the cells' ability to produce energy efficiently.

The hallmark features of MELAS include muscle weakness, seizures, stroke-like episodes that do not follow typical vascular patterns, and elevated levels of lactic acid in the blood and cerebrospinal fluid. It is one of the most common mitochondrial disorders and can lead to significant neurological disability.

As there is currently no cure, treatment focuses on managing symptoms and slowing disease progression through supportive care and targeted therapies.

Causes

MELAS syndrome is caused by mutations in mitochondrial DNA (mtDNA), most commonly the m.3243A>G mutation in the MT-TL1 gene, which encodes mitochondrial tRNA for leucine. This mutation disrupts the normal function of mitochondria, the organelles responsible for producing cellular energy in the form of ATP.

Key features of the disease mechanism include:

• Impaired oxidative phosphorylation: The mutation leads to reduced efficiency in ATP production, especially in high-energy-demand tissues like the brain and muscles.

• Increased lactic acid production: Cells compensate for poor energy output by shifting to anaerobic metabolism, producing excess lactic acid.

• Mitochondrial inheritance: MELAS is typically inherited in a maternal pattern because mitochondria (and mitochondrial DNA) are passed from mothers to their children via the egg cell. However, not all children of an affected mother will develop the condition due to variable expression and heteroplasmy (mixed populations of normal and mutant mtDNA).

Symptoms

MELAS syndrome affects multiple organ systems, with symptoms that typically begin between the ages of 2 and 20. However, the age of onset and severity can vary. Common symptoms include:

Neurological Symptoms

• Stroke-like episodes: Sudden neurological deficits that resemble strokes but do not correspond to specific vascular territories. They may include weakness, vision loss, or altered consciousness.

• Seizures: Often generalized or focal, frequently triggered by stroke-like episodes.

• Headaches: Often migrainous in nature and may precede stroke-like events.

• Cognitive decline and dementia: Progressive memory loss, confusion, or changes in behavior.

Muscular Symptoms

• Muscle weakness: Especially in the proximal limbs

• Exercise intolerance: Fatigue with minimal exertion

• Myopathy: Muscle wasting over time

Other Systemic Symptoms

• Lactic acidosis: Elevated lactic acid levels causing fatigue, vomiting, abdominal pain, or rapid breathing

• Hearing loss: Sensorineural deafness, often progressive

• Diabetes mellitus: Occurs in some patients due to pancreatic involvement

• Cardiomyopathy: Thickening or weakening of the heart muscle

• Short stature and delayed puberty

Because of the variable expression of the mtDNA mutation, no two individuals with MELAS will have the exact same symptom profile.

Diagnosis

The diagnosis of MELAS syndrome is based on clinical features, biochemical testing, imaging studies, muscle biopsy, and genetic testing. Key diagnostic steps include:

1. Clinical Evaluation

• Identification of core features: stroke-like episodes before age 40, seizures, lactic acidosis, and progressive neurological symptoms.

• Family history of mitochondrial disease or maternal inheritance pattern.

2. Laboratory Tests

• Elevated blood and CSF lactate levels: A hallmark of mitochondrial dysfunction.

• Serum pyruvate: May also be elevated.

3. Imaging Studies

• MRI of the brain: Shows stroke-like lesions that do not respect vascular boundaries, often in the occipital and parietal lobes.

• MRS (Magnetic Resonance Spectroscopy): May show elevated lactate in affected brain regions.

4. Muscle Biopsy

• Ragged-red fibers: Abnormal mitochondria seen on histological staining

• Cytochrome c oxidase (COX)-negative fibers may also be present

5. Genetic Testing

• Testing for the m.3243A>G mutation in the MT-TL1 gene confirms the diagnosis in most cases

Due to the variability in symptoms, a high index of suspicion and a multidisciplinary approach are often required for accurate diagnosis.

Treatment

There is no cure for MELAS syndrome. Treatment is supportive and aims to manage symptoms, prevent complications, and slow disease progression. Therapeutic strategies include:

1. Nutritional and Metabolic Support

• L-arginine: Administered intravenously or orally during stroke-like episodes to improve blood flow

• L-citrulline: May be used as an alternative or adjunct to L-arginine

• Coenzyme Q10 and other mitochondrial cocktails: Antioxidants and vitamins (e.g., riboflavin, thiamine, alpha-lipoic acid, creatine) are sometimes used to support mitochondrial function, although evidence is limited

2. Seizure Management

• Antiepileptic drugs (AEDs): Used to control seizures, but valproate should be avoided due to mitochondrial toxicity

3. Management of Lactic Acidosis

• Hydration, bicarbonate therapy, and dietary modifications may help reduce symptoms

4. Hearing and Vision Support

• Hearing aids or cochlear implants for deafness

• Vision therapy and accommodations if stroke-like episodes affect visual cortex

5. Cardiac and Endocrine Management

• Monitoring and treating cardiomyopathy, diabetes, and other systemic complications

6. Physical and Cognitive Rehabilitation

• Physical therapy, occupational therapy, and speech therapy

• Special education and cognitive support services

Regular follow-up with a multidisciplinary team including neurology, genetics, cardiology, endocrinology, and audiology is essential.

Prognosis

The prognosis for MELAS syndrome is generally poor, as it is a progressive disorder with no curative treatment. Life expectancy is reduced, and many patients experience increasing disability over time. Key prognostic considerations include:

• Age of onset: Earlier onset is typically associated with more severe progression

• Frequency and severity of stroke-like episodes: A major determinant of neurological decline

• Extent of organ involvement: Cardiac, renal, and endocrine complications worsen prognosis

Despite these challenges, some individuals with milder forms of MELAS live into adulthood with appropriate management and support. Ongoing research into mitochondrial function and gene therapy offers hope for future treatments.