Mitochondrial diseases are estimated to affect approximately 1 in 4,000 to 1 in 5,000 individuals worldwide, though some experts suggest the rate may be higher due to underdiagnosis and variable clinical presentations. They can be present at birth or manifest later in life.

These disorders result from mutations in genes that are critical to mitochondrial function. These mutations can occur in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA), which encodes most of the proteins needed for mitochondrial function. mtDNA is inherited maternally, meaning it is passed only from mothers to offspring, while nDNA mutations follow typical Mendelian inheritance patterns (autosomal dominant, autosomal recessive, or X-linked) (see Rareshare Guide on Genetic Inheritance). The resulting defects impair the mitochondrial respiratory chain, reducing the cell’s ability to produce energy efficiently.

Symptoms vary widely depending on the organs affected and the specific genetic mutation but may include:

• Muscle weakness, fatigue, or exercise intolerance

• Neurological issues: seizures, developmental delay, stroke-like episodes, ataxia (lack of coordination in muscle movements)

• Vision and hearing loss

• Cardiomyopathy or arrhythmias

• Diabetes mellitus

• Liver dysfunction or failure

• Gastrointestinal issues such as dysmotility or vomiting

• Growth delays or failure to thrive in children

• Lactic acidosis due to impaired energy metabolism

Diagnosing mitochondrial diseases is complex due to the heterogeneity of symptoms and overlapping features with other disorders. A multidisciplinary approach is usually required, involving neurology, genetics, metabolic specialists, and other fields. Diagnosis is based on clinical suspicion, supported by biochemical, genetic, and sometimes histological findings.

• Blood and urine tests: May show elevated lactate and pyruvate levels, indicating impaired oxidative metabolism.

• Genetic testing: Includes sequencing of mtDNA and nuclear genes associated with mitochondrial function.

• Muscle biopsy: Can reveal structural abnormalities such as ragged red fibers, and enzyme assays can evaluate respiratory chain complex activity.

• Brain MRI: May show characteristic lesions, especially in syndromes like MELAS or Leigh syndrome.

• MR spectroscopy: Used to detect lactic acid accumulation in the brain.

• Electromyography (EMG) and nerve conduction studies: Evaluate neuromuscular involvement.

There is no cure for mitochondrial diseases, and treatment is mainly supportive and symptomatic.

• Vitamin and cofactor supplementation: Often includes a "mitochondrial cocktail" such as coenzyme Q10, L-carnitine, riboflavin, thiamine, and alpha-lipoic acid.

• Management of specific symptoms: Includes anti-epileptics for seizures, insulin for diabetes, cardiac medications for cardiomyopathy, and physical therapy for muscle weakness.

• Avoidance of mitochondrial toxins: Certain medications (e.g., valproic acid in some cases) and stressors that worsen mitochondrial function should be avoided.

• Experimental therapies: Gene therapy and mitochondrial replacement therapy are active research areas.

The prognosis for individuals with mitochondrial diseases is highly variable. Some forms are relatively mild and compatible with a near-normal life expectancy, while others are severe and lead to significant disability or early death. Early diagnosis and comprehensive multidisciplinary care can improve quality of life and, in some cases, slow disease progression. The specific mutation, onset age, and organ involvement influence prognosis.

1. Cleveland Clinic - Mitochondrial Diseases

2. Cleveland Clinic - MELAS Syndrome

3. Cleveland Clinic - LHON

4. Cleveland Clinic - Leigh Syndrome

5. Cleveland Clinic - Kearns-Sayre Syndrome

6. Medline Plus - MERRF