Makindo Medical Notes

Related Subjects: |Dementias |DNA replication |DNA structure in Nucleus |Mitosis and Meiosis |Ribosomes |Microtubules |Mitochondria |Smooth and Rough Endoplasmic Reticulum

Mitochondrial diseases are typically presumed to result from maternal inheritance or de novo mutations, but since 95% of mitochondrial proteins are produced by nuclear DNA and transported into the mitochondria from the cytoplasm, these diseases may follow autosomal dominant or even X-linked inheritance patterns. About 40 years ago, American biologist Lynn Margulis suggested that mitochondria originated from specialized bacteria that were incorporated into eukaryotic cells through a symbiotic relationship.

About

• Mitochondrial diseases arise due to defects in the mitochondria, which are responsible for energy production in cells.
• Mitochondria have their own double-stranded circular DNA (mtDNA), which is inherited maternally, distinct from nuclear DNA.
• Faulty mtDNA and related diseases follow the maternal line of inheritance.
• It is believed that mitochondria evolved from aerobic bacteria that entered into a symbiotic relationship with primitive eukaryotic cells.

Aetiology

• Mitochondrial diseases result from genetic mutations, often due to less effective error-checking processes in mitochondrial DNA replication compared to nuclear DNA.
• These mutations lead to abnormalities in oxidative phosphorylation, causing defects in energy production through faulty enzymes and protein synthesis.
• The prevalence of mitochondrial diseases is approximately 1 in 10,000 live births, with mutations in mtDNA being the most frequent cause.

Mitochondrial Genetics

• Mitochondrial protein complexes produce over 90% of the body’s energy, and defects in these complexes can lead to significant tissue damage.
• High-energy consuming tissues, such as muscles, nerves, and the brain, are most commonly affected by mitochondrial diseases.
• The key mitochondrial complexes include:
  • Complex I: Reduced nicotinamide adenine dinucleotide-coenzyme Q oxidoreductase
  • Complex II: Succinate dehydrogenase
  • Complex III: Coenzyme Q-cytochrome c oxidoreductase
  • Complex IV: Cytochrome c oxidase
  • Complex V: ATPase synthetase

Mitochondrial DNA Encoding

• Mitochondrial DNA encodes for:
  • 22 transfer RNAs (tRNAs)
  • 2 ribosomal RNAs (rRNAs)
  • 13 messenger RNAs (mRNAs), which are translated into polypeptides that form subunits of the respiratory chain complexes. Mutations in mitochondrial tRNA genes can impair translation, affecting energy production.
• Only about 5% of mitochondrial proteins are encoded by mtDNA; the majority are encoded by nuclear DNA and transported into the mitochondria from the cytoplasm.

Clinical Clues to Mitochondrial Disease

• Sensorineural hearing loss
• Retinitis pigmentosa (a retinal degeneration disorder)
• Muscle weakness, ataxia (lack of coordination), and recurrent strokes
• Cardiomyopathy and insulin-dependent diabetes mellitus
• Complete heart block and lactic acidosis

Clinical Presentations

• MELAS: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. Symptoms include cognitive impairment, dementia, migraine-like headaches, lactic acidosis, transient ischaemic attacks, hearing loss, gastrointestinal dysmotility, and weight loss.
• MERRF: Myoclonic epilepsy with ragged-red fibers. Progressive myoclonic epilepsy, muscle weakness, short stature, cardiomyopathy, and cutaneous lipomas. Ragged-red fibers appear in muscle biopsies stained with modified Gomori trichrome stain.
• KSS (Kearns-Sayre Syndrome): External ophthalmoplegia, cardiac conduction defects, sensorineural hearing loss, and retinitis pigmentosa. Also associated with short stature, peripheral neuropathy, and delayed puberty.
• PEO (Progressive External Ophthalmoplegia): Characterized by progressive weakness of the eye muscles, severe ptosis, and overlap with other mitochondrial myopathies.

Investigations

• Muscle biopsy: Shows accumulation of abnormal mitochondria, often seen as ragged-red fibers with trichrome staining, and may show cytochrome c oxidase deficiency.
• Blood tests: Elevated serum lactic acid levels at rest or after exertion, elevated CK, and myopathic findings on electromyography (EMG).
• Cerebrospinal fluid: Often shows elevated protein levels in mitochondrial diseases.

Features of Mitochondrial Syndromes

• Neuropathy, ataxia, and retinitis pigmentosa
• Mitochondrial encephalomyopathy, lactic acidosis, and stroke
• Myoclonic epilepsy with ragged red fibers
• Myopathy and external ophthalmoplegia
• Neuropathy and gastrointestinal encephalopathy
• Leber's hereditary optic neuropathy
• Kearns-Sayre Syndrome: Caused by mtDNA deletions and duplications, symptoms appear before age 20. Symptoms include short stature, pigmentary retinal degeneration, ophthalmoplegia, ptosis, ataxia, heart conduction abnormalities, diabetes, and hearing loss.
• Chronic Progressive External Ophthalmoplegia (CPEO): Can be maternally inherited, autosomal dominant, or due to de novo mutations. Symptoms include ptosis, myopathy, depression, cataracts, and ketoacidosis.
• Leigh’s Syndrome: Subacute sclerosing encephalopathy, a severe neurological disorder.

Management of Mitochondrial Diseases

There is currently no cure for mitochondrial diseases, so management focuses on symptom control, improving quality of life, and slowing disease progression where possible. A multidisciplinary approach is crucial, involving neurologists, cardiologists, endocrinologists, and other specialists depending on the systems affected.

General Management Strategies

• Symptom-Based Treatment: Management focuses on alleviating the symptoms related to specific organ or system involvement, such as controlling seizures, managing heart problems, or addressing muscle weakness and fatigue.
• Avoidance of Stressors: Patients should avoid situations that increase metabolic stress, such as fasting, extreme physical exertion, and exposure to cold, as these can worsen symptoms.
• Exercise: Moderate aerobic exercise can improve muscle function and endurance in some patients, but strenuous activity should be avoided to prevent lactic acidosis or rhabdomyolysis.
• Nutritional Support: Maintaining adequate nutrition is essential. In patients with gastrointestinal involvement or dysmotility, diet modification or the use of enteral feeding may be necessary.

Pharmacological Treatments

• Coenzyme Q10 (CoQ10): Often used to support mitochondrial function since it plays a key role in the electron transport chain. It may help alleviate muscle weakness and fatigue in some patients.
• L-Carnitine: Carnitine supplementation is used to support fatty acid metabolism, helping improve energy production and reduce muscle symptoms.
• Creatine: Creatine supplements are sometimes recommended to improve muscle strength and endurance, as they may help replenish ATP in muscle cells.
• Antioxidants: Antioxidants like vitamin E and alpha-lipoic acid are used to reduce oxidative stress in cells, which is thought to contribute to mitochondrial damage.
• B-complex Vitamins: Supplements like riboflavin (B2) and thiamine (B1) may help improve mitochondrial function and reduce symptoms in some patients.
• Dichloroacetate (DCA): In some cases, DCA is used to treat lactic acidosis by reducing lactate production, though its use must be carefully monitored due to potential side effects.

Management of Specific Symptoms

• Seizures: Antiepileptic drugs (AEDs) are used to manage seizures, though certain drugs that affect mitochondrial function (e.g., valproic acid) should be avoided.
• Cardiac Involvement: Cardiac arrhythmias or cardiomyopathy may require pacemaker placement, beta-blockers, or other cardiology treatments. Regular monitoring of cardiac function is important.
• Endocrine Issues: Insulin may be required to manage diabetes, which is common in mitochondrial disorders. Thyroid or adrenal insufficiencies should also be managed with appropriate hormone replacement therapy.
• Gastrointestinal Dysmotility: Prokinetic agents may be prescribed for gastrointestinal motility issues. In severe cases, gastrostomy or jejunostomy tubes may be needed for feeding.

Genetic Counseling and Future Considerations

• Genetic Counseling: Genetic counseling is essential for affected families to understand the inheritance patterns and risks of transmission to future generations. In cases of maternally inherited mitochondrial diseases, families may consider reproductive options such as preimplantation genetic diagnosis (PGD).
• Experimental Treatments: Research into mitochondrial gene therapy and mitochondrial replacement techniques (e.g., “three-parent” IVF) is ongoing, offering potential future treatment options.

Supportive Care

• Physical Therapy: Regular physical therapy helps improve mobility, prevent contractures, and maintain muscle strength.
• Occupational Therapy: Assists in adapting daily activities and using assistive devices to maintain independence and quality of life.
• Palliative Care: For patients with severe disease, palliative care focuses on providing comfort, managing symptoms, and offering emotional support.

Prognosis

The prognosis for mitochondrial diseases varies depending on the specific mutation and the severity of the symptoms. Some patients may experience a slowly progressive course with manageable symptoms, while others may face rapid deterioration in multi-organ systems. Early diagnosis and comprehensive management can significantly improve quality of life and extend life expectancy.