Leigh syndrome

Disease Description (Causes and Symptoms)

• Definition summary: Leigh syndrome is a progressive degenerative disorder of the central nervous system that mainly develops during infancy and early childhood, causing necrotic lesions in the brainstem, basal ganglia, thalamus, optic nerves, and other areas. There is currently no curative treatment.
• Causes/pathophysiology:
  • Main cause: Defects in oxidative phosphorylation due to mitochondrial dysfunction. Mitochondrial (mtDNA) mutations are commonly involved (e.g., MT‑ATP6 gene T8993G/T8993C; identified in approximately 10–20% of patients). However, it can also result from nuclear gene defects (e.g., SURF1 and genes related to the PDH complex).
  • Pathophysiology: Reduced mitochondrial electron transport chain (Complexes I–V) function and energy (ATP) production → energy deficiency in tissues, particularly high-energy-demand tissues such as the brain and muscles → metabolic lactic acidosis, cell necrosis, and neurological damage.
• Main symptoms (typical):
  • Age at onset: Usually begins at 3–12 months of age and progresses rapidly. Rarely, it may present during school age or adulthood, with slower progression.
  • Early symptoms: Feeding difficulties, aspiration/weak sucking, loss of head control, developmental delay, and recurrent vomiting.
  • Neurological: Developmental delay and motor impairment (muscle weakness and changes in muscle tone), convulsions/seizures, abnormal eye movements (nystagmus and external ophthalmoplegia), and reduced vision.
  • Systemic: Lactic acidosis/metabolic acidosis (which can cause worsening respiratory and kidney function), cardiomyopathy (heart failure), and respiratory difficulty (one of the main causes of death).
  • Prognosis: In the typical infantile form, the majority of diagnosed patients die from respiratory difficulty or heart failure by 2–3 years of age (approximately 75% reported). The prognosis may be relatively better in adult-onset forms.

Treatment Methods and Precautions

• Treatment principles: There is no definitive treatment. Symptomatic and supportive treatment, as well as prevention and management of complications, are provided.
• Medication and nutritional treatment:
  • Management of acidosis (lactic acidosis): Sodium bicarbonate and sodium citrate may be used. Dichloroacetic acid may be considered depending on the situation, based on specialist judgment.
  • Adjunctive therapy (attempted depending on the case): Mitochondrial supplements such as thiamine, coenzyme Q10, riboflavin, and L‑carnitine may be used; effectiveness varies by case. A high-fat, low-carbohydrate diet (ketogenic diet) is recommended when pyruvate dehydrogenase deficiency is suspected.
  • Seizure management: Anticonvulsants should be administered in consultation with a pediatric neurologist. Some anticonvulsants (e.g., valproate) may be dangerous in the presence of certain gene abnormalities (such as POLG), so consult a specialist.
  • Control of muscle tone and involuntary movements: Start at low doses and adjust trihexyphenidyl (benzhexol), baclofen, tetrabenazine, gabapentin, and other medications. Botulinum toxin injections may be considered for focal hypertonic/spastic muscles.
  • Cardiomyopathy treatment: Standard heart failure and cardiomyopathy treatment by a cardiologist, including heart failure medications.
• Procedures/surgery:
  • Long-term mechanical ventilation may be required in cases of respiratory failure, and nutritional management such as tube feeding may also be necessary.
  • Anesthesia: Patients with mitochondrial disease are at risk of anesthesia-related complications, so prior consultation with the anesthesiology department is necessary.
• Lifestyle management and preventive measures:
  • Avoid stress situations such as infection, fever, fasting, and dehydration, or correct them promptly to prevent metabolic deterioration.
  • Provide regular nutrition, maintain body weight, and prevent dehydration.
  • Regular cardiac, respiratory, ophthalmologic, and neurological monitoring.
• Precautions (including the risk of complications):
  • Emergency treatment is necessary if an acute metabolic crisis occurs, such as hyperlactatemia or acute respiratory failure.
  • Certain medications (e.g., valproate) require assessment of genetic and liver-function risks before use. Always inform the medical team of the patient’s history of mitochondrial disease before anesthesia or surgery.
  • Ensure prompt treatment of infections and prevent dehydration and nutritional imbalance.
• Prognosis: Varies depending on the disease variant and age at onset. The typical infantile form progresses rapidly and has a poor prognosis.

Checklist Before an Outpatient Visit (Including Items to Bring and Sample Questions)

• Items to bring (recommended for outpatient visits):
  • A list of all medications and nutritional supplements currently being taken, including doses and administration times
  • Records of past illnesses, surgeries, and hospitalizations, as well as family history (similar symptoms, early deaths, etc.)
  • Previous test results, if available (blood tests, blood and cerebrospinal fluid lactate levels, MRI images, muscle biopsy, and genetic test results)
  • A symptom diary (age or date of onset, changes in symptoms, seizure frequency and patterns, and changes in eating and sleeping)
  • Recent test results related to kidney and liver function, if available
• Materials for the patient or caregiver to show directly to the doctor during the outpatient visit:
  • Growth chart (for infants and young children)
  • Video recordings of seizures (recorded with a smartphone)
• Clinical signs to check before the outpatient visit (recommended to record in advance):
  • Whether there is difficulty breathing (apnea during sleep or rapid breathing)
  • Decreased intake or recurrent vomiting
  • Decreased urine output or signs of dehydration
  • Rapid weight loss or growth stagnation

Examples of General Questions to Ask the Doctor

• What is the purpose of this medication (or supplement), and what short- and long-term side effects are expected?
• What monitoring tests are recommended for the current symptoms, including how often they should be performed?
• What emergency measures should be taken immediately if acute worsening occurs, such as severe vomiting, difficulty breathing, or seizures?
• Are there any special precautions when vaccinations or anesthesia are needed?
• Is genetic testing (or family testing) necessary, and what significance would the results have for the prognosis?

Examples of Disease-Specific Questions

• How is the variant identified in our child’s (or the patient’s) genetic test (e.g., MT‑ATP6 T8993G/C) related to the prognosis? What is the likelihood that this variant could be inherited by family members (siblings and parents)?
• We have recent MRI (or blood/cerebrospinal fluid lactate) results. What do these results indicate about disease progression? What will the future treatment and monitoring plan be?

(If necessary, printing the questions above and presenting them in the consultation room may help with the consultation.)