MERRF syndrome

Disease Description (Causes and Symptoms)

• Definition: Leigh syndrome is an inherited metabolic disease (subacute necrotizing encephalomyelitis) characterized by progressive degeneration of the central nervous system due to impaired mitochondrial energy production. Typical onset occurs at 3–12 months of age, while some cases present during school age or adulthood and progress more slowly.
• Causes and pathophysiology: Abnormalities in mitochondrial DNA (mtDNA) or nuclear genes impair the function of the electron transport system/respiratory chain, reducing energy (ATP) production and causing lactate accumulation (lactic acidosis). Due to genetic heterogeneity (heteroplasmy), the phenotype and prognosis vary. Some mutations, such as T8993G/T8993C in the MT-ATP6 gene, have been reported in approximately 10–20% of cases.
• Major symptoms:
  • Early symptoms: Feeding difficulty, growth delay, vomiting, persistent crying, loss of head control
  • Neurological: Abnormal muscle tone (hypotonia or hypertonia), delayed motor and cognitive development, convulsions/seizures, ataxia
  • Metabolic: Recurrent or persistent lactic acidosis (increased lactate in the blood and cerebrospinal fluid)
  • Imaging/ophthalmic: Brainstem and basal ganglia lesions (MRI), optic atrophy, reduced vision, and eye movement disorders (nystagmus, extraocular muscle palsy)
  • Cardiac and respiratory: Cardiomyopathy, respiratory failure (a major cause of death as the disease progresses)
• Diagnostic elements (summary): Progressive neurological symptoms, increased lactate in the blood/cerebrospinal fluid, characteristic brainstem and basal ganglia lesions (MRI), histological findings or a history in an identical-phenotype sibling, and molecular genetic testing (mitochondrial and related nuclear gene testing).

Treatment

• Principle: There is currently no definitive treatment. Treatment focuses on preventing and managing symptoms and complications and providing supportive and metabolic therapies where possible. Personalized treatment based on the genetic and metabolic type is needed.
• Metabolic management
  • Lactic acidosis: Correct acidosis by administering sodium bicarbonate or sodium citrate.
  • Dichloroacetic acid: May be used in some studies to lower lactate, but adverse effects such as neurotoxicity (peripheral neuropathy) and limitations on its use should be considered.
  • Cofactors and vitamins: Thiamine, riboflavin, coenzyme Q10, and L-carnitine may be used as supportive treatments (effects vary by patient).
  • Dietary therapy for specific deficiencies: A high-fat, low-carbohydrate diet (ketogenic diet) may be recommended for patients with pyruvate dehydrogenase (PDH) deficiency.
• Management of neurological symptoms
  • Seizures (epilepsy): Use anticonvulsants under the guidance of a neurologist. In patients with mitochondrial disease, avoiding valproate is recommended because of the risk of hepatotoxicity and worsening of metabolic abnormalities.
  • Abnormal muscle tone and movement disorders: Low-dose baclofen, benzhexol, gabapentin, and other treatments; botulinum toxin injections may be used for focal myoclonus. Physical and occupational therapy help preserve function.
• Cardiac and respiratory management
  • Cardiomyopathy: Cardiology treatment (including heart failure medications), with transplant evaluation if necessary.
  • Respiratory failure: Noninvasive or invasive mechanical ventilation, prevention of aspiration (dietary management and tube feeding), and other measures.
• Other
  • Infection prevention, including vaccinations, nutritional management, and consideration of tube feeding (PEG) for dysphagia.
  • Regular multidisciplinary management (neurology, cardiology, nutrition, respiratory medicine, ophthalmology, and clinical genetics).
  • Genetic counseling: Counseling regarding the risk of recurrence in the family and options for preconception diagnosis (molecular genetic testing, embryo testing, etc.).

Checklist Before an Outpatient Visit (Including Preparation and Sample Questions)

• Items/documents to prepare
  • List of currently used medications and supplements (including doses and administration times)
  • Previous test results (brain MRI, blood and cerebrospinal fluid lactate, muscle biopsy/tissue examination, respiratory chain enzyme testing, and genetic test results)
  • The time of onset and course of seizures and symptoms (records of changes in imaging findings, fever, feeding, sleep, etc.)
  • Growth records (weight and height), feeding status, and notes on respiratory symptoms (sleep apnea and breathing difficulty)
• Priority items to show the doctor during the outpatient visit
  • Recent blood and cerebrospinal fluid lactate levels, the latest MRI images, and the genetic test report
  • Records of emergency management during acute worsening (hospitalizations and history of acidosis treatment)

Examples of General Questions to Ask the Doctor

• "If there are current genetic test results for me (or my child), what variant was identified, and how does this variant affect the prognosis?"
• "What are the major side effects of the prescribed medication, and are there any precautions to take while using it?"
• "What emergency measures should be taken if seizures (or lactic acidosis) worsen, and what are the criteria for visiting a hospital?"
• "Are there any particular precautions regarding lifestyle and dietary management, such as fasting, hydration, or exercise restrictions?"
• "What is the schedule for follow-up tests, such as blood lactate, MRI, and cardiac function tests?"

Examples of Disease-Specific Questions

• "What is the heteroplasmy ratio of the variant identified by genetic testing? How does this value predict symptom onset and prognosis?"
• "If a specific metabolic type (for example, PDH deficiency) is confirmed, would a ketogenic or high-fat diet be helpful? What are the expected benefits and risks of implementing it?"