Medium-chain acyl-CoA dehydrogenase deficiency

Disease Description (Causes and Symptoms)

• Definition: Propionic acidemia is an autosomal recessive metabolic disorder in which propionic acid (propionyl-related metabolites) accumulates in peripheral tissues due to a deficiency of the propionyl‑CoA carboxylase (PCC) enzyme. It is caused by mutations in the PCCA gene (long arm of chromosome 13) and the PCCB gene (long arm of chromosome 3). The incidence has been reported to be approximately 1 in 100,000 people.
• Pathophysiology: PCC deficiency blocks the metabolism of “propiogenic” amino acids such as valine, isoleucine, methionine, and threonine, as well as fatty acids and sulfur compounds, leading to the accumulation of toxic organic acids (e.g., propionyl-related metabolites and methylcitric acid), hyperammonemia, metabolic acidosis, and elevated glycine. Propionic acid production by intestinal bacteria also contributes.
• Main symptoms: Neonatal acute form — vomiting, feeding difficulties, lethargy, respiratory distress (respiratory and metabolic acidosis), dehydration, hypoglycemia, hyperammonemia, petechiae and bleeding tendency (thrombocytopenia), and susceptibility to infection due to leukopenia. Chronic/delayed-onset form — growth and developmental delay, intellectual disability, seizures, dystonia and movement disorders, and recurrent metabolic crises.

Treatment

• Standard treatment during the acute phase (metabolic crisis)
  • Rapid suppression of catabolism: stop oral and intravenous protein (a source of propiogenic substrates) and administer high-carbohydrate (high-glucose) intravenous fluids to suppress catabolism. Provide lipid nutrition if necessary (based on medical judgment).
  • Fluid and electrolyte replacement and correction of metabolic acidosis (e.g., bicarbonate).
  • Treatment of hyperammonemia: ammonia-scavenging medications (e.g., sodium benzoate, sodium phenylacetate, etc.) and, in severe cases, hemofiltration (dialysis/continuous renal replacement therapy).
  • Intravenous carnitine: L‑carnitine 50–100 mg/kg/day (oral/intravenous, as directed by a physician) to promote excretion of toxic organic acids and support remission.
  • Antibiotics (reduction of intestinal bacteria): short-term oral antibiotics to suppress intestinal propionic acid production (medication listed: neomycin; metronidazole is commonly used in clinical practice because of toxicity concerns)
  • Biotin (effective in some patients): example of a standard dose: 10 mg/day (adjusted depending on the circumstances).
• Long-term management
  • Dietary therapy: individualized dietary management that restricts total protein intake while meeting growth requirements (using special formulas/preparations). In particular, restrict isoleucine, valine, methionine, and threonine, etc. (as directed by a physician and dietitian)
  • Ongoing carnitine supplementation (oral) and regular metabolic monitoring (ammonia, organic acids, acylcarnitines, etc.)
  • Intermittent preventive antibiotic administration (at the physician’s discretion)
  • Liver transplantation may be considered in cases of severe or frequent attacks/metabolic crises or failure of metabolic control (it cannot completely restore systemic metabolite levels) — liver transplantation may reduce the frequency and severity of metabolic crises.
• Precautions (points of caution and risk of complications)
  • Because the risk of metabolic crisis is high during stressful situations such as fasting, fever, infection, and surgery, always carry an emergency plan (hospital contact information and emergency treatment instructions).
  • Some medications (e.g., valproate and other antiepileptic drugs; consultation with a physician is necessary) may trigger worsening — consult a metabolic specialist before taking medication.
  • Long-term complications: neurodevelopmental disorders (cognitive and motor), cardiomyopathy (heart failure, QT prolongation), recurrent pancreatitis, cytopenias (risk of infection and bleeding), and liver and kidney problems, etc. Regular cardiac and neurodevelopmental monitoring is necessary.
• Prognosis
  • Severe neonatal-onset disease may have a poor neurological prognosis despite appropriate acute treatment and long-term management. Early diagnosis and appropriate management can reduce the frequency of metabolic crises and improve survival and quality of life. Liver transplantation is expected to reduce metabolic crises, but neurological damage may have already occurred.

Checklist Before an Outpatient Visit (Including Example Questions)

• Items to prepare (recommended to bring)
  • A list of all medications and supplements currently being taken (including dosage and time of administration)
  • Information about the special formula/diet being used (product name and daily intake)
  • Recent test results (ammonia, electrolytes, blood tests, acylcarnitine/organic acid tests, genetic test results, etc.)
  • A record of when symptoms such as worsening symptoms, fever, vomiting, and loss of appetite occurred, how long they lasted, and possible triggers
  • Emergency treatment instructions (a copy, if available), previous hospitalizations/intensive care admissions, and surgical history
• Information to tell the healthcare provider in advance at the outpatient visit
  • Recent infections, vaccinations, surgery, long-distance flights, fasting, and other stress factors
  • Growth and developmental problems (feeding difficulties, poor weight gain, developmental delay)

Examples of General Questions to Ask the Doctor

• What are the side effects and monitoring requirements for this medication (e.g., carnitine or antibiotics)?
• What emergency measures should be taken immediately if a metabolic crisis occurs (vomiting, lethargy, fever, etc.)? When and how should we contact the hospital?
• How should the child’s growth and nutritional management be planned? What are the protein and calorie targets?
• Which long-term complications should be monitored (heart, pancreas, neurodevelopment, etc.)?

Examples of Disease-Specific Questions

• What are the daily target amounts (g/kg/day) for the proteins that should be restricted (especially isoleucine, valine, methionine, and threonine), and which special formula (product) is recommended?
• What are the criteria for liver transplantation (frequency and severity of metabolic crises, failure to maintain growth, etc.), and what are the expected benefits and limitations after liver transplantation?

Important: If acute symptoms (severe vomiting, decreased consciousness, respiratory distress, high fever, seizures, etc.) occur, immediately visit an emergency room or contact the treating specialist to receive emergency metabolic management (intravenous nutrition, ammonia-lowering treatment, dialysis, etc.).