Methylmalonic acidemia

Disease Description (Causes and Pathophysiology, Main Symptoms)

• Definition summary: Amyloidosis is a group of diseases in which amyloid proteins (abnormally folded proteins) are deposited in tissues and organs, impairing their function. It is divided into localized (involving one area) and systemic (involving multiple organs) forms.
• Causes and pathophysiology: Amyloid originates from various precursor proteins (e.g., immunoglobulin light chains → AL, SAA → AA, transthyretin (TTR) → ATTR), and accumulates faster than it can be broken down, causing fibrosis and organ dysfunction. Causes include hereditary (familial TTR mutations) and secondary (chronic inflammation, infection, or multiple myeloma, etc.) forms.
• Main symptoms (by organ):
  • Heart: Heart failure (shortness of breath, exercise intolerance), arrhythmias, cardiac enlargement (findings of restrictive cardiomyopathy)
  • Kidneys: Proteinuria, kidney failure (edema, elevated uric acid, etc.)
  • Nervous system: Peripheral neuropathy (numbness and tingling), autonomic neuropathy (orthostatic hypotension, diarrhea and constipation)
  • Digestive tract: Difficulty swallowing, chronic diarrhea, gastrointestinal bleeding
  • General symptoms: Fatigue, weight loss, bleeding tendency (petechiae, etc.), enlargement of the liver and spleen, etc.
• Clinical importance: The extent of involvement of the affected organs (especially the heart and kidneys) determines the prognosis.

Treatment Methods and Precautions

• Definitive treatment (inhibiting amyloid formation or eliminating the cause)
  • AL (immunoglobulin light-chain) amyloidosis: Chemotherapy is standard (bortezomib-based regimens [e.g., CyBorD: cyclophosphamide + bortezomib + dexamethasone]; combination therapy with daratumumab has also recently been used). Autologous hematopoietic stem cell transplantation may be considered when indicated.
  • AA (associated with chronic inflammation): Actively treat the underlying inflammatory disease (such as rheumatoid arthritis) to reduce SAA production.
  • ATTR (transthyretin): Depending on whether it is hereditary or acquired, drug treatment (tafamidis: a TTR stabilizer — particularly for cardiac involvement), gene-silencing agents (patisiran, inotersen — mainly for polyneuropathy due to hereditary TTR), and, in some cases, liver transplantation may be considered.
• Supportive (organ-specific) treatment and complication management
  • Heart failure: Use diuretics (fluid management); ACE inhibitors/ARBs and β-blockers require caution because of limited efficacy and tolerability issues. Antiarrhythmic treatment, pacemakers, and, in severe cases, transplantation or device therapy may be considered.
  • Kidneys: Control proteinuria, manage blood pressure, and use dialysis when necessary.
  • Autonomic symptoms: For orthostatic hypotension, consider walking and positional management, fluid and salt supplementation, and medications (such as midodrine).
  • Pain and sensory disturbances: Treat neuropathic pain (with antidepressants, anticonvulsants, etc.).
  • Bleeding tendency: Anticoagulants and antiplatelet agents should be decided after weighing the risks and benefits. Endoscopic management of bleeding may be necessary.
• Lifestyle management and precautions
  • Avoid dehydration and activities that induce low blood pressure (excessive use of diuretics and sudden changes in posture).
  • NSAIDs are contraindicated or should be used cautiously when kidney function is impaired.
  • Actively treat infections and underlying chronic inflammatory diseases.
  • Consult about bleeding risk before anticoagulation or procedures.

Checklist Before an Outpatient Visit (Items to Bring, Tests, Symptom Records, etc.)

• Items to bring and prepare
  • A list of all medications and supplements currently being taken (including doses and times of administration)
  • Previous test results (blood tests, urine tests, protein electrophoresis, echocardiography, electrocardiography, kidney and liver tests) and biopsy results (if available, pathology slides or reports)
  • Records of recent weight changes, urine volume and presence of edema, changes in bowel movements and urination, history of falls or fainting, and photographs of bleeding findings (if available)
  • Family history (heart disease, peripheral neuropathy, premature death, etc.) and genetic test results (if available)
• Preparation for tests and measurements (items commonly checked during an outpatient visit)
  • Blood: CBC, electrolytes, creatinine, liver enzymes, NT-proBNP/BNP, protein electrophoresis and immunofixation electrophoresis (serum/urine)
  • Urine: Proteinuria (24-hour or spot ACR)
  • Imaging/functional tests: Echocardiography (extent of cardiac involvement), electrocardiography, cardiac MRI when necessary, somatosensory nerve testing/nerve conduction studies
  • Biopsy (if one has not been performed previously): Abdominal fat-pad biopsy, biopsy of an affected organ (Congo red staining), bone marrow examination (if suspected)
  • Genetic testing: TTR mutation testing (when familial disease is suspected)
• Examples of sentence-form symptoms that are useful to record during an outpatient visit (for communicating to the doctor)
  • “I have lost X kg over the past 6 months. What is my shortness of breath like when I rest?”
  • “I often feel dizzy when standing, and I have fainted recently.”

Examples of General Questions to Ask the Doctor

• What are the expected benefits and main side effects of this medication (the proposed treatment)?
• How is the extent of involvement of my organs (heart, kidneys, and nerves) assessed, and what is the prognosis?
• What should I be careful about in daily life (exercise, diet, medication use, driving, etc.)?
• What are the treatment goals (relieving symptoms, inhibiting amyloid production, extending survival, etc.)?
• Is additional genetic testing or family testing necessary?

Examples of Disease-Specific Questions

• Regarding cardiac involvement: “How is the extent of involvement of my heart determined (such as by echocardiography and NT-proBNP criteria), and which medications do you recommend prioritizing for heart failure management?”
• If hereditary disease is suspected: “Is hereditary ATTR possible? If the TTR genetic test result is positive, should testing also be recommended for my family?”