Amino Acid Disorders, Fatty Acid Oxidation & Ketone Metabolism

PKU · MSUD · Homocystinuria · Tyrosinemia · Urea cycle defects · Organic acidemias · MCAD deficiency · VLCAD · Ketone synthesis/utilisation defects
🧬 Key concepts: Amino acid restricted diets, hypoketotic hypoglycemia (FAO), metabolic acidosis with ketosis (organic acidemias), hyperammonemia, newborn screening by tandem MS.

📖 Amino acid disorders, FAO & ketone metabolism

🧬 Amino acid disorders
PKU (Phe), MSUD (Leu, Ile, Val), homocystinuria (Met, homocysteine), tyrosinemia (Tyr), nonketotic hyperglycinemia (Gly). Urea cycle defects (hyperammonemia). Organic acidemias (propionic, methylmalonic, isovaleric) – acidosis, ketosis, hyperammonemia.
🔥 Fatty acid oxidation disorders (FAO)
MCAD (most common), VLCAD, LCHAD, CPT2. Hypoketotic hypoglycemia, cardiomyopathy, rhabdomyolysis. Newborn screening by acylcarnitine profile. Avoid fasting, IV glucose during illness.
🧪 Disorders of ketone metabolism
Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency, beta-ketothiolase deficiency (mitochondrial acetoacetyl-CoA thiolase). Ketoacidosis with normal anion gap, hyperammonemia, hyperglycinemia. Treat with glucose, bicarbonate, carnitine.
⚠️ Metabolic red flags: Hypoketotic hypoglycemia (FAO), maple syrup urine odor (MSUD), sweaty feet (isovaleric acidemia), metabolic acidosis with ketosis (organic acidemia), hyperammonemia (UCD, organic acidemia).

🩺 Symptom-based approach to IEM: amino acids, FAO, ketone disorders

1
Hypoketotic hypoglycemia + hepatomegaly + cardiomyopathy → Fatty acid oxidation defect (MCAD, VLCAD, LCHAD). Labs: low ketones, elevated CK, acylcarnitine profile.
2
Metabolic acidosis + ketosis + hyperammonemia + neutropenia → Organic acidemia (propionic, methylmalonic, isovaleric). Urine organic acids, acylcarnitine (C3).
3
Hyperammonemia + respiratory alkalosis (normal anion gap) → Urea cycle defect (OTC, CPS1). Plasma amino acids (citrulline, arginine).
4
Maple syrup urine odor + encephalopathy + seizures → MSUD (leucine elevation). Dialysis, dietary restriction of branched-chain amino acids.
5
Ectopia lentis (downward) + thromboembolism + intellectual disability → Homocystinuria (CBS deficiency). Elevated methionine, homocysteine.
📌 Clinical pearl: A child with hypoketotic hypoglycemia (low or absent ketones despite low glucose) suggests a fatty acid oxidation disorder until proven otherwise. Urgent newborn screening review.

📋 Stepwise management: amino acid disorders, FAO, ketone defects

1
PKU (phenylalanine hydroxylase deficiency) – Low-phenylalanine diet, Phe-free amino acid formula. Monitor blood Phe. BH4 (sapropterin) for responsive cases. Pregnancy management to prevent maternal PKU syndrome.
2
MSUD (maple syrup urine disease) – Restrict leucine, isoleucine, valine. Special formula. Acute crisis: dialysis, IV glucose, thiamine (some responsive).
3
MCAD deficiency (medium-chain acyl-CoA dehydrogenase) – Avoid fasting, frequent meals, carnitine supplementation. IV glucose during illness. Prevent metabolic decompensation.
4
Propionic acidemia / Methylmalonic acidemia – Protein restriction, special formula. L-carnitine. B12 for responsive MMA. Ammonia scavengers if hyperammonemia. Liver/kidney transplant for severe.
5
Disorders of ketone metabolism (SCOT, beta-ketothiolase) – Avoid fasting, IV glucose during illness, bicarbonate, carnitine. Treat acidosis aggressively.
🚨 Emergency: decompensated MSUD or organic acidemia – High-dose IV glucose (stop catabolism), IV lipids (if not contraindicated), hemodialysis for severe acidosis/hyperammonemia. Urgent metabolic consultation.

🧠 Reflex prompts: amino acid disorders, FAO, ketone defects

🧬 3-day-old with poor feeding, encephalopathy, urine smells like maple syrup. Diagnosis?
Maple syrup urine disease (MSUD). Leucine, isoleucine, valine accumulation. Dialysis, dietary restriction.
🍼 Infant with vomiting, metabolic acidosis, hyperammonemia, neutropenia. Acylcarnitine shows elevated C3. Diagnosis?
Propionic acidemia or methylmalonic acidemia. Urine organic acids, specific enzyme assay.
🔥 18-month-old with vomiting, lethargy, hypoketotic hypoglycemia after fasting. Most likely?
MCAD deficiency. Acylcarnitine profile: elevated C8, C6, C10. Avoid fasting.
👁️ 10-year-old with lens dislocation (downward), intellectual disability, thromboembolism. Diagnosis?
Homocystinuria (cystathionine beta-synthase deficiency). Elevated methionine, homocysteine. B6 responsive in some.
🧬 Neonate with hyperammonemia 600 µmol/L, respiratory alkalosis, normal anion gap. Diagnosis?
Urea cycle defect (most common OTC deficiency). Plasma amino acids (low citrulline).
💊 What is the dietary treatment for PKU?
Low-phenylalanine diet + Phe-free amino acid medical formula.
🧪 What is the characteristic urine organic acid in isovaleric acidemia?
Isovalerylglycine. Sweaty feet odor.
🩸 What is the most common FAO disorder detected by newborn screening?
MCAD deficiency (medium-chain acyl-CoA dehydrogenase).
🧬 Which disorder presents with normal anion gap ketoacidosis and is due to defect in ketone utilization?
SCOT deficiency (succinyl-CoA:3-ketoacid CoA transferase) or beta-ketothiolase deficiency.
💊 What is the emergency treatment for hyperammonemia in organic acidemia?
IV glucose, IV carnitine, ammonia scavengers (sodium benzoate/phenylbutyrate), hemodialysis if severe.