Special Metabolic Pathways — Sugars, Amino Acids & Fats — USMLE Step 1 Notes

Fructose metabolism disorders

• Essential fructosuria: fructokinase deficiency — benign; fructose appears in the blood and urine but there are no symptoms (a reducing substance in urine without disease).
• Hereditary fructose intolerance: aldolase B deficiency — fructose-1-phosphate accumulates, trapping phosphate and inhibiting glycogenolysis and gluconeogenesis, so eating fructose/sucrose causes hypoglycaemia, vomiting, jaundice and liver failure. Treat by removing fructose, sucrose and sorbitol.

Galactose metabolism disorders

• Galactokinase deficiency: relatively mild — galactitol accumulates causing infantile cataracts (and failure to track/social smile), without severe systemic disease.
• Classic galactosaemia: galactose-1-phosphate uridyltransferase (GALT) deficiency — toxic galactose-1-phosphate accumulates → failure to thrive, jaundice, hepatomegaly, cataracts, intellectual disability, and a classic susceptibility to E. coli neonatal sepsis. Exclude galactose/lactose from the diet.
• Lactase deficiency: the intestinal disaccharidase falls (congenital, or common adult-onset/secondary after gastroenteritis) → osmotic, non-inflammatory diarrhoea, bloating and flatus after dairy; stool is acidic with a low pH and a positive hydrogen breath test.

Essential amino acids & hyperammonaemia

• Essential amino acids (must be eaten): PVT TIM HaLL — Phenylalanine, Valine, Threonine, Tryptophan, Isoleucine, Methionine, Histidine, Leucine, Lysine (arginine is conditionally essential in children).
• Hyperammonaemia: ammonia from amino-acid breakdown is normally converted to urea; when the urea cycle fails (inherited defects or acquired liver failure) ammonia rises → vomiting, lethargy, asterixis, cerebral oedema and coma (ammonia depletes alpha-ketoglutarate/glutamate in the brain).
• Ornithine transcarbamylase (OTC) deficiency: the commonest urea-cycle defect (X-linked) — hyperammonaemia with HIGH orotic acid and low BUN but NO megaloblastic anaemia (distinguishing it from orotic aciduria). Treat with low-protein diet, benzoate/phenylbutyrate scavengers and lactulose.

Amino-acid derivatives (products)

• Phenylalanine → tyrosine → dopa → dopamine → noradrenaline → adrenaline (catecholamine synthesis; tyrosine hydroxylase is rate-limiting); tyrosine also makes melanin and thyroid hormone.
• Tryptophan → serotonin → melatonin (and niacin/NAD).
• Glycine + succinyl-CoA → haem (via ALA synthase, the rate-limiting step, needing vitamin B6).
• Histidine → histamine (histidine decarboxylase, needs B6).
• Glutamate → GABA (glutamic acid decarboxylase, needs B6) — the main inhibitory neurotransmitter.
• Arginine → nitric oxide (nitric oxide synthase; a vasodilator) and also to creatine (with glycine and methionine) for muscle phosphocreatine energy storage.

Tyrosine catabolism disorders

• Phenylketonuria: phenylalanine hydroxylase (or BH4) deficiency — phenylalanine accumulates → intellectual disability, seizures, musty odour and fair skin (low melanin). Diet-restrict phenylalanine and supplement tyrosine.
• Albinism: defective tyrosinase (or tyrosine transport) → little/no melanin, with visual problems and a high skin-cancer risk; unlike PKU, amino-acid handling is otherwise normal.
• Alkaptonuria: homogentisate oxidase deficiency further down the tyrosine pathway → homogentisic acid accumulates, darkening urine on standing with ochronosis and arthritis (benign).

Fatty-acid oxidation & carnitine

• Carnitine shuttle: long-chain fatty acids need carnitine (via carnitine acyltransferase I/II) to enter mitochondria for beta-oxidation; malonyl-CoA inhibits CPT-1, linking synthesis and oxidation reciprocally.
• Primary carnitine deficiency: impaired long-chain fatty-acid entry → weakness, hypoketotic hypoglycaemia and cardiomyopathy.
• Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: the commonest fatty-acid-oxidation defect — during fasting/illness the child cannot oxidise fats, causing hypoketotic hypoglycaemia, vomiting and lethargy, with a risk of sudden death; avoid fasting.

Ketone bodies & the fed-vs-fasted state

• Ketogenesis: in prolonged fasting/starvation (and uncontrolled diabetes) the liver converts acetyl-CoA (from fat) to acetoacetate and beta-hydroxybutyrate (HMG-CoA synthase is rate-limiting) for the brain and heart; the liver itself cannot use ketones (no thiophorase).
• Ketosis/ketoacidosis: excess ketones lower blood pH (diabetic or alcoholic/starvation ketoacidosis); the urine dipstick detects acetoacetate but underestimates beta-hydroxybutyrate.
• Fed state (insulin): glycolysis, glycogenesis and fatty-acid synthesis are on. Fasted state (glucagon): glycogenolysis then gluconeogenesis; starvation: ketogenesis. Fructose-2,6-bisphosphate is the master switch (high fed, low fasted).

High-yield revision notes; verify against a primary source before clinical use.