High anion-gap metabolic acidosis
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A child with a metabolic acidosis (low pH, low bicarbonate) and an anion gap above ~12 mEq/L (the upper bound is age- and lab-specific). The clinical picture is tachypnea, vomiting, lethargy, dehydration, and a sense that something is "off" out of proportion to the history. Clinicians know the MUDPILES adult mnemonic (methanol, uremia, DKA, paraldehyde, isoniazid/iron, lactic acidosis, ethylene glycol, salicylates); in pediatric genetics, the question is which inborn error of metabolism is generating the unmeasured anion.
Three labs, drawn together, narrow the entire pediatric genetic differential:
- Are ketones present? Ketotic vs non-ketotic separates the most common categories.
- Is lactate predominant? Lactic-acidosis-predominant disorders behave differently from ketoacidosis.
- Is ammonia elevated? Hyperammonemia + acidosis points to organic acidemia or FAOD.
The combinatorics give four operationally useful patterns:
| Pattern | Likely category |
|---|---|
| Ketotic + hyperammonemia + high anion gap | Organic acidemia (PA, MMA, IVA) |
| Ketotic + branched-chain amino acid elevation + sweet-smelling urine | Maple syrup urine disease |
| Lactic acidosis predominant, ketones modest | Mitochondrial disease (Leigh, respiratory chain), PDH deficiency, pyruvate carboxylase |
| Hypoketotic + hyperammonemia + hypoglycemia | Fatty acid oxidation defect (e.g. MCAD) |
Ketones are the body's normal response to a low-glucose state, so the absence of ketones in the setting of acidosis or hypoglycemia is the diagnostic abnormality, not a reassurance.
Ketotic with hyperammonemia (organic acidemias)
- Propionic acidemia (PCCA/PCCB): vomiting, encephalopathy, neutropenia, thrombocytopenia, ketotic acidosis, hyperammonemia. C3 carnitine on acylcarnitines; methylcitrate and 3-hydroxypropionate on urine organic acids.
- Methylmalonic acidemia (MUT, MMAA, MMAB, MMADHC): same clinical picture as PA; urine methylmalonic acid is the discriminator. B12-responsive subtypes exist (cblA, cblB), so trial hydroxocobalamin.
- Isovaleric acidemia (IVD): the "sweaty-feet" smell. C5 on acylcarnitines; isovalerylglycine on urine organics.
Ketotic without hyperammonemia (amino-acid-only)
- Maple syrup urine disease (BCKDHA/BCKDHB/DBT): sweet/burnt-sugar urine smell, opisthotonos, encephalopathy. Branched-chain amino acids (leucine, isoleucine, valine, alloisoleucine) on plasma amino acids; positive 2,4-DNPH on urine.
Lactic acidosis predominant
- Leigh syndrome and other mitochondrial / respiratory chain defects: progressive encephalopathy, brainstem lesions on MRI, multisystem. Lactate/pyruvate ratio is elevated (> 25).
- Pyruvate dehydrogenase deficiency: X-linked, often male infants. Lactic acidosis with a normal lactate/pyruvate ratio (because pyruvate also rises). Corpus callosum agenesis is associated.
- Pyruvate carboxylase deficiency: lactic acidosis with hyperammonemia, hypoglycemia (gluconeogenesis defect), and an elevated lactate/pyruvate ratio.
- Fructose-1,6-bisphosphatase deficiency: episodic lactic acidosis with fasting hypoglycemia.
- GLUT1 deficiency (less acute, but lactate-normal CSF/serum lactate ratio is the giveaway).
Hypoketotic with hyperammonemia and hypoglycemia (fatty acid oxidation)
- MCAD deficiency: the prototypical FAOD; viral illness or fasting triggers hypoketotic hypoglycemia + secondary hyperammonemia + Reye-like encephalopathy. C8 acylcarnitine elevation.
- VLCAD and LCHAD/TFP: add cardiomyopathy and rhabdomyolysis in the older child.
Liver-failure pictures (acidosis + transaminitis)
- Tyrosinemia type 1: succinylacetone on urine organic acids; cabbage smell; liver failure + coagulopathy + renal Fanconi.
- Classic galactosemia: jaundice + cataracts + sepsis (especially E. coli) + reducing substances in urine on milk feeds.
- Hereditary fructose intolerance: triggered by fructose/sucrose introduction.
- Ketotic acidosis + hyperammonemia in an infant → organic acidemia. C3 on acylcarnitines = PA or MMA; C5 = IVA.
- Hypoketotic acidosis + hyperammonemia + hypoglycemia → FAOD. Acylcarnitine profile localizes the chain length.
- Lactic acidosis with high L/P ratio (> 25) → mitochondrial respiratory chain or pyruvate carboxylase.
- Lactic acidosis with normal L/P ratio → pyruvate dehydrogenase deficiency.
- Sweet/burnt-sugar urine + opisthotonos → MSUD.
- Sweaty-feet smell → isovaleric acidemia.
- Cabbage smell + liver failure + coagulopathy + renal tubular dysfunction → tyrosinemia type 1.
Order in parallel; treat in parallel. The metabolic emergency does not wait on the lab.
- Venous blood gas, electrolytes (compute anion gap), glucose, lactate, ammonia, ketones (β-hydroxybutyrate), CBC.
- Plasma amino acids: MSUD (leucine, alloisoleucine), UCD (citrulline), nonspecific elevations in mitochondrial disease.
- Plasma acylcarnitine profile: FAOD chain lengths, PA/MMA (C3), IVA (C5).
- Urine organic acids: methylmalonic acid (MMA), 3-hydroxypropionate + methylcitrate (PA), isovalerylglycine (IVA), 2-ketoacids (MSUD), succinylacetone (tyrosinemia 1).
- Lactate/pyruvate ratio if lactate-predominant (distinguishes mito vs PDH vs pyruvate carboxylase).
- Urine reducing substances if galactosemia or HFI suspected.
- Liver enzymes, INR, ammonia to assess for hepatic failure.
- Empiric treatment: stop protein, D10 IV at 1.5× maintenance, IV carnitine (organic acidemias), IV thiamine (MSUD adjunct, PDH-responsive subtypes), IV hydroxocobalamin (cblA/cblB), scavengers + dialysis if ammonia > 500 (see hyperammonemia).
- Targeted gene sequencing or broad metabolic panel once biochemistry localizes.
- Ketones tell you which way to look. Their absence in acidosis or hypoglycemia is the FAOD-pointing finding.
- MUDPILES is for adults. In a sick infant or child, the genetic differential is organic acidemia, MSUD, mitochondrial disease, PDH, and FAOD. Anchor there.
- L/P ratio splits the lactic acidoses. > 25 = respiratory chain or pyruvate carboxylase. Normal = PDH.
- C3 acylcarnitine is the single most useful marker for PA and MMA; C5 for IVA. Knowing what each chain length means short-circuits a lot of follow-up.
- Newborn screening covers most of these. A child in metabolic crisis is often pre-screen, false-negative, or has a milder allele that escaped detection. Re-pull the screen.