Organic Acidemias & Approach to Neonatal Metabolic Crisis

The propionate pathway

Where propionyl-CoA comes from. Four amino acids and one class of fat are catabolized to propionyl-CoA in mitochondria: valine, odd-chain fatty acids, methionine, isoleucine and threonine (mnemonic: VOMIT). The side chain of cholesterol contributes as well. Propionyl-CoA is then converted in three steps to succinyl-CoA, a TCA cycle intermediate.

Two vitamin cofactors. Propionyl-CoA carboxylase is one of four biotin-dependent carboxylases (with pyruvate carboxylase, acetyl-CoA carboxylase and 3-methylcrotonyl-CoA carboxylase), all using biotin, ATP and CO2. Methylmalonyl-CoA mutase is one of only two human B12-dependent enzymes: it uses adenosylcobalamin in mitochondria, whereas methionine synthase uses methylcobalamin in the cytosol.

Because their final three carbons become propionyl-CoA and then succinyl-CoA, odd-chain fatty acids are the only fatty acids that can feed gluconeogenesis (glycerol is the other fat-derived substrate).

Propionic and methylmalonic acidemia

Genetics. Both are autosomal recessive. Propionic acidemia is deficiency of propionyl-CoA carboxylase (PCCA or PCCB subunit). Methylmalonic acidemia (MMA) results from a defect in the mutase itself or in the steps that build adenosylcobalamin.

Presentation. The infant is typically well at birth and deteriorates within the first days of life, once protein feeds begin: poor feeding, vomiting, lethargy and hypotonia, then seizures, coma and cerebral edema. The picture closely mimics neonatal sepsis. Milder forms present later with episodic decompensation triggered by infection, fasting or a protein load.

Laboratory signature. Accumulating organic acids produce a high anion gap metabolic acidosis with ketosis; significant ketonuria in a neonate is abnormal and a red flag. Hyperammonemia, hypoglycemia and marrow suppression (neutropenia, thrombocytopenia, sometimes pancytopenia) are common. Urine organic acids show 3-hydroxypropionate and methylcitrate in both disorders, plus large amounts of methylmalonic acid in MMA. Plasma propionylcarnitine (C3) is elevated.

Why ammonia rises. Propionyl-CoA competes with acetyl-CoA at N-acetylglutamate synthase. Less N-acetylglutamate is made, and carbamoyl phosphate synthetase I (CPS1), which cannot work without this activator, slows the urea cycle. Carglumic acid, a synthetic N-acetylglutamate analog, reactivates CPS1 and is used for hyperammonemia in NAGS deficiency and in propionic or methylmalonic acidemia.

Long-term course. Survivors risk developmental delay, basal ganglia "metabolic strokes" and pancreatitis. Cardiomyopathy is a notable complication of propionic acidemia, and chronic kidney disease of MMA.

Isovaleric acidemia and biotinidase deficiency

Isovaleric acidemia. An autosomal recessive deficiency of isovaleryl-CoA dehydrogenase in the leucine pathway. Isovaleric acid gives a characteristic sweaty-feet odor, and neonates show ketoacidosis, hyperammonemia and marrow suppression like other organic acidemias. The screening marker is isovalerylcarnitine (C5). Treatment restricts leucine and supplies glycine and carnitine, which conjugate isovaleric acid into isovalerylglycine and isovalerylcarnitine for urinary excretion.

Biotinidase deficiency. Biotinidase frees biotin from biocytin and dietary protein so it can be reused. Its autosomal recessive deficiency starves all four carboxylases at once (multiple carboxylase deficiency). Symptoms usually begin after a few months: seizures, hypotonia, ataxia, alopecia, an eczematous rash, sensorineural hearing loss and optic atrophy, with lactic acidosis and organic aciduria. Lifelong oral biotin prevents or reverses most features, but hearing loss and optic atrophy may persist if treatment is late. Holocarboxylase synthetase deficiency causes a similar, usually neonatal, biotin-responsive picture.

Periorificial rash with alopecia also suggests zinc deficiency (acrodermatitis enteropathica), but seizures, lactic acidosis and organic aciduria point to biotinidase deficiency. Odor clues: sweaty feet in isovaleric acidemia, maple syrup in MSUD, musty in PKU.

Approach to the sick neonate

Suspect an inborn error when a baby who was well for the first days deteriorates after feeds, when sepsis workup is unrevealing, or when there is consanguinity, a prior unexplained neonatal death or an unusual odor. Measure ammonia in every encephalopathic newborn, even while sepsis is being treated.

First-line labs. Ammonia, blood gas with electrolytes and anion gap, glucose, lactate and urine ketones sort the patient into a category. Plasma amino acids, urine organic acids, a plasma acylcarnitine profile and urine orotic acid then pinpoint the defect.

Hyperammonemia with respiratory alkalosis and no ketoacidosis points to the urea cycle; the same ammonia with anion-gap ketoacidosis points to an organic acidemia.

Newborn screening and treatment

Screening. Tandem mass spectrometry of dried blood spots measures amino acids and acylcarnitines: C3 flags propionic or methylmalonic acidemia, C5 isovaleric acidemia, C8 MCAD deficiency, and phenylalanine or leucine flag PKU or MSUD. Biotinidase deficiency and galactosemia are screened by enzyme activity assays. Positive screens are confirmed with acylcarnitines, organic acids and enzyme or genetic testing.

Avoid IV lipid until a long-chain fatty acid oxidation defect has been ruled out.

Chronic care. Natural protein is limited with a formula low in isoleucine, valine, methionine and threonine. L-carnitine replaces carnitine lost as urinary acylcarnitines, hydroxocobalamin helps B12-responsive MMA, and metronidazole reduces propionate produced by gut bacteria. Severe disease may require liver transplantation, combined with kidney transplantation in MMA with renal failure.