A Neonate With Hyperammonemia

Dinesh Rakheja, MD; Michael B. Bober, MD, PhD; Susan L. Fisher, MT(ASCP); Patricia M. Jones, PhD


Lab Med. 2005;36(5):292-295. 

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Possible Answers

  1. Low birth weight, failure to thrive, lethargy, feeding intolerance, strong body odor, dehydration, generalized hypotonia with brisk reflexes and ankle clonus; mild acidosis, hyperglycemia, hypoalbuminemia, hyperammonemia, hypocalcemia, pancytopenia, and hyperargininemia ( Table 1 ); bilaterally symmetric increased periventricular and thalamic echogenicity; abnormal urine organic acid screen with increased levels of lactic acid, 3-hydroxyisovaleric acid, methylsuccinic acid, methylfumaric acid, and isovalerylglycine (Figure 1).

  2. The patient's clinical signs and symptoms are suggestive of an inborn error of metabolism. The markedly elevated serum ammonia level suggests a urea cycle disorder; however, other metabolic causes of hyperammonemia including organic acidemias are in the differential diagnosis ( Table 2 ).

  3. Marked hyperammonemia in the absence of significant acidosis is suggestive of a urea cycle disorder, which should prompt serum amino acid analysis by high performance liquid chromatography (HPLC) and urine organic acid analysis by gas chromatography/mass spectrometry (GC/MS). Since a urea cycle disorder was considered the most likely possibility among the possible causes of hyperammonemia in infants ( Table 2 ), the patient was started on parenteral arginine in an effort to reduce the ammonia levels. This led to the observed increase in serum arginine. In the absence of this history, the elevated arginine levels would have suggested a deficiency of arginase, a urea cycle disorder. However, arginase deficiency does not have this type of neonatal presentation. Moreover, the patient's acidosis and urine organic acid profile (Figure 1) are consistent with an organic acidemia.

  4. Most likely diagnosis: Isovaleric acidemia (or Isovaleryl-coenzyme A dehydrogenase deficiency; OMIM #243500). The presence of 3-hydroxyisovaleric acid, isovalerylglycine, methylsuccinic acid, and methylfumaric acid in the patient's urine sample is characteristic for isovaleric acidemia. The diagnosis can be confirmed by an assay for isovaleryl-coenzyme A dehydrogenase in cultured fibroblasts of the patient. However, the enzyme assay is not readily available and the urine organic acid profile by GC/MS is virtually diagnostic for this disease.[1]

  5. Isovaleryl-coenzyme A dehydrogenase ( EC ) is a mitochondrial enzyme that catalyzes a step in the catabolic pathway of the ketogenic branched chain amino acid leucine (Figure 2). More specifically, it catalyzes the oxidation of isovaleryl-coenzyme A to 3-methylcrotonyl-coenzyme A. Therefore, a deficiency of isovaleryl-coenzyme A dehydrogenase leads to an excessive accumulation of isovaleryl-coenzyme A. Isovaleryl-coenzyme A is converted to isovalerylglycine, which is non-toxic and readily excreted in the urine. Another non-toxic conjugate product is isovalerylcarnitine, which can be detected by liquid chromatography/tandem mass spectrometry (LC/MS/MS) in urine and blood. Other metabolites of isovaleric acid that are formed include 3-hydroxyisovaleric acid and 4-hydroxyvaleric acid; the latter is further oxidized to methylsuccinic acid, which is then dehydrogenated to methylfumaric acid. Some other minor metabolites that may be detected include 3-hydroxyisoheptanoic acid, isovalerylglutamic acid, isovalerylglucuronide, isovalerylalanine, and isovalerylsarcosine.[1] The pathophysiologic basis of the toxicity of isovaleric acid and its metabolites is yet to be completely elucidated. In high concentrations seen in symptomatic isovaleric acidemia patients, isovaleric acid inhibits succinate-coenzyme A ligase in the Krebs cycle and is also toxic to granulopoietic precursors in bone marrow cultures.[2,3] Inhibition of the urea cycle enzyme, N-acetylglutamate synthetase, by isovaleryl-coenzyme A may explain the occasional occurrence of hyperammonemia in patients with isovaleric acidemia.[4]

  6. Isovaleric acidemia, first described in 1966, is an autosomal recessive disorder caused by a deficiency of the enzyme isovaleryl-coenzyme A dehydrogenase.[5] Isovaleryl-coenzyme A dehydrogenase is encoded by a gene that resides on chromosome 15q14-q15.[6] The enzyme is synthesized in the cytoplasm as a 45 kDa precursor protein. During transport into the mitochondria, the precursor protein is processed to form the mature 43 kDa protein. Four of these 43 kDa peptides come together to form a homotetramer that has the dehydrogenase activity.[7,8] Six molecular variants have been identified in patients with isovaleric acidemia. Class I mutant alleles show point mutations in the gene encoding isovaleryl-coenzyme A dehydrogenase so that the molecular weights of the precursor and mature peptides are normal. Class II-IV mutant alleles produce smaller precursor and/or mature peptides and represent point mutations or small deletions. Class V and VI mutant alleles form no protein product. Class V mutants have an abnormality in mRNA translation, while class VI mutants have defective transcription with no mRNA being formed.[9,10] A genotype-phenotype correlation has been suggested with the identification of a common mutation [932Cytosine (C)Õ Thymidine (T)] in association with a mild phenotype.[11]

  7. Patients with isovaleric acidemia may present in early neonatal life with a sudden onset, severe illness or may present later in infancy with a chronic intermittent form of the disease.[1] Patients with neonatal onset, if they survive the acute illness, go on to follow a chronic intermittent course. Usually, the illness begins within a few days of birth with increasing lethargy and difficulty in feeding leading to dehydration and weight loss. An "odor of sweaty feet" may be found and represents the accumulation in the body of isovaleric acid and related compounds. Laboratory investigation typically shows metabolic acidosis with mild lactic acidemia and ketosis. In addition, there is pancytopenia and hypocalcemia. Marked hyperammonemia has also been described but is not a common finding.[12,13,14] Many patients do not survive the acute illness and die of acidosis, cerebral edema, infections, and/or bleeding. Patients with the chronic intermittent form of the disease usually have their first illness before their first birthday, usually following a minor respiratory infection, or other type of stress, and sometimes following increased intake of protein-rich foods. The symptoms include lethargy, vomiting, and "sweaty feet odor," with laboratory investigations revealing acidosis and pancytopenia. There may be hyperglycemia, which along with ketosis, may be mistaken for diabetic ketoacidosis.[14,15] The patient's signs and symptoms resolve with treatment including protein restriction and administration of carnitine and/or glycine. The diagnosis of isovaleric acidemia can be made on the basis of the characteristic urine organic acid profile for this disorder. Newborn screening with LC/MS/MS can detect isovalerylcarnitine in microliter quantities of blood.[16,17,18] In addition, LC/MS/MS can detect isovalerylcarnitine in amniotic fluid which can be used for prenatal diagnosis of isovaleric acidemia.[19,20] Newborn screening programs have established the prevalence of isovaleric acidemia to be 1 in 62,500 newborns in Germany.[17] A review of the literature suggests that this case report is the first description of isovaleric acidemia in an African-American neonate.

  8. The principle behind the treatment of patients with isovaleric acidemia includes restriction of leucine in their diets and treatment with carnitine and/or glycine, both of which conjugate with isovaleric acid to form the non-toxic and easily excreted products-isovalerylcarnitine and isovalerylglycine.[21,22,23]

Gas chromatography/mass spectrometry results from the patient’s initial urine specimen showed elevated levels of lactic acid (peak #1), 3-hydroxyisovaleric acid (peak #2), methylsuccinic acid (peak #3), methylfumaric acid (peak #5), and isovalerylglycine (peak #6). Peak #4 represents the internal standard (2-phenylbutyric acid).

Isovaleryl-coenzyme A dehydrogenase catalyzes the oxidation of isovaleryl-coenzyme A to 3-methylcrotonyl-coenzyme A, a step in the catabolic pathway of the amino acid leucine.1 Its deficiency leads to isovaleric acidemia.


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