Laboratory Findings
The biochemical profiles of the disorders to consider in the differential diagnosis of CA-VA deficiency are summarized in Table 3.
Table 3.
Comparison of Biochemical Findings in CA-VA Deficiency and Other Inborn Errors of Metabolism in the Differential Diagnosis
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Analyte | CA-VA Deficiency | Differential Diagnosis |
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PC deficiency | Multiple carboxylase deficiency | CPS1 or NAGS deficiency | UQCRC2 deficiency |
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Plasma ammonia | ↑ | ↑ | Nl | ↑ | ↑ |
Serum lactate | ↑ | ↑ | ↑ | Nl | ↑ |
Serum glucose | Nl to ↓ | ↓ | Nl | Nl | ↓ |
Plasma citrulline | Nl to ↓ | ↑ | Nl | ↓ | Nl |
Plasma glutamine | ↑ | ↓ | Nl | ↑ | Nl |
Plasma lysine | Nl | ↑ | Nl | Nl | Nl |
HCO3, base excess | ↓ | Nl to ↓ 1 | ↓ | Nl | ↓ |
Urine 3-OH butyrate | ↑ | ↑ | ↑ | Nl | ↑3 |
Urine alpha-ketoglutarate | ↑ | ↓ | ↑ | Nl | Nl |
Urine 3-OH propionic acid, propionylglycine, methylcitrate | ↑ | Nl | ↑ | Nl | Nl |
Urine 3-methyl-crotonylglycine, 3-OH isovaleric acid | ↑ | Nl | ↑ | Nl | Nl |
Fatty acids, total & free carnitine, acylcarnitine profiles | Nl | Nl | Abnormal 2 | Nl | ↑ C2 & 3-OH-acylcarnitines |
↑ = elevated; ↓ = decreased; CA-VA = carbonic anhydrase VA; CPS1 = carbamoyl phosphate synthetase 1; NAGS = N-acetyl-glutamate synthase; Nl = normal; PC = pyruvate carboxylase; UQCRC2 = ubiquinol-cytochrome c oxidoreductase core 2 subunit
- 1.
HCO3 as low as 5 mmol/L and base excess as low as -21 found in some affected individuals
- 2.
Low C0 (free carnitine) and elevated C2, C3, and C5OH
- 3.
Elevated ketones, dicarboxylic acids, and tricarboxylic acid cycle intermediates
Pyruvate carboxylase (PC) deficiency. As in individuals with PC deficiency, individuals with CA-VA have hyperammonemia and hyperlactatemia (± hypoglycemia) in common. The differences, however, include the following:
Glutamine levels are elevated in CA-VA deficiency but normal to decreased in PC deficiency.
Citrulline levels are decreased to normal in CA-VA deficiency but often elevated in PC deficiency.
Lysine levels are normal, and 2-ketoglutarate and other Krebs cycle intermediates are relatively mildly elevated in CA-VA deficiency. In PC deficiency, lysine is elevated and 2-ketoglutarate and other Krebs cycle metabolites are decreased.
The biochemical profiles in children with CA-VA deficiency support a predominant effect of (secondary) CPS1 deficiency vs PC deficiency.
Multiple carboxylase deficiency (holocarboxylase synthetase and
biotinidase deficiency). Although biotinidase deficiency and holocarboxylase synthetase (HCS) deficiency share the metabolite profiles of secondary deficiencies of PC, propionyl-CoA-carboxylase (PCC), and 3-methylcrotonyl-CoA-carboxylase (3MCC), the three major differences relative to primary CA-VA deficiency are:
The significantly higher level of PCC and 3MCC metabolites in (even well-controlled) individuals with the two former disorders compared to those with CA-VA deficiency during metabolic decompensation;
The presence of secondary CPS1 deficiency (high plasma glutamine and low plasma citrulline) as the (likely) major cause of hyperammonemia in CA-VA deficiency;
The presence of acetyl-CoA carboxylase deficiency in HCS deficiency and biotinidase deficiency. Individuals with CA-VA deficiency exhibited normal levels of free fatty acids and total and free carnitine, as well as normal acylcarnitine profiles (data not shown), mostly likely as a result of the activity of the cytosolic acetyl-CoA carboxylase 2 isoform that is not affected by impaired provision of mitochondrial HCO3-.
Urea cycle defects. Severe deficiency or total absence of activity of any of the first four enzymes (CPS1, OTC, ASS, ASL) in the urea cycle or the cofactor producer (NAGS) results in the accumulation of ammonia and other precursor metabolites during the first few days of life [Häberle 2013]. In particular, the proximal urea cycle defects (NAGS deficiency and CPS1 deficiency) show the following similarities with CA-VA deficiency: hyperammonemia, low plasma citrulline and high plasma glutamine, and no orotic aciduria; and good response to carglumic acid. Differences include:
Ubiquinol-cytochrome c oxidoreductase core 2 subunit (UQCRC2) deficiency (OMIM 615160) can present with a similar combination of lactic acidosis and episodes of hyperammonemia and hypoglycemia. The pathogenesis of the biochemical phenotype is currently unclear.