Table 4.

Genetic Disorders to Consider in the Differential Diagnosis of a Urea Cycle Disorder

DisorderGene(s)MOIClinical Features of This Disorder
Overlapping w/UCDDistinguishing from UCD
Propionic acidemia PCCA, PCCB ARHyperammonemiaMetabolic acidosis, hyperglycinemia, diagnostic organic acids, cylcarnitine profile
Isolated methylmalonic acidemia MUT, MMAA, MMAB, and othersARHyperammonemiaMetabolic acidosis, diagnostic organic acids, acylcarnitine profile
Isovaleric acidemia IVD ARHyperammonemiaMetabolic acidosis (possibly), diagnostic organic acids, acylcarnitine profile
Carbonic anhydrase VA deficiency CA5A ARHyperammonemia↑ lactate or abnormal urine organic acids
Lysinuric protein intolerance SLC7A7 ARHyperammonemia↑ lysine, ornithine, arginine in the urine
Fatty acid oxidation disorders (See SCAD, MCAD, VLCAD.)ManyARLiver dysfunction↑ diagnostic acylcarnitines
Hyperinsulinism-hyperammonemia syndrome (See Familial Hyperinsulinism.) GLUD1 ADHyperammonemiaHypoglycemia, hyperinsulinism
OAT deficiency (in neonates)
(OMIM 258870)		 OAT ARHyperammonemiaOrnithine may be ↓ in affected neonates who present w/hyperammonemia. However, older patients w/OAT deficiency have markedly ↑ levels of ornithine & do not present w/hyperammonemia.
Tyrosinemia type I FAH ARLiver dysfunctionDiagnostic amino acids, succinylacetone
Classic galactosemia GALT ARLiver dysfunction↑ galactose-1-phosphate, ↓ galactose-1-phosphate uridyltransferase enzyme activity
Mitochondrial disorders ManyAR, mt, XLLiver dysfunction, ↓ citrulline (occasionally)Plasma amino acids w/↑ alanine, plasma lactate elevation

AD = autosomal dominant; AR = autosomal recessive; MCAD = medium-chain acyl-coenzyme A dehydrogenase deficiency; MOI = mode of inheritance; mt = mitochondrial; OAT = ornithine aminotransferase; SCAD = short-chain acyl-coenzyme A dehydrogenase deficiency; VLCAD = very long-chain acyl-coenzyme A dehydrogenase deficiency; XL = X-linked

From: Urea Cycle Disorders Overview

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