Table 4b.

Genes of Interest in the Differential Diagnosis of a Symptomatic Individual with Findings Suggestive of Late-Onset or Untreated Infantile-Onset Classic Isovaleric Acidemia

Gene(s)DisorderMOILaboratory FindingsClinical Findings
GCDH Glutaric acidemia type 1 ARMetabolic acidosis 1, 2
  • Acute encephalopathic crises
  • Macrocephaly
  • Seizures
MCEE
MMAA
MMAB
MMADHC
MMUT 		Isolated methylmalonic acidemia AR
  • Metabolic acidosis
  • Hyperammonemia
  • Methylmalonic acid in urine
  • Propionylcarnitine on acylcarnitine analysis 1, 3
  • Metabolic decompensations
  • Cardiomyopathy
  • Kidney failure
  • Pancreatitis
PCCA
PCCB 		Propionic acidemia AR
  • Metabolic acidosis
  • Hyperammonemia
  • 3-hydroxy-propionic acid & 2-methylcitrate in urine
  • Propionylcarnitine on acylcarnitine analysis 1, 3
ARG1 Arginase deficiency AR
  • Hyperammonemia
  • ↑ arginine in plasma
  • ↑ liver enzymes 1, 4
  • Altered level of consciousness
  • Encephalopathy
  • Seizures
  • Vomiting
  • Cognitive impairment
  • Hepatomegaly
ASL Argininosuccinate lyase deficiency AR
  • Hyperammonemia
  • Argininosuccinic acid in plasma or urine
  • ↑ liver enzymes 1, 4
ASS1 Citrullinemia type I AR
  • Hyperammonemia
  • ↑ citrulline in plasma
  • ↑ liver enzymes 1, 4
CPS1 Carbamoylphosphate synthetase I deficiency (See Urea Cycle Disorders Overview.)AR
  • Hyperammonemia
  • Low citrulline in plasma
  • Normal/low orotic acid in urine
  • ↑ liver enzymes 1, 4
OTC Ornithine transcarbamylase deficiency XL
  • Hyperammonemia
  • Low citrulline in plasma
  • ↑ orotic acid in urine
  • ↑ liver enzymes 1, 4
NAGS N-acetylglutamate synthase deficiency (See Urea Cycle Disorders Overview.)AR
  • Hyperammonemia
  • Low citrulline in plasma
  • Normal/low orotic acid in urine
  • ↑ liver enzymes 1, 4
SLC25A13 Citrin deficiency AR
  • Hyperammonemia
  • ↑ citrulline, arginine, methionine, threonine, tyrosine, & lysine in plasma
  • ↑ liver enzymes 1, 4
SLC25A15 Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome AR
  • Hyperammonemia
  • ↑ homocitrulline in urine
  • ↑ liver enzymes 1, 4

AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked

1.
2.
3.
4.

From: Classic Isovaleric Acidemia

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