Table 2. [Selected Disorders in the Differential Diagnosis of Acute Neonatal ("Classic") Citrullinemia Type I]. - GeneReviews®

Gene	Disorder	MOI	Laboratory Findings / Clinical Characteristics
ASL	Argininosuccinate lyase (ASL) deficiency	AR	↑ citrulline on NBS. Severe neonatal-onset ASL deficiency is assoc w/hyperammonemia w/in 1st few days after birth that can manifest as ↑ lethargy, somnolence, refusal to feed, vomiting, tachypnea, & respiratory alkalosis.
CPS1	Carbamoyl phosphate synthase (CPS1) deficiency (See Urea Cycle Disorders Overview.)	AR	Most severe of urea cycle disorders. Persons w/complete CPS1 deficiency rapidly develop hyperammonemia in newborn period.
DLD	Dihydrolipoamide dehydrogenase (DLD) deficiency	AR	↑ citrulline on NBS. ↑ ammonia & glutamine. ¹ Early-onset DLD deficiency typically manifests in infancy as hypotonia w/lactic acidosis. Affected infants frequently do not survive their initial metabolic decompensation, or die w/in 1st few yrs of life during a recurrent metabolic decompensation.
OTC	Ornithine transcarbamylase (OTC) deficiency	XL	Males w/severe neonatal-onset OTC deficiency are asymptomatic at birth but become symptomatic from hyperammonemia in 1st week of life, most often on day 2 to 3 of life, & are usually catastrophically ill when they come to medical attention.
PC	Pyruvate carboxylase deficiency	AR	↑ citrulline on NBS. Type A (infantile form): most affected children die in infancy or early childhood. Type B (severe neonatal form): biochemical abnormalities, hypoglycemia, hyperammonemia, hypernatremia, anorexia, hepatomegaly, convulsions, stupor, hypotonia, pyramidal tract signs, abnormal movements (incl high-amplitude tremor & dyskinesia), & abnormal ocular behavior.
SLC25A13	Neonatal-onset citrullinemia type II (See Citrin Deficiency.)	AR	↑ citrulline on NBS. Mild hyperammonemia & citrullinemia. Transient intrahepatic cholestasis. Other findings: diffuse fatty liver w/hepatomegaly & parenchymal cellular infiltration assoc w/hepatic fibrosis, history of low birth weight, growth restriction, hypoproteinemia, ↓ coagulation factors, hemolytic anemia, variable (mainly mild) liver dysfunction, &/or hypoglycemia.

Gene

Disorder

MOI

Laboratory Findings / Clinical Characteristics

ASL

Argininosuccinate lyase (ASL) deficiency

↑ citrulline on NBS. Severe neonatal-onset ASL deficiency is assoc w/hyperammonemia w/in 1st few days after birth that can manifest as ↑ lethargy, somnolence, refusal to feed, vomiting, tachypnea, & respiratory alkalosis.

CPS1

Carbamoyl phosphate synthase (CPS1) deficiency (See Urea Cycle Disorders Overview.)

Most severe of urea cycle disorders. Persons w/complete CPS1 deficiency rapidly develop hyperammonemia in newborn period.

DLD

Dihydrolipoamide dehydrogenase (DLD) deficiency

↑ citrulline on NBS. ↑ ammonia & glutamine. ¹ Early-onset DLD deficiency typically manifests in infancy as hypotonia w/lactic acidosis. Affected infants frequently do not survive their initial metabolic decompensation, or die w/in 1st few yrs of life during a recurrent metabolic decompensation.

OTC

Ornithine transcarbamylase (OTC) deficiency

Males w/severe neonatal-onset OTC deficiency are asymptomatic at birth but become symptomatic from hyperammonemia in 1st week of life, most often on day 2 to 3 of life, & are usually catastrophically ill when they come to medical attention.

Pyruvate carboxylase deficiency

↑ citrulline on NBS. Type A (infantile form): most affected children die in infancy or early childhood. Type B (severe neonatal form): biochemical abnormalities, hypoglycemia, hyperammonemia, hypernatremia, anorexia, hepatomegaly, convulsions, stupor, hypotonia, pyramidal tract signs, abnormal movements (incl high-amplitude tremor & dyskinesia), & abnormal ocular behavior.

SLC25A13

Neonatal-onset citrullinemia type II (See Citrin Deficiency.)

↑ citrulline on NBS. Mild hyperammonemia & citrullinemia. Transient intrahepatic cholestasis. Other findings: diffuse fatty liver w/hepatomegaly & parenchymal cellular infiltration assoc w/hepatic fibrosis, history of low birth weight, growth restriction, hypoproteinemia, ↓ coagulation factors, hemolytic anemia, variable (mainly mild) liver dysfunction, &/or hypoglycemia.

From: Citrullinemia Type I

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Adam MP, Feldman J, Mirzaa GM, et al., editors.

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