Citrullinemia type I

Citrullinemia type I is the urea cycle disorder caused by deficiency of argininosuccinate synthetase, the enzyme one step upstream of the argininosuccinate lyase that fails in argininosuccinic aciduria. The screening signal on the dried blood spot is the same elevated citrulline that prompts the ASA workup. The two conditions are distinguished by what is or is not downstream: ASA shows accumulated argininosuccinate, citrullinemia I shows the citrulline elevation without it. The clinical course of citrullinemia I is similar to other urea cycle disorders in its acute hyperammonemic biology, with subtype-specific differences in long-term complications.

What citrullinemia I is

Citrullinemia type I is an autosomal recessive urea cycle disorder caused by deficiency of argininosuccinate synthetase 1 (ASS1), encoded by ASS1 on chromosome 9q34. ASS1 condenses citrulline with aspartate to form argininosuccinate as the third step of the urea cycle. When ASS1 activity is reduced or absent, citrulline accumulates, the urea cycle cannot complete, and ammonia rises. Plasma citrulline is markedly elevated and arginine is low because the cycle cannot produce it.

The clinical phenotype splits into two main forms. Classic neonatal-onset citrullinemia I presents in the first days to weeks of life with hyperammonemic encephalopathy: poor feeding, vomiting, lethargy, hypotonia, tachypnea, and progression to coma if untreated. Without rapid intervention, mortality is high. Survivors of the neonatal crisis face a chronic course with recurrent metabolic decompensations triggered by infection or catabolic stress, developmental delay, intellectual disability of variable severity, and the long-term consequences of recurrent hyperammonemic insults.

A milder later-onset form presents in older children or adults with episodic hyperammonemia, often triggered by high-protein meals, illness, or postpartum stress. The neurological course in late-onset disease can include episodic encephalopathy or progressive cognitive features without the dramatic neonatal crisis. The genotype-phenotype correlation is incomplete; the same ASS1 variant can produce different clinical pictures in different individuals.

A separate condition, citrullinemia type II, is caused by citrin deficiency (variants in SLC25A13) and produces a different clinical picture that includes neonatal cholestatic liver disease, adult-onset neuropsychiatric symptoms, and a distinctive dietary preference. Citrullinemia II is not detected reliably by the standard newborn screening citrulline cutoff and is not the focus here.

Reported live-birth incidence of citrullinemia type I in newborn screening programs runs roughly 1 in 50,000 to 1 in 200,000.

Detection

Newborn screening uses tandem mass spectrometry on the dried blood spot to flag elevated citrulline. Citrulline elevation is shared with argininosuccinic aciduria, and second-tier testing distinguishes the two: citrullinemia type I shows citrulline elevation without argininosuccinate accumulation, while ASA shows both. Plasma ammonia, plasma amino acids (with citrulline elevation, low arginine, and elevated alanine and glutamine in many cases), urine orotic acid, and ASS1 sequencing complete the workup.

What management looks like

Standard of care is lifelong protein-restricted diet using essential amino acid medical formula combined with measured natural protein, supplemented with arginine to replace the failing urea cycle output. Sodium phenylbutyrate or glycerol phenylbutyrate is used as an ammonia scavenger when dietary management alone does not adequately control ammonia. Sick-day protocols use high-calorie low-protein intake to suppress catabolism during illness.

Acute decompensations are managed with intravenous dextrose at high infusion rates, ammonia scavengers (intravenous sodium phenylbutyrate or sodium benzoate), arginine, and hemodialysis for severe hyperammonemia. Carglumic acid is occasionally used adjunctively in citrullinemia type I in centers familiar with its off-label application; the labeled urea cycle indication is N-acetylglutamate synthase deficiency.

Liver transplantation is offered for severe cases with intractable metabolic decompensations or significant neurological morbidity from recurrent hyperammonemic episodes. Transplant provides a functional urea cycle in the largest tissue source and substantially reduces the frequency of metabolic crises. Neurological recovery after transplant depends on the cumulative damage that has occurred before the procedure.

Gene therapy and mRNA-based programs for citrullinemia type I are in preclinical and early clinical development.

What this looks like for a family

A baby is born and the heel-prick is sent. On day 4, the state lab reports an elevated citrulline. On day 5, plasma argininosuccinic acid is normal, ruling out ASA. Plasma amino acids confirm the citrullinemia I biochemical signature. ASS1 sequencing returns biallelic pathogenic variants. The metabolic team starts protein restriction, arginine, and ammonia scavenger therapy. Plasma ammonia is monitored closely.

That child grows up with the same management framework that other urea cycle disorders use. Sick-day protocols are part of every febrile illness. Decompensations occur but at lower frequency and severity than in unscreened cohorts. Developmental and cognitive surveillance tracks the long-term effects of residual hyperammonemic exposure. In adolescence or young adulthood, the conversation about liver transplantation is on the table for cases with frequent decompensations or progressive cognitive concerns.

That is what citrullinemia type I care looks like in practice. The screen prevents the neonatal death. The medicine controls the urea cycle. The long-term cognitive trajectory depends on how successfully the recurrent hyperammonemic episodes can be prevented.