Citrullinemia Type I

Clinical characteristics: Citrullinemia type I (CTLN1) presents as a spectrum that includes a neonatal acute form (the "classic" form), a milder late-onset form (the "non-classic" form), a form in which women have onset of symptoms at pregnancy or post partum, and a form without symptoms or hyperammonemia. Distinction between the forms is based primarily on clinical findings, although emerging evidence suggests that measurement of residual argininosuccinate synthase enzyme activity may help to predict those who are likely to have a severe phenotype and those who are likely to have an attenuated phenotype.

Infants with the acute neonatal form appear normal at birth. Shortly thereafter, they develop hyperammonemia and become progressively lethargic, feed poorly, often vomit, and may develop signs of increased intracranial pressure (ICP). Without prompt intervention, hyperammonemia and the accumulation of other toxic metabolites (e.g., glutamine) result in increased ICP, increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death. Children with the severe form who are treated promptly may survive for an indeterminate period of time, but usually with significant neurologic deficits. Even with chronic protein restriction and scavenger therapy, long-term complications such as liver failure and other (rarely reported) organ system manifestations are possible.

The late-onset form may be milder than that seen in the acute neonatal form, but commences later in life for reasons that are not completely understood. The episodes of hyperammonemia are similar to those seen in the acute neonatal form, but the initial neurologic findings may be more subtle because of the older age of the affected individuals. Women with onset of severe symptoms including acute hepatic decompensation during pregnancy or in the postpartum period have been reported. Furthermore, previously asymptomatic and non-pregnant individuals have been described who remained asymptomatic up to at least age ten years, with the possibility that they could remain asymptomatic lifelong.

Diagnosis/testing: The diagnosis of CTLN1 is established in a proband with elevated plasma ammonia concentration (>150 µmol/L; may range to ≥2000-3000 µmol/L), elevated plasma citrulline concentration (usually >500 µmol/L), and absent argininosuccinate and/or by identification of biallelic pathogenic variants in ASS1 on molecular genetic testing.

Management: Treatment of manifestations: Liver transplantation is the only known curative therapy and eliminates the need for dietary restriction. Transplantation is ideally performed in affected individuals who are younger than age one year (prior to the development of any neurocognitive impairment) but older than age three months and/or above 5 kg body weight.

1. Daily routine treatment in those who have not undergone a liver transplantation includes lifelong protein restriction in conjunction with a metabolic nutritionist; nitrogen scavenger medications; arginine supplementation; consideration of carnitine supplementation in those with secondary carnitine deficiency; addressing increased energy/caloric demands through tube feedings (as needed); and routine treatment of developmental delay / intellectual disability.

2. Acute inpatient treatment of a metabolic crisis includes addressing hyperammonemia through withholding of all protein intake for a maximum of 24 to 28 hours; pharmacologic nitrogen scavenger therapy; and consideration of dialysis (the most effective means of reducing plasma ammonia concentration rapidly). To address increased catabolism, administration of high-energy fluids (and insulin, as needed) and intravenous intralipids is typically required. However, care must be taken to avoid electrolyte imbalance and fluid overload, which can contribute to the development of increased intracranial pressure. The patient should be maintained on the dry side of fluid balance (approximately 85 mL/kg of body weight per day in infants and appropriate corresponding fluid restriction in children and adults).

Prevention of secondary complications: Education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors; written protocols for maintenance and emergency treatment should be provided to parents and primary care providers / pediatricians, and to teachers and school staff. For those affected individuals requiring any sedated procedure where a person cannot eat for an extended period of time, drug treatment should be switched to IV and nutrition with 10% glucose with age-appropriate electrolytes should be administered via IV to promote anabolism starting as soon as the patient is NPO.

Surveillance: Follow up in a metabolic clinic with a qualified metabolic nutritionist and clinical biochemical geneticist is required. Measurement of growth parameters; evaluation of nutrition status and safety of oral intake; assessment for early warning signs of impending hyperammonemic episodes (mood changes, headache, lethargy, nausea, refusal to eat); review of dietary assessment; monitoring of developmental progress/educational needs; assessment of mobility and self-help skills; and measurement of carnitine levels (for those on sodium benzoate) at each visit. Plasma amino acid analysis at least every three months during the first year of life and every six to 12 months in the teenage/adult years (depending on clinical stability).

Agents/circumstances to avoid: Excessive protein intake, prolonged fasting, and obvious exposure to communicable diseases.

Evaluation of relatives at risk: It is important that at-risk sibs be identified as soon as possible, either through molecular genetic testing (if the pathogenic variants in the family are known) or measurement of plasma concentrations of ammonia and citrulline on the first day of life. Elevation of either above acceptable levels (ammonia >100 µmol/L or plasma citrulline >~100 µmol/L) is sufficient evidence to initiate treatment in a newborn.

Pregnancy management: Because women with onset of severe symptoms during pregnancy or in the postpartum period have been reported, scrupulous attention needs to be paid to diet and medication during these periods.

Genetic counseling: CTLN1 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the pathogenic variants in the family are known.