Clinical Guidance

While certain ASS1 pathogenic variants are identified with particular phenotypes, the phenotype cannot be predicted in all instances .

• Severe, classic (neonatal-onset) CTLN1 typically results from 22 defined pathogenic variants . The pathogenic variant in exon 15, p.Gly390Arg, remains the most prevalent associated with the classic phenotype. Other variants in this category include p.Gly14Ser, p.Arg157His, p.Glu191Lys, p.Gly324Ser, and p.Arg363Trp .

• Mild (i.e., late-onset) CTLN1 is associated with 12 pathogenic variants, including , p.Tyr190Asp, p.Ala202Glu, , and p.Val269Met .

Source: GeneReviews — "Citrullinemia Type I"

Diagnostic Criteria

Citrullinemia type I (CTLN1) results from deficiency of the enzyme argininosuccinate synthase, the third step in the urea cycle, in which citrulline is condensed with aspartate to form arginosuccinic acid (see Urea Cycle Disorders Overview Figure 1).

Suggestive Findings

Scenario 1: Abnormal Newborn Screening (NBS) Result

NBS for CTLN1 is primarily based on quantification of the analyte citrulline on dried blood spots. Citrulline values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing, which usually demonstrates the following:

Source: GeneReviews — "Citrullinemia Type I"

Differential Diagnosis

Neonatal ("Classic") Presentation Elevated citrulline on newborn screening (NBS). Conditions that may result in elevated citrulline on NBS are citrullinemia type II (citrin deficiency), argininosuccinate lyase deficiency (argininosuccinic aciduria), and pyruvate carboxylase deficiency. Hyperammonemia. It is critical to distinguish hyperammonemia caused by a defect in the urea cycle from the secondary hyperammonemia caused by an organic acidemia, which may cause inhibition of N-acetylglutamate synthase (see Urea Cycle Disorders Overview Figure 2). Urea Cycle Disorders Overview Figure 3 shows a diagnostic strategy to identify which steps in the urea cycle are defective in an individual with hyperammonemia. Classic citrullinemia type I (a defect in step 3 of the urea cycle) shares the phenotype of the typical acute neonatal hyperammonemia displayed by other defects in the first four steps in the urea cycle pathway: carbamoylphosphate synthetase I deficiency (step 1), ornithine transcarbamylase deficiency (step 2), and argininosuccinate lyase deficiency (step 4). Table 2. Selected Disorders in the Differential Diagnosis of Acute Neonatal ("Classic") Citrullinemia Type I

Management Guidelines

Clinical practice guidelines for citrullinemia type I (CTLN1) have been published. See , , , , (full text). When CTLN1 is suspected during the diagnostic evaluation due to elevated citrulline on newborn screening, metabolic treatment should be initiated immediately. Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (i.e., malnutrition, growth failure) require a multidisciplinary approach including multiple subspecialists, with oversight and expertise from a specialized metabolic center.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CTLN1, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis of Citrullinemia Type I

Evaluation | Comment

Consultation w/metabolic physician/ biochemical geneticist specialist metabolic dietitian1 | • Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended).

• Consider short hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance emergency treatment, prognosis, risks for acute encephalopathic crises).

Metabolic control | Consider measurement of following, based on clinical status, to aid in nutritional mgmt:

Source: GeneReviews — "Citrullinemia Type I"

Clinical Guidance

Avoid the following:

• Excess protein intake

• Prolonged fasting

• Obvious exposure to communicable diseases

Source: GeneReviews — "Citrullinemia Type I"

Therapies Under Investigation

Gene therapy has been suggested; success has not been achieved to date. Phase I and Phase II clinical trials to assess the safety and efficacy of human hepatocyte transplantation as either an alternative to liver transplantation or a temporizing measure for individuals with CTLN1 awaiting transplantation have completed. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "Citrullinemia Type I"

Surveillance Guidelines

Follow up in a metabolic clinic with a qualified metabolic nutritionist and clinical biochemical geneticist is required .

Table 9.

Recommended Surveillance for Individuals with Citrullinemia Type I

Manifestation/Concern | Evaluation | Frequency

Poor growth

| • Measurement of growth parameters

• Eval of nutritional status safety of oral intake

| At each visit

Early warning signs

of impending

hyperammonemic

episodes | Monitor for mood changes, headache, lethargy, nausea, vomiting, refusal to eat, hyperreflexia, ankle clonus.1

Nutrition review

| Dietary assessment (whether by diary or recall) to review adequate/complete nutrition is being received

Nutritional status

monitoring | Carnitine levels to monitor for secondary carnitine deficiency in patients on sodium benzoate

Plasma amino acids analysis to identify deficiency of EAA, monitor arginine, citrulline, EAA supplementation | • During 1st yr of life: at least every 3 mos

• In teen/adult yrs: every 6-12 mos, depending on clinical stability

Development

| Monitor developmental progress educational needs. | At each visit

Musculoskeletal

| Physical medicine, OT/PT assessment of mobility, self-help skills

Family/Community

| Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).

EEA = essential amino acids; OT = occupational therapy; PT = physical therapy

Source: GeneReviews — "Citrullinemia Type I"