Clinical Guidance

No clinically relevant genotype-phenotype correlations are known for this disorder.

Source: GeneReviews — "Citrin Deficiency"

Penetrance

Notably, the penetrance is not 100% for citrin deficiency as an autosomal recessive condition. In addition, there appears to be a difference in penetrance of the CTLN2 phenotype related to the sex of the individual.

• Of 418 individuals with biallelic SLC25A13 pathogenic variants, seven individuals had no clinical manifestations, indicating a penetrance of 98.3% .

• The male-to-female ratio in individuals with NICCD is roughly equal (73:80), while the male-to-female ratio in individuals with CTLN2 is 2.4 to 1 (120:50) . The unequal male-to-female ratio in CTLN2 suggests that for unknown reasons, among individuals with biallelic SLC25A13 pathogenic variants, females are more resistant to the CTLN2 phenotype than males.

Source: GeneReviews — "Citrin Deficiency"

Diagnostic Criteria

Citrin deficiency has three clinical phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and citrullinemia type II (CTLN2) . A symptomatic individual may have either untreated NICCD due to newborn screening (NBS) not performed, false negative NBS result, caregivers not adherent to recommended treatment following a positive NBS result, or manifestations associated with later-onset citrin deficiency (FTTDCD or CTLN2).

Suggestive Findings

Scenario 1: NICCD (includes abnormal NBS result and symptomatic newborn)

Abnormal NBS result. NBS for citrin deficiency is primarily based on quantification of the analyte citrulline on dried blood spots. Note: Dried blood spots also show elevated galactose, ...

Source: GeneReviews — "Citrin Deficiency"

Differential Diagnosis

Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency (NICCD)

Increased plasma concentration of citrulline is also present in citrullinemia type 1, argininosuccinate lyase deficiency, pyruvate carboxylase deficiency, and lysinuric protein intolerance . Hyperammonemia also occurs in urea cycle disorders, which result from defects in the metabolism of the nitrogen produced by the breakdown of protein and other nitrogen-containing molecules (see Urea Cycle Disorders Overview). Severe deficiency or total absence of activity of any of the first four enzymes in the pathway (CPSI, OTC, ASS1, ASL) or the cofactor producer (NAGS) results in the accumulation of ammonia and other precursor metabolites during the first few days of life in most affected individuals.

Source: GeneReviews — "Citrin Deficiency"

Management Guidelines

Although progress has been made [, , , ], no well-recognized clinical practice guidelines for citrin deficiency have been published. The following recommendations are based on the authors' personal experience managing large cohorts of individuals with this disorder over a long period of time.

Evaluations Following Initial Diagnosis

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

Table 5.

Citrin Deficiency: Recommended Evaluations Following Initial Diagnosis by Phenotype

Evaluation | Phenotype

NICCD | FTTDCD | CTLN2

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

• Plasma amino acid analysis to measure citrulline other amino acids

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

| Referral to specialist center w/experience in mgmt of inherited metabolic diseases; includes plasma amino acid analysis

Growth/ Nutrition assessment

| Perform detailed anthropometric exam eval using age- sex-matched growth standards. | Assess weight.

Investigate feeding pattern. | Investigate carbohydrate, protein, lipid composition of diet.

Source: GeneReviews — "Citrin Deficiency"

Clinical Guidance

Low-protein/high-caloric (high-carbohydrate) diet. Although a low-protein/high-caloric diet helps prevent hyperammonemia in urea cycle enzyme deficiencies, it is harmful for individuals with all forms of citrin deficiency (i.e., neonatal intrahepatic cholestasis caused by citrin deficiency [NICCD)], failure to thrive and dyslipidemia caused by citrin deficiency [FTTDCD], or citrullinemia type II [CTLN2]) [, , , ]. A high-carbohydrate diet may increase nicotinamide adenine dinucleotide hydrogen (NADH) production, disturb urea synthesis, and stimulate the citrate-malate shuttle, resulting in hyperammonemia, fatty liver, and hypertriglyceridemia [, , , ]. Infusion of sugars including glycerol, fructose, and glucose. Severe brain edema treated with glycerol-containing osmotic agents has resulted in continued deterioration and is contraindicated in those with CTLN2 . Degradation of large amounts of glycerol and fructose generates NADH in liver cytosol, which may disturb liver function . Infusion of high-concentration glucose may also exacerbate hyperammonemia . Mannitol infusion appears to be safer . Alcohol. Drinking alcohol can trigger the onset of CTLN2 because alcohol dehydrogenase generates NADH in the cytosol of the liver.

Source: GeneReviews — "Citrin Deficiency"

Therapies Under Investigation

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. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Citrin Deficiency"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended. Table 7. Citrin Deficiency: Recommended Surveillance

Source: GeneReviews — "Citrin Deficiency"