Citrullinemia type I belongs to the class of urea cycle disorders. It is caused by deficiency of ASS1 (CTLN1) encoding the enzyme argininosuccinate synthetase (reviewed in PMID:24889030).
Citrullinemia type I can be confirmed by a decrease or complete absence of ASS1 activity in liver tissue and skin fibroblasts (PMID:24508627). Two sub-types can be distinguished: acute neonatal citrullinemia type I and adult-onset citrullinemia type I.
Severe vomiting spells beginning at the age of 9 months and mental retardation were features of the first reported case, offspring of first-cousin parents; McMurray et al. (1962) found citrulline in very high concentration in serum, spinal fluid, ... Severe vomiting spells beginning at the age of 9 months and mental retardation were features of the first reported case, offspring of first-cousin parents; McMurray et al. (1962) found citrulline in very high concentration in serum, spinal fluid, and urine. (The amino acid citrulline gets its name from its high concentration in the watermelon Citrullus vulgaris.) Visakorpi (1962) also described a case of citrullinuria. Ammonia intoxication is another manifestation. The enzyme defect concerns argininosuccinic acid synthetase (EC 6.3.4.5). Tedesco and Mellman (1967) found that the enzyme has an altered Michaelis constant. Most cases of citrullinemia have pursued a severe course with symptoms from birth and death in the neonatal period in more than half of cases. Orotic aciduria is present as well as hyperammonemia. In Japan, a distinct, late-onset form of citrullinemia has been reported (reviewed by Walser, 1983); see adult-onset citrullinemia (CTLN2; 603471). Significant clinical abnormality had onset in childhood or not until adulthood--age 48 years in 1 case. Symptoms included enuresis, delayed menarche, insomnia, sleep reversal, nocturnal sweats and terrors, recurrent vomiting (especially at night), diarrhea, tremors, episodes of confusion after meals, lethargy, convulsions, delusions and hallucinations, and brief episodes of coma. Delayed mental and physical development was shown by some patients. Most had a peculiar fondness for beans, peas, and peanuts from early childhood and a dislike for rice, other vegetables, and sweets. Since the preferred foods are high in arginine, the dietary predilection of these patients may reflect an arginine deficiency. As the patients get older, episodic disturbances become more frequent and bizarre behavior, including manic episodes, echolalia, and frank psychosis, appears. Citrulline concentrations in the plasma are increased and ASS activity is deficient. The late-onset form is apparently autosomal recessive because sibs have been affected and some of the parents have been consanguineous. The mutation may be allelic to that responsible for the classic form of the disorder. Most of the reports of the late-onset form have appeared in Japanese journals (see Walser (1983) for references). An exception is the report by Matsuda et al. (1976). Also see Scott-Emuakpor et al. (1972) for a similar case reported from the United States. Most adult citrullinemic patients in Japan have a quantitative type of abnormality of ASS (type II). Issa et al. (1988) described an instructive family with variable severity in the same sibship. A girl showed a severe clinical course attributable to hyperammonemia, whereas identical twin brothers with similar plasma citrulline concentrations were asymptomatic, perhaps due to development of alternative pathways of ammonia metabolism. The similarity in the twins may indicate that the alternative pathways determining interindividual variability are genetically determined. Gucer et al. (2004) reported a 17-month-old girl with type I citrullinemia who developed early cirrhosis of the liver. She was diagnosed in infancy during investigation of 2 sib deaths and was found to have a homozygous truncating mutation in the ASS gene (603470.0018). From 5 months of age, she showed failure to thrive, several mental and motor retardation, and persistent hepatomegaly with fluctuating transaminase levels. She had 1 hyperammonemic episode precipitated by infection. At 17 months, she presented with lethargy, vomiting, spasticity, and coagulopathy. She died of hyperammonemia and hepatic encephalopathy. Postmortem liver examination showed early cirrhosis without steatosis. Gucer et al. (2004) noted that liver fibrosis and hepatomegaly can occur in late-onset ASS deficiency, but the early presentation in this child was unusual. In a review of inherited metabolic disorders and stroke, Testai and Gorelick (2010) noted that patients with urea cycle defects, including CPS1 deficiency (237300), OTC deficiency (311250), and citrullinemia can rarely have strokes.
Kobayashi et al. (1989) found that since most patients with citrullinemia express stable mRNA in fibroblasts, the disorder is ideally suited for gene amplification with PCR and sequence analysis of mutant cDNA. They sequenced cDNA from 11 independent ... Kobayashi et al. (1989) found that since most patients with citrullinemia express stable mRNA in fibroblasts, the disorder is ideally suited for gene amplification with PCR and sequence analysis of mutant cDNA. They sequenced cDNA from 11 independent chromosomes and identified 9 different mutations: 3 showed absence of exon 5, 6 or 7, and 6 showed point mutations. Five of the 6 involved C:G-to-T:A transitions in CpG dinucleotides, and 3 of these resulted in loss of MspI sites. Kobayashi et al. (1990) further demonstrated the marked heterogeneity of mutations causing citrullinemia: among 13 unrelated patients with the neonatal form of the disease, they found 10 different mutations. Seven were single missense mutations. Two had deletions of single exons (no. 7 and no. 13) and one had a G-to-C substitution in the last position of intron 15 resulting in splicing to a cryptic splice site within exon 16. In the course of studying the molecular nature of mutations in Japanese patients with classic citrullinemia, Kobayashi et al. (1994) found that 10 of 23 affected alleles had the same mutation, deletion of exon 7 (IVS6-2A-G; 603470.0003). This differed from the situation in the United States, where far greater heterogeneity of mutations had been found. Kobayashi et al. (1995) reported that 20 mutations had been identified in ASS mRNA in classic citrullinemia, including 14 single base changes causing missense mutations, 4 mutations associated with an absence of exons 5, 6, 7, or 13 in mRNA, 1 mutation with a deletion of the first 7 bases in exon 16 (caused by abnormal splicing), and 1 mutation with an insertion of 37 bases between the exon 15 and 16 regions of mRNA. In an extension of their previous studies, Kobayashi et al. (1995) reported that 19 of 33 Japanese ASS alleles had the IVS6AS-2 mutation. In the so-called RNA-negative phenotype of citrullinemia, in which no stable mRNA can be detected, Li et al. (2001) determined the molecular basis to be a nonsense mutation (603470.0013) in exon 12 of the ASS gene. The most likely event responsible for the mRNA reduction appeared to be nonsense-mediated nucleus-associated mRNA decay. Most reported patients with citrullinemia have presented with the classic form of the disease. There are also patients with a mild form of citrullinemia in whom the exact molecular basis and clinical relevance are uncertain. Mutations in the ASS gene had not been described in mildly affected or asymptomatic patients with citrullinemia until the work of Haberle et al. (2002), who described mutations in the ASS gene of patients with both the classic and the mild form of the disease. The mutations gly390 to arg (G390R; 603470.0009), IVS13+5G-A (603470.0017), and arg108 to leu (R108L; 603470.0014) were associated with classic citrullinemia, whereas the mutations trp179 to arg (W179R; 603470.0015) and gly362 to val (G362V; 603470.0016) were detected on alleles of mildly affected patients. These were cases of asymptomatic children with biochemical abnormalities. The authors concluded that the elucidation of the structure of the human ASS gene made it possible to use intronic primers for molecular analysis of patients with mild disease and the classic form, and provided another option for prenatal diagnostics in affected families with the severe type. Engel et al. (2009) provided a review of mutations in the ASS1 gene. They listed 87 mutations, including 27 novel mutations, in patients with citrullinemia. Mutations are distributed throughout the gene, and it is usually difficult to predict the phenotype based on genotype. However, the G390R mutation (603470.0009) in exon 15 was found to be the single most common mutation in patients with the classic phenotype. Engel et al. (2009) also provided a map of the geographic distribution of ASS1 mutations worldwide.
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)....
DiagnosisClinical DiagnosisCitrullinemia 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).Classic neonatal-onset CTLN1 is suspected in infants who have been on a full protein diet and who present in the first week of life with:Hyperammonemia resulting in increasing lethargy, somnolence, refusal to feed, vomiting, and tachypnea or stroke. Initial plasma ammonia concentration in the severe form may be 1000-3000 µmol/L (normal: 40-50 µmol/L). Increased intracranial pressure (secondary to hyperammonemia) resulting in increased neuromuscular tone, spasticity, and ankle clonus.Milder, adult-onset citrullinemia type I is suspected in individuals with recurrent lethargy and somnolence; intellectual disability; and chronic or recurrent hyperammonemia. In these forms, a lower plasma concentration may be seen than in the classic form (adult upper limit of normal: <35 µmol/L).TestingPlasma quantitative amino acid analysisCitrulline. Usually greater than 1000 µmol/L (normal: <50 µmol/L)Argininosuccinic acid. AbsentArginine and ornithine. Low to normal range; see Urea Cycle Disorders Overview Figure 3.Lysine, glutamine, and alanine. Increased; these are surrogate markers of hyperammonemia.Urinary organic acids. Normal, except orotic acid may be detected as part of urinary organic acid analysis by gas chromatography/mass spectrometry; however, the sensitivity depends on the extraction method.Argininosuccinate synthase (ASS) enzyme activity. Incorporation of radiolabeled citrulline into argininosuccinic acid is measured in cultured fibroblasts. ASS activity is also determined by a method based on the conversion of radiolabeled (14C)-aspartate to (14C)-argininosuccinate [Gao et al 2003]:The normal enzyme activity in fibroblasts is 0.8-3.8 nmol/min/mg protein, but this is specific to tissue, method, and laboratory.Cultured chorionic villus cells or cultured amniocytes from the fetus may be used for prenatal diagnosis.Newborn screening. As of this writing, all states include CTLN1 in their newborn screening programs. Elevated citrulline is detected in dried blood spots on newborn screen by tandem mass spectroscopy (MS/MS). Citrullinemia is confirmed by plasma amino acid analysis that demonstrates the findings described above. Other conditions that may result in elevated citrulline on NBS are argininosuccinic acidemia, citrullinemia II (citrin deficiency), and pyruvate carboxylase deficiency.Molecular Genetic TestingGene. ASS1 is the only gene in which mutations are known to cause citrullinemia type I.Clinical testingSequence analysis. Sequencing of genomic DNA from a variety of cells or cDNA from cultured fibroblasts detected 154 of 160 (96%) abnormal alleles [Häberle, personal communication]. In Japan, a small number of mutations account for the majority of cases of CTLN1; however, a large number of mutations are found in individuals of European origin. Deletion/duplication analysis. Exonic and multiexonic deletions were reported by Engel et al [2009].Linkage analysis. An intragenic dinucleotide repeat is informative in 60%-70% of families.Table 1. Summary of Molecular Genetic Testing Used in Citrullinemia Type IView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityASS1Sequence analysisSequence variants 296% 3ClinicalDeletion / duplication analysis 4Exonic, multiexonic, or whole-gene deletionsUnknownLinkage analysisIntragenic dinucleotide repeatInformative in 60%-70%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations. 3. In 80 individuals evaluated, both abnormal alleles were identified in 75 (94%), one abnormal allele in four (5%), and no abnormal alleles in one (1%).4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in the Molecular Genetics section (see Table A and/or Molecular Genetics, Pathologic Allelic Variants).Testing StrategyTo confirm/establish the diagnosis in a symptomatic probandThe finding of elevated plasma ammonia concentration (>150; may range to ≥2000-3000 µmol/L) and plasma citrulline concentration (usually >1000 µmol/L) establishes the diagnosis of CTLN1. Note: Following the work up described in Urea Cycle Disorders leads to the diagnosis of citrullinemia type 1 when present. See Urea Cycle Disorders Overview Figure 3.Molecular genetic testing (sequence analysis of ASS1 followed by deletion/duplication analysis if neither or only one mutation is identified) may be helpful when the phenotype is unclear or biochemical values are borderline; it is especially helpful in distinguishing CTLN1 in its mild form from citrin deficiency. Note: (1) Determining the prognosis prospectively can be difficult in some individuals who fit the biochemical phenotype but may or may not have serious clinical illness. (2) Enzyme assay is not widely used because the clinical presentation and relatively specific pattern of metabolites found in affected individuals are sufficient to establish the diagnosis.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Linkage analysis can be considered for carrier testing if neither or only one mutation has been identified in an affected family member. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis for at-risk pregnancies requires either prior confirmation of enzyme deficiency in an affected family member or prior identification of the disease-causing mutations in the family. In certain instances, linkage analysis may be considered to improve prenatal testing accuracy if neither or only one mutation has been identified in an affected family member. Linkage must be established in the family before prenatal testing can be performed.Preimplantation genetic diagnosis (PGD) for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are associated with mutations in ASS1.
Citrullinemia type I (CTLN1) presents as a spectrum that includes a neonatal acute form (the "classic" form), a milder late-onset form, a form in which women have onset of symptoms at pregnancy or post partum, and a form without symptoms or hyperammonemia....
Natural HistoryCitrullinemia type I (CTLN1) presents as a spectrum that includes a neonatal acute form (the "classic" form), a milder late-onset form, a form in which women have onset of symptoms at pregnancy or post partum, and a form without symptoms or hyperammonemia.In the acute neonatal form, the infant appears normal at birth. After an interval of one to a few days, the infant becomes progressively lethargic, feeds poorly, may vomit, and may develop signs of increased intracranial pressure [Brusilow & Horwich 2006]. Fifty-six percent of infants with classic citrullinemia type I are symptomatic by age four days and 67% by age one week [Bachmann 2003a].Recently, two infants with classic CTLN1 with ammonia concentrations in the range of 400-500 µmol/L presented at age two and three months with cerebral infarcts [Choi et al 2006].Children diagnosed and referred for appropriate treatment (see Management) survive for an indeterminate period of time, usually with significant neurologic deficits. All children with a peak plasma ammonia concentration greater than 480 µmol/L or an initial plasma ammonia concentration greater than 300 µmol/L have cognitive impairment [Bachmann 2003b]. The longest survival of an untreated infant with classic citrullinemia type I is 17 days. In the late-onset form, the clinical course may be similar to or milder than that seen in the acute neonatal form, but for unknown reasons commences later in life. When episodes of hyperammonemia occur, they are similar to those seen in the acute neonatal form, but the neurologic findings may be more subtle because of the older age of the affected individuals. These can include intense headache, scotomas, migraine-like episodes, ataxia, slurred speech, lethargy, and somnolence. Individuals with hyperammonemia also display respiratory alkalosis and tachypnea [Brusilow & Horwich 2006]. Without prompt intervention, increased intracranial pressure occurs, with increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death. Liver failure is being increasingly recognized as a primary presentation of CTLN1, contradicting established dogma of CNS symptoms as the primary findings. Two examples include: A 25-year old woman who presented with two episodes of acute liver failure, and who was ultimately shown to have CTLN1 by metabolite testing and molecular genetic testing [Salek et al 2010] A 15-month old female with CTLN1 who "...presented with encephalopathy and seizures with hyperammonemia requiring emergency treatment. Although there was a rapid resolution of her hyperammonemia, she developed fulminant liver failure. The severe increase of transaminases (aspartate aminotransferase and alanine aminotransferase levels peaking at 19,794 UI/L and 19,938 UI/L, respectively) and concurrent disturbances in her hepatic synthetic functions led to the consideration of a liver transplantation… " [Faghfoury et al 2011].Pregnancy. Although a healthy woman with untreated CTLN1 underwent two successful pregnancies [Potter et al 2004], women with onset of severe symptoms during pregnancy or in the postpartum period have been reported [Gao et al 2003, Ruitenbeek et al 2003]. Three women not known to have citrullinemia presented in hyperammonemic coma shortly after delivery: one died and two survived without neurologic sequelae [Häberle et al 2009]. CTLN1 has been implicated in postpartum psychosis [Häberle et al 2010].Individuals remaining asymptomatic up to at least age ten years have been reported; it seems possible that they may remain asymptomatic lifelong [Häberle et al 2002, Häberle et al 2003].Neuroimaging. CT scan of infants with citrullinemia type I demonstrates cerebral atrophy, particularly in the cingulate gyrus, the insula, and the temporal lobes, as well as general cortical hypo-attenuation (i.e., the cortex appears darker than in unaffected individuals) [Albayram et al 2002].
Although certain mutations are identified with some phenotypes, the phenotype cannot be predicted in all instances [Engel et al 2009]. ...
Genotype-Phenotype CorrelationsAlthough certain mutations are identified with some phenotypes, the phenotype cannot be predicted in all instances [Engel et al 2009]. Severe, classic citrullinemia type I typically results from 22 defined mutations [Engel et al 2009]. The mutation in exon 15, p.Gly390Arg, remains the most prevalent associated with the classic phenotype [Engel et al 2009, Laróvere et al 2009].Mild (i.e., late-onset) citrullinemia type I is associated with 12 mutations [Engel et al 2009].
Citrullinemia type II (CTLN2) is caused by citrin deficiency resulting from mutations in SLC25A13, which encodes the mitochondrial solute carrier protein, citrin. In citrin deficiency aspartate and glutamate fail to shuttle to and from the mitochondrion, leading to a mild hyperammonemia and citrullinemia. Mutation in SLC25A13 also leads to intrahepatic cholestasis in the neonate [Saheki & Kobayashi 2002]. The clinical course in adults with citrullinemia type II is milder than that of CTLN1, possibly distinguishing it from milder late-onset citrullinemia type I. It is not known why CTLN2 is milder and later in onset than CTLN1; distinguishing between the two disorders is difficult. The prevalence of citrullinemia type II has not been reported....
Differential DiagnosisCitrullinemia type II (CTLN2) is caused by citrin deficiency resulting from mutations in SLC25A13, which encodes the mitochondrial solute carrier protein, citrin. In citrin deficiency aspartate and glutamate fail to shuttle to and from the mitochondrion, leading to a mild hyperammonemia and citrullinemia. Mutation in SLC25A13 also leads to intrahepatic cholestasis in the neonate [Saheki & Kobayashi 2002]. The clinical course in adults with citrullinemia type II is milder than that of CTLN1, possibly distinguishing it from milder late-onset citrullinemia type I. It is not known why CTLN2 is milder and later in onset than CTLN1; distinguishing between the two disorders is difficult. The prevalence of citrullinemia type II has not been reported.It is critical to distinguish hyperammonemia caused by a defect in the urea cycle from the secondary hyperammonemia caused by an organic acidemia (see Organic Acidemias Overview), which may cause inhibition of N-acetylglutamate synthase (see Urea Cycle Disorders Overview Figure 2).Classic citrullinemia type I shares the phenotype of the typical acute neonatal hyperammonemia displayed by other defects in the first four steps in the urea cycle pathway. The mild phenotype shares a later onset with other disorders such as late-onset ornithine transcarbamylase (OTC) deficiency. 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.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Acute neonatal formLate-onset form
To establish the extent of disease in an individual diagnosed with citrullinemia type I (CTLN1), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with citrullinemia type I (CTLN1), the following evaluations are recommended:Measurement of: concentration of plasma ammonia, amino acids, and electrolytes; blood gases; urinary organic acids; and urinary orotic acidAssessment of intracranial pressure and overall neurologic statusGenetics consultationTreatment of ManifestationsAcute management of individuals with citrullinemia type I depends on early diagnosis, control of hyperammonemia, and control of intracranial pressure. Regular attendance at a metabolic clinic with access to a trained metabolic nutritionist is essential to proper management. See the American College of Medical Genetics and [www.acmg.net].Ucyclyd protocol. The protocol designed by Brusilow and colleagues (Ucyclyd Pharma®) should be followed. This protocol uses alternative means of waste nitrogen disposition (sodium benzoate and phenylacetate). Buphenyl® (Ammonaps®) (oral form of sodium phenylbutyrate) is approved by the FDA. Sodium phenylacetate/sodium benzoate, 10% intravenous solution, received FDA approval as Ammonul® in February 2005.Hemodialysis. Failure to control hyperammonia with the Ucyclyd protocol after two doses of medications described above requires emergency use of hemodialysis to reduce the plasma ammonia concentration to an acceptable level, following which institution of the sustaining infusion may be attempted, supplemented with additional doses over one hour as in the initial bolus infusion as needed to control plasma ammonia concentration [Lo et al 2003].Diet. Concomitant with the Ucyclyd protocol, appropriate protein and calorie nutrition must be provided so that the affected individual does not become catabolic. In small infants, the 40 cal/100 mL given as D10W can be significant in averting catabolism. As soon as possible, osmolar load permitting, the individual should receive total parenteral nutrition (TPN) providing 0.25 g/kg/day of protein and 50 cal/kg/day, advancing (as plasma ammonia concentration allows) to 1.0-1.5 g/kg/day of protein and 100-120 cal/kg/day. Standard TPN solutions of dextrose, aminosol, and intralipid are used.Prevention of increased intracranial pressure. It is critical to monitor fluid balance, intake, and output and body weight, and to maintain the individual on the dry side of fluid balance: approximately 85 mL/kg of body weight per day in infants; appropriate corresponding fluid restriction in children and adults. Increased intracranial pressure is manifested by tension in the fontanel, acute enlargement of the liver, edema, and worsening neurologic signs including fisting, scissoring, ankle clonus, and coma. Cerebral edema and ischemia may be documented by MRI.Prevention of Primary ManifestationsMedication. When the affected individual is able to tolerate solid food, the oral medication sodium phenylbutyrate (Buphenyl®, Ammonaps®), at a dose of 450-600 mg/kg/day divided into three doses, and arginine-free base of 400 and 700 mg/kg/day are begun. Success of therapy is defined by a plasma ammonia concentration lower than 100 µmol/L and near-normal plasma glutamine concentration. Plasma arginine concentration may be up to 250% above upper normal limit for age.As children grow, doses change to 9.9-13 g/m2/day of sodium phenylbutyrate and 8.8-15.4 g/m2/day of arginine. For details of management, the reader is referred to Brusilow & Horwich [2006].Treatment with L-carnitine has been advocated as auxiliary treatment to prevent systemic hypocarnitinemia, which may result from therapy with acylating agents.Diet. Lifelong dietary management is necessary and requires the services of a metabolic nutritionist.Liver transplantation. Liver transplantation for treatment of urea cycle disorders has been reported by several groups. Of sixteen individuals undergoing liver transplantation, 14 lived 11 months to six years post transplantation; their neurologic outcomes correlated closely with their pre-transplantation neurologic status. Few problems with long-term health were related to the liver transplantation itself and the quality of life was much improved [Whitington et al 1998]. A successful living related-donor liver transplantation (240 g) from mother to six-year-old daughter has been reported. The allopurinol challenge test was normalized in this child, who previously had very brittle control with four to six hyperammonemic episodes per year [Ito et al 2003].A living related-donor liver transplantation from mother to son resulted in continued elevation in plasma concentration of citrulline (200-400µmol/L). The mother, a heterozygote, had 28% residual ASS 1 enzyme activity [Ando et al 2003].A larger series of successful auxiliary partial liver transplants has been reported in CTLN type II [Yazaki et al 2004].Prevention of Secondary ComplicationsIntercurrent infections (particularly some viral exanthems) may induce a catabolic state. Patients must be observed carefully during such episodes and medical attention sought to prevent hyperammonemia.SurveillanceAppropriate monitoring of concentration of plasma amino acids to identify deficiency of essential amino acids as well as impending hyperammonemia is indicated.Routine follow-up in a metabolic clinic with a qualified metabolic nutritionist and clinical biochemical geneticist is required.Monitoring for early warning signs of impending hyperammonic episodes including mood changes, headache, lethargy, nausea, vomiting, refusal to feed, ankle clonus, and elevated plasma concentration of glutamine and other surrogate markers is warranted in older individuals. Plasma glutamine concentration may rise 48 hours in advance of increases in plasma ammonia concentration in such individuals [Brusilow & Horwich 2006].Agents/Circumstances to AvoidAvoid the following:Excess protein intakeObvious exposure to communicable diseasesEvaluation of Relatives at RiskBecause the long-term outlook for individuals with citrullinemia type I depends on initial and peak plasma ammonia concentration, it is important that at-risk sibs are identified as soon as possible. Current practice dictates either in utero diagnosis, which permits appropriate oral therapy beginning with first feeds, or measurement of plasma concentrations of ammonia and citrulline on day one of life. Elevation of either above acceptable levels (ammonia >100 µmol/L or plasma citrulline >~100 µmol/L) is sufficient evidence to initiate treatment.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementBecause 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.Therapies Under InvestigationGene therapy has been suggested; success has not been achieved to date. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherKetoacids of essential amino acids were an early form of auxiliary waste nitrogen disposal enhancement, now replaced by the agents described in Treatment of Manifestations.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Citrullinemia Type I: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDASS19q34.11Argininosuccinate synthaseASS1 @ LOVDASS1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Citrullinemia Type I (View All in OMIM) View in own window 215700CITRULLINEMIA, CLASSIC 603470ARGININOSUCCINATE SYNTHETASE 1; ASS1Normal allelic variants. ASS1 comprises 16 exons; the primary transcript is 1239 bp. Transcription starts at the 5' end of exon 3. In the homozygous state, mutations p.Trp179Arg, c.1168G>A, and p.Gly362Val are associated with mild or no clinical symptoms, as is heterozygosity for c.[323G>T]+[970+5G>A] [Häberle et al 2002]. At least 14 ASS1 pseudogenes are known.Pathologic allelic variants. See Table 2. Engel et al [2009] defined 87 ASS1 mutations from all available ethnicities; 27 were previously undescribed. They were found to occur in most exons and several intervening sequences leading to abnormal mRNA splicing. Seven mutations are associated with severe disease; three of them (p.Arg304Trp, c.421-2A>G, and p.Gly390Arg) account for the majority of citrullinemia type I [Gao et al 2003]. See Table A.Table 2. Selected ASS1 Allelic VariantsView in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid ChangeReference Sequencesc.257G>Ap.Arg86His 2NM_000050.4 NP_000041.2c.323G>T 3p.Arg108Leu 3c.421-2A>G (IVS6-2A>G)--c.535T>C 3p.Trp179Arg 2, 3c.794G>Ap.Arg265His 2c.910C>Tp.Arg304Trpc.970+5G>A 3(IVS13+5G>A)--c.1085G>T 3p.Gly362Val 2, 3c.1168G>A 3p.Gly390ArgSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventions2. Associated with late-onset citrullinemia type I; see Genotype-Phenotype Correlations.3. Variants associated with no clinical or mild clinical symptoms; see Table A.Normal gene product. The translational product, argininosuccinate synthase, is a homotetramer of 186 kd. It catalyzes an essential reaction in the biosynthesis of urea, causing the condensation of citrulline and aspartate to argininosuccinic acid in the cytosol, and requiring 1 mol of ATP.Abnormal gene product. The argininosuccinate synthase enzyme is inactive or absent. Mutant ASS with abnormal KM (Michaelis constant) or very low ASS protein detected by ELISA using anti-ASS antibody (low CRIM: cross-reacting immunologic materials) has been found.