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Citrullinemia

MedGen UID:
104491
•Concept ID:
C0175683
•
Disease or Syndrome
Synonyms: Argininosuccinate Synthase Deficiency Disease; Argininosuccinate Synthetase Deficiencies; Argininosuccinate Synthetase Deficiency; Argininosuccinic Acid Synthase Deficiency Disease; Argininosuccinic Acid Synthetase Deficiency; Argininosuccinic Acid Synthetase Deficiency Disease; ASS Deficiencies; ASS Deficiency; Citrullinemias; Citrullinuria; Citrullinurias; Deficiencies, Argininosuccinate Synthetase; Deficiency Disease, Argininosuccinate Synthase; Deficiency Disease, Argininosuccinic Acid Synthase; Deficiency, Argininosuccinate Synthetase; Deficiency, ASS
SNOMED CT: Citrullinemia (398680004); Argininosuccinate synthase deficiency (398680004); ASS deficiency (398680004); ASA synthase deficiency (398680004); Argininosuccinase deficiency (398680004); ASAS deficiency (398680004); Arginosuccinate synthetase deficiency (398680004); Deficiency of citrulline-aspartate ligase (124711003); Deficiency of argininosuccinate synthase (124711003)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
•Concept ID:
C0441748
•
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (Orphanet)
 
Related gene: ASS1
 
Monarch Initiative: MONDO:0015991
OMIM®: 215700
OMIM® Phenotypic series: PS215700
Orphanet: ORPHA187

Definition

Citrullinemia is an autosomal recessively inherited disorder of urea cycle metabolism and ammonia detoxification (see this term) characterized by elevated concentrations of serum citrulline and ammonia. The disease presents with a large range of manifestations including neonatal hyperammonemic encephalopathy with lethargy, seizures and coma; hepatic dysfunction in all age groups; episodes of hyperammonemia and neuropsychiatric symptoms in children or adults, or, can be asymptomatic in some cases (detected in newborn screening programs). Citrullinemia is divided into two main groups that are encoded by different genes: citrullinemia type I (comprised of acute neonatal citrullinemia type I and adult-onset citrullinemia type I) and citrin deficiency (comprised of adult-onset citrullinemia type II and neonatal intrahepatic cholestasis due to citrin deficiency) (see these terms). [from ORDO]

Professional guidelines

PubMed

Pathogenesis and Management of Citrin Deficiency.
Hayasaka K
Intern Med 2024 Jul 15;63(14):1977-1986. Epub 2023 Nov 13 doi: 10.2169/internalmedicine.2595-23. PMID: 37952953Free PMC Article
High Risk Stratified Neonatal Screening.
ICMR Task Force on Inherited Metabolic Disorders
Indian J Pediatr 2018 Dec;85(12):1050-1054. Epub 2018 Mar 15 doi: 10.1007/s12098-017-2545-4. PMID: 29542068
Aminoacidopathies: Prevalence, Etiology, Screening, and Treatment Options.
Wasim M, Awan FR, Khan HN, Tawab A, Iqbal M, Ayesha H
Biochem Genet 2018 Apr;56(1-2):7-21. Epub 2017 Nov 1 doi: 10.1007/s10528-017-9825-6. PMID: 29094226

Recent clinical studies

Etiology

Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders.
Posset R, Garbade SF, Gleich F, Scharre S, Okun JG, Gropman AL, Nagamani SCS, Druck AC, Epp F, Hoffmann GF, Kölker S, Zielonka M; Urea Cycle Disorders Consortium (UCDC); European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group
Genet Med 2024 Apr;26(4):101039. Epub 2023 Dec 3 doi: 10.1016/j.gim.2023.101039. PMID: 38054409
Citrin Deficiency: Clinical and Nutritional Features.
Komatsu M, Tanaka N, Kimura T, Yazaki M
Nutrients 2023 May 12;15(10) doi: 10.3390/nu15102284. PMID: 37242166Free PMC Article
Episodic Ataxias: Primary and Secondary Etiologies, Treatment, and Classification Approaches.
Hassan A
Tremor Other Hyperkinet Mov (N Y) 2023;13:9. Epub 2023 Mar 28 doi: 10.5334/tohm.747. PMID: 37008993Free PMC Article
Early prediction of phenotypic severity in Citrullinemia Type 1.
Zielonka M, Kölker S, Gleich F, Stützenberger N, Nagamani SCS, Gropman AL, Hoffmann GF, Garbade SF, Posset R; Urea Cycle Disorders Consortium (UCDC) and the European Registry and Network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group
Ann Clin Transl Neurol 2019 Sep;6(9):1858-1871. Epub 2019 Aug 30 doi: 10.1002/acn3.50886. PMID: 31469252Free PMC Article
Aminoacidopathies: Prevalence, Etiology, Screening, and Treatment Options.
Wasim M, Awan FR, Khan HN, Tawab A, Iqbal M, Ayesha H
Biochem Genet 2018 Apr;56(1-2):7-21. Epub 2017 Nov 1 doi: 10.1007/s10528-017-9825-6. PMID: 29094226

Diagnosis

Citrin Deficiency: Clinical and Nutritional Features.
Komatsu M, Tanaka N, Kimura T, Yazaki M
Nutrients 2023 May 12;15(10) doi: 10.3390/nu15102284. PMID: 37242166Free PMC Article
Episodic Ataxias: Primary and Secondary Etiologies, Treatment, and Classification Approaches.
Hassan A
Tremor Other Hyperkinet Mov (N Y) 2023;13:9. Epub 2023 Mar 28 doi: 10.5334/tohm.747. PMID: 37008993Free PMC Article
Early prediction of phenotypic severity in Citrullinemia Type 1.
Zielonka M, Kölker S, Gleich F, Stützenberger N, Nagamani SCS, Gropman AL, Hoffmann GF, Garbade SF, Posset R; Urea Cycle Disorders Consortium (UCDC) and the European Registry and Network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group
Ann Clin Transl Neurol 2019 Sep;6(9):1858-1871. Epub 2019 Aug 30 doi: 10.1002/acn3.50886. PMID: 31469252Free PMC Article
Aminoacidopathies: Prevalence, Etiology, Screening, and Treatment Options.
Wasim M, Awan FR, Khan HN, Tawab A, Iqbal M, Ayesha H
Biochem Genet 2018 Apr;56(1-2):7-21. Epub 2017 Nov 1 doi: 10.1007/s10528-017-9825-6. PMID: 29094226
Hyperammonemia in review: pathophysiology, diagnosis, and treatment.
Auron A, Brophy PD
Pediatr Nephrol 2012 Feb;27(2):207-22. Epub 2011 Mar 23 doi: 10.1007/s00467-011-1838-5. PMID: 21431427

Therapy

Impact of supplementation with L-citrulline/arginine after liver transplantation in individuals with Urea Cycle Disorders.
Posset R, Garbade SF, Gleich F, Nagamani SCS, Gropman AL, Epp F, Ramdhouni N, Druck AC, Hoffmann GF, Kölker S, Zielonka M; Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) consortia study group
Mol Genet Metab 2024 Mar;141(3):108112. Epub 2023 Dec 10 doi: 10.1016/j.ymgme.2023.108112. PMID: 38301530
Treatment and management for children with urea cycle disorder in chronic stage.
Huang X
Zhejiang Da Xue Xue Bao Yi Xue Ban 2023 Oct 3;52(6):744-750. doi: 10.3724/zdxbyxb-2023-0378. PMID: 37807629Free PMC Article
Episodic Ataxias: Primary and Secondary Etiologies, Treatment, and Classification Approaches.
Hassan A
Tremor Other Hyperkinet Mov (N Y) 2023;13:9. Epub 2023 Mar 28 doi: 10.5334/tohm.747. PMID: 37008993Free PMC Article
Metabolic basis and treatment of citrin deficiency.
Hayasaka K
J Inherit Metab Dis 2021 Jan;44(1):110-117. Epub 2020 Aug 26 doi: 10.1002/jimd.12294. PMID: 32740958
Molecular diagnosis of pediatric patients with citrin deficiency in China: SLC25A13 mutation spectrum and the geographic distribution.
Lin WX, Zeng HS, Zhang ZH, Mao M, Zheng QQ, Zhao ST, Cheng Y, Chen FP, Wen WR, Song YZ
Sci Rep 2016 Jul 11;6:29732. doi: 10.1038/srep29732. PMID: 27405544Free PMC Article

Prognosis

ASS1 metabolically contributes to the nuclear and cytosolic p53-mediated DNA damage response.
Lim LQJ, Adler L, Hajaj E, Soria LR, Perry RB, Darzi N, Brody R, Furth N, Lichtenstein M, Bab-Dinitz E, Porat Z, Melman T, Brandis A, Malitsky S, Itkin M, Aylon Y, Ben-Dor S, Orr I, Pri-Or A, Seger R, Shaul Y, Ruppin E, Oren M, Perez M, Meier J, Brunetti-Pierri N, Shema E, Ulitsky I, Erez A
Nat Metab 2024 Jul;6(7):1294-1309. Epub 2024 Jun 10 doi: 10.1038/s42255-024-01060-5. PMID: 38858597Free PMC Article
Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders.
Posset R, Garbade SF, Gleich F, Scharre S, Okun JG, Gropman AL, Nagamani SCS, Druck AC, Epp F, Hoffmann GF, Kölker S, Zielonka M; Urea Cycle Disorders Consortium (UCDC); European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group
Genet Med 2024 Apr;26(4):101039. Epub 2023 Dec 3 doi: 10.1016/j.gim.2023.101039. PMID: 38054409
Incidence and genetic variants of inborn errors of metabolism identified through newborn screening: A 7-year study in eastern coastal areas of China.
Men S, Liu S, Zheng Q, Yang S, Mao H, Wang Z, Gu Y, Tang X, Wang L
Mol Genet Genomic Med 2023 Jun;11(6):e2152. Epub 2023 Feb 14 doi: 10.1002/mgg3.2152. PMID: 36787440Free PMC Article
Pathogenic variants of the mitochondrial aspartate/glutamate carrier causing citrin deficiency.
Tavoulari S, Lacabanne D, Thangaratnarajah C, Kunji ERS
Trends Endocrinol Metab 2022 Aug;33(8):539-553. Epub 2022 Jun 17 doi: 10.1016/j.tem.2022.05.002. PMID: 35725541Free PMC Article
Early prediction of phenotypic severity in Citrullinemia Type 1.
Zielonka M, Kölker S, Gleich F, Stützenberger N, Nagamani SCS, Gropman AL, Hoffmann GF, Garbade SF, Posset R; Urea Cycle Disorders Consortium (UCDC) and the European Registry and Network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group
Ann Clin Transl Neurol 2019 Sep;6(9):1858-1871. Epub 2019 Aug 30 doi: 10.1002/acn3.50886. PMID: 31469252Free PMC Article

Clinical prediction guides

Impact of supplementation with L-citrulline/arginine after liver transplantation in individuals with Urea Cycle Disorders.
Posset R, Garbade SF, Gleich F, Nagamani SCS, Gropman AL, Epp F, Ramdhouni N, Druck AC, Hoffmann GF, Kölker S, Zielonka M; Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) consortia study group
Mol Genet Metab 2024 Mar;141(3):108112. Epub 2023 Dec 10 doi: 10.1016/j.ymgme.2023.108112. PMID: 38301530
Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders.
Posset R, Garbade SF, Gleich F, Scharre S, Okun JG, Gropman AL, Nagamani SCS, Druck AC, Epp F, Hoffmann GF, Kölker S, Zielonka M; Urea Cycle Disorders Consortium (UCDC); European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group
Genet Med 2024 Apr;26(4):101039. Epub 2023 Dec 3 doi: 10.1016/j.gim.2023.101039. PMID: 38054409
Incidence and genetic variants of inborn errors of metabolism identified through newborn screening: A 7-year study in eastern coastal areas of China.
Men S, Liu S, Zheng Q, Yang S, Mao H, Wang Z, Gu Y, Tang X, Wang L
Mol Genet Genomic Med 2023 Jun;11(6):e2152. Epub 2023 Feb 14 doi: 10.1002/mgg3.2152. PMID: 36787440Free PMC Article
Pathogenic variants of the mitochondrial aspartate/glutamate carrier causing citrin deficiency.
Tavoulari S, Lacabanne D, Thangaratnarajah C, Kunji ERS
Trends Endocrinol Metab 2022 Aug;33(8):539-553. Epub 2022 Jun 17 doi: 10.1016/j.tem.2022.05.002. PMID: 35725541Free PMC Article
Early prediction of phenotypic severity in Citrullinemia Type 1.
Zielonka M, Kölker S, Gleich F, Stützenberger N, Nagamani SCS, Gropman AL, Hoffmann GF, Garbade SF, Posset R; Urea Cycle Disorders Consortium (UCDC) and the European Registry and Network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group
Ann Clin Transl Neurol 2019 Sep;6(9):1858-1871. Epub 2019 Aug 30 doi: 10.1002/acn3.50886. PMID: 31469252Free PMC Article

Recent systematic reviews

Episodic Ataxias: Primary and Secondary Etiologies, Treatment, and Classification Approaches.
Hassan A
Tremor Other Hyperkinet Mov (N Y) 2023;13:9. Epub 2023 Mar 28 doi: 10.5334/tohm.747. PMID: 37008993Free PMC Article

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