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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); Deficiency of citrulline-aspartate ligase (124711003); Deficiency of argininosuccinate synthase (124711003); Argininosuccinate synthase deficiency (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: Gene(s) associated with related conditions. For conditions in a hierarchy, the parent condition will list the genes associated with the children conditions.	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]

Term Hierarchy

GTR
MeSH
Orphanet

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

Congenital, Hereditary, and Neonatal Diseases and Abnormalities
- Inborn genetic diseases
  - Inborn errors of metabolism
    - Brain Diseases, Metabolic, Inborn
      - Disorder of the urea cycle metabolism
        Citrullinemia
        Citrullinemia type I
        Acute neonatal citrullinemia type I
        Adult-onset citrullinemia type I
        Citrullinemia type II
        Citrullinemia, type II, adult-onset
        Neonatal intrahepatic cholestasis due to citrin deficiency

Follow this link to review classifications for Citrullinemia in Orphanet.

Professional guidelines

PubMed

Lessons for the clinical nephrologist: dietary management of adult-onset type II citrullinemia in chronic kidney disease: a nutritional dilemma.

Weng HL, Yang FJ, Chien YH, Chen PR, Lin ZX, Lee NC, Hwu WL
J Nephrol 2020 Oct;33(5):1111-1113. Epub 2020 Jul 27 doi: 10.1007/s40620-020-00813-1. PMID: 32720136

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

Management of neonatal citrullinemia.

Sanjurjo P, Rodríguez-Soriano J
J Pediatr 1993 Nov;123(5):838-9. doi: 10.1016/s0022-3476(05)80880-7. PMID: 8292188

See all (42)

Recent clinical studies

Etiology

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: 37242166 Free 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: 37008993 Free 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

Molecular diagnosis of urea cycle disorders: current global scenario.

Vaidyanathan K
Indian J Biochem Biophys 2013 Oct;50(5):357-62. PMID: 24772957

See all (116)

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: 37242166 Free 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: 37008993 Free 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

The human argininosuccinate synthetase locus and citrullinemia.

Beaudet AL, O'Brien WE, Bock HG, Freytag SO, Su TS
Adv Hum Genet 1986;15:161-96, 291-2. doi: 10.1007/978-1-4615-8356-1_3. PMID: 3513483

See all (278)

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

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: 37008993 Free PMC Article

A Somnolent Neonate With Hypothermia and Posturing.

Nguyen JM, Kaushal S, Glinton KE, Marom R
Clin Pediatr (Phila) 2020 Jul;59(8):841-843. Epub 2020 May 13 doi: 10.1177/0009922820920018. PMID: 32400174

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: 27405544 Free PMC Article

Citrullinemia.

Leibowitz J, Thoene J, Spector E, Nyhan W
Virchows Arch A Pathol Anat Histol 1978 Mar 10;377(3):249-58. doi: 10.1007/BF00426934. PMID: 148153

See all (77)

Prognosis

ASS1 deficiency is associated with impaired neuronal differentiation in zebrafish larvae.

Seidl MJ, Scharre S, Posset R, Druck AC, Epp F, Okun JG, Dimitrov B, Hoffmann GF, Kölker S, Zielonka M
Mol Genet Metab 2024 Jan;141(1):108097. Epub 2023 Nov 28 doi: 10.1016/j.ymgme.2023.108097. PMID: 38113552

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: 35725541 Free 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: 31469252 Free PMC Article

PRMT7 Interacts with ASS1 and Citrullinemia Mutations Disrupt the Interaction.

Verma M, Charles RCM, Chakrapani B, Coumar MS, Govindaraju G, Rajavelu A, Chavali S, Dhayalan A
J Mol Biol 2017 Jul 21;429(15):2278-2289. Epub 2017 Jun 3 doi: 10.1016/j.jmb.2017.05.026. PMID: 28587924

The human argininosuccinate synthetase locus and citrullinemia.

Beaudet AL, O'Brien WE, Bock HG, Freytag SO, Su TS
Adv Hum Genet 1986;15:161-96, 291-2. doi: 10.1007/978-1-4615-8356-1_3. PMID: 3513483

See all (116)

Clinical prediction guides

ASS1 deficiency is associated with impaired neuronal differentiation in zebrafish larvae.

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: 35725541 Free PMC Article

The diagnostic challenge of mild citrulline elevation at newborn screening.

Siri B, Olivieri G, Angeloni A, Cairoli S, Carducci C, Cotugno G, Di Michele S, Giovanniello T, La Marca G, Lepri FR, Novelli A, Rossi C, Semeraro M, Dionisi-Vici C
Mol Genet Metab 2022 Apr;135(4):327-332. Epub 2022 Feb 20 doi: 10.1016/j.ymgme.2022.02.008. PMID: 35279366

Early prediction of phenotypic severity in Citrullinemia Type 1.

PRMT7 Interacts with ASS1 and Citrullinemia Mutations Disrupt the Interaction.

See all (105)