CTLN1
MCID: CTR172
MIFTS: 65

Citrullinemia, Classic (CTLN1)

Categories: Genetic diseases, Metabolic diseases, Rare diseases
Data Licensing
For inquiries, contact:

Aliases & Classifications for Citrullinemia, Classic

MalaCards integrated aliases for Citrullinemia, Classic:

Name: Citrullinemia, Classic 57
Citrullinemia 57 11 42 58 75 28 12 53 5 43 14 71
Argininosuccinate Synthetase Deficiency 57 24 19 58 75 73
Classic Citrullinemia 11 24 19 58 73 14
Citrullinemia Type I 24 19 58 73 28 5
Ass Deficiency 57 11 24 19 58 73
Citrullinuria 57 19 42 73
Ctln1 57 24 58 73
Argininosuccinic Acid Synthetase Deficiency 24 58
Citrullinemia, Type I 57 38
Citrullinemia 1 19 73
Ctnl1 19 71
Deficiency of Citrulline-Aspartate Ligase 11
Argininosuccinic Acid Synthase Deficiency 58
Argininosuccinate Synthase Deficiency 58
Citrullinemia Classical 53
Citrullinemia Type 1 58
Cit 42

Characteristics:


Inheritance:

Citrullinemia, Classic: Autosomal recessive 57
Citrullinemia Type I: Autosomal recessive 58
Citrullinemia: Autosomal recessive 58

Prevelance:

Citrullinemia Type I: 1-9/100000 (Europe, Austria, Korea, Republic of) 1-9/1000000 (Taiwan, Province of China) 58

Age Of Onset:

Citrullinemia Type I: All ages 58
Citrullinemia: Adult,Neonatal 58

Age Of Death:

Citrullinemia: adult,infantile 58

OMIM®:

57 (Updated 24-Oct-2022)
Miscellaneous:
highly variable phenotype
neonatal onset
incidence of 1 in 57,000
prevalence of 1 in 100,000
patients may be asymptomatic, but are at risk for metabolic decompensation


Classifications:

Orphanet: 58  
Inborn errors of metabolism


Summaries for Citrullinemia, Classic

MedlinePlus Genetics: 42 Citrullinemia is an inherited disorder that causes ammonia and other toxic substances to accumulate in the blood. Two types of citrullinemia have been described; they have different signs and symptoms and are caused by mutations in different genes.Type I citrullinemia (also known as classic citrullinemia) usually becomes evident in the first few days of life. Affected infants typically appear normal at birth, but as ammonia builds up, they experience a progressive lack of energy (lethargy), poor feeding, vomiting, seizures, and loss of consciousness. Some affected individuals develop serious liver problems. The health problems associated with type I citrullinemia are life-threatening in many cases. Less commonly, a milder form of type I citrullinemia can develop later in childhood or adulthood. This later-onset form is associated with intense headaches, blind spots (scotomas), problems with balance and muscle coordination (ataxia), and lethargy. Some people with gene mutations that cause type I citrullinemia never experience signs and symptoms of the disorder.Type II citrullinemia chiefly affects the nervous system, causing confusion, restlessness, memory loss, abnormal behaviors (such as aggression, irritability, and hyperactivity), seizures, and coma. Affected individuals often have specific food preferences, preferring protein-rich and fatty foods and avoiding carbohydrate-rich foods. The signs and symptoms of this disorder typically appear during adulthood (adult-onset) and can be triggered by certain medications, infections, surgery, and alcohol intake. These signs and symptoms can be life-threatening in people with adult-onset type II citrullinemia.Adult-onset type II citrullinemia may also develop in people who as infants had a liver disorder called neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). This liver condition is also known as neonatal-onset type II citrullinemia. NICCD blocks the flow of bile (a digestive fluid produced by the liver) and prevents the body from processing certain nutrients properly. In many cases, the signs and symptoms of NICCD go away within a year. In rare cases, affected individuals develop other signs and symptoms in early childhood after seeming to recover from NICCD, including delayed growth, extreme tiredness (fatigue), specific food preferences (mentioned above), and abnormal amounts of fats (lipids) in the blood (dyslipidemia). This condition is known as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD). Years or even decades later, some people with NICCD or FTTDCD develop the features of adult-onset type II citrullinemia.

MalaCards based summary: Citrullinemia, Classic, also known as citrullinemia, is related to carbamoyl phosphate synthetase i deficiency, hyperammonemia due to and ornithine transcarbamylase deficiency, hyperammonemia due to, and has symptoms including ataxia, lethargy and seizures. An important gene associated with Citrullinemia, Classic is ASS1 (Argininosuccinate Synthase 1), and among its related pathways/superpathways are Metabolism and Regulation of expression of SLITs and ROBOs. The drugs Ornithine and Nitric Oxide have been mentioned in the context of this disorder. Affiliated tissues include liver, bone marrow and bone, and related phenotypes are hyperammonemia and elevated plasma citrulline

Orphanet 58 Citrullinemia: 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).

Citrullinemia type i: Citrullinemia type I is a rare autosomal recessive urea cycle defect characterized biologically by hyperammonemia and clinically by progressive lethargy, poor feeding and vomiting in the neonatal form (Acute neonatal citrullinemia type I, see this term) and by variable hyperammonemia in the later-onset form (Adult-onset citrullinemia type I, see this term).

GARD: 19 Citrullinemia type 1 is an inherited disorder that causes ammonia and other toxic substances to accumulate in the blood. Symptoms usually begin shorlty after birth and include excessive sleepiness, poor appetite, vomiting, and irritability. As ammonia builds up, muscle weakness and more serious symptoms may develop. Citrullinemia is caused by genetic changes in the ASS1 gene and is inherited in an autosomal recessive pattern. This disorder is often detected through newborn screening and confirmed by additional medical and genetic tests.

UniProtKB/Swiss-Prot: 73 The classic form of citrullinemia, an autosomal recessive disease characterized primarily by elevated serum and urine citrulline levels. Ammonia intoxication is another manifestation. It is a disorder of the urea cycle, usually manifesting in the first few days of life. Affected infants appear normal at birth, but as ammonia builds up in the body they present symptoms such as lethargy, poor feeding, vomiting, seizures and loss of consciousness. Less commonly, a milder form can develop later in childhood or adulthood.

Disease Ontology 11 Classic citrullinemia: A citrullinemia that has material basis in homozygous or compound heterozygous mutation in the ASS1 gene, which encodes argininosuccinate synthetase, on chromosome 9q34.

Citrullinemia: An inherited urea cycle disorder that involves the accumulation of ammonia and other toxic substances in the blood.

Wikipedia: 75 Citrullinemia is an autosomal recessive urea cycle disorder that causes ammonia and other toxic... more...

More information from OMIM: 215700
GeneReviews: NBK1458

Related Diseases for Citrullinemia, Classic

Diseases related to Citrullinemia, Classic via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 312)
# Related Disease Score Top Affiliating Genes
1 carbamoyl phosphate synthetase i deficiency, hyperammonemia due to 32.1 SLC25A15 OTC NAGS CPS1 ASS1
2 ornithine transcarbamylase deficiency, hyperammonemia due to 31.6 SLC25A15 SLC25A13 OTC NAGS MMACHC CPS1
3 argininemia 31.2 SLC25A15 SLC25A13 PRODH OTC NAGS HADHA
4 carbonic anhydrase va deficiency, hyperammonemia due to 30.8 SLC25A15 OTC NAGS CPS1 ASS1
5 abdominal obesity-metabolic syndrome 1 30.3 OTC HADHA ETFDH
6 hypermethioninemia 30.1 SLC25A13 OTC MMACHC ACADS
7 tyrosinemia 29.9 SLC25A13 PRODH OTC ACADVL
8 reye syndrome 29.9 SLC22A5 PRODH OTC NAGS HADHA ETFDH
9 lysinuric protein intolerance 29.8 PRODH OTC NAGS ASS1 ASL
10 orotic aciduria 29.8 SLC25A15 PRODH OTC NAGS CPS1 ASS1
11 citrullinemia, type ii, adult-onset 29.5 SLC25A2 SLC25A15 SLC25A13 SLC25A12 OTC NAGS
12 maple syrup urine disease 29.5 PRODH OTC NAGS HADHA ASL ACADVL
13 argininosuccinic aciduria 29.4 SLC25A15 SLC25A13 PRODH OTC NAGS CPS1
14 urea cycle disorder 29.1 SLC25A2 SLC25A15 SLC25A13 SLC25A12 PRODH OTC
15 citrullinemia, type ii, neonatal-onset 11.7
16 adult-onset citrullinemia type i 11.6
17 microcephaly 17, primary, autosomal recessive 11.4
18 acute neonatal citrullinemia type i 11.4
19 schizophrenia 11.2
20 microcephaly 11.2
21 bipolar disorder 11.1
22 lissencephaly 11.1
23 cerebellar hypoplasia 11.1
24 primary microcephaly 10.9
25 primary autosomal recessive microcephaly 10.9
26 microcephaly 6, primary, autosomal recessive 10.9
27 microcephaly 5, primary, autosomal recessive 10.9
28 congenital nervous system abnormality 10.9
29 parkinsonism 10.9
30 parkinson disease, late-onset 10.8
31 dementia, lewy body 10.6
32 dementia 10.6
33 essential tremor 10.6
34 movement disease 10.5
35 multiple system atrophy 1 10.5
36 supranuclear palsy, progressive, 1 10.5
37 schilbach-rott syndrome 10.4
38 hepatic encephalopathy 10.4
39 encephalopathy 10.4
40 vascular parkinsonism 10.4
41 brain edema 10.4
42 dystonia 10.4
43 multiple system atrophy, parkinsonian type 10.3
44 cholestasis 10.3
45 liver disease 10.3
46 rem sleep behavior disorder 10.3
47 intrahepatic cholestasis 10.3
48 alzheimer disease, familial, 1 10.3
49 adult syndrome 10.2
50 tremor 10.2

Graphical network of the top 20 diseases related to Citrullinemia, Classic:



Diseases related to Citrullinemia, Classic

Symptoms & Phenotypes for Citrullinemia, Classic

Human phenotypes related to Citrullinemia, Classic:

58 30 (show all 42)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 hyperammonemia 58 30 Hallmark (90%) Very frequent (99-80%)
HP:0001987
2 elevated plasma citrulline 58 30 Very rare (1%) Very frequent (99-80%)
HP:0011966
3 hepatic failure 58 30 Frequent (33%) Frequent (79-30%)
HP:0001399
4 spasticity 58 30 Occasional (7.5%) Occasional (29-5%)
HP:0001257
5 failure to thrive 58 30 Occasional (7.5%) Occasional (29-5%)
HP:0001508
6 vomiting 58 30 Occasional (7.5%) Occasional (29-5%)
HP:0002013
7 intellectual disability, moderate 58 30 Occasional (7.5%) Occasional (29-5%)
HP:0002342
8 lethargy 58 30 Occasional (7.5%) Occasional (29-5%)
HP:0001254
9 intellectual disability, borderline 58 30 Occasional (7.5%) Occasional (29-5%)
HP:0006889
10 feeding difficulties 58 30 Occasional (7.5%) Occasional (29-5%)
HP:0011968
11 hepatic encephalopathy 58 30 Occasional (7.5%) Occasional (29-5%)
HP:0002480
12 respiratory alkalosis 58 30 Occasional (7.5%) Occasional (29-5%)
HP:0001950
13 stroke 30 Occasional (7.5%) HP:0001297
14 seizure 30 Occasional (7.5%) HP:0001250
15 ataxia 58 30 Very rare (1%) Very rare (<4-1%)
HP:0001251
16 increased intracranial pressure 58 30 Very rare (1%) Very rare (<4-1%)
HP:0002516
17 gastroesophageal reflux 58 30 Very rare (1%) Very rare (<4-1%)
HP:0002020
18 intellectual disability, mild 58 30 Very rare (1%) Very rare (<4-1%)
HP:0001256
19 slurred speech 58 30 Very rare (1%) Very rare (<4-1%)
HP:0001350
20 migraine 58 30 Very rare (1%) Very rare (<4-1%)
HP:0002076
21 scotoma 58 30 Very rare (1%) Very rare (<4-1%)
HP:0000575
22 tachypnea 58 30 Very rare (1%) Very rare (<4-1%)
HP:0002789
23 coma 58 30 Very rare (1%) Very rare (<4-1%)
HP:0001259
24 loss of consciousness 58 30 Very rare (1%) Very rare (<4-1%)
HP:0007185
25 ankle clonus 58 30 Very rare (1%) Very rare (<4-1%)
HP:0011448
26 torticollis 58 30 Very rare (1%) Very rare (<4-1%)
HP:0000473
27 oroticaciduria 30 Very rare (1%) HP:0003218
28 hyperglutaminemia 30 Very rare (1%) HP:0003217
29 hypotonia 30 Very rare (1%) HP:0001252
30 intellectual disability 30 HP:0001249
31 seizures 58 Occasional (29-5%)
32 muscular hypotonia 58 Very rare (<4-1%)
33 global developmental delay 30 HP:0001263
34 hepatomegaly 30 HP:0002240
35 cirrhosis 30 HP:0001394
36 irritability 30 HP:0000737
37 headache 58 Very rare (<4-1%)
38 abnormality of the nervous system 58 Occasional (29-5%)
39 hypoargininemia 30 HP:0005961
40 episodic ammonia intoxication 30 HP:0001951
41 cerebral edema 30 HP:0002181
42 protein avoidance 30 HP:0002038

Symptoms via clinical synopsis from OMIM®:

57 (Updated 24-Oct-2022)
Neurologic Central Nervous System:
seizures
ataxia
lethargy
coma
cerebral edema
more
Abdomen Liver:
hepatomegaly
cirrhosis (in late-onset cases)

Neurologic Behavioral Psychiatric Manifestations:
irritability

Metabolic Features:
episodic ammonia intoxication
respiratory alkalosis

Growth Other:
failure to thrive

Abdomen Gastrointestinal:
vomiting
protein avoidance

Laboratory Abnormalities:
hyperammonemia
orotic aciduria
high plasma glutamine
high plasma citrulline (1000-5000 micromolar)
low plasma arginine
more

Clinical features from OMIM®:

215700 (Updated 24-Oct-2022)

UMLS symptoms related to Citrullinemia, Classic:


ataxia; lethargy; seizures; vomiting

GenomeRNAi Phenotypes related to Citrullinemia, Classic according to GeneCards Suite gene sharing:

25 (show all 29)
# Description GenomeRNAi Source Accession Score Top Affiliating Genes
1 no effect GR00402-S-1 10.17 ACADS ACADVL ARG1 ARG2 ASL ASS1
2 no effect GR00402-S-2 10.17 ARG1 ARG2 ASL ASS1 CPS1 ETFDH
3 Increased shRNA abundance (Z-score > 2) GR00366-A-113 10.1 ARG1
4 Increased shRNA abundance (Z-score > 2) GR00366-A-121 10.1 ETFDH
5 Increased shRNA abundance (Z-score > 2) GR00366-A-122 10.1 SLC25A13
6 Increased shRNA abundance (Z-score > 2) GR00366-A-124 10.1 ETFDH
7 Increased shRNA abundance (Z-score > 2) GR00366-A-13 10.1 PRODH
8 Increased shRNA abundance (Z-score > 2) GR00366-A-146 10.1 ARG1
9 Increased shRNA abundance (Z-score > 2) GR00366-A-147 10.1 ETFDH
10 Increased shRNA abundance (Z-score > 2) GR00366-A-148 10.1 PRODH
11 Increased shRNA abundance (Z-score > 2) GR00366-A-149 10.1 SLC25A13
12 Increased shRNA abundance (Z-score > 2) GR00366-A-156 10.1 ETFDH
13 Increased shRNA abundance (Z-score > 2) GR00366-A-173 10.1 ARG1
14 Increased shRNA abundance (Z-score > 2) GR00366-A-198 10.1 ARG1
15 Increased shRNA abundance (Z-score > 2) GR00366-A-2 10.1 PRODH
16 Increased shRNA abundance (Z-score > 2) GR00366-A-204 10.1 SLC25A13
17 Increased shRNA abundance (Z-score > 2) GR00366-A-21 10.1 ARG1
18 Increased shRNA abundance (Z-score > 2) GR00366-A-23 10.1 PRODH
19 Increased shRNA abundance (Z-score > 2) GR00366-A-33 10.1 PRODH
20 Increased shRNA abundance (Z-score > 2) GR00366-A-42 10.1 SLC25A13
21 Increased shRNA abundance (Z-score > 2) GR00366-A-50 10.1 ETFDH
22 Increased shRNA abundance (Z-score > 2) GR00366-A-58 10.1 PRODH
23 Increased shRNA abundance (Z-score > 2) GR00366-A-66 10.1 PRODH
24 Increased shRNA abundance (Z-score > 2) GR00366-A-68 10.1 ARG1
25 Increased shRNA abundance (Z-score > 2) GR00366-A-7 10.1 ARG1
26 Increased shRNA abundance (Z-score > 2) GR00366-A-70 10.1 ETFDH PRODH
27 Increased shRNA abundance (Z-score > 2) GR00366-A-83 10.1 SLC25A13
28 Increased shRNA abundance (Z-score > 2) GR00366-A-9 10.1 PRODH
29 Increased shRNA abundance (Z-score > 2) GR00366-A-99 10.1 PRODH

MGI Mouse Phenotypes related to Citrullinemia, Classic:

45
# Description MGI Source Accession Score Top Affiliating Genes
1 renal/urinary system MP:0005367 9.86 ACADS ASL HADHA MMACHC OTC SLC22A5
2 homeostasis/metabolism MP:0005376 9.86 ACADS ACADVL ARG1 ARG2 ASL ASS1
3 liver/biliary system MP:0005370 9.76 ACADS ACADVL ARG1 HADHA HSD3B7 OTC
4 mortality/aging MP:0010768 9.53 ACADS ACADVL ARG1 ASL ASS1 CPS1

Drugs & Therapeutics for Citrullinemia, Classic

Drugs for Citrullinemia, Classic (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB):

(show all 6)
# Name Status Phase Clinical Trials Cas Number PubChem Id
1
Ornithine Approved, Nutraceutical Phase 2 70-26-8, 3184-13-2 6262
2
Nitric Oxide Approved 10102-43-9 145068
3
Carbamide peroxide Approved 124-43-6
4
L-Glutamine Approved, Investigational, Nutraceutical 56-85-9 5961
5 Liver Extracts
6
Arginine Investigational, Nutraceutical 74-79-3 6322

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 Open, Prospective, Uncontrolled, Multicentre Study to Evaluate The Safety and Efficacy of Multiple Applications of Liver Cell Suspension Into The Portal Vein in Children With Urea Cycle Disorders (UCDs) Completed NCT00718627 Phase 2
2 Evaluation of Citrullinemia as a Marker of Bowel Damage After Allogeneic Bone Marrow Transplantation in Children Unknown status NCT00751452
3 Citrullinemia for the Prediction of Enteral Nutrition Tolerance Among Critically Ill Patients Unknown status NCT03967795 N2-L-Alanyl-L-Glutamine (Substance)
4 RDCRN 5110, Nitric Oxide Flux and Ureagenesis in Argininosuccinate Synthetase Deficiency (ASSD)(Citrullinemia I)(Version 24Feb12, NIH Approved 4/5/2012) Completed NCT01610089
5 Hepatic Histopathology in Urea Cycle Disorders Recruiting NCT04908319
6 Noninvasive Biomarkers of Hepatic Fibrosis in Urea Cycle Disorders Recruiting NCT04612764
7 The NIH UNI Study: Urea Cycle Disorders, Nutrition and Immunity Terminated NCT01421888

Search NIH Clinical Center for Citrullinemia, Classic

Cochrane evidence based reviews: citrullinemia

Genetic Tests for Citrullinemia, Classic

Genetic tests related to Citrullinemia, Classic:

# Genetic test Affiliating Genes
1 Citrullinemia Type I 28 ASS1
2 Citrullinemia 28

Anatomical Context for Citrullinemia, Classic

Organs/tissues related to Citrullinemia, Classic:

MalaCards : Liver, Bone Marrow, Bone, Brain, Heart, Skin, Prostate

Publications for Citrullinemia, Classic

Articles related to Citrullinemia, Classic:

(show top 50) (show all 608)
# Title Authors PMID Year
1
Mutations and polymorphisms in the human argininosuccinate synthetase (ASS1) gene. 53 62 24 57 5
19006241 2009
2
Pregnancy in a healthy woman with untreated citrullinemia. 53 62 24 57 5
15266621 2004
3
Structure of the human argininosuccinate synthetase gene and an improved system for molecular diagnostics in patients with classical and mild citrullinemia. 53 62 24 57 5
11941481 2002
4
Additional mutations in argininosuccinate synthetase causing citrullinemia. 53 62 24 57 5
1943692 1991
5
Nature and frequency of mutations in the argininosuccinate synthetase gene that cause classical citrullinemia. 53 62 57 5
7557970 1995
6
Mutations in argininosuccinate synthetase mRNA of Japanese patients, causing classical citrullinemia. 53 62 57 5
7977368 1994
7
Heterogeneity of mutations in argininosuccinate synthetase causing human citrullinemia. 53 62 57 5
2358466 1990
8
Early cirrhosis in a patient with type I citrullinaemia (CTLN1). 62 57 5
15334737 2004
9
Mild citrullinemia in Caucasians is an allelic variant of argininosuccinate synthetase deficiency (citrullinemia type 1). 53 62 24 5
14680976 2003
10
Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients. 53 62 24 5
12815590 2003
11
Citrullinemia: phenotypic variations. 62 57 5
934749 1976
12
Early prediction of phenotypic severity in Citrullinemia Type 1. 62 24 5
31469252 2019
13
Mutations in the Human Argininosuccinate Synthetase (ASS1) Gene, Impact on Patients, Common Changes, and Structural Considerations. 62 24 5
28111830 2017
14
Improved standards for prenatal diagnosis of citrullinemia. 62 24 5
24889030 2014
15
High prevalence of neonatal presentation in Korean patients with citrullinemia type 1, and their shared mutations. 62 24 5
23246278 2013
16
Transient fulminant liver failure as an initial presentation in citrullinemia type I. 62 24 5
21227727 2011
17
First manifestation of citrullinemia type I as differential diagnosis to postpartum psychosis in the puerperal period. 62 24 5
20005624 2010
18
Citrullinemia type I, classical variant. Identification of ASS-p~G390R (c.1168G>A) mutation in families of a limited geographic area of Argentina: a possible population cluster. 62 24 5
19358837 2009
19
A nonsense mutation is responsible for the RNA-negative phenotype in human citrullinaemia. 57 5
11571557 2001
20
A longitudinal study of urea cycle disorders. 24 57
25135652 2014
21
Cross-sectional observational study of 208 patients with non-classical urea cycle disorders. 24 5
23780642 2014
22
Investigation of citrullinemia type I variants by in vitro expression studies. 53 62 5
18473344 2008
23
Postpartum "psychosis" in mild argininosuccinate synthetase deficiency. 53 62 5
15863597 2005
24
Argininosuccinate synthetase deficiency: mutation analysis in 3 Thai patients. 53 62 5
16124451 2005
25
Mutation analysis of Korean patients with citrullinemia. 53 62 5
10987146 2000
26
Mutations and DNA diagnoses of classical citrullinemia. 53 62 5
9090528 1997
27
Characterization of human wild-type and mutant argininosuccinate synthetase proteins expressed in bacterial cells. 53 62 5
8792870 1994
28
The diagnostic challenge of mild citrulline elevation at newborn screening. 62 57
35279366 2022
29
Variants associated with urea cycle disorders in Japanese patients: Nationwide study and literature review. 62 5
33851512 2021
30
Urea cycle disorders in India: clinical course, biochemical and genetic investigations, and prenatal testing. 62 5
30285816 2018
31
Identification of three novel mutations in fourteen patients with citrullinemia type 1. 62 5
28132756 2017
32
Modelling urea-cycle disorder citrullinemia type 1 with disease-specific iPSCs. 62 5
28302489 2017
33
Kinetic mutations in argininosuccinate synthetase deficiency: characterisation and in vitro correction by substrate supplementation. 62 5
27287393 2016
34
Functional analysis of novel splicing and missense mutations identified in the ASS1 gene in classical citrullinemia patients. 62 5
25179242 2015
35
Concurrent triplication and uniparental isodisomy: evidence for microhomology-mediated break-induced replication model for genomic rearrangements. 62 5
24713661 2015
36
Urea cycle disorders in Spain: an observational, cross-sectional and multicentric study of 104 cases. 62 5
25433810 2014
37
[ASS1 gene mutation in a neonate with citrullinemia type I]. 62 5
25537548 2014
38
Molecular genetics of citrullinemia types I and II. 62 5
24508627 2014
39
Prenatal diagnosis of citrullinemia type 1: a Chinese family with a novel mutation of the ASS1 gene. 62 5
23611581 2014
40
Mutation spectrum of the ASS1 gene in Korean patients with citrullinemia type I. 62 5
23099195 2013
41
Citrullinemia type I and hypertrophic pyloric stenosis in a 1-month old male infant. 62 5
24765495 2013
42
Unrecognized citrullinemia mimicking encephalitis in a 14-year-old boy: unexpected result through the use of a standardized lumbar puncture protocol. 62 5
22473243 2012
43
Molecular epidemiology of citrullinemia type I in a risk region of Argentina: a first step to preconception heterozygote detection. 62 5
23430935 2012
44
Successful prospective management of neonatal citrullinemia. 62 5
22768672 2012
45
Leishmania donovani argininosuccinate synthase is an active enzyme associated with parasite pathogenesis. 62 5
23094117 2012
46
The role of molecular testing and enzyme analysis in the management of hypomorphic citrullinemia. 62 5
18925679 2008
47
Prenatal diagnosis of citrullinemia and argininosuccinic aciduria: evidence for a transmission ratio distortion in citrullinemia. 62 5
16475226 2006
48
The 1.6 A crystal structure of E. coli argininosuccinate synthetase suggests a conformational change during catalysis. 62 5
11738042 2001
49
Phenotype and genotype heterogeneity in Mediterranean citrullinemia. 62 5
11708871 2001
50
The first successful prenatal diagnosis on a Korean family with citrullinemia. 62 5
11211875 2000

Variations for Citrullinemia, Classic

ClinVar genetic disease variations for Citrullinemia, Classic:

5 (show top 50) (show all 526)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 ASS1 ASS1, EX5DEL DEL Pathogenic
6321 GRCh37:
GRCh38:
2 ASS1 ASS1, EX6DEL DEL Pathogenic
6322 GRCh37:
GRCh38:
3 ASS1 NC_000009.12:g.(?_130458401)_(130458589_?)del DEL Pathogenic
458669 GRCh37:
GRCh38: 9:130458401-130458589
4 ASS1 NM_054012.4(ASS1):c.689-2A>C SNV Pathogenic
813460 rs374586230 GRCh37: 9:133355101-133355101
GRCh38: 9:130479714-130479714
5 ASS1 NC_000009.12:g.(?_130452214)_(130454383_?)del DEL Pathogenic
649068 GRCh37: 9:133327601-133329770
GRCh38: 9:130452214-130454383
6 ASS1 NM_054012.4(ASS1):c.421-2A>C SNV Pathogenic
Pathogenic
Pathogenic
813407 rs751930594 GRCh37: 9:133342110-133342110
GRCh38: 9:130466723-130466723
7 ASS1 NM_054012.4(ASS1):c.830A>G (p.Lys277Arg) SNV Pathogenic
973471 rs1846142065 GRCh37: 9:133355828-133355828
GRCh38: 9:130480441-130480441
8 ASS1 NM_054012.4(ASS1):c.479T>C (p.Leu160Pro) SNV Pathogenic
993037 rs969835605 GRCh37: 9:133342170-133342170
GRCh38: 9:130466783-130466783
9 ASS1 NM_054012.4(ASS1):c.364-2A>G SNV Pathogenic
1339499 GRCh37: 9:133339496-133339496
GRCh38: 9:130464109-130464109
10 ASS1 NM_054012.4(ASS1):c.256C>T (p.Arg86Cys) SNV Pathogenic
Pathogenic
6332 rs121908644 GRCh37: 9:133333869-133333869
GRCh38: 9:130458482-130458482
11 ASS1 NM_054012.4(ASS1):c.1194-1G>C SNV Pathogenic
Pathogenic
166704 rs727503814 GRCh37: 9:133376362-133376362
GRCh38: 9:130500975-130500975
12 ASS1 NM_054012.4(ASS1):c.814C>T (p.Arg272Cys) SNV Pathogenic
Pathogenic
371132 rs762387914 GRCh37: 9:133355812-133355812
GRCh38: 9:130480425-130480425
13 ASS1 NM_054012.4(ASS1):c.1128-6_1188dup DUP Pathogenic
Pathogenic
495381 rs1554725677 GRCh37: 9:133374882-133374883
GRCh38: 9:130499495-130499496
14 ASS1 NM_054012.4(ASS1):c.1088G>A (p.Arg363Gln) SNV Pathogenic
203631 rs771937610 GRCh37: 9:133370371-133370371
GRCh38: 9:130494984-130494984
15 ASS1 NM_054012.4(ASS1):c.370G>A (p.Asp124Asn) SNV Pathogenic
Pathogenic
458673 rs936192871 GRCh37: 9:133339504-133339504
GRCh38: 9:130464117-130464117
16 ASS1 NM_054012.4(ASS1):c.352G>A (p.Ala118Thr) SNV Pathogenic
Pathogenic
813406 rs775305020 GRCh37: 9:133333965-133333965
GRCh38: 9:130458578-130458578
17 ASS1 NM_054012.4(ASS1):c.469C>T (p.Arg157Cys) SNV Pathogenic
Pathogenic
813408 rs770585183 GRCh37: 9:133342160-133342160
GRCh38: 9:130466773-130466773
18 ASS1 NM_054012.4(ASS1):c.484dup (p.Glu162fs) DUP Pathogenic
Pathogenic
813409 rs1313340299 GRCh37: 9:133342173-133342174
GRCh38: 9:130466786-130466787
19 ASS1 NM_054012.4(ASS1):c.774-2A>G SNV Pathogenic
Likely Pathogenic
813462 rs1588496214 GRCh37: 9:133355770-133355770
GRCh38: 9:130480383-130480383
20 ASS1 NC_000009.12:g.(?_130464091)_(130464187_?)del DEL Pathogenic
Pathogenic
583445 GRCh37: 9:133339478-133339574
GRCh38: 9:130464091-130464187
21 ASS1 NM_054012.4(ASS1):c.846C>A (p.Tyr282Ter) SNV Pathogenic
Likely Pathogenic
Uncertain Significance
Likely Benign
840768 rs549085827 GRCh37: 9:133364727-133364727
GRCh38: 9:130489340-130489340
22 ASS1 NM_054012.4(ASS1):c.349G>A (p.Gly117Ser) SNV Pathogenic
Likely Pathogenic
556029 rs770944877 GRCh37: 9:133333962-133333962
GRCh38: 9:130458575-130458575
23 ASS1 NM_054012.4(ASS1):c.838+1G>T SNV Pathogenic
Likely Pathogenic
555072 rs750214431 GRCh37: 9:133355837-133355837
GRCh38: 9:130480450-130480450
24 ASS1 NM_054012.4(ASS1):c.571G>A (p.Glu191Lys) SNV Pathogenic
Pathogenic/Likely Pathogenic
208153 rs777828000 GRCh37: 9:133346876-133346876
GRCh38: 9:130471489-130471489
25 ASS1 NM_054012.4(ASS1):c.892del (p.Glu298fs) DEL Pathogenic
Pathogenic/Likely Pathogenic
188832 rs770362721 GRCh37: 9:133364773-133364773
GRCh38: 9:130489386-130489386
26 ASS1 NM_054012.4(ASS1):c.539G>A (p.Ser180Asn) SNV Pathogenic
Pathogenic/Likely Pathogenic
Likely Pathogenic
Likely Pathogenic
6326 rs121908638 GRCh37: 9:133346264-133346264
GRCh38: 9:130470877-130470877
27 ASS1 NM_054012.4(ASS1):c.919C>T (p.Arg307Cys) SNV Pathogenic
Pathogenic/Likely Pathogenic
265044 rs183276875 GRCh37: 9:133364800-133364800
GRCh38: 9:130489413-130489413
28 ASS1 NM_054012.4(ASS1):c.1048C>T (p.Gln350Ter) SNV Pathogenic
1071097 GRCh37: 9:133370331-133370331
GRCh38: 9:130494944-130494944
29 ASS1 NC_000009.11:g.133355101_133355102insG DUP Pathogenic
1071462 GRCh37: 9:133355101-133355102
GRCh38: 9:130479714-130479715
30 ASS1 NC_000009.11:g.(?_133333768)_(133333996_?)del DEL Pathogenic
1071505 GRCh37: 9:133333768-133333996
GRCh38:
31 ASS1 NM_054012.4(ASS1):c.812dup (p.Asn271fs) DUP Pathogenic
1034022 rs759483921 GRCh37: 9:133355808-133355809
GRCh38: 9:130480421-130480422
32 ASS1 NC_000009.11:g.(?_133327596)_(133329780_?)del DEL Pathogenic
1075498 GRCh37: 9:133327596-133329780
GRCh38:
33 ASS1 NM_054012.4(ASS1):c.832del (p.Ser278fs) DEL Pathogenic
845376 rs1846142146 GRCh37: 9:133355830-133355830
GRCh38: 9:130480443-130480443
34 ASS1 NM_054012.4(ASS1):c.175-1119G>A SNV Pathogenic
Pathogenic
847924 rs1488840592 GRCh37: 9:133332669-133332669
GRCh38: 9:130457282-130457282
35 ASS1 NM_054012.4(ASS1):c.339T>G (p.Tyr113Ter) SNV Pathogenic
945859 rs1845506282 GRCh37: 9:133333952-133333952
GRCh38: 9:130458565-130458565
36 ASS1 NM_054012.4(ASS1):c.1138C>T (p.Gln380Ter) SNV Pathogenic
Likely Pathogenic
188776 rs786204460 GRCh37: 9:133374902-133374902
GRCh38: 9:130499515-130499515
37 ASS1 NM_054012.4(ASS1):c.412dup (p.Gln138fs) DUP Pathogenic
Likely Pathogenic
550398 rs1554983717 GRCh37: 9:133339540-133339541
GRCh38: 9:130464153-130464154
38 ASS1 NM_054012.4(ASS1):c.773+1G>A SNV Pathogenic
Pathogenic/Likely Pathogenic
371254 rs982830431 GRCh37: 9:133355188-133355188
GRCh38: 9:130479801-130479801
39 ASS1 NM_054012.4(ASS1):c.944T>A (p.Leu315Ter) SNV Pathogenic
1355373 GRCh37: 9:133364825-133364825
GRCh38: 9:130489438-130489438
40 ASS1 NM_054012.4(ASS1):c.1117G>T (p.Glu373Ter) SNV Pathogenic
1424757 GRCh37: 9:133370400-133370400
GRCh38: 9:130495013-130495013
41 ASS1 NM_054012.4(ASS1):c.611del (p.Pro204fs) DEL Pathogenic
1400634 GRCh37: 9:133352270-133352270
GRCh38: 9:130476883-130476883
42 ASS1 NM_054012.4(ASS1):c.1072_1073insGC (p.Val358fs) INSERT Pathogenic
1408725 GRCh37: 9:133370355-133370356
GRCh38: 9:130494968-130494969
43 ASS1 NM_054012.4(ASS1):c.621C>A (p.Tyr207Ter) SNV Pathogenic
1434677 GRCh37: 9:133352281-133352281
GRCh38: 9:130476894-130476894
44 ASS1 NM_054012.4(ASS1):c.373C>T (p.Gln125Ter) SNV Pathogenic
1460356 GRCh37: 9:133339507-133339507
GRCh38: 9:130464120-130464120
45 ASS1 NM_054012.4(ASS1):c.489C>G (p.Tyr163Ter) SNV Pathogenic
1457339 GRCh37: 9:133342180-133342180
GRCh38: 9:130466793-130466793
46 ASS1 NM_054012.4(ASS1):c.536G>A (p.Trp179Ter) SNV Pathogenic
1425929 GRCh37: 9:133346261-133346261
GRCh38: 9:130470874-130470874
47 ASS1 NM_054012.4(ASS1):c.1010_1011delinsAA (p.Cys337Ter) INDEL Pathogenic
1352022 GRCh37: 9:133370293-133370294
GRCh38: 9:130494906-130494907
48 ASS1 NM_054012.4(ASS1):c.1030C>T (p.Arg344Ter) SNV Pathogenic
Pathogenic/Likely Pathogenic
188885 rs786204537 GRCh37: 9:133370313-133370313
GRCh38: 9:130494926-130494926
49 ASS1 NM_054012.4(ASS1):c.971G>T (p.Gly324Val) SNV Pathogenic
Likely Pathogenic
458676 rs1554725034 GRCh37: 9:133370254-133370254
GRCh38: 9:130494867-130494867
50 ASS1 NM_054012.4(ASS1):c.319del (p.Gln107fs) DEL Pathogenic
Likely Pathogenic
573823 rs1564903969 GRCh37: 9:133333930-133333930
GRCh38: 9:130458543-130458543

UniProtKB/Swiss-Prot genetic disease variations for Citrullinemia, Classic:

73 (show top 50) (show all 86)
# Symbol AA change Variation ID SNP ID
1 ASS1 p.Gly14Ser VAR_000681 rs121908636
2 ASS1 p.Ser18Leu VAR_000682 rs121908643
3 ASS1 p.Arg86Cys VAR_000683 rs121908644
4 ASS1 p.Ala118Thr VAR_000684 rs775305020
5 ASS1 p.Arg157His VAR_000685 rs121908637
6 ASS1 p.Ser180Asn VAR_000686 rs121908638
7 ASS1 p.Ala192Val VAR_000687
8 ASS1 p.Arg272Cys VAR_000688 rs762387914
9 ASS1 p.Gly280Arg VAR_000689
10 ASS1 p.Arg304Trp VAR_000690 rs121908642
11 ASS1 p.Gly324Ser VAR_000691 rs121908639
12 ASS1 p.Arg363Leu VAR_000692
13 ASS1 p.Arg363Trp VAR_000693 rs121908640
14 ASS1 p.Gly390Arg VAR_000694 rs121908641
15 ASS1 p.Cys19Arg VAR_015891
16 ASS1 p.Arg86His VAR_015892 rs575001023
17 ASS1 p.Arg95Ser VAR_015893
18 ASS1 p.Pro96Ser VAR_015894
19 ASS1 p.Gly117Ser VAR_015895 rs770944877
20 ASS1 p.Gly117Asp VAR_015896
21 ASS1 p.Arg157Cys VAR_015897 rs770585183
22 ASS1 p.Trp179Arg VAR_015898 rs121908646
23 ASS1 p.Glu191Lys VAR_015899 rs777828000
24 ASS1 p.Arg265His VAR_015900 rs398123131
25 ASS1 p.Val269Met VAR_015901 rs370595480
26 ASS1 p.Glu283Lys VAR_015902 rs765338121
27 ASS1 p.Lys310Arg VAR_015903 rs199751308
28 ASS1 p.Gly362Val VAR_015904 rs121908647
29 ASS1 p.Glu270Gln VAR_016007 rs775163147
30 ASS1 p.Arg279Gln VAR_016008 rs371265106
31 ASS1 p.Lys310Gln VAR_016009 rs121908648
32 ASS1 p.Arg363Gly VAR_016010
33 ASS1 p.Arg363Gln VAR_016011 rs771937610
34 ASS1 p.Thr389Ile VAR_016012 rs1474017319
35 ASS1 p.Val69Ala VAR_016013 rs771594651
36 ASS1 p.Arg108Leu VAR_016014 rs35269064
37 ASS1 p.Thr119Ile VAR_016015
38 ASS1 p.Gln40Leu VAR_058337
39 ASS1 p.Ser79Pro VAR_058338
40 ASS1 p.Pro96His VAR_058339
41 ASS1 p.Asp124Asn VAR_058340 rs936192871
42 ASS1 p.Arg127Gln VAR_058341 rs201623252
43 ASS1 p.Arg127Trp VAR_058342 rs771794639
44 ASS1 p.Leu160Pro VAR_058343 rs969835605
45 ASS1 p.Tyr190Asp VAR_058344
46 ASS1 p.Glu191Gln VAR_058345
47 ASS1 p.Ala202Glu VAR_058346 rs376371866
48 ASS1 p.Leu206Pro VAR_058347
49 ASS1 p.Val263Met VAR_058348 rs192838388
50 ASS1 p.Arg265Cys VAR_058349 rs148918985

Expression for Citrullinemia, Classic

Search GEO for disease gene expression data for Citrullinemia, Classic.

Pathways for Citrullinemia, Classic

Pathways related to Citrullinemia, Classic according to GeneCards Suite gene sharing:

(show all 11)
# Super pathways Score Top Affiliating Genes
1
Show member pathways
13.08 TMLHE SLC25A2 SLC25A15 SLC25A13 SLC25A12 SLC22A5
2
Show member pathways
12.85 ARG1 ARG2 ASL ASS1 CPS1 NAGS
3 12.28 SLC25A12 ASS1 ARG2 ARG1
4
Show member pathways
11.78 PRODH OTC CPS1 ASS1 ARG2 ARG1
5
Show member pathways
11.72 SLC25A2 SLC25A15 SLC25A13 SLC25A12 PRODH OTC
6
Show member pathways
11.54 HADHA ACADVL ACADS
7
Show member pathways
11.15 HADHA ACADVL ACADS
8 10.73 OTC NAGS ASS1 ASL ARG1
9
Show member pathways
10.59 SLC25A13 SLC25A12
10 10.54 ASS1 ASL
11 10.01 ARG2 ARG1

GO Terms for Citrullinemia, Classic

Cellular components related to Citrullinemia, Classic according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 mitochondrial matrix GO:0005759 10.11 TMLHE PRODH OTC NAGS ETFDH CPS1
2 mitochondrial inner membrane GO:0005743 9.93 ACADVL CPS1 ETFDH HADHA OTC PRODH
3 mitochondrion GO:0005739 9.75 TMLHE SLC25A2 SLC25A15 SLC25A13 SLC25A12 PRODH
4 mitochondrial nucleoid GO:0042645 9.73 HADHA CPS1 ACADVL

Biological processes related to Citrullinemia, Classic according to GeneCards Suite gene sharing:

(show all 30)
# Name GO ID Score Top Affiliating Genes
1 response to xenobiotic stimulus GO:0009410 10.32 OTC HADHA CPS1 ASS1 ARG1
2 liver development GO:0001889 10.08 OTC CPS1 ASS1 ARG1
3 response to amino acid GO:0043200 9.97 CPS1 ASS1 ARG1
4 response to growth hormone GO:0060416 9.94 CPS1 ASS1
5 aspartate transmembrane transport GO:0015810 9.94 SLC25A13 SLC25A12
6 L-aspartate transmembrane transport GO:0070778 9.93 SLC25A13 SLC25A12
7 cellular response to ammonium ion GO:0071242 9.92 CPS1 ASS1
8 aspartate family amino acid metabolic process GO:0009066 9.91 SLC25A12 SLC25A13
9 citrulline biosynthetic process GO:0019240 9.91 CPS1 OTC
10 fatty acid beta-oxidation using acyl-CoA dehydrogenase GO:0033539 9.91 ETFDH ACADVL ACADS
11 malate-aspartate shuttle GO:0043490 9.9 SLC25A12 SLC25A13
12 mitochondrial L-ornithine transmembrane transport GO:1990575 9.89 SLC25A2 SLC25A15
13 cellular response to oleic acid GO:0071400 9.88 CPS1 ASS1
14 cellular response to glucagon stimulus GO:0071377 9.88 CPS1 ASS1 ARG1
15 arginine biosynthetic process via ornithine GO:0042450 9.86 ASL OTC
16 response to zinc ion GO:0010043 9.86 ARG1 ASS1 CPS1 OTC
17 response to amine GO:0014075 9.85 CPS1 ASS1 ARG1
18 midgut development GO:0007494 9.85 OTC CPS1 ASS1
19 arginine catabolic process to ornithine GO:0019547 9.83 ARG1 ARG2
20 L-arginine transmembrane transport GO:1903826 9.82 SLC25A2 SLC25A15
21 anion homeostasis GO:0055081 9.81 CPS1 OTC
22 L-lysine transmembrane transport GO:1903401 9.8 SLC25A2 SLC25A15
23 modified amino acid transport GO:0072337 9.8 SLC25A12 SLC25A13
24 response to steroid hormone GO:0048545 9.72 CPS1 ASS1 ARG1
25 amino acid biosynthetic process GO:0008652 9.65 OTC ASS1 ASL
26 arginine metabolic process GO:0006525 9.62 ASL ARG2 ARG1
27 urea cycle GO:0000050 9.58 SLC25A2 SLC25A15 OTC NAGS CPS1 ASS1
28 ornithine metabolic process GO:0006591 9.57 OTC SLC25A2
29 arginine biosynthetic process GO:0006526 9.5 OTC NAGS ASS1 ASL
30 transport GO:0006810 9.46 SLC25A2 SLC25A15 SLC25A13 SLC25A12

Molecular functions related to Citrullinemia, Classic according to GeneCards Suite gene sharing:

(show all 14)
# Name GO ID Score Top Affiliating Genes
1 transmembrane transporter activity GO:0022857 10.02 SLC22A5 SLC25A12 SLC25A13 SLC25A15 SLC25A2
2 flavin adenine dinucleotide binding GO:0050660 9.99 ETFDH ACADVL ACADS
3 L-glutamate transmembrane transporter activity GO:0005313 9.84 SLC25A13 SLC25A12
4 acyl-CoA dehydrogenase activity GO:0003995 9.83 ACADVL ACADS
5 L-aspartate transmembrane transporter activity GO:0015183 9.78 SLC25A13 SLC25A12
6 L-ornithine transmembrane transporter activity GO:0000064 9.73 SLC25A2 SLC25A15
7 acidic amino acid transmembrane transporter activity GO:0015172 9.71 SLC25A13 SLC25A12
8 L-arginine transmembrane transporter activity GO:0061459 9.67 SLC25A2 SLC25A15
9 L-lysine transmembrane transporter activity GO:0015189 9.63 SLC25A2 SLC25A15
10 arginase activity GO:0004053 9.62 ARG2 ARG1
11 aspartate:glutamate, proton antiporter activity GO:0000515 9.56 SLC25A13 SLC25A12
12 3-sulfino-L-alanine: proton, glutamate antiporter activity GO:0000514 9.46 SLC25A13 SLC25A12
13 oxidoreductase activity GO:0016491 9.32 TMLHE PRODH MMACHC HSD3B7 HADHA ETFDH
14 hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amidines GO:0016813 8.96 ARG2 ARG1

Sources for Citrullinemia, Classic

2 CDC
6 CNVD
8 Cosmic
9 dbSNP
10 DGIdb
16 EFO
17 ExPASy
18 FMA
19 GARD
27 GO
28 GTR
29 HMDB
30 HPO
31 ICD10
32 ICD10 via Orphanet
33 ICD11
34 ICD9CM
35 IUPHAR
36 LifeMap
38 LOVD
40 MedGen
43 MeSH
44 MESH via Orphanet
45 MGI
48 NCI
49 NCIt
50 NDF-RT
52 NINDS
53 Novoseek
55 ODiseA
56 OMIM via Orphanet
57 OMIM® (Updated 24-Oct-2022)
61 PubChem
62 PubMed
64 QIAGEN
69 SNOMED-CT via HPO
70 Tocris
71 UMLS
72 UMLS via Orphanet
Content
Loading form....