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Citrullinemia type I(CTNL1)

MedGen UID:
1648491
Concept ID:
C4721769
Disease or Syndrome
Synonyms: argininosuccinate synthetase deficiency; ASS deficiency; Citrullinemia 1; Classic citrullinemia; CTNL1
SNOMED CT: Citrullinemia type I (1149103000); Citrullinemia type 1 (1149103000); Classic citrullinemia (1149103000)
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).
 
Gene (location): ASS1 (9q34.11)
 
Monarch Initiative: MONDO:0008988
OMIM®: 215700
Orphanet: ORPHA247525

Definition

Citrullinemia type I (CTLN1) presents as a spectrum that includes a neonatal acute form (the "classic" form), a milder late-onset form (the "non-classic" form), a form in which women have onset of symptoms at pregnancy or post partum, and a form without symptoms or hyperammonemia. Distinction between the forms is based primarily on clinical findings, although emerging evidence suggests that measurement of residual argininosuccinate synthase enzyme activity may help to predict those who are likely to have a severe phenotype and those who are likely to have an attenuated phenotype. Infants with the acute neonatal form appear normal at birth. Shortly thereafter, they develop hyperammonemia and become progressively lethargic, feed poorly, often vomit, and may develop signs of increased intracranial pressure (ICP). Without prompt intervention, hyperammonemia and the accumulation of other toxic metabolites (e.g., glutamine) result in increased ICP, increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death. Children with the severe form who are treated promptly may survive for an indeterminate period of time, but usually with significant neurologic deficits. Even with chronic protein restriction and scavenger therapy, long-term complications such as liver failure and other (rarely reported) organ system manifestations are possible. The late-onset form may be milder than that seen in the acute neonatal form, but commences later in life for reasons that are not completely understood. The episodes of hyperammonemia are similar to those seen in the acute neonatal form, but the initial neurologic findings may be more subtle because of the older age of the affected individuals. Women with onset of severe symptoms including acute hepatic decompensation during pregnancy or in the postpartum period have been reported. Furthermore, previously asymptomatic and non-pregnant individuals have been described who remained asymptomatic up to at least age ten years, with the possibility that they could remain asymptomatic lifelong. [from GeneReviews]

Additional description

From MedlinePlus Genetics
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.

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.

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.  https://medlineplus.gov/genetics/condition/citrullinemia

Clinical features

From HPO
Orotic aciduria
MedGen UID:
78642
Concept ID:
C0268128
Finding
Orotic aciduria is a rare autosomal recessive disorder characterized by megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by Webster et al., 2001). Bailey (2009) stated that only 2 cases of orotic aciduria without megaloblastic anemia (OAWA) had been reported.
Stroke disorder
MedGen UID:
52522
Concept ID:
C0038454
Disease or Syndrome
Sudden impairment of blood flow to a part of the brain due to occlusion or rupture of an artery to the brain.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Cirrhosis of liver
MedGen UID:
7368
Concept ID:
C0023890
Disease or Syndrome
A chronic disorder of the liver in which liver tissue becomes scarred and is partially replaced by regenerative nodules and fibrotic tissue resulting in loss of liver function.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Protein avoidance
MedGen UID:
326521
Concept ID:
C1839531
Finding
Cerebral edema
MedGen UID:
2337
Concept ID:
C0006114
Pathologic Function
Abnormal accumulation of fluid in the brain.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
The complete absence of wakefulness and consciousness, which is evident through a lack of response to any form of external stimuli.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of disinterest, listlessness, and indifference, resulting in difficulty performing simple tasks or concentrating.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Respiratory alkalosis
MedGen UID:
1411
Concept ID:
C0002064
Pathologic Function
Alkalosis due to excess loss of carbon dioxide from the body.
Hyperglutaminemia
MedGen UID:
326901
Concept ID:
C1839533
Finding
An increased concentration of glutamine in the blood.
Episodic ammonia intoxication
MedGen UID:
333343
Concept ID:
C1839541
Finding
Elevated plasma citrulline
MedGen UID:
868699
Concept ID:
C4023102
Finding
An increased concentration of citrulline in the blood.
Hypoargininemia
MedGen UID:
892673
Concept ID:
C4025095
Finding
A decreased concentration of arginine in the blood.
Hyperammonemia
MedGen UID:
1802066
Concept ID:
C5574662
Laboratory or Test Result
An increased concentration of ammonia in the blood.

Professional guidelines

PubMed

Gramer G, Fang-Hoffmann J, Feyh P, Klinke G, Monostori P, Okun JG, Hoffmann GF
World J Pediatr 2018 Oct;14(5):470-481. Epub 2018 Jun 15 doi: 10.1007/s12519-018-0159-1. PMID: 29948967
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
Miller MJ, Soler-Alfonso CR, Grund JE, Fang P, Sun Q, Elsea SH, Sutton VR
Mol Genet Metab 2014 Jul;112(3):205-9. Epub 2014 May 16 doi: 10.1016/j.ymgme.2014.05.004. PMID: 24889030

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, [Elevated Citrulline], Amino Acidemia/Urea Cycle Disorder, 2022

American College of Medical Genetics and Genomics, Elevated Citrulline: Amino Acidemia Algorithm, 2022

American College of Medical Genetics and Genomics, Transition to Adult Health Care ACT Sheet, Citrullinemia I, Urea Cycle Disorder, 2012

Recent clinical studies

Etiology

Zhou Y, Dou X, Zhang C, He R, Ding Y
BMC Pregnancy Childbirth 2022 Dec 19;22(1):950. doi: 10.1186/s12884-022-05298-3. PMID: 36536326Free PMC Article
Liu Y, Luo Y, Xia L, Qiu B, Zhou T, Feng M, Wang C, Xue F, Chen X, Han L, Zhang J, Xia Q
Transplantation 2021 Mar 1;105(3):569-576. doi: 10.1097/TP.0000000000003261. PMID: 33617202
Waisbren SE, Cuthbertson D, Burgard P, Holbert A, McCarter R, Cederbaum S; Members of the Urea Cycle Disorders Consortium
J Inherit Metab Dis 2018 Jul;41(4):657-667. Epub 2018 Feb 8 doi: 10.1007/s10545-017-0132-5. PMID: 29423830Free PMC Article
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
Berning C, Bieger I, Pauli S, Vermeulen T, Vogl T, Rummel T, Höhne W, Koch HG, Rolinski B, Gempel K, Häberle J
Hum Mutat 2008 Oct;29(10):1222-7. doi: 10.1002/humu.20784. PMID: 18473344

Diagnosis

Zhou Y, Dou X, Zhang C, He R, Ding Y
BMC Pregnancy Childbirth 2022 Dec 19;22(1):950. doi: 10.1186/s12884-022-05298-3. PMID: 36536326Free PMC Article
Shibuya M, Iwamoto R, Kimura Y, Kamekura N, Fujisawa T
Anesth Prog 2021 Oct 1;68(3):158-162. doi: 10.2344/anpr-68-02-04. PMID: 34606567Free PMC Article
Liu Y, Luo Y, Xia L, Qiu B, Zhou T, Feng M, Wang C, Xue F, Chen X, Han L, Zhang J, Xia Q
Transplantation 2021 Mar 1;105(3):569-576. doi: 10.1097/TP.0000000000003261. PMID: 33617202
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
Engel K, Höhne W, Häberle J
Hum Mutat 2009 Mar;30(3):300-7. doi: 10.1002/humu.20847. PMID: 19006241

Therapy

Jiang Y, Almannai M, Sutton VR, Sun Q, Elsea SH
Mol Genet Metab 2017 Nov;122(3):39-45. Epub 2017 Aug 31 doi: 10.1016/j.ymgme.2017.08.011. PMID: 28888854
Patel H, Kim J, Huncke TK
J Clin Anesth 2016 Sep;33:403-5. Epub 2016 Jun 2 doi: 10.1016/j.jclinane.2016.04.045. PMID: 27555199
de Groot MJ, Cuppen M, Eling M, Verheijen FW, Rings EH, Reijngoud DJ, de Vries MM, van Spronsen FJ
J Inherit Metab Dis 2010 Dec;33 Suppl 3(Suppl 3):S413-6. Epub 2010 Sep 18 doi: 10.1007/s10545-010-9207-2. PMID: 20852933Free PMC Article

Prognosis

Liu Y, Luo Y, Xia L, Qiu B, Zhou T, Feng M, Wang C, Xue F, Chen X, Han L, Zhang J, Xia Q
Transplantation 2021 Mar 1;105(3):569-576. doi: 10.1097/TP.0000000000003261. PMID: 33617202
Lin Y, Gao H, Lu B, Zhou S, Zheng T, Lin W, Zhu L, Jiang M, Fu Q
BMC Med Genet 2019 Jun 17;20(1):110. doi: 10.1186/s12881-019-0836-5. PMID: 31208364Free PMC Article
Waisbren SE, Cuthbertson D, Burgard P, Holbert A, McCarter R, Cederbaum S; Members of the Urea Cycle Disorders Consortium
J Inherit Metab Dis 2018 Jul;41(4):657-667. Epub 2018 Feb 8 doi: 10.1007/s10545-017-0132-5. PMID: 29423830Free PMC Article
Engel K, Höhne W, Häberle J
Hum Mutat 2009 Mar;30(3):300-7. doi: 10.1002/humu.20847. PMID: 19006241
Berning C, Bieger I, Pauli S, Vermeulen T, Vogl T, Rummel T, Höhne W, Koch HG, Rolinski B, Gempel K, Häberle J
Hum Mutat 2008 Oct;29(10):1222-7. doi: 10.1002/humu.20784. PMID: 18473344

Clinical prediction guides

Shibuya M, Iwamoto R, Kimura Y, Kamekura N, Fujisawa T
Anesth Prog 2021 Oct 1;68(3):158-162. doi: 10.2344/anpr-68-02-04. PMID: 34606567Free PMC Article
Lin Y, Gao H, Lu B, Zhou S, Zheng T, Lin W, Zhu L, Jiang M, Fu Q
BMC Med Genet 2019 Jun 17;20(1):110. doi: 10.1186/s12881-019-0836-5. PMID: 31208364Free PMC Article
Waisbren SE, Cuthbertson D, Burgard P, Holbert A, McCarter R, Cederbaum S; Members of the Urea Cycle Disorders Consortium
J Inherit Metab Dis 2018 Jul;41(4):657-667. Epub 2018 Feb 8 doi: 10.1007/s10545-017-0132-5. PMID: 29423830Free PMC Article
Jiang Y, Almannai M, Sutton VR, Sun Q, Elsea SH
Mol Genet Metab 2017 Nov;122(3):39-45. Epub 2017 Aug 31 doi: 10.1016/j.ymgme.2017.08.011. PMID: 28888854
de Groot MJ, Cuppen M, Eling M, Verheijen FW, Rings EH, Reijngoud DJ, de Vries MM, van Spronsen FJ
J Inherit Metab Dis 2010 Dec;33 Suppl 3(Suppl 3):S413-6. Epub 2010 Sep 18 doi: 10.1007/s10545-010-9207-2. PMID: 20852933Free PMC Article

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.
    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG, ACT Sheet, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, [Elevated Citrulline], Amino Acidemia/Urea Cycle Disorder, 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Elevated Citrulline: Amino Acidemia Algorithm, 2022
    • ACMG ACT, 2012
      American College of Medical Genetics and Genomics, Transition to Adult Health Care ACT Sheet, Citrullinemia I, Urea Cycle Disorder, 2012

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