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Citrullinemia type I(CTNL1)

MedGen UID:
104491
Concept ID:
C0175683
Disease or Syndrome
Synonyms: argininosuccinate synthetase deficiency; ASS deficiency; Citrullinemia; Citrullinemia 1; Citrullinuria; Classic citrullinemia; CTNL1
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Citrullinemia (398680004); Citrullinuria (398630005); 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)
 
Gene (location): ASS1 (9q34.11)
OMIM®: 215700
Orphanet: ORPHA187

Definition

Citrullinemia type I (CTLN1) presents as a clinical spectrum that includes an acute neonatal form (the "classic" form), a milder late-onset form (the “non-classic” form), a form without symptoms or hyperammonemia, and a form in which women have onset of severe symptoms during pregnancy or post partum. Distinction between the clinical forms is based on clinical findings and is not clear-cut. 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. The late-onset form may be milder than that seen in the acute neonatal form, for unknown reasons. 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. [from GTR]

Additional descriptions

From GeneReviews
Citrullinemia type I (CTLN1) presents as a clinical spectrum that includes an acute neonatal form (the "classic" form), a milder late-onset form (the “non-classic” form), a form without symptoms or hyperammonemia, and a form in which women have onset of severe symptoms during pregnancy or post partum. Distinction between the clinical forms is based on clinical findings and is not clear-cut. 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. The late-onset form may be milder than that seen in the acute neonatal form, for unknown reasons. 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.  https://www.ncbi.nlm.nih.gov/books/NBK1458
From GHR
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.  https://ghr.nlm.nih.gov/condition/citrullinemia

Clinical features

Stroke
MedGen UID:
52522
Concept ID:
C0038454
Disease or Syndrome
A group of pathological conditions characterized by sudden, non-convulsive loss of neurological function due to BRAIN ISCHEMIA or INTRACRANIAL HEMORRHAGES. Stroke is classified by the type of tissue NECROSIS, such as the anatomic location, vasculature involved, etiology, age of the affected individual, and hemorrhagic vs. non-hemorrhagic nature. (From Adams et al., Principles of Neurology, 6th ed, pp777-810)
Failure to thrive
MedGen UID:
115900
Concept ID:
C0231246
Finding
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormal enlargement of the liver.
Liver Cirrhosis
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
Sign or Symptom
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- oder 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
A profound state of unconsciousness associated with depressed cerebral activity from which the individual cannot be aroused. Coma generally occurs when there is dysfunction or injury involving both cerebral hemispheres or the brain stem RETICULAR FORMATION.
Seizure Disorders
MedGen UID:
4506
Concept ID:
C0014544
Disease or Syndrome
A brain disorder characterized by episodes of abnormally increased neuronal discharge resulting in transient episodes of sensory or motor neurological dysfunction, or psychic dysfunction. These episodes may or may not be associated with loss of consciousness or convulsions.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to DEPRESSION or DRUG ADDICTION.
Stroke
MedGen UID:
52522
Concept ID:
C0038454
Disease or Syndrome
A group of pathological conditions characterized by sudden, non-convulsive loss of neurological function due to BRAIN ISCHEMIA or INTRACRANIAL HEMORRHAGES. Stroke is classified by the type of tissue NECROSIS, such as the anatomic location, vasculature involved, etiology, age of the affected individual, and hemorrhagic vs. non-hemorrhagic nature. (From Adams et al., Principles of Neurology, 6th ed, pp777-810)
Cognitive delay
MedGen UID:
351243
Concept ID:
C1864897
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
Feelings of annoyance, impatience, and anger.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Respiratory alkalosis
MedGen UID:
1411
Concept ID:
C0002064
Pathologic Function
A condition in which the blood pH is greater than normal, secondary to impaired gas exchange.
Cerebral edema
MedGen UID:
2337
Concept ID:
C0006114
Pathologic Function
Abnormal accumulation of fluid in the brain.
Hyperammonaemia
MedGen UID:
113136
Concept ID:
C0220994
Disease or Syndrome
A laboratory test result demonstrating an increased concentration of ammonia in the blood.
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.
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
Hypoargininemia
MedGen UID:
395333
Concept ID:
C1859735
Finding
A decreased concentration of arginine in the blood.

Recent clinical studies

Etiology

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
Woo HI, Ki CS, Lee SY, Kim JW, Song J, Jin DK, Park WS, Lee DH, Lee YW, Park HD
Clin Biochem 2013 Feb;46(3):209-13. Epub 2012 Oct 22 doi: 10.1016/j.clinbiochem.2012.10.008. PMID: 23099195
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

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
Faghfoury H, Baruteau J, de Baulny HO, Häberle J, Schulze A
Mol Genet Metab 2011 Apr;102(4):413-7. Epub 2010 Dec 16 doi: 10.1016/j.ymgme.2010.12.007. PMID: 21227727
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:S413-6. Epub 2010 Sep 18 doi: 10.1007/s10545-010-9207-2. PMID: 20852933Free PMC Article
Marquis-Nicholson R, Glamuzina E, Prosser D, Wilson C, Love DR
Genet Mol Res 2010 Aug 3;9(3):1483-9. doi: 10.4238/vol9-3gmr834. PMID: 20690080
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

Therapy

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:S413-6. Epub 2010 Sep 18 doi: 10.1007/s10545-010-9207-2. PMID: 20852933Free PMC Article

Prognosis

Woo HI, Ki CS, Lee SY, Kim JW, Song J, Jin DK, Park WS, Lee DH, Lee YW, Park HD
Clin Biochem 2013 Feb;46(3):209-13. Epub 2012 Oct 22 doi: 10.1016/j.clinbiochem.2012.10.008. PMID: 23099195
Faghfoury H, Baruteau J, de Baulny HO, Häberle J, Schulze A
Mol Genet Metab 2011 Apr;102(4):413-7. Epub 2010 Dec 16 doi: 10.1016/j.ymgme.2010.12.007. PMID: 21227727
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:S413-6. Epub 2010 Sep 18 doi: 10.1007/s10545-010-9207-2. PMID: 20852933Free PMC Article
Marquis-Nicholson R, Glamuzina E, Prosser D, Wilson C, Love DR
Genet Mol Res 2010 Aug 3;9(3):1483-9. doi: 10.4238/vol9-3gmr834. PMID: 20690080
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

Kimani JK, Wei T, Chol K, Li Y, Yu P, Ye S, Huang X, Qi M
Clin Chim Acta 2015 Jan 1;438:323-9. Epub 2014 Aug 30 doi: 10.1016/j.cca.2014.08.028. PMID: 25179242
Ruder J, Legacy J, Russo G, Davis R
Pediatr Neurol 2014 Oct;51(4):553-6. Epub 2014 Jul 16 doi: 10.1016/j.pediatrneurol.2014.07.010. PMID: 25266618
Faghfoury H, Baruteau J, de Baulny HO, Häberle J, Schulze A
Mol Genet Metab 2011 Apr;102(4):413-7. Epub 2010 Dec 16 doi: 10.1016/j.ymgme.2010.12.007. PMID: 21227727
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:S413-6. Epub 2010 Sep 18 doi: 10.1007/s10545-010-9207-2. PMID: 20852933Free PMC Article

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