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Citrullinemia type I(CTNL1)

MedGen UID:
104491
Concept ID:
C0175683
Disease or Syndrome
Synonyms: Argininosuccinate synthetase deficiency; 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
Autosomal recessive inheritance refers to genetic conditions that occur only when mutations are present in both copies of a given gene (i.e., the person is homozygous for a mutation, or carries two different mutations of the same gene, a state referred to as compound heterozygosity).
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: ASS1
Cytogenetic location: 9q34.11
OMIM: 215700

Disease characteristics

Excerpted from the GeneReview: Citrullinemia Type I
Citrullinemia type I (CTLN1) presents as a clinical spectrum that includes an acute neonatal form (the "classic" form), a milder late-onset 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 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 GeneReviews]
Full text of GeneReview (by section):
Summary  |  Diagnosis  |  Clinical Description  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
Authors:
Shane C Quinonez  |  Jess G Thoene   view full author information

Additional description

From GHR
Citrullinemia is an inherited disorder that causes ammonia and other toxic substances to accumulate in the blood. Two forms 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 in the body they experience a progressive lack of energy (lethargy), poor feeding, vomiting, seizures, and loss of consciousness. These medical problems 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, partial loss of vision, 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. In some cases, the signs and symptoms of this disorder appear during adulthood (adult-onset). These signs and symptoms can be life-threatening, and are known to be triggered by certain medications, infections, surgery, and alcohol intake in people with adult-onset type II citrullinemia. The features of 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 resolve within a year. Years or even decades later, however, some of these people develop the characteristic features of adult-onset type II citrullinemia.  http://ghr.nlm.nih.gov/condition/citrullinemia

Clinical features

Irritability
MedGen UID:
5898
Concept ID:
C0022107
Finding
Abnormal or excessive excitability with easily triggered anger, annoyance, or impatience.
Ataxia
MedGen UID:
504767
Concept ID:
CN001146
Finding
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).
Lethargy
MedGen UID:
504769
Concept ID:
CN001149
Finding
A state of disinterestedness, listlessness, and indifference, resulting in difficulty performing simple tasks or concentrating.
Coma
MedGen UID:
446396
Concept ID:
CN001154
Finding
Complete absence of wakefulness and content of conscience, which manifests itself as a lack of response to any kind of external stimuli.
Global developmental delay
MedGen UID:
504774
Concept ID:
CN001157
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.
Cerebral edema
MedGen UID:
505145
Concept ID:
CN001977
Finding
Abnormal accumulation of fluid in the brain.
Hepatomegaly
MedGen UID:
505165
Concept ID:
CN002031
Finding
Abnormally `increased size` (PATO:0000586) of the `liver` (FMA:7197).
Respiratory alkalosis
MedGen UID:
505022
Concept ID:
CN001764
Finding
Alkalosis due to excess loss of carbon dioxide from the body.
Hyperammonemia
MedGen UID:
505040
Concept ID:
CN001799
Finding
An increased concentration of `ammonia` (CHEBI:16134) in the `blood` (FMA:9670).
Cerebral edema
MedGen UID:
505145
Concept ID:
CN001977
Finding
Abnormal accumulation of fluid in the brain.
Oroticaciduria
MedGen UID:
505486
Concept ID:
CN002906
Finding
An increased concentration of `orotic acid` (CHEBI:16742) in the urine (FMA:12274).

Recent clinical studies

Etiology

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. [Epub ahead of print] 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

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. [Epub ahead of print] 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. [Epub ahead of print] PMID: 20852933Free PMC Article
Salek J, Byrne J, Box T, Longo N, Sussman N
Liver Transpl 2010 Sep;16(9):1049-53. doi: 10.1002/lt.22118. PMID: 20818742
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

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. [Epub ahead of print] 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. [Epub ahead of print] 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. [Epub ahead of print] 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. [Epub ahead of print] 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

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. [Epub ahead of print] 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. [Epub ahead of print] PMID: 20852933Free PMC Article

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