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Citrullinemia type II(CTLN2)

MedGen UID:
350276
Concept ID:
C1863844
Disease or Syndrome
Synonym: Citrullinemia type 2
SNOMED CT: Citrullinemia type II (716863007); Adult onset citrin deficiency (716863007); Adult onset type 2 citrullinemia (716863007)
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): SLC25A13 (7q21.3)
 
Monarch Initiative: MONDO:0016603
OMIM®: 603471; 603859
Orphanet: ORPHA247585

Disease characteristics

Excerpted from the GeneReview: Citrin Deficiency
Citrin deficiency can manifest in newborns or infants as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), in older children as failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD), and in adults as recurrent hyperammonemia with neuropsychiatric symptoms in citrullinemia type II (CTLN2). Often citrin deficiency is characterized by strong preference for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods. NICCD. Children younger than age one year have a history of low birth weight with growth restriction and transient intrahepatic cholestasis, hepatomegaly, diffuse fatty liver, and parenchymal cellular infiltration associated with hepatic fibrosis, variable liver dysfunction, hypoproteinemia, decreased coagulation factors, hemolytic anemia, and/or hypoglycemia. NICCD is generally not severe and symptoms often resolve by age one year with appropriate treatment, although liver transplantation has been required in rare instances. FTTDCD. Beyond age one year, many children with citrin deficiency develop a protein-rich and/or lipid-rich food preference and aversion to carbohydrate-rich foods. Clinical abnormalities may include growth restriction, hypoglycemia, pancreatitis, severe fatigue, anorexia, and impaired quality of life. Laboratory changes are dyslipidemia, increased lactate-to-pyruvate ratio, higher levels of urinary oxidative stress markers, and considerable deviation in tricarboxylic acid (TCA) cycle metabolites. One or more decades later, some individuals with NICCD or FTTDCD develop CTLN2. CTLN2. Presentation is sudden and usually between ages 20 and 50 years. Manifestations are recurrent hyperammonemia with neuropsychiatric symptoms including nocturnal delirium, aggression, irritability, hyperactivity, delusions, disorientation, restlessness, drowsiness, loss of memory, flapping tremor, convulsive seizures, and coma. Symptoms are often provoked by alcohol and sugar intake, medication, and/or surgery. Affected individuals may or may not have a prior history of NICCD or FTTDCD. [from GeneReviews]
Authors:
Takeyori Saheki  |  Yuan-Zong Song   view full author information

Additional description

From MedlinePlus Genetics
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.

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.

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

Clinical features

From HPO
Argininosuccinate lyase deficiency
MedGen UID:
78687
Concept ID:
C0268547
Disease or Syndrome
Deficiency of argininosuccinate lyase (ASL), the enzyme that cleaves argininosuccinic acid to produce arginine and fumarate in the fourth step of the urea cycle, may present as a severe neonatal-onset form or a late-onset form: The severe neonatal-onset form is characterized by hyperammonemia within the first few days after birth that can manifest as increasing lethargy, somnolence, refusal to feed, vomiting, tachypnea, and respiratory alkalosis. Absence of treatment leads to worsening lethargy, seizures, coma, and even death. In contrast, the manifestations of late-onset form range from episodic hyperammonemia triggered by acute infection or stress to cognitive impairment, behavioral abnormalities, and/or learning disabilities in the absence of any documented episodes of hyperammonemia. Manifestations of ASL deficiency that appear to be unrelated to the severity or duration of hyperammonemic episodes: Neurocognitive deficiencies (attention-deficit/hyperactivity disorder, developmental delay, seizures, and learning disability). Liver disease (hepatitis, cirrhosis). Trichorrhexis nodosa (coarse brittle hair that breaks easily). Systemic hypertension.
Hepatic fibrosis
MedGen UID:
116093
Concept ID:
C0239946
Disease or Syndrome
The presence of excessive fibrous connective tissue in the liver. Fibrosis is a reparative or reactive process.
Hepatocellular carcinoma
MedGen UID:
389187
Concept ID:
C2239176
Neoplastic Process
Hepatocellular carcinoma is the major histologic type of malignant primary liver neoplasm. It is the fifth most common cancer and the third most common cause of death from cancer worldwide. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. Hepatoblastomas comprise 1 to 2% of all malignant neoplasms of childhood, most often occurring in children under 3 years of age. Hepatoblastomas are thought to be derived from undifferentiated hepatocytes (Taniguchi et al., 2002).
Hepatic steatosis
MedGen UID:
398225
Concept ID:
C2711227
Disease or Syndrome
Steatosis is a term used to denote lipid accumulation within hepatocytes.
Portal inflammation
MedGen UID:
412612
Concept ID:
C2748698
Pathologic Function
Infiltration of portal fields by inflammatory cells.
Ballooning hepatocyte degeneration
MedGen UID:
1743374
Concept ID:
C5421675
Cell or Molecular Dysfunction
Swelling of the hepatocyte, rounding of its contour, and alteration of the cytoplasm, which takes on a reticulated, rarefied, or flocculant quality. The cytoplasm of the ballooned hepatocytes often contains clumps of eosinophilic ropey material known as Mallory-Denk bodies (MDBs) or Mallory hyaline, which is composed of hyperphosphorylated misfolded intermediate filaments, ubiquitin, and ubiquitin-binding protein P62.
Cerebral edema
MedGen UID:
2337
Concept ID:
C0006114
Pathologic Function
Abnormal accumulation of fluid in the brain.
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.
Confusion
MedGen UID:
3587
Concept ID:
C0009676
Mental or Behavioral Dysfunction
Lack of clarity and coherence of thought, perception, understanding, or action.
Protein craving
MedGen UID:
1054055
Concept ID:
CN377934
Finding
Unusually strong preference for protein-rich foods.
Pancreatitis
MedGen UID:
14586
Concept ID:
C0030305
Disease or Syndrome
The presence of inflammation in the pancreas.
Elevated circulating alanine aminotransferase concentration
MedGen UID:
57740
Concept ID:
C0151905
Finding
An abnormally high concentration in the circulation of alanine aminotransferase (ALT).
Hypertriglyceridemia
MedGen UID:
167238
Concept ID:
C0813230
Finding
An abnormal increase in the level of triglycerides in the blood.
Elevated plasma citrulline
MedGen UID:
868699
Concept ID:
C4023102
Finding
An increased concentration of citrulline in the blood.
Elevated gamma-glutamyltransferase level
MedGen UID:
1370086
Concept ID:
C4476869
Finding
Increased level of the enzyme gamma-glutamyltransferase (GGT). GGT is mainly present in kidney, liver, and pancreatic cells, but small amounts are present in other tissues.
Hyperargininemia
MedGen UID:
1733308
Concept ID:
C5399765
Finding
An increased amount of arginine levels in the blood.
Hyperammonemia
MedGen UID:
1802066
Concept ID:
C5574662
Laboratory or Test Result
An increased concentration of ammonia in the blood.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Citrullinemia type II in Orphanet.

Professional guidelines

PubMed

Hayasaka K
J Inherit Metab Dis 2021 Jan;44(1):110-117. Epub 2020 Aug 26 doi: 10.1002/jimd.12294. PMID: 32740958
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
Kimura N, Kubo N, Narumi S, Toyoki Y, Ishido K, Kudo D, Umehara M, Yakoshi Y, Hakamada K
Transplant Proc 2013 Nov;45(9):3432-7. doi: 10.1016/j.transproceed.2013.06.016. PMID: 24182831

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

Recent clinical studies

Etiology

Kim MJ, Kim SY, Lee JS, Kang S, Park LJ, Choi W, Jung JY, Kim T, Park SS, Ko JM, Seong MW, Chae JH
Ann Lab Med 2023 May 1;43(3):280-289. Epub 2022 Dec 22 doi: 10.3343/alm.2023.43.3.280. PMID: 36544340Free PMC Article
Palmieri F, Scarcia P, Monné M
Biomolecules 2020 Apr 23;10(4) doi: 10.3390/biom10040655. PMID: 32340404Free PMC Article
Waisbren SE, Gropman AL; Members of the Urea Cycle Disorders Consortium (UCDC), Batshaw ML
J Inherit Metab Dis 2016 Jul;39(4):573-84. Epub 2016 May 23 doi: 10.1007/s10545-016-9942-0. PMID: 27215558Free PMC Article
Song YZ, Zhang ZH, Lin WX, Zhao XJ, Deng M, Ma YL, Guo L, Chen FP, Long XL, He XL, Sunada Y, Soneda S, Nakatomi A, Dateki S, Ngu LH, Kobayashi K, Saheki T
PLoS One 2013;8(9):e74544. Epub 2013 Sep 19 doi: 10.1371/journal.pone.0074544. PMID: 24069319Free PMC Article
Tonini MC, Bignamini V, Mattioli M
Neurol Sci 2011 May;32 Suppl 1:S157-9. doi: 10.1007/s10072-011-0518-3. PMID: 21533735

Diagnosis

Kim MJ, Kim SY, Lee JS, Kang S, Park LJ, Choi W, Jung JY, Kim T, Park SS, Ko JM, Seong MW, Chae JH
Ann Lab Med 2023 May 1;43(3):280-289. Epub 2022 Dec 22 doi: 10.3343/alm.2023.43.3.280. PMID: 36544340Free PMC Article
Moreira-Silva H, Maio I, Bandeira A, Gomes-Martins E, Santos-Silva E
Eur J Pediatr 2019 Apr;178(4):515-523. Epub 2019 Jan 28 doi: 10.1007/s00431-019-03328-5. PMID: 30693370
Kuhara T
J Chromatogr B Analyt Technol Biomed Life Sci 2002 Dec 5;781(1-2):497-517. doi: 10.1016/s1570-0232(02)00670-0. PMID: 12450676
Shigematsu Y, Hirano S, Hata I, Tanaka Y, Sudo M, Sakura N, Tajima T, Yamaguchi S
J Chromatogr B Analyt Technol Biomed Life Sci 2002 Aug 25;776(1):39-48. doi: 10.1016/s1570-0232(02)00077-6. PMID: 12127323
Maruyama H, Ogawa M, Nishio T, Kobayashi K, Saheki T, Sunohara N
J Neurol Sci 2001 Jan 1;182(2):167-70. doi: 10.1016/s0022-510x(00)00449-4. PMID: 11137523

Therapy

Avdjieva-Tzavella DM, Ivanova MB, Todorov TP, Todorova AP, Panteleeva EI, Tincheva SS, Lazarova EA, Kathom HM, Yaneva PG, Tincheva RS
Genet Couns 2014;25(3):271-6. PMID: 25365849

Prognosis

Kim MJ, Kim SY, Lee JS, Kang S, Park LJ, Choi W, Jung JY, Kim T, Park SS, Ko JM, Seong MW, Chae JH
Ann Lab Med 2023 May 1;43(3):280-289. Epub 2022 Dec 22 doi: 10.3343/alm.2023.43.3.280. PMID: 36544340Free PMC Article
Avdjieva-Tzavella DM, Ivanova MB, Todorov TP, Todorova AP, Panteleeva EI, Tincheva SS, Lazarova EA, Kathom HM, Yaneva PG, Tincheva RS
Genet Couns 2014;25(3):271-6. PMID: 25365849
Tsai CW, Yang CC, Chen HL, Hwu WL, Wu MZ, Liu KL, Wu MS
J Formos Med Assoc 2006 Oct;105(10):852-6. doi: 10.1016/S0929-6646(09)60274-6. PMID: 17000460

Clinical prediction guides

Choi JJ, Kim HS, Lee KC, Shin Y, Jo YY
BMC Anesthesiol 2016 Oct 11;16(1):92. doi: 10.1186/s12871-016-0253-7. PMID: 27724842Free PMC Article
Häberle J, Pauli S, Schmidt E, Schulze-Eilfing B, Berning C, Koch HG
Mol Genet Metab 2003 Nov;80(3):302-6. doi: 10.1016/j.ymgme.2003.08.002. PMID: 14680976

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.

    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

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