Citrullinemia type II

General Information (adopted from Orphanet):

Synonyms, Signs: CTLN2
Adult-onset citrin deficiency
Adult-onset citrullinemia type 2
Citrullinemia type 2
Number of Symptoms 42
OrphanetNr: 247585
OMIM Id: 603471
ICD-10: E72.2
UMLs:
MeSH:
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: No data available.
Inheritance: Autosomal recessive
26109823 [IBIS]
Age of onset: Adolescent
Adult
17323144 [IBIS]

Disease classification (adopted from Orphanet):

Parent Diseases: Citrin deficiency
 -Rare genetic disease

Comment:

Citrullinemia type II belongs to the class of urea cycle disorders and is caused by mutations in the gene SLC25A13 (CTLN2, citrin) encoding the liver-type aspartate-glutamate carrier located in the mitochondrial membrane. Most cases are reported in Japan (PMID:24508627). Citrullinemia type II is characterized by increased serum citrulline and ammonia levels, but patients also display various neuropsychiatric symptoms. Citrullinemia type II can be confirmed by a decrease in CTLN2 activity with normal kinetic properties in liver, but normal ASS1 activity in other tissues (PMID:24508627).

Symptom Information: Sort by abundance 

1
(OMIM) Hyperarginemia 20301360 IBIS 3 / 7739
2
(HPO:0009916) Anisocoria 21533735 IBIS 11 / 7739
3
(HPO:0000505) Visual impairment 24182831 IBIS 297 / 7739
4
(HPO:0002151) Increased serum lactate 21647347 IBIS 92 / 7739
5
(HPO:0003218) Oroticaciduria 21533735 IBIS 10 / 7739
6
(HPO:0011966) Elevated plasma citrulline Very Frequent [IBIS] 24413235 IBIS 5 / 7739
7
(HPO:0010909) Abnormality of arginine metabolism Very Frequent [IBIS] 20301360 IBIS 3 / 7739
8
(HPO:0002181) Cerebral edema 16449956 IBIS 19 / 7739
9
(HPO:0002155) Hypertriglyceridemia 12787807 IBIS 67 / 7739
10
(HPO:0001397) Hepatic steatosis 18620775 IBIS 75 / 7739
11
(HPO:0001987) Hyperammonemia Very frequent [IBIS] 24413235 IBIS 50 / 7739
12
(HPO:0002480) Hepatic encephalopathy 24182831 IBIS 6 / 7739
13
(HPO:0003474) Sensory impairment 21533735 IBIS 54 / 7739
14
(HPO:0000708) Behavioral abnormality Frequent [IBIS] 22554431 IBIS 212 / 7739
15
(HPO:0000711) Restlessness 22554431 IBIS 18 / 7739
16
(HPO:0000718) Aggressive behavior 21647347 IBIS 109 / 7739
17
(HPO:0001260) Dysarthria 21533735 IBIS 329 / 7739
18
(HPO:0001289) Confusion 24182831 IBIS 36 / 7739
19
(HPO:0001249) Intellectual disability 12512993 IBIS 1089 / 7739
20
(HPO:0000716) Depression 21533735 IBIS 99 / 7739
21
(HPO:0000737) Irritability 24182831 IBIS 93 / 7739
22
(HPO:0001254) Lethargy 18958581 IBIS 104 / 7739
23
(HPO:0001259) Coma 21533735 IBIS 65 / 7739
24
(HPO:0002329) Drowsiness 17620496 IBIS 19 / 7739
25
(HPO:0001262) Somnolence 21647347 IBIS 20 / 7739
26
(HPO:0100543) Cognitive impairment 22554431 IBIS 230 / 7739
27
(HPO:0004372) Reduced consciousness/confusion 24889030 IBIS 73 / 7739
28
(HPO:0007185) Loss of consciousness Frequent [IBIS] 17323144 IBIS 9 / 7739
29
(HPO:0012228) Tension-type headache 21533735 IBIS 1 / 7739
30
(HPO:0001250) Seizures 21533735 IBIS 1245 / 7739
31
(HPO:0001402) Hepatocellular carcinoma 17000460 IBIS 25 / 7739
32
(HPO:0002910) Elevated hepatic transaminases 24413235 IBIS 158 / 7739
33
(HPO:0001395) Hepatic fibrosis 11343053 IBIS 67 / 7739
34
(HPO:0001732) Abnormality of the pancreas 21647347 IBIS 5 / 7739
35
(HPO:0001733) Pancreatitis 18620775 IBIS 46 / 7739
36
(HPO:0000020) Urinary incontinence 21647347 IBIS 75 / 7739
37
(HPO:0001510) Growth delay 18958581 IBIS 295 / 7739
38
(HPO:0002060) Abnormality of the cerebrum 24182831 IBIS 3 / 7739
39
(OMIM) Hepatocyte ballooning 21647347 IBIS 1 / 7739
40
(OMIM) Increased serum pancreatic secretory trypsin inhibitor (PSTI) 18620775 IBIS 1 / 7739
41
(OMIM) Nonalcoholic fatty liver disease 18620775 IBIS 1 / 7739
42
(OMIM) Sudden onset of neuropsychiatric symptoms Frequent [IBIS] 18620775 IBIS 1 / 7739

Associated genes:

SLC25A13;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Description: (OMIM) Adult-onset type II citrullinemia is an autosomal recessive metabolic disorder characterized clinically by the sudden onset of various neuropsychologic symptoms such as disorientation, abnormal behavior, convulsions, and coma due to hyperammonemia. In some cases, rapid progression can lead ...
Clinical Description OMIM In Japan a distinct late-onset form of citrullinemia was reported; see review by Walser (1983). Significant clinical abnormality had onset in childhood or not until adulthood, age 48 years in 1 case. Symptoms included enuresis, delayed menarche, insomnia, ...
Molecular genetics OMIM - Exclusion of Mutations in the ASS1 Gene

Kobayashi et al. (1993) found on sequence analysis no mutation in the ASS1 mRNA from 2 patients with adult-onset type II citrullinemia. They also reported RFLP analysis of ...

Population genetics OMIM Kobayashi et al. (1999) stated that the frequency of CTLN2 in Japan is approximately 1 in 100,000.

Yasuda et al. (2000) calculated the frequency of homozygotes of SLC25A13 mutations to be more than 1 in 20,000 ...

Diagnosis GeneReviews Citrin deficiency has two distinct well-recognized phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and citrullinemia type II (CTLN2) (see Figure 1) [Saheki & Kobayashi 2002, Yamaguchi et al 2002, Kobayashi & Saheki 2004, Saheki & Kobayashi 2005, Kobayashi et al 2006]. Failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD was recently proposed as a novel intermediate phenotype [Song et al 2011]....
Clinical Description GeneReviews Citrin deficiency can manifest in newborns 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 FTTDCD and CTLN2 are characterized by fondness for protein-rich and/or lipid-rich foods and aversion to carbohydrate-rich foods. Individuals with CTLN2 may or may not have a prior history of NICCD or FTTDCD. The proportion of persons with NICCD or FTTDCD that evolves into CTLN2 is unknown....
Genotype-Phenotype Correlations GeneReviews No significant correlation between SLC25A13 mutation types and decreased level of hepatic enzyme ASS activity/protein or age of onset in individuals with CTLN2 is observed [Yasuda et al 2000]. ...
Differential Diagnosis GeneReviews Plasma concentration of citrulline is increased in citrin deficiency as well as in the following disorders:...
Management GeneReviews To establish the extent of disease and needs of an individual diagnosed with citrin deficiency the following are recommended by phenotype:...
Molecular genetics GeneReviews Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....