Neonatal intrahepatic cholestasis due to citrin deficiency

General Information (adopted from Orphanet):

Synonyms, Signs: NICCD
Neonatal intrahepatic cholestasis caused by citrin deficiency
Cholestasis, neonatal intrahepatic, caused by citrin deficiency
Number of Symptoms 40
OrphanetNr: 247598
OMIM Id: 605814
ICD-10: E72.2
UMLs:
MeSH:
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence: 400 cases - PMID: 19517266 [IBIS]
Inheritance: Autosomal recessive
- PMID: 26109823 [IBIS]
Age of onset: Neonatal
Infancy
- PMID: 26109823 [IBIS]

Disease classification (adopted from Orphanet):

Parent Diseases: Citrin deficiency
 -Rare genetic disease

Comment:

Neonatal intrahepatic cholestasis due to citrin deficiency 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 (PMID:26109823).

Symptom Information: Sort by abundance 

1
(HPO:0002014) Diarrhea Rare [IBIS] 2% (n=45) 17323144 IBIS 225 / 7739
2
(HPO:0004396) Poor appetite Occasional [IBIS] 25% (n=12) 19185551 IBIS 7 / 7739
3
(HPO:0002239) Gastrointestinal hemorrhage Occasional [IBIS] 8% (n=13) 19185551 IBIS 97 / 7739
4
(HPO:0001933) Subcutaneous hemorrhage Rare [IBIS] 2% (n=45) 17323144 IBIS 50 / 7739
5
(HPO:0001508) Failure to thrive Frequent [IBIS] 54% (n=13) 19185551 IBIS 454 / 7739
6
(HPO:0001518) Small for gestational age Frequent [IBIS] 19185551 IBIS 107 / 7739
7
(HPO:0002173) Hypoglycemic seizures Rare [IBIS] 2% (n=45) 17323144 IBIS 19 / 7739
8
(HPO:0012024) Hypergalactosemia Occasional [IBIS] 27% (n=30) 17323144 IBIS 6 / 7739
9
(HPO:0004337) Abnormality of amino acid metabolism Very frequent [IBIS] 17323144 IBIS 45 / 7739
10
(HPO:0004923) Hyperphenylalaninemia Occasional [IBIS] 17% (n=30) 17323144 IBIS 7 / 7739
11
(HPO:0003235) Hypermethioninemia Occasional [IBIS] 13% (n=30) 17323144 IBIS 8 / 7739
12
(HPO:0003354) Hyperthreoninemia 24586645 IBIS 3 / 7739
13
(HPO:0011966) Elevated plasma citrulline Frequent [IBIS] 26109823 IBIS 5 / 7739
14
(HPO:0010909) Abnormality of arginine metabolism Very frequent [IBIS] 26109823 IBIS 3 / 7739
15
(HPO:0003231) Hypertyrosinemia Frequent [IBIS] 26109823 IBIS 8 / 7739
16
(HPO:0012202) Increased serum bile acid concentration 24586645 IBIS 2 / 7739
17
(HPO:0001637) Abnormality of the myocardium Rare [IBIS] 25381944 IBIS 76 / 7739
18
(HPO:0003075) Hypoproteinemia 25381944 IBIS 27 / 7739
19
(HPO:0001928) Abnormality of coagulation Frequent [IBIS] 26109823 IBIS 44 / 7739
20
(HPO:0008151) Prolonged prothrombin time Frequent [IBIS] 50% (n=8) 19185551 IBIS 13 / 7739
21
(HPO:0001903) Anemia Occasional [IBIS] 23% (n=13) 19185551 IBIS 289 / 7739
22
(HPO:0001878) Hemolytic anemia Rare [IBIS] 2% (n=45) 17323144 IBIS 83 / 7739
23
(HPO:0003119) Abnormality of lipid metabolism Occasional [IBIS] 21424115 IBIS 60 / 7739
24
(HPO:0003233) Hypoalphalipoproteinemia Very frequent [IBIS] 100% (n=11) 19185551 IBIS 18 / 7739
25
(HPO:0003124) Hypercholesterolemia Occasional [IBIS] 18% (n=11) 19185551 IBIS 53 / 7739
26
(HPO:0002155) Hypertriglyceridemia Very frequent [IBIS] 91% (n=11) 19185551 IBIS 67 / 7739
27
(HPO:0001987) Hyperammonemia Frequent [IBIS] 56% (n=9) 19185551 IBIS 50 / 7739
28
(HPO:0001254) Lethargy Rare [IBIS] 2% (n=45) 17323144 IBIS 104 / 7739
29
(HPO:0001406) Intrahepatic cholestasis Very frequent [IBIS] 26109823 IBIS 16 / 7739
30
(HPO:0000952) Jaundice Frequent [IBIS] 87% (n=45) 17323144 IBIS 105 / 7739
31
(HPO:0001394) Cirrhosis Rare [IBIS] 26109823 IBIS 102 / 7739
32
(HPO:0001399) Hepatic failure Occasional [IBIS] 26109823 IBIS 80 / 7739
33
(HPO:0002240) Hepatomegaly Frequent [IBIS] 46% (n=13) 19185551 IBIS 467 / 7739
34
(HPO:0001433) Hepatosplenomegaly Occasional [IBIS] 15% (n=13) 19185551 IBIS 78 / 7739
35
(HPO:0001541) Ascites Rare [IBIS] 2% (n=45) 17323144 IBIS 94 / 7739
36
(HPO:0002919) Ketonuria Occasional [IBIS] 9% (n=11) 19185551 IBIS 18 / 7739
37
(HPO:0001510) Growth delay Very frequent [IBIS] 100% (n=13) 19185551 IBIS 295 / 7739
38
(HPO:0002904) Hyperbilirubinemia Frequent [IBIS] 26109823 IBIS 32 / 7739
39
(HPO:0002908) Conjugated hyperbilirubinemia 24586645 IBIS 21 / 7739
40
(HPO:0003573) Increased total bilirubin Frequent [IBIS] 24586645 IBIS 10 / 7739

Associated genes:

SLC25A13;

ClinVar (via SNiPA)

Gene symbol Variation Clinical significance Reference

Additional Information:

Description: (OMIM) Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is an autosomal recessive metabolic disorder characterized by poor growth, intrahepatic cholestasis, and increased serum citrulline. Most patients show spontaneous improvement by 1 year of age. However, some patients may ...
Clinical Description OMIM Ohura et al. (2001) reported 3 neonates who presented with intrahepatic cholestasis associated with hypermethioninemia or hypergalactosemia detected by a neonatal mass screening. One infant was of average gestational age and had a methionine level of 134 micromol/l. ...
Molecular genetics OMIM In 3 neonates with neonatal-onset type II citrullinemia, Ohura et al. (2001) identified mutations in the SLC25A13 gene. The sibs were homozygous for an IVS11+1G-A mutation (603859.0002), and the third child was a compound heterozygote for the same ...
Population genetics OMIM Type II citrullinemia, both neonatal and adult onset, appears to be found almost exclusively in Japan.

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