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BMC Pediatrics
Published in: BMC Pediatrics 1/2020

Open Access 01-12-2020 | Hypoglycemia | Case report

Citrin deficiency mimicking mitochondrial depletion syndrome

Authors: S. C. Grünert, A. Schumann, P. Freisinger, S. Rosenbaum-Fabian, M. Schmidts, A. J. Mueller, S. Beck-Wödl, T. B. Haack, H. Schneider, H. Fuchs, U. Teufel, G. Gramer, L. Hannibal, U. Spiekerkoetter

Published in: BMC Pediatrics | Issue 1/2020

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Abstract

Background

Neonatal intrahepatic cholestasis caused by citrin deficiency (CD) is a rare inborn error of metabolism due to variants in the SLC25A13 gene encoding the calcium-binding protein citrin. Citrin is an aspartate-glutamate carrier located within the inner mitochondrial membrane.

Case presentation

We report on two siblings of Romanian-Vietnamese ancestry with citrin deficiency. Patient 1 is a female who presented at age 8 weeks with cholestasis, elevated lactate levels and recurrent severe hypoglycemia. Diagnosis was made by whole exome sequencing and revealed compound heterozygosity for the frameshift variant c.852_855del, p.Met285Profs*2 and a novel deletion c.(69 + 1_70–1)_(212 + 1_231–1)del in SLC25A13. The girl responded well to dietary treatment with a lactose-free, MCT-enriched formula. Her younger brother (Patient 2) was born 1 year later and also found to be carrying the same gene variants. Dietary treatment from birth was able to completely prevent clinical manifestation until his current age of 4.5 months.

Conclusions

As CD is a well-treatable disorder it should be ruled out early in the differential diagnosis of neonatal cholestasis. Due to the combination of hepatopathy, lactic acidosis and recurrent hypoglycemia the clinical presentation of CD may resemble hepatic mitochondrial depletion syndrome.
Literature
1.
Saheki T, Inoue K, Tushima A, Mutoh K, Kobayashi K. Citrin deficiency and current treatment concepts. Mol Genet Metab. 2010;100(Suppl 1):S59–64.CrossRef
2.
3.
Saheki T, Kobayashi K. Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD). J Hum Genet. 2002;47:333–41.CrossRef
4.
Saheki T, Kobayashi K, Terashi M, Ohura T, Yanagawa Y, Okano Y, et al. Reduced carbohydrate intake in citrin-deficient subjects. J Inherit Metab Dis. 2008;31:386–94.CrossRef
5.
Palmieri L, Pardo B, Lasorsa FM, del Arco A, Kobayashi K, Iijima M, et al. Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. EMBO J. 2001;20:5060–9.CrossRef
6.
Dimmock D, Maranda B, Dionisi-Vici C, Wang J, Kleppe S, Fiermonte G, et al. Citrin deficiency, a perplexing global disorder. Mol Genet Metab. 2009;96:44–9.CrossRef
7.
Dimmock D, Kobayashi K, Iijima M, Tabata A, Wong L-J, Saheki T, et al. Citrin deficiency: a novel cause of failure to thrive that responds to a high-protein, low-carbohydrate diet. Pediatrics. 2007;119:e773–7.CrossRef
8.
Ben-Shalom E, Kobayashi K, Shaag A, Yasuda T, Gao H-Z, Saheki T, et al. Infantile citrullinemia caused by citrin deficiency with increased dibasic amino acids. Mol Genet Metab. 2002;77:202–8.CrossRef
9.
Hutchin T, Preece MA, Hendriksz C, Chakrapani A, McClelland V, Okumura F, et al. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) as a cause of liver disease in infants in the UK. J Inherit Metab Dis. 2009;32(Suppl 1):S151–5.CrossRef
10.
Fiermonte G, Soon D, Chaudhuri A, Paradies E, Lee PJ, Krywawych S, et al. An adult with type 2 citrullinemia presenting in Europe. N Engl J Med. 2008;358:1408–9.CrossRef
11.
Wang J-S, Wang X-H, Zheng Y-J, Fu H-Y, Chen R, Lu Y, et al. Biochemical characteristics of neonatal cholestasis induced by citrin deficiency. World J Gastroenterol. 2012;18:5601–7.CrossRef
12.
Ohura T, Kobayashi K, Tazawa Y, Abukawa D, Sakamoto O, Tsuchiya S, et al. Clinical pictures of 75 patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). J Inherit Metab Dis. 2007;30:139–44.CrossRef
13.
Tamamori A, Okano Y, Ozaki H, Fujimoto A, Kajiwara M, Fukuda K, et al. Neonatal intrahepatic cholestasis caused by citrin deficiency: severe hepatic dysfunction in an infant requiring liver transplantation. Eur J Pediatr. 2002;161:609–13.CrossRef
14.
Shigeta T, Kasahara M, Kimura T, Fukuda A, Sasaki K, Arai K, et al. Liver transplantation for an infant with neonatal intrahepatic cholestasis caused by citrin deficiency using heterozygote living donor. Pediatr Transplant. 2010;14:E86–8.CrossRef
15.
Zhao X-J, Tang X-M, Zha Q-B, Shi S-S, Song Y-Z, Xiao X-M. Prenatal diagnosis of citrin deficiency in a Chinese family with a fatal proband. Tohoku J Exp Med. 2011;225:273–6.CrossRef
16.
Okano Y, Ohura T, Sakamoto O, Inui A. Current treatment for citrin deficiency during NICCD and adaptation/compensation stages: strategy to prevent CTLN2. Mol Genet Metab. 2019;127:175–83.CrossRef
17.
Hachisu M, Oda Y, Goto M, Kobayashi K, Saheki T, Ohura T, et al. Citrin deficiency presenting with ketotic hypoglycaemia and hepatomegaly in childhood. Eur J Pediatr. 2005;164:109–10.CrossRef
18.
Saheki T, Kobayashi K, Iijima M, Moriyama M, Yazaki M, Takei Y-I, et al. Metabolic derangements in deficiency of citrin, a liver-type mitochondrial aspartate-glutamate carrier. Hepatol Res. 2005;33:181–4.CrossRef
19.
Chong SC, Lo P, Chow CW, Yuen L, Chu WCW, Leung TY, et al. Molecular and clinical characterization of citrin deficiency in a cohort of Chinese patients in Hong Kong. Mol Genet Metab Rep. 2018;17:3–8.CrossRef
20.
Wada Y, Arai-Ichinoi N, Kikuchi A, Sakamoto O, Kure S. Hypoketotic hypoglycemia in citrin deficiency: a case report. BMC Pediatr. 2020;20:444.CrossRef
21.
Freisinger P, Fütterer N, Lankes E, Gempel K, Berger TM, Spalinger J, et al. Hepatocerebral mitochondrial DNA depletion syndrome caused by deoxyguanosine kinase (DGUOK) mutations. Arch Neurol. 2006;63:1129–34.CrossRef
22.
Song Y-Z, Deng M, Chen F-P, Wen F, Guo L, Cao S-L, et al. Genotypic and phenotypic features of citrin deficiency: five-year experience in a Chinese pediatric center. Int J Mol Med. 2011;28:33–40.PubMed
23.
Lin W-X, Zeng H-S, Zhang Z-H, Mao M, Zheng Q-Q, Zhao S-T, et al. Molecular diagnosis of pediatric patients with citrin deficiency in China: SLC25A13 mutation spectrum and the geographic distribution. Sci Rep. 2016;6:29732.CrossRef
24.
Fu H-Y, Zhang S-R, Wang X-H, Saheki T, Kobayashi K, Wang J-S. The mutation spectrum of the SLC25A13 gene in Chinese infants with intrahepatic cholestasis and aminoacidemia. J Gastroenterol. 2011;46:510–8.CrossRef
25.
Vitoria I, Dalmau J, Ribes C, Rausell D, García AM, López-Montiel J, et al. Citrin deficiency in a Romanian child living in Spain highlights the worldwide distribution of this defect and illustrates the value of nutritional therapy. Mol Genet Metab. 2013;110:181–3.CrossRef
26.
Zhang Z-H, Yang Z-G, Chen F-P, Kikuchi A, Liu Z-H, Kuang L-Z, et al. Screening for five prevalent mutations of SLC25A13 gene in Guangdong, China: a molecular epidemiologic survey of citrin deficiency. Tohoku J Exp Med. 2014;233:275–81.CrossRef
27.
Abuduxikuer K, Chen R, Wang Z-L, Wang J-S. Risk factors associated with mortality in neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and clinical implications. BMC Pediatr. 2019;19:18.CrossRef
28.
Saheki T, Inoue K, Ono H, Fujimoto Y, Furuie S, Yamamura K-I, et al. Oral aversion to dietary sugar, ethanol and glycerol correlates with alterations in specific hepatic metabolites in a mouse model of human citrin deficiency. Mol Genet Metab. 2017;120:306–16.CrossRef
29.
Imamura Y, Kobayashi K, Shibatou T, Aburada S, Tahara K, Kubozono O, et al. Effectiveness of carbohydrate-restricted diet and arginine granules therapy for adult-onset type II citrullinemia: a case report of siblings showing homozygous SLC25A13 mutation with and without the disease. Hepatol Res. 2003;26:68–72.CrossRef
30.
Takahashi H, Kagawa T, Kobayashi K, Hirabayashi H, Yui M, Begum L, et al. A case of adult-onset type II citrullinemia--deterioration of clinical course after infusion of hyperosmotic and high sugar solutions. Med Sci Monit. 2006;12:CS13–5.PubMed
31.
Yazaki M, Takei Y, Kobayashi K, Saheki T, Ikeda S. Risk of worsened encephalopathy after intravenous glycerol therapy in patients with adult-onset type II citrullinemia (CTLN2). Intern Med. 2005;44:188–95.CrossRef
32.
Fukushima K, Yazaki M, Nakamura M, Tanaka N, Kobayashi K, Saheki T, et al. Conventional diet therapy for hyperammonemia is risky in the treatment of hepatic encephalopathy associated with citrin deficiency. Intern Med. 2010;49:243–7.CrossRef
33.
Mutoh K, Kurokawa K, Kobayashi K, Saheki T. Treatment of a citrin-deficient patient at the early stage of adult-onset type II citrullinaemia with arginine and sodium pyruvate. J Inherit Metab Dis. 2008;31(Suppl 2):S343–7.CrossRef
34.
Lin Y, Liu Y, Zhu L, Le K, Shen Y, Yang C, et al. Combining newborn metabolic and genetic screening for neonatal intrahepatic cholestasis caused by citrin deficiency. J Inherit Metab Dis. 2019;43(3):467.CrossRef
35.
Tang CF, Liu SC, Feng Y, Mei HF, Liu HP, Feng JW, et al. Newborn screening program and blood amino acid profiling in early neonates with citrin deficiency. Zhonghua Er Ke Za Zhi. 2019;57:797–801.PubMed
36.
Estrella J, Wilcken B, Carpenter K, Bhattacharya K, Tchan M, Wiley V. Expanded newborn screening in New South Wales: missed cases. J Inherit Metab Dis. 2014;37:881–7.CrossRef
37.
Sander J, Janzen N, Sander S, Steuerwald U, Das AM, Scholl S, et al. Neonatal screening for citrullinaemia. Eur J Pediatr. 2003;162:417–20.CrossRef
38.
Tamamori A, Fujimoto A, Okano Y, Kobayashi K, Saheki T, Tagami Y, et al. Effects of citrin deficiency in the perinatal period: feasibility of newborn mass screening for citrin deficiency. Pediatr Res. 2004;56:608–14.CrossRef
Metadata
Title
Citrin deficiency mimicking mitochondrial depletion syndrome
Authors
S. C. Grünert
A. Schumann
P. Freisinger
S. Rosenbaum-Fabian
M. Schmidts
A. J. Mueller
S. Beck-Wödl
T. B. Haack
H. Schneider
H. Fuchs
U. Teufel
G. Gramer
L. Hannibal
U. Spiekerkoetter
Publication date
01-12-2020
Publisher
BioMed Central
Published in
BMC Pediatrics / Issue 1/2020
Electronic ISSN: 1471-2431
DOI
https://doi.org/10.1186/s12887-020-02409-x

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