Top

BMC Pediatrics

Published in:

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

Hypoketotic hypoglycemia in citrin deficiency: a case report

Authors: Yoichi Wada, Natsuko Arai-Ichinoi, Atsuo Kikuchi, Osamu Sakamoto, Shigeo Kure

Published in: BMC Pediatrics | Issue 1/2020

Abstract

Background

Citrin deficiency (CD) is a recessive metabolic disease caused by biallelic pathogenic variants in SLC25A13. Although previous studies have reported ketosis in CD, it was observed at the time of euglycemia or mild hypoglycemia. Blood ketone levels concomitant with symptomatic or severe hypoglycemia in CD have not been a topic of focus despite its importance in identifying the etiology of hypoglycemia and assessing the ability of fatty acid utilization. Herein, we describe a patient with CD who had repeated episodes of hypoglycemia with insufficient ketosis.

Case presentation

A 1-year-old boy with repetitive hypoglycemia was referred to us to investigate its etiology. The fasting load for 13 h led to hypoketotic hypoglycemia, indicating the possibility of partial β-oxidation dysfunction. A genetic test led to the diagnosis of CD. The hypoglycemic episodes disappeared after switching to a medium-chain triglyceride-containing formula.

Conclusions

This case report suggests that symptomatic or severe hypoglycemia in patients with CD could be associated with relatively low levels of ketone bodies, implying that β-oxidation in these patients might possibly be partially disrupted. When encountering a patient with hypoglycemia, clinicians should check blood ketone levels and bear in mind the possibility of CD because excessive intravenous administration of glucose can cause decompensated symptoms in patients with CD as opposed to other disorders presenting with hypoketotic hypoglycemia, such as fatty acid oxidation disorders. Further studies in a large-scale cohort are warranted to confirm our speculation.

Kobayashi K, Sinasac DS, Iijima M, et al. The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nat Genet. 1999;22(2):159–63. https://doi.org/10.1038/9667.CrossRefPubMed

Ohura T, Kobayashi K, Tazawa Y, et al. Neonatal presentation of adult-onset type II citrullinemia. Hum Genet. 2001;108(2):87–90. https://doi.org/10.1007/s004390000448.CrossRefPubMed

Palmieri L, Pardo B, Lasorsa FM, et al. Citrin and aralar1 are Ca(2+)-stimulated aspartate/glutamate transporters in mitochondria. EMBO J. 2001;20(18):5060–9. https://doi.org/10.1093/emboj/20.18.5060.CrossRefPubMedPubMedCentral

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(7):333–41. https://doi.org/10.1007/s100380200046.CrossRefPubMed

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(3):175–83. https://doi.org/10.1016/j.ymgme.2019.06.004.CrossRefPubMed

Morris AA, Thekekara A, Wilks Z, Clayton PT, Leonard JV, Aynsley-Green A. Evaluation of fasts for investigating hypoglycaemia or suspected metabolic disease. Arch Dis Child. 1996;75(2):115–9. https://doi.org/10.1136/adc.75.2.115.CrossRefPubMedPubMedCentral

Hachisu M, Oda Y, Goto M, et al. Citrin deficiency presenting with ketotic hypoglycaemia and hepatomegaly in childhood. Eur J Pediatr. 2005;164(2):109–10. https://doi.org/10.1007/s00431-004-1549-z.CrossRefPubMed

Bonnefont JP, Specola NB, Vassault A, et al. The fasting test in paediatrics: application to the diagnosis of pathological. Eur J Pediatr. 1990;150(2):80–5. https://doi.org/10.1007/bf02072043.CrossRefPubMed

Kikuchi A, Arai-Ichinoi N, Sakamoto O, et al. Simple and rapid genetic testing for citrin deficiency by screening 11 prevalent mutations in SLC25A13. Mol Genet Metab. 2012;105(4):553–8. https://doi.org/10.1016/j.ymgme.2011.12.024.CrossRefPubMed

10.

Song Y-Z, Deng M, Chen F-P, et al. Genotypic and phenotypic features of citrin deficiency: five-year experience in a Chinese pediatric center. Int J Mol Med. 2011;28(1):33–40. https://doi.org/10.3892/ijmm.2011.653.CrossRefPubMed

11.

Otsuka H, Sasai H, Abdelkreem E, et al. Effectiveness of medium-chain triglyceride oil therapy in two Japanese Citrin-deficient siblings: evaluation using Oral glucose tolerance tests. Tohoku J Exp Med. 2016;240(4):323–8. https://doi.org/10.1620/tjem.240.323.CrossRefPubMed

12.

Zhao Y, Yang Y. Real-time and high-throughput analysis of mitochondrial metabolic states in living cells using genetically encoded NAD(+)/NADH sensors. Free Radic Biol Med. 2016;100:43–52. https://doi.org/10.1016/j.freeradbiomed.2016.05.027.CrossRefPubMed

13.

Hayasaka K, Numakura C, Toyota K, et al. Medium-chain triglyceride supplementation under a low-carbohydrate formula is a promising therapy for adult-onset type II citrullinemia. Mol Genet Metab Rep. 2014;1:42–50. https://doi.org/10.1016/j.ymgmr.2013.12.002.CrossRefPubMedPubMedCentral

14.

Wu J, Jin Z, Zheng H, Yan L-J. Sources and implications of NADH/NAD(+) redox imbalance in diabetes and its complications. Diabetes Metab Syndr Obes. 2016;9:145–53. https://doi.org/10.2147/DMSO.S106087.CrossRefPubMedPubMedCentral

15.

Wang Y, Nakajima T, Gonzalez FJ, Tanaka N. PPARs as metabolic regulators in the liver: lessons from liver-specific PPAR-null mice. Int J Mol Sci. 2020;21(6):2061. https://doi.org/10.3390/ijms21062061.CrossRefPubMedCentral

16.

Komatsu M, Kimura T, Yazaki M, et al. Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARalpha. Biochim Biophys Acta. 2015;1852(3):473–81. https://doi.org/10.1016/j.bbadis.2014.12.011.CrossRefPubMed

17.

Wakabayashi M, Kamijo Y, Nakajima T, et al. Fatty acid accumulation and resulting PPARα activation in fibroblasts due to trifunctional Protein deficiency. PPAR Res. 2012;2012:371691. https://doi.org/10.1155/2012/371691.CrossRefPubMedPubMedCentral

18.

Yang Y, Feng Y, Zhang X, et al. Activation of PPAR<i>α</i> by fatty acid accumulation enhances fatty acid degradation and Sulfatide synthesis. Tohoku J Exp Med. 2016;240(2):113–22. https://doi.org/10.1620/tjem.240.113.CrossRefPubMed

19.

Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W. Peroxisome proliferator–activated receptor α mediates the adaptive response to fasting. J Clin Invest. 1999;103(11):1489–98. https://doi.org/10.1172/JCI6223.CrossRefPubMedPubMedCentral

20.

Finck BN, Lehman JJ, Leone TC, et al. The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest. 2002;109(1):121–30. https://doi.org/10.1172/JCI14080.CrossRefPubMedPubMedCentral

21.

Burkart EM, Sambandam N, Han X, et al. Nuclear receptors PPARbeta/delta and PPARalpha direct distinct metabolic regulatory programs in the mouse heart. J Clin Invest. 2007;117(12):3930–9. https://doi.org/10.1172/JCI32578.CrossRefPubMedPubMedCentral

22.

Iemitsu M, Shimojo N, Maeda S, et al. The benefit of medium-chain triglyceride therapy on the cardiac function of SHRs is associated with a reversal of metabolic and signaling alterations. Am J Physiol Heart Circ Physiol. 2008;295(1):H136–44. https://doi.org/10.1152/ajpheart.01417.2006.CrossRefPubMed

23.

Liberato MV, Nascimento AS, Ayers SD, et al. Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR) γ activators and pan-PPAR partial agonists. Moschetta A, ed. PloS one. 2012;7(5):e36297. https://doi.org/10.1371/journal.pone.0036297.CrossRefPubMedPubMedCentral

24.

Uhlén M, Fagerberg L, Hallström BM, et al. Proteomics. Tissue-based map of the human proteome. Science (New York, NY). 2015;347(6220):1260419. https://doi.org/10.1126/science.1260419.CrossRef

Title: Hypoketotic hypoglycemia in citrin deficiency: a case report
Authors: Yoichi Wada
Natsuko Arai-Ichinoi
Atsuo Kikuchi
Osamu Sakamoto
Shigeo Kure
Publication date: 01-12-2020
Publisher: BioMed Central
Keyword: Hypoglycemia
Published in: BMC Pediatrics / Issue 1/2020
Electronic ISSN: 1471-2431
DOI: https://doi.org/10.1186/s12887-020-02349-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Hypoketotic hypoglycemia in citrin deficiency: a case report

Abstract

Background

Case presentation

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Case presentation

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2020

High fetal hemoglobin level is associated with increased risk of cerebral vasculopathy in children with sickle cell disease in Mayotte

Encephalitis due to herpes zoster without rash in an immunocompetent 12-year-old girl: case report and review of the literature

Oral health behavior among school children aged 11–13 years in Saveh, Iran: an evaluation of a theory-driven intervention

Prevalence and associated factors of acute diarrhea among under-five children in Kamashi district, western Ethiopia: community-based study

The effects of serial casting on lower limb function for children with Cerebral Palsy: a systematic review with meta-analysis

Newborn hearing screening coverage and detection rates of hearing impairment across China from 2008-2016