Hypoketotic hypoglycemia in citrin deficiency: a case report

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.

Hypoglycemic attacks and growth failure are the most common manifestations of citrin deficiency after 1 year of age

“…On the basis of our findings and those of previous studies, we should consider citrin deficiency when individuals experience severe hypoglycemia in childhood. 17,18 This report included nine patients with symptomatic hypoglycemia, which might indicate failed glucose homeostasis due to citrin deficiency. These attacks were recorded during a catabolic state after 1 year of life but never in infancy, except in neonates.…”

“…Thus far, there have been few reports on the symptoms of or diagnostic approaches for citrin deficiency in childhood. 5,[15][16][17][18] Chong et al reported a characterization of citrin deficiency and that two patients were diagnosed after 1 year of age by family screening the siblings of NICCD infants. 16 Of the two patients, one presented growth failure, and the other had no symptoms.…”

“…These hypoglycemic attacks in the early childhood period (median: 33.5 months of age) often appear after poor oral intake and/or during illness and catabolic states, such as fever, vomiting, or enteritis, and some of these symptoms are repetitive or intractable with dextrose infusion. Thus far, there have been few reports on the symptoms of or diagnostic approaches for citrin deficiency in childhood 5,15‐18 . Chong et al reported a characterization of citrin deficiency and that two patients were diagnosed after 1 year of age by family screening the siblings of NICCD infants 16 .…”

“…Some case reports have shown that patients in childhood with citrin deficiency exhibit fatigue, hypoglycemia, hyperlipidemia, growth failure, or liver dysfunction. 5,[15][16][17][18] Nutritional analysis in patients revealed that they have peculiar food preferences, such as a preference for lipidrich or protein-rich foods and an aversion to highcarbohydrate foods, which might compensate for the metabolic failure caused by citrin deficiency. 19 Okano et al reported that citrin-deficient patients had lower fatigue and quality of life scores during the adaptation and compensation stages than controls.…”

Usefulness of serum BUN or BUN/creatinine ratio as markers for citrin deficiency in positive cases of newborn screening

“…The symptoms of NICCD include prolonged jaundice, cholestatic liver injury, and growth retardation. After NICCD, obvious symptoms seem to disappear during childhood, but hypoglycemia is frequently noted, especially with hypoketosis or growth failure [6] , [7] . Adult-onset type II citrullinemia can manifest as hyperammonemia and encephalopathy in adulthood [8] .…”