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

Abstract

Citrin deficiency develops in different symptomatic periods from the neonatal period to adulthood. Some infantile patients are diagnosed by newborn mass screening or symptoms of neonatal intrahepatic cholestasis caused by citrin deficiency, some patients in childhood may develop hepatopathy or dyslipidemia as failure to thrive and dyslipidemia caused by citrin deficiency, and some adults are diagnosed after developing adult-onset type 2 citrullinemia (CTLN2) with hyperammonemia or encephalopathy. A diagnosis is needed before the development of severe phenotypic CTLN2 but is often difficult to obtain because newborn mass screening cannot detect all patients with citrin deficiency, and undiagnosed patients often appear healthy in childhood. There are only a few reports that have described patients in childhood. To explore the clinical features of undiagnosed patients with citrin deficiency in childhood, we studied 20 patients who were diagnosed after the first year of life. Of these patients, 45% experienced hypoglycemic attacks in childhood. The acetoacetic acid level during hypoglycemic attacks was lower than expected.Growth failure at diagnosis (45%) was also noted. From the patients' history, fat-and protein-rich food preferences (80%), a low birth weight (70%), and prolonged jaundice or infantile hepatopathy (40%) were identified. To diagnose citrin deficiency in childhood, we should ask about food preferences and a history of infantile hepatopathy for all children with severe hypoglycemia or growth failure and consider the genetic test for citrin deficiency if the patient has characteristic food preferences or a history of infantile hepatopathy. K E Y W O R D S citrullinemia, failure to thrive, SGA, SLC25A13 1 | INTRODUCTION Citrin deficiency is an autosomal-recessive inherited metabolic disorder caused by biallelic SLC25A13 (HGNC: 10983) mutations. 1 Citrin deficiency develops in several symptomatic and phenotypic phases: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD, OMIM #605814), growth failure and dyslipidemia caused by citrin deficiency (FTTDCD), and adult-onset type 2 citrullinemia (CTLN2, OMIM #605814). 2-5 In the neonatal or infantile

Clinical manifestation and long‐term outcome of citrin deficiency: Report from a nationwide study in Japan

“…Of the total 222 patients enrolled in this study, 59 patients with citrin deficiency had already been published before: 1 patient in, 22 8 patients in, 23 and 52 patients in 24 ; two patients were part of two independent publications 23,24 …”

“…Of the total 222 patients enrolled in this study, 59 patients with citrin deficiency had already been published before: 1 patient in, 22 8 patients in, 23 and 52 patients in 24 ; two patients were part of two independent publications. 23,24 Patients with confirmed pathogenic SLC25A13 variants on both alleles (74%, 164/222) were considered as being definitely diagnosed. Patients in whom only a single pathogenic variant was detected (8%, 18/222) and patients without any pathogenic SLC25A13 variants (18%, 40/222) were only considered citrin deficient patients in the presence of typical manifestations such as elevated transaminases (>100 U/L) together with cholestasis and together with elevated amino acids concentrations including threonine (Thr), citrulline (Cit), and methionine (Met).…”

“…Of the total 222 patients enrolled in this study, 59 patients with citrin deficiency had already been published before: 1 patient in, 22 8 patients in, 23 and 52 patients in 24 ; two patients were part of two independent publications. 23,24 Patients with confirmed pathogenic SLC25A13 variants on both alleles (74%, 164/222) were considered as being definitely diagnosed.…”

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] .…”

Obstacles to home-based dietary management for caregivers of children with citrin deficiency: a qualitative study

“…Infancy and early childhood are critical periods for the formation of dietary preferences in children with citrin deficiency [8]. Therefore, parents of children with citrin deficiency-as the main managers and caregivers in the early stage of the disease-play a crucial role in their dietary management.…”