Early Detection and Diagnosis of Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency Missed by Newborn Screening Using Tandem Mass Spectrometry

Self Cite

Citrin deficiency is an autosomal recessive disorder caused by mutations in the SLC25A13 gene. The disease can present with age‐dependent clinical manifestations: neonatal intrahepatic cholestasis by citrin deficiency (NICCD), failure to thrive, and dyslipidemia by citrin deficiency (FTTDCD), and adult‐onset type II citrullinemia (CTLN2). As a nationwide study to investigate the clinical manifestations, medical therapy, and long‐term outcome in Japanese patients with citrin deficiency, we collected clinical data of 222 patients diagnosed and/or treated at various different institutions between January 2000 and December 2019. In the entire cohort, 218 patients were alive while 4 patients (1 FTTDCD and 3 CTLN2) had died. All patients <20 years were alive. Patients with citrin deficiency had an increased risk for low weight and length at birth, and CTLN2 patients had an increased risk for growth impairment during adolescence. Liver transplantation has been performed in only 4 patients (1 NICCD, 3 CTLN2) with a good response thereafter. This study reports the diagnosis and clinical course in a large cohort of patients with citrin deficiency and suggests that early intervention including a low carbohydrate diet and MCT supplementation can be associated with improved clinical course and long‐term outcome.

Section: Methodsmentioning

confidence: 99%

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

Kido

Häberle

Sugawara

et al. 2022

Self Cite

“…However, a study in Texas in which 10 patients received genetic testing found evidence for Arabic, Pakistani, French Canadian, and Northern European family origin . NBS with tandem mass spectrometry now takes place in Japan and Taiwan …”

Section: Resultsmentioning

confidence: 99%

“…88 NBS with tandem mass spectrometry now takes place in Japan and Taiwan. 89,90 In the neonatal period, the buildup of bile caused by NICCD is associated with failure to thrive and dyslipidemia. 86 Early signs may involve a "chubby face," which resolves after 1 year.…”

Section: Urea Cycle Mitochondrial Transporter Defects 331 | Citrin Deficiencymentioning

confidence: 99%

Neuropsychological attributes of urea cycle disorders: A systematic review of the literature

Waisbren

Stefanatos

Kok

et al. 2019

“…Of the five patients eventually diagnosed with CITRIN deficiency, only one had significantly elevated citrulline on NBS and none had elevated orotic acid. It has previously been shown that most newborns with CITRIN deficiency have citrulline levels below the cutoff 33 . Furthermore, it is not surprising that including orotic acid determination in the screen did not contribute to the diagnosis of CITRIN deficiency.…”

Section: Discussionmentioning

confidence: 99%

The role of orotic acid measurement in routine newborn screening for urea cycle disorders

Staretz‐Chacham¹,

Daas

Ulanovsky

et al. 2020

Urea cycle disorders (UCDs), including OTC deficiency (OTCD), are life‐threatening diseases with a broad clinical spectrum. Early diagnosis and initiation of treatment based on a newborn screening (NBS) test for OTCD with high specificity and sensitivity may contribute to reduction of the significant complications and high mortality. The efficacy of incorporating orotic acid determination into routine NBS was evaluated. Combined measurement of orotic acid and citrulline in archived dried blood spots from newborns with urea cycle disorders and normal controls was used to develop an algorithm for routine NBS for OTCD in Israel. Clinical information and genetic confirmation results were obtained from the follow‐up care providers. About 1147986 newborns underwent routine NBS including orotic acid determination, 25 of whom were ultimately diagnosed with a UCD. Of 11 newborns with OTCD, orotate was elevated in seven but normal in two males with early‐onset and two males with late‐onset disease. Orotate was also elevated in archived dried blood spots of all seven retrospectively tested historical OTCD patients, only three of whom had originally been identified by NBS with low citrulline and elevated glutamine. Among the other UCDs emerge, three CPS1D cases and additional three retrospective CPS1D cases otherwise reported as a very rare condition. Combined levels of orotic acid and citrulline in routine NBS can enhance the detection of UCD, especially increasing the screening sensitivity for OTCD and differentiate it from CPS1D. Our data and the negligible extra cost for orotic acid determination might contribute to the discussion on screening for proximal UCDs in routine NBS.