Chubby Face and the Biochemical Parameters for the Early Diagnosis of Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency

Chen, Hung−Wen; Chen, Huey‐Ling; Ni, Yen‐Hsuan; Lee, Ni‐Chung; Chien, Yin‐Hsiu; Hwu, Wuh‐Liang; Huang, Yuan-Te; Chiu, Pao-Chin; Chang, Mei–Hwei

doi:10.1097/mpg.0b013e318162d96d

Cited by 20 publications

(12 citation statements)

References 16 publications

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“…In citrin deficiency, the three mutations we screened (c.851_854del, c.1638_1660dup23, and IVS6+ 5 G>A) represent 95% of all mutations in Taiwanese patients [23] and 98% of all mutations in carrier screening [21]. In CUD, the p.R254X mutation accounts for 50% of all mutated alleles in clinical cases, but the prevalence of this mutation is lower in asymptomatic mothers and in screened newborns [17].…”

Section: Discussionmentioning

confidence: 99%

Newborn screening for citrin deficiency and carnitine uptake defect using second-tier molecular tests

Wang

Chen

et al. 2013

BMC Med Genet

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BackgroundTandem mass spectrometry (MS/MS) analysis is a powerful tool for newborn screening, and many rare inborn errors of metabolism are currently screened using MS/MS. However, the sensitivity of MS/MS screening for several inborn errors, including citrin deficiency (screened by citrulline level) and carnitine uptake defect (CUD, screened by free carnitine level), is not satisfactory. This study was conducted to determine whether a second-tier molecular test could improve the sensitivity of citrin deficiency and CUD detection without increasing the false-positive rate.MethodsThree mutations in the SLC25A13 gene (for citrin deficiency) and one mutation in the SLC22A5 gene (for CUD) were analyzed in newborns who demonstrated an inconclusive primary screening result (with levels between the screening and diagnostic cutoffs).ResultsThe results revealed that 314 of 46 699 newborns received a second-tier test for citrin deficiency, and two patients were identified; 206 of 30 237 newborns received a second-tier testing for CUD, and one patient was identified. No patients were identified using the diagnostic cutoffs. Although the incidences for citrin deficiency (1:23 350) and CUD (1:30 000) detected by screening are still lower than the incidences calculated from the mutation carrier rates, the second-tier molecular test increases the sensitivity of newborn screening for citrin deficiency and CUD without increasing the false-positive rate.ConclusionsUtilizing a molecular second-tier test for citrin deficiency and carnitine transporter deficiency is feasible.

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Section: Discussionmentioning

confidence: 99%

Newborn screening for citrin deficiency and carnitine uptake defect using second-tier molecular tests

Wang

Chen

et al. 2013

BMC Med Genet

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“…For example, neonatal cholestasis caused by citrin deficiency (NICCD) is an important cause of cholestasis in East Asian children [ 77 , 78 ]. We have previously identified facial features and biochemical characteristics for the phenotypic diagnosis of NICCD [ 79 , 80 ]. Alpha 1-antitrypsin (A1AT/SERPINA1) deficiency and cystic fibrosis are important causes in western countries but how lower incidences in Asian populations.…”

Section: Main Textmentioning

confidence: 99%

Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases

et al. 2018

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BackgroundJaundice is a common symptom of inherited or acquired liver diseases or a manifestation of diseases involving red blood cell metabolism. Recent progress has elucidated the molecular mechanisms of bile metabolism, hepatocellular transport, bile ductular development, intestinal bile salt reabsorption, and the regulation of bile acids homeostasis.Main bodyThe major genetic diseases causing jaundice involve disturbances of bile flow. The insufficiency of bile salts in the intestines leads to fat malabsorption and fat-soluble vitamin deficiencies. Accumulation of excessive bile acids and aberrant metabolites results in hepatocellular injury and biliary cirrhosis. Progressive familial intrahepatic cholestasis (PFIC) is the prototype of genetic liver diseases manifesting jaundice in early childhood, progressive liver fibrosis/cirrhosis, and failure to thrive. The first three types of PFICs identified (PFIC1, PFIC2, and PFIC3) represent defects in FIC1 (ATP8B1), BSEP (ABCB11), or MDR3 (ABCB4). In the last 5 years, new genetic disorders, such as TJP2, FXR, and MYO5B defects, have been demonstrated to cause a similar PFIC phenotype. Inborn errors of bile acid metabolism also cause progressive cholestatic liver injuries. Prompt differential diagnosis is important because oral primary bile acid replacement may effectively reverse liver failure and restore liver functions. DCDC2 is a newly identified genetic disorder causing neonatal sclerosing cholangitis. Other cholestatic genetic disorders may have extra-hepatic manifestations, such as developmental disorders causing ductal plate malformation (Alagille syndrome, polycystic liver/kidney diseases), mitochondrial hepatopathy, and endocrine or chromosomal disorders. The diagnosis of genetic liver diseases has evolved from direct sequencing of a single gene to panel-based next generation sequencing. Whole exome sequencing and whole genome sequencing have been actively investigated in research and clinical studies. Current treatment modalities include medical treatment (ursodeoxycholic acid, cholic acid or chenodeoxycholic acid), surgery (partial biliary diversion and liver transplantation), symptomatic treatment for pruritus, and nutritional therapy. New drug development based on gene-specific treatments, such as apical sodium-dependent bile acid transporter (ASBT) inhibitor, for BSEP defects are underway.Short conclusionUnderstanding the complex pathways of jaundice and cholestasis not only enhance insights into liver pathophysiology but also elucidate many causes of genetic liver diseases and promote the development of novel treatments.

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“…86 Early signs may involve a "chubby face," which resolves after 1 year. 91 Other clinical symptoms may include hypoglycemia, pancreatitis, fatigue, and anorexia. 86 In NICCD, almost all signs of failure to thrive and liver disease disappear within the first year of life after treatment with medium-chain triglyceride-rich formula or lactose-free formula (for those with secondary galactosemia).…”

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

J of Inher Metab Disea

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Chubby Face and the Biochemical Parameters for the Early Diagnosis of Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency

Cited by 20 publications

References 16 publications

Newborn screening for citrin deficiency and carnitine uptake defect using second-tier molecular tests

Newborn screening for citrin deficiency and carnitine uptake defect using second-tier molecular tests

Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases

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

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