Infantile citrullinemia caused by citrin deficiency with increased dibasic amino acids (original) (raw)
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Pediatric Research, 2004
Deficiency of citrin due to mutations of the SLC25A13 gene causes adult-onset type II citrullinemia (CTLN2) and one type of neonatal intrahepatic cholestasis (NICCD). About half of the NICCD patients are detected based on high galactose, phenylalanine, and/or methionine concentrations on newborn mass screening (NMS). To clarify the perinatal and neonatal effects and the inconsistent results on NMS, we examined aminograms, the levels of bile acids and galactose in dried blood spots for NMS from 20 patients with NICCD. Birth weight was low for gestational age (-1.4 +/- 0.7 SD). Affected fetuses may have suffered intrauterine citrin deficiency. The first abnormality detected after birth was citrullinemia, and 19 of 20 patients had citrulline levels higher than +2 SD of controls. Tyrosine, phenylalanine, methionine, galactose, and bile acids were less affected than citrulline on d 5 after birth. Galactose and bile acids levels were increased at 1 mo in comparison with d 5 after birth due to impairment of the cytosolic NADH reducing-equivalent supply into mitochondria of hepatocytes. Patients with negative findings on NMS had low levels of total 20 amino acids. Citrulline/serine, citrulline /leucine plus isoleucine, and citrulline/total amino acids ratios, controlled for the confounding effect of low amount of total amino acids, were higher in all patients than +2 SD, +2 SD, and +3 SD of controls, respectively. NMS for citrin deficiency (frequency of homozygote with SLC25A13 mutation: 1/10,000-1/38,000 in East Asia) will be useful for clarification of the clinical course, treatment, and prevention of this disease.
Molecular Genetics and Metabolism, 2013
We report citrin deficiency in a neonatal non-East-Asian patient, the ninth Caucasian reported with this disease. The association of intrahepatic cholestasis, galactosuria, very high alpha-fetoprotein and increased plasma and urine citrulline, tyrosine, methionine and threonine levels suggested citrin deficiency. Identification of a proteintruncating mutation (c.1078C>T;p.Arg360*) in the SLC25A13 gene confirmed the diagnosis. An immediate response to a high-protein, lactose-free, low-carbohydrate formula was observed. Our report illustrates the need for awareness on citrin deficiency in Western countries.
Biochemical and molecular characteristics of citrin deficiency in Korean children
Journal of human genetics, 2016
Mutations in SLC25A13 cause citrin deficiency, which has three phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) and adult-onset type 2 citrullinemia (CTLN2). The purpose of this study was to determine the mutation spectrum and the clinical and biochemical characteristics of citrin deficiency in Korean patients. Thirty-four patients were diagnosed with citrin deficiency based on mutations in SLC25A13, as verified by direct sequencing and long PCR screening of a large transposon insertion. A total of 66 alleles from 33 unrelated families of 34 patients with citrin deficiency (27 NICCD, 2 FTTDCD and 5 CTLN2) were retrospectively identified. The common pathogenic alleles were IVS16ins3kb (33%), c.851_854del (30%) and c.1177+1G>A (12%), and three novel variants were identified. Levels of citrulline, threonine, methionine, tyrosine and arginine and the threonine-to-serine ratio wer...
Molecular Genetics and Metabolism
Citrin is the liver-specific isoform of the mitochondrial aspartate/glutamate carrier (AGC2). AGC2 deficiency is an autosomal recessive disorder with two age related phenotypes: neonatal intrahepatic cholestasis (NICCD, OMIM#605814) and adult-onset type II citrullinemia (CTLN2, OMIM#603471). NICCD arises within the first few weeks of life resulting in prolonged cholestasis and metabolic abnormalities including aminoacidemia and galactosuria. Usually symptoms disappear within the first year of life, thus making a diagnosis difficult after this time. In this study we report a new Caucasian case of NICCD, a seven week old Romanian boy with prolonged jaundice. Sequencing of the AGC2 gene showed a novel homozygous missense double-nucleotide (doublet) mutation, which produces the change of the glycine at position 437 into glutamate. Functional studies, carried out on the recombinant mutant protein, for the first time demonstrated, that NICCD is caused by a reduced transport activity of AGC2. The presence of AGC2 deficiency in other ethnic groups besides Asian population suggests further consideration for NICCD diagnosis of any neonate with an unexplained cholestasis; a prompt diagnosis is crucial to resolve the metabolic decompensation with an appropriate dietary treatment.
PEDIATRICS, 2007
The proband was born at 36 weeks, appropriate for gestational age, to nonconsanguineous white parents. There was no evidence of hyperbilirubinemia or intrahepatic cholestasis in the neonatal period, and she had normal newborn screen results. She presented with 3 episodes of life-threatening bleeding and anemia. The diagnostic evaluation for her bleeding diathesis revealed an abnormal clotting profile with no biochemical evidence for hepatocellular damage. She was incidentally noted to have severe growth deceleration that failed to respond to 502 kJ/kg (120 kcal/kg) per day of protein-hydrolyzed formula. An extensive diagnostic workup for failure to thrive, which was otherwise normal, included plasma amino acid analysis that revealed hyperglutaminemia and citrulline levels within the reference range. Testing of a repeat sample revealed isolated hypercitrullinemia. No argininosuccinic acid was detected. Her ammonia level and urine orotic acid were within the reference ranges. Subsequent plasma amino acid analysis exhibited a profile suggestive of neonatal intrahepatic cholestasis caused by citrin deficiency with elevations in citrulline, methionine, and threonine. Western blotting of fibroblasts demonstrated citrin deficiency, and a deletion for exon 3 was found in the patient's coding DNA of the SLC25A13 gene. On the basis of the experience with adults carrying this condition, the patient was given a high-protein, low-carbohydrate diet. The failure to thrive and bleeding diathesis resolved. When compliance with the dietary prescription was relaxed, growth deceleration was again noted, although significant bleeding did not recur. This is the first report of an infant of Northern European descent with citrin deficiency. The later age at presentation with failure to thrive and bleeding diathesis and without obvious evidence of neonatal intrahepatic cholestasis expands the clinical spectrum of citrin deficiency. This case emphasizes the importance of continued dietary control and growth monitoring in children with neonatal intrahepatic cholestasis caused by citrin deficiency and identifies a new metabolic entity responsible for failure to thrive.
Journal of the Korean Society of Neonatology, 2011
Citrin deficiency caused by the SLC25A13 gene mutations is associated with both neonatal-onset type II citrullinemia (CTLN2), also known as neonatal intrahepatic cholestasis caused by citrin deficiency and adult-onset CTLN2. Neonatal-onset CTLN2 is an autosomal recessive disorder characterized by poor growth, intrahepatic cholestasis, and increased serum citrulline. A 16-days old infant with hyperammonemia was referred for evaluation of increased plasma citrulline diagnosed using tandem mass spectrometry. Blood amino acid analysis showed significant elevation of citrulline. Mild elevation in serum galactose levels had been found. DNA analysis of the SLC25A13 gene in this patient showed two novel compound heterozygous mutations, c.221C>T in exon4 and c.1645C in exon16 (p.[Ser74Phe]+[Gln549X]). We suggest that infants with a high serum citrulline level on a tandem mass screening test are candidates for gene analysis and blood amino acid analysis for neonatal-onset CTLN2.
Molecular Genetics and Metabolism Reports, 2018
Background and objectives: This retrospective study analysed a case series of subjects with citrin deficiency, and aims to present the molecular and clinical characterization of this disease in the Hong Kong Chinese population for the first time. Patients and Methods: Data from medical records of eighteen patients with citrin deficiency (years 2006-2015) were retrieved. Demographic data, biochemical parameters, radiological results, genetic testing results, management, and clinical outcome were collected and analysed. Results: Eighteen patients with diagnosis of citrin deficiency were recruited. All 18 patients carried at least one common pathogenic variant c.852_855delTATG in SLC25A13. Prolonged jaundice (neonatal intrahepatic cholestasis caused by citrin deficiency, NICCD) was the most common presenting symptom, in conjunction with elevated plasma citrulline, threonine, alkaline phosphatase, and alpha-fetoprotein levels. The abnormal biochemical parameters including liver derangement returned to normal range in most of the cases by 6 months of age after the introduction of a lactose-free formula. There were a few cases with atypical presentations. Two subjects did not present with NICCD, and were subsequently diagnosed later in life after their siblings presented with symptoms of citrin deficiency at one month of age and subsequently received a molecular diagnosis. One patient with citrin deficiency also exhibited multiple liver hemangioendotheliomas, which subsided gradually after introduction of a lactose-free formula. Only one patient from this cohort was offered expanded metabolic screening at birth. She was not ascertained by conducted newborn screening and was diagnosed upon presentation with cholestatic jaundice by 1 month of age. Conclusion: This is the first report of the clinical and molecular characterization of a large cohort of patients with citrin deficiency in Hong Kong. The presentation of this cohort of patients expands the clinical phenotypic spectrum of NICCD. Benign liver tumors such as hemangioendotheliomas may be associated with citrin deficiency in addition to the well-known association with hepatocellular carcinoma. Citrin deficiency may manifest in later infancy period with an NICCD-like phenotype. Furthermore, this condition is not always ascertained by expanded newborn metabolic screening testing.
Journal of Human Genetics, 2008
Deficiency of citrin, liver-type mitochondrial aspartate-glutamate carrier, is an autosomal recessive disorder caused by mutations of the SLC25A13 gene on chromosome 7q21.3 and has two phenotypes: neonatal intrahepatic cholestatic hepatitis (NICCD) and adult-onset type II citrullinemia (CTLN2). So far, we have described 19 SLC25A13 mutations. Here, we report 13 novel SLC25A13 mutations (one insertion, two deletion, three splice site, two nonsense, and five missense) in patients with citrin deficiency from Japan, Israel, UK, and Czech Republic. Only R360X was detected in both Japanese and Caucasian. IVS16ins3kb identified in a Japanese CTLN2 family seems to be a retrotransposal insertion, as the inserted sequence (2,667-nt) showed an antisense strand of processed complementary DNA (cDNA) from a gene on chromosome 6 (C6orf68), and the repetitive sequence (17nt) derived from SLC25A13 was found at both ends of the insert. All together, 30 different mutations found in 334 Japanese, 47 Chinese, 11 Korean, four Vietnamese and seven non-East Asian families have been summarized. In Japan, IVS16ins3kb was relatively frequent in 22 families, in addition to known mutations IVS11 + 1G [ A, 851del4, IVS13 + 1G [ A, and S225X in 189, 173, 48 and 30 families, respectively; 851del4 and IVS16ins3kb were found in all East Asian patients tested, suggesting that these mutations may have occurred very early in some area of East Asia.
Citrin deficiency, a perplexing global disorder
Molecular Genetics and Metabolism, 2009
Intro duc tion Cit rin, the mito chon drial aspar tate/glu ta mate car rier (AGC2) plays a sig nif cant role in nitro gen metab o lism by vir tue of its shut tle activ ity. Def ciency of this pro tein has pre vi ously been described as the cause of cit rul line mia type 2 (CTLN2) [1]. CTLN2 was ini tially described as an adult onset hepatic and neu ro log i cal dis or der in indi vid u als of Jap a nese ances try. CTLN2, was orig i nally dif fer en ti ated from clas si cal cit rul line mia by a tis sue spe cifc defciency of argi ni no suc ci nate syn the tase (ASS) activ ity (E.C. 6.3.4.5) in the liver but nor mal enzy matic activ ity in renal tis sue or skin fbro blast cul ture [2]. Cit rin def ciency has sub se quently been shown to be a cause of neo na tal intra he patic cho le sta sis through mech a nisms that are not well under stood [3,4]. Although ini tially reported among indi vid u als of East Asian ances try, sev eral recent reports have described indi vid u als with liver dis ease sec ond ary to cit rin def ciency from other eth nic groups [5-8]. Cit rin def ciency is a dif cult met a bolic dis or der to reli ably dis tin guish from other causes of hepatic dis ease, par tic u larly as the char ac ter is tic plasma amino acid pro fle is not con sis tently pres ent [9-11]. How ever, in Tai wan, cit rin def ciency has been shown to be the lead ing cause of hepatic ste a to sis in infants [11]. There fore, rapid and inex pen sive diag nos tic test ing is of sig nif cant value in eval u at ing chil dren with hepatic ste a to sis or intra he patic cho le sta sis. Con se quently, more recent efforts have focused on using Western blot to diag nose patients, as all muta tions reported to date have resulted in no detect able pro tein [12]. Meth ods Sequenc ing Clin i cal sam ples on patients with sus pected cit rin def ciency were referred to the Med i cal Genet ics lab o ra to ries at Bay lor College of Med i cine, Hous ton, Texas for DNA anal y sis of the SCL25A13