Expression of transcobalamin II by amniocytes

Rosenblatt, David S.; Hosack, Angela; Matiaszuk, Nora

doi:10.1002/pd.1970070107

Cited by 23 publications

(10 citation statements)

References 19 publications

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“…Because amniocytes synthesize and secrete transcobalamin, incubation of amniocytes in medium lacking any exogenous source of transcobalamin supplemented with radiolabeled cobalamin followed by measurement of transcobalamin‐bound cobalamin can be used to diagnose the disorder [Rosenblatt et al, 1987; Morel et al, 2005]. Components of the pathway for intestinal uptake of cobalamin are not expressed in cultured amniocytes, and therefore no biochemical test for inherited intrinsic factor deficiency or Imerslund–Gräsbeck syndrome is possible.…”

Section: Introductionmentioning

confidence: 99%

Inborn errors of cobalamin absorption and metabolism

Watkins

Rosenblatt²

2011

American J of Med Genetics Pt C

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174

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Derivatives of cobalamin (vitamin B(12)) are required for activity of two enzymes in humans. Adenosylcobalamin is required for activity of mitochondrial methylmalonylCoA mutase and methylcobalamin is required for activity of cytoplasmic methionine synthase. Deficiency in cobalamin, or inability to absorb cobalamin normally, can result in accumulation of methylmalonic acid and homocysteine in blood and urine. Methylmalonic acidemia can result in metabolic acidosis which in severe cases may be fatal. Hyperhomocysteinemia along with hypomethioninemia can result in hematologic (megaloblastic anemia, neutropenia, thrombocytopenia) and neurologic (subacute combined degeneration of the cord, dementia, psychosis) defects. Inborn errors affecting cobalamin absorption (inherited intrinsic factor deficiency, Imerslund–Gra¨ sbeck syndrome) and transport (transcobalamin deficiency) have been described. A series of inborn errors of intracellular cobalamin metabolism, designated cblA-cblG, have been differentiated by complementation analysis. These can give rise to isolated methylmalonic acidemia (cblA, cblB, cblD variant 2), isolated hyperhomocysteinemia (cblD variant 1, cblE, cblG) or combined methylmalonic acidemia and hyperhomocysteinemia (cblC, classic cblD, cblF). All these disorders are inherited as autosomal recessive traits. The genes underlying each of these disorders have been identified. Two other disorders, haptocorrin deficiency and transcobalamin receptor deficiency, have been described, but it is not clear that they have any consistent clinical phenotype.

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Section: Introductionmentioning

confidence: 99%

Inborn errors of cobalamin absorption and metabolism

Watkins

Rosenblatt²

2011

American J of Med Genetics Pt C

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174

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“…Alleles of a number of folate‐related genes may contribute to SB, some of them acting in mothers during pregnancy. Between 1995 and 2001, the contribution of alleles of the C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) to SB has been assessed in at least 31 studies [Rosenblatt et al, 1987; van der Put et al, 1995, 1996; Whitehead et al, 1995; Kirke et al, 1996; Ou et al, 1996; Papapetrou et al, 1996; Bjorke‐Monsen et al, 1997; Mornet et al, 1997; Speer et al, 1997, 1999; Boduroglu et al, 1998; de Franchis et al, 1998; Koch et al, 1998; Morrison et al, 1998; Shaw et al, 1998; Weitkamp et al, 1998; Christensen et al, 1999; Johnson et al, 1999; Shields et al, 1999; Stegmann et al, 1999; Trembath et al, 1999; Ubbink et al, 1999; Wilson et al, 1999; Barber et al, 2000; Davalos et al, 2000; Johanning et al, 2000; Li et al, 2000; Wenstrom et al, 2000; Martinez et al, 2001; Richter et al, 2001]. The 677T allele appears to contribute to SB in some populations although the evidence is often conflicting.…”

Section: Introductionmentioning

confidence: 99%

New 19 bp deletion polymorphism in intron‐1 of dihydrofolate reductase (DHFR): A risk factor for spina bifida acting in mothers during pregnancy?

Johnson

Stenroos

Spychala

et al. 2003

American J of Med Genetics Pt A

134

106

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Up to 72% of spina bifida cystica (SB) is preventable by maternal periconceptual folic acid supplementation. The C677T allele of the methylenetetrahydrofolate reductase (MTHFR) gene and some other functional polymorphisms are risk factors for SB in some populations. However, despite extensive study, the genetic risk factors for SB are incompletely understood. Polymorphic alleles that diminish bioavailability of reduced folate in the mother during pregnancy could contribute to SB in her fetus, acting in the mother as teratogenic alleles. We recently discovered a polymorphic 19 bp deletion allele (frequency 0.45) within intron-1 of dihydrofolate reductase (DHFR) that is a good candidate for such a genetic factor. Since there is precedence for intron-1 regulatory elements and the deletion allele removes a potential Sp1 transcription factor binding site, we hypothesized that the deletion allele could be functional and act in SB mothers to increase the risk of SB in her fetus. We found that homozygosity for this deletion allele was significantly more frequent in SB mothers, but not in SB fathers or patients, compared with controls and was associated with a significantly increased odds ratio (OR) (2.035) of being an SB mother compared with other genotypes. Genotype distribution obeyed the constraints of Hardy-Weinberg equilibrium in controls, SB patients and fathers, but not in SB mothers. If confirmed, these findings could lead to improved forms of folate supplementation for pregnancy. About half of dietary folates and all of folic acid supplements must be reduced by DHFR to be available for mother and fetus. Reduced folates could be preferable for supplements during pregnancy to prevent SB.

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“…Genetic counseling should be provided to affected families. Neonatal screening could be useful in the early diagnosis of the syndrome:some studies suggest that prenatal diagnosis of TC de ciency is possible by means of measuring TC production in amniotic-uid cells (18)(19)(20)(21).…”

Section: Diagnostic Assessmentmentioning

confidence: 99%

Long-term Outcome of a Patient With Transcobalamin Deficiency Caused by Tcn2 Mutation: A Case Report

Martino

Magenta

Troccoli

et al. 2020

Preprint

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Background:Transcobalamin deficiency is a rare autosomal recessive inborn error of cobalamin transport (prevalence: <1/1000000)whichclinically manifests in early infancy. Case presentation:We describe the case of a 30 year old woman who at the age of 30 days presented with the classical clinical and laboratory signs of an inborn error of vitamin B12 metabolism. Family history revealed a sister who died at the age of 3 months with a similar clinical syndrome and with pancytopenia.Shewas started on empirical intramuscular (IM) cobalamin supplements (injections of hydroxocobalamin 1 mg/day for 1 week and then 1 mg twice a week) and several transfusions of washed and concentrated red blood cells.With thesetreatments a clear improvement in symptoms was observed, with the disappearance of vomiting, diarrhea and normalization of the full blood count.At 8 years of age injections were stopped for 3 monthscausing the reappearance of megaloblastic anemia.IM hydroxocobalamin was then restartedsine die.The definitive diagnosis could only be established at 29 years of age when a genetic evaluation revealed homozygous nonsense variation in exon 8 of the TCN2 gene.Currently she is a 30-year old healthy lady taking 1 mg of IM hydroxocobalamin once a week.Conclusions: Our case report highlights that early detection of TC deficiency and early initiation of aggressive IM treatment is likely associated with disease control and an overall favorable outcome.

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Expression of transcobalamin II by amniocytes

Cited by 23 publications

References 19 publications

Inborn errors of cobalamin absorption and metabolism

Inborn errors of cobalamin absorption and metabolism

New 19 bp deletion polymorphism in intron‐1 of dihydrofolate reductase (DHFR): A risk factor for spina bifida acting in mothers during pregnancy?

Long-term Outcome of a Patient With Transcobalamin Deficiency Caused by Tcn2 Mutation: A Case Report

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