Transcobalamin deficiency caused by compound heterozygosity for two novel mutations in the <i>TCN2</i> gene: a study of two affected siblings, their brother, and their parents

Nissen, Peter H.; Nordwall, Maria; Hoffmann-Lücke, Elke; Sørensen, Boe Sandahl; Nexø, Ebba

doi:10.1007/s10545-010-9145-z

Cited by 13 publications

(7 citation statements)

References 23 publications

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“…The affected child displays few symptoms at birth, but within months a severe deficiency develops and, if left untreated, it leads to lifelong impair ments due to neurological damage. [23][24][25][26][27] Several different kinds of mutations leading to a lack of transcobalamin have been identified, including deletions and mutations resulting in erroneous RNA editing. [23][24][25][26][27] Haptocorrin is heavily glycosylated and is expressed in many, but not all, mammals.…”

Section: Introductionmentioning

confidence: 99%

Vitamin B12 transport from food to the body's cells—a sophisticated, multistep pathway

Nielsen

Rasmussen

Andersen

et al. 2012

Nat Rev Gastroenterol Hepatol

314

329

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Vitamin B(12) (B(12); also known as cobalamin) is a cofactor in many metabolic processes; deficiency of this vitamin is associated with megaloblastic anaemia and various neurological disorders. In contrast to many prokaryotes, humans and other mammals are unable to synthesize B(12). Instead, a sophisticated pathway for specific uptake and transport of this molecule has evolved. Failure in the gastrointestinal part of this pathway is the most common cause of nondietary-induced B(12) deficiency disease. However, although less frequent, defects in cellular processing and further downstream steps in the transport pathway are also known culprits of functional B(12) deficiency. Biochemical and genetic approaches have identified novel proteins in the B(12) transport pathway--now known to involve more than 15 gene products--delineating a coherent pathway for B(12) trafficking from food to the body's cells. Some of these gene products are specifically dedicated to B(12) transport, whereas others embrace additional roles, which explains the heterogeneity in the clinical picture of the many genetic disorders causing B(12) deficiency. This Review describes basic and clinical features of this multistep pathway with emphasis on gastrointestinal transport of B(12) and its importance in clinical medicine.

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Section: Introductionmentioning

confidence: 99%

Vitamin B12 transport from food to the body's cells—a sophisticated, multistep pathway

Nielsen

Rasmussen

Andersen

et al. 2012

Nat Rev Gastroenterol Hepatol

314

329

View full text Add to dashboard Cite

show abstract

“…No genotype-phenotype correlation was reported in TC deficiency. Previously, insertions, deletions, splice-site, and nonsense mutations were reported [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] (Table 2). In our patients, we revealed a novel nonsense premature stop codon variation in exon two of the TCN2 gene.…”

Section: Discussionmentioning

confidence: 99%

“…Further biochemical investigations revealed elevated serum homocysteine levels (44.8 mmol/L [5][6][7][8][9][10][11][12][13][14][15]) and elevated urine methylmalonic acid levels (756.4 μmol/L [<3.6]). Plasma ammonia and lactate levels were within the normal range.…”

Section: Casementioning

confidence: 99%

Transcobalamin II deficiency in twins with a novel variant in the TCN2 gene: case report and review of literature

Köse

Besci

Güdeloğlu

et al. 2020

Journal of Pediatric Endocrinology and Metabolism

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ObjectivesTranscobalamin II (TC) is an essential plasma protein for the absorption, transportation, and cellular uptake of cobalamin. TC deficiency presents in the first year of life with failure to thrive, hypotonia, lethargy, diarrhea, pallor, mucosal ulceration, anemia, pancytopenia, and agammaglobulinemia. Herein, we present TC deficiency diagnosed in two cases (twin siblings) with a novel variant in the TCN2 gene.Case presentation4-month-old twins were admitted with fever, respiratory distress, vomiting, diarrhea, and failure to thrive. Physical examination findings revealed developmental delay and hypotonia with no head control, and laboratory findings were severe anemia, neutropenia, and hypogammaglobulinemia. Despite normal vitamin B12 and folate levels, homocysteine and urine methylmalonic acid levels were elevated in both patients. Bone marrow examinations revealed hypocellular bone marrow in both cases. The patients had novel pathogenic homozygous c.241C>T (p.Gln81Ter) variant in the TCN2 gene. In both cases, with intramuscular hydroxycobalamin therapy, laboratory parameters improved, and a successful clinical response was achieved.ConclusionsIn infants with pancytopenia, growth retardation, gastrointestinal manifestations, and immunodeficiency, the inborn error of cobalamin metabolism should be kept in mind. Early diagnosis and treatment are crucial for better clinical outcomes. What is new? In literature, to date, less than 50 cases with TC deficiency were identified. In this report, we presented twins with TCN2 gene mutation. Both patients emphasized that early and aggressive treatment is crucial for achieving optimal outcomes. In this report, we identified a novel variation in TCN2 gene.

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“… Namour et al 2003 [ 7 ] 1 c.64 + 4A > T p.? Nashabat et al 2017 [ 14 ] 7 c.1106 + 1G > A p.Met315fs Nissen et al 2010 [ 15 ] 8 deletion ex. 8 p.?…”

Section: Introductionmentioning

confidence: 99%

Identification of transcobalamin deficiency with two novel mutations in the TCN2 gene in a Chinese girl with abnormal immunity: a case report

Zhan

Cheng

et al. 2020

BMC Pediatr

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Background Transcobalamin (TC) transports vitamin B12 from blood into cells. TC II deficiency is a rare autosomal recessive disorder. It is characterized by failure to thrive, diarrhoea, pallor, anaemia, pancytopenia or agammaglobulinemia. It is usually confirmed by molecular analysis of the TCN2 gene. We report a 2-month-old girl with two novel mutations, which were first reported in humans. Case presentation We present a 2-month-old Chinese girl with pancytopenia, severe combined immunodeficiency disease, and megaloblastic anaemia. Targeted next-generation sequencing (NGS) was performed, which detected compound heterozygous variants in exon 7 of the TCN2 gene (Mutation 1: c.1033 C > T; Mutation 2: c.1017-1031delinsGTAACAGAGATGGTT). These mutations result in stop codons in TCN2. The c.1033C > T mutation causes a stop at codon 345 (p.Gln345Ter), and the c.1017-1031delinsGTAACAGAGATGGTT mutation causes a stop at codon 340 (p.Leu340Ter). After being diagnosed, she was treated with intramuscular 1 mg hydroxycobalamin (OH-Cbl) every day for 2 months. The CBC value returned to normal after half a month. The peripheral blood lymphocyte subsets and immunoglobulin recovered after 2 months. Then, the dosage of OH-Cbl was gradually reduced. Conclusions TC II deficiency is a serious complication that requires lifelong treatment. Its diagnosis is difficult due to the lack of clearly identifiable symptoms. Genetic testing should be performed as early as possible if this disease is suspected. The specific observations of this case report make a considerable contribution to the literature and provide a reference for the diagnosis and treatment of future cases.

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Transcobalamin deficiency caused by compound heterozygosity for two novel mutations in the TCN2 gene: a study of two affected siblings, their brother, and their parents

Cited by 13 publications

References 23 publications

Vitamin B12 transport from food to the body's cells—a sophisticated, multistep pathway

Vitamin B12 transport from food to the body's cells—a sophisticated, multistep pathway

Transcobalamin II deficiency in twins with a novel variant in the TCN2 gene: case report and review of literature

Identification of transcobalamin deficiency with two novel mutations in the TCN2 gene in a Chinese girl with abnormal immunity: a case report

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