Abstract: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, … Show more
“…Our hypothesis was con rmed genetically only at the age of 29 years of age when we found a c.115_116delCA homozigous mutation in TCN2 gene, further con rmed by the parents'genetic analysis that showed the same mutation in the heterozygous status. About 50 cases have been reported in the literature of TCN2 variants (20), our mutation c.115_116delCA in exon 8 was cited among these, indeed it was reported in only one patient in which this mutation was present in association with c.501_503delCCA in exon 4. In silico analysis demonstrate that exon 8 is the region involved in cobalamin binding site, whereas mutation in exon 4 should affect TC-TC receptor interaction (15).…”
Section: Discussionmentioning
confidence: 58%
“…Twenty-ve pathogenic mutations in TCN2 gene have been identi ed (10). Nonsense mutations and point mutations that activate exonic cryptic splice sites have also been reported (12,13), as well as, polymorphic variants have also been described (8,13).…”
Background: Transcobalamin deficiency is a rare autosomal recessive inborn error of cobalamin transport (prevalence: <1/1000000) which clinically manifests in early infancy.Case presentation: We describe the case of a 31 years 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. She was 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 these treatments 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 about two and a half months causing the appearance of pancytopenia. IM hydroxocobalamin was then restarted sine die. The definitive diagnosis could only be established at 29 years of age when a genetic evaluation revealed the homozygous c.1115_1116delCA mutation of TCN2 gene (p.Q373GfsX38).Currently she is healthy and she is 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.
“…Our hypothesis was con rmed genetically only at the age of 29 years of age when we found a c.115_116delCA homozigous mutation in TCN2 gene, further con rmed by the parents'genetic analysis that showed the same mutation in the heterozygous status. About 50 cases have been reported in the literature of TCN2 variants (20), our mutation c.115_116delCA in exon 8 was cited among these, indeed it was reported in only one patient in which this mutation was present in association with c.501_503delCCA in exon 4. In silico analysis demonstrate that exon 8 is the region involved in cobalamin binding site, whereas mutation in exon 4 should affect TC-TC receptor interaction (15).…”
Section: Discussionmentioning
confidence: 58%
“…Twenty-ve pathogenic mutations in TCN2 gene have been identi ed (10). Nonsense mutations and point mutations that activate exonic cryptic splice sites have also been reported (12,13), as well as, polymorphic variants have also been described (8,13).…”
Background: Transcobalamin deficiency is a rare autosomal recessive inborn error of cobalamin transport (prevalence: <1/1000000) which clinically manifests in early infancy.Case presentation: We describe the case of a 31 years 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. She was 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 these treatments 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 about two and a half months causing the appearance of pancytopenia. IM hydroxocobalamin was then restarted sine die. The definitive diagnosis could only be established at 29 years of age when a genetic evaluation revealed the homozygous c.1115_1116delCA mutation of TCN2 gene (p.Q373GfsX38).Currently she is healthy and she is 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.
“…Later, when transcobalamin defect and its associated increased homocysteine level was suspected, plasma homocysteine level was measured using a separate specific test. Less than 60 patients and 50 TCN2 variants have been reported worldwide in which many cases were reported from regions with a high rate of consanguinity, including Turkey [1,2,[11][12][13][14]. To our knowledge, the present patient is the first case report from a Southeast Asian country with a novel TCN2 variant, c.428-2A > G. The variant was subsequently submitted to ClinVar database and now is accessible using a number SCV001981507 (https:// www.…”
Section: Discussionmentioning
confidence: 99%
“…A case report of a TC deficiency patient who exhibited urinary methylmalonic acid excretion at birth may indicate intrauterine onset of the metabolic derangement and neurologic damage of this intriguing disorder [18]. This may explain neurocognitive impairment in some patients despite receiving prompt diagnosis and treatment at birth [14].…”
Background
Transcobalamin deficiency is a rare inborn metabolic disorder, characterized by pancytopenia, megaloblastic anemia, failure to thrive, diarrhea, and psychomotor retardation.
Case presentation
We describe a patient who first presented at 3 months of age, with pancytopenia, hepatosplenomegaly, recurrent infection, metabolic acidosis, and acute hemolytic crisis. Extensive hematologic and immunologic investigations did not identify inherited bone marrow failure syndrome, acute leukemia or its related disorders. Whole exome sequencing identified a novel homozygous TCN2 mutation, c.428-2A > G and mRNA study confirmed an aberrant transcription of exon 4 skipping. The mutant protein is predicted to have an in-fame 51 amino acids deletion (NP_000346:p.Gly143_Val193del). The patient exhibited marked clinical improvement following hydroxocobalamin treatment.
Conclusions
Transcobalamin deficiency should be investigated in infants with unexplained pancytopenia and acute hemolytic crisis with or without typical evidence of vitamin B12 deficiency.
“…The aberrant expression of TCN2 gene is a mechanism contributing to the pathogenesis of TC deficiency. Currently, about 60 cases of TC deficiency have been reported worldwide (Trakadis et al, 2014;Kose et al, 2020), with only one case from China (Zhan et al, 2020). A total of 48 variants in TCN2 gene have been reported in HGMD to date, including 38 diseasecausing mutations (Figure 2).…”
Transcobalamin (TC) deficiency is a rare autosomal recessive disease characterized by megaloblastic anemia. It is caused by cellular vitamin B12 depletion, which subsequently results in elevated levels of homocysteine and methylmalonic acid. This disease is usually diagnosed by genetic analysis of the TCN2 gene. Here, we described a 2.2-month-old Chinese girl with TC deficiency presenting with diarrhea, fever and poor feeding. Whole-exome sequencing detected a pair of compound-heterozygous mutations in TCN2 gene, c.754-12C>G and c.1031_1032delGA (p.R344Tfs*20). To our knowledge, it is the first time that they were identified and reported in TC deficiency. This study contributes to a better understanding of the TC deficiency, expanding the spectrum of TCN2 mutations in this disorder and also supporting the early diagnosis and proper treatment of similar cases in the future.
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