Long-term outcome of a patient with Transcobalamin deficiency caused by the homozygous c.1115_1116delCA mutation in TCN2 gene: a case report.

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.

Transcobalamin deficiency: vitamin B12 deficiency with normal serum B12 levels.

Transcobalamin (TC) deficiency is a rare autosomal recessive inborn error of cobalamin transport which clinically manifests in early infancy. We describe a child with TC deficiency who presented with classical clinical and lab stigmata of inborn error of vitamin B12 metabolism except normal serum B12 levels. He was started on empirical parenteral cobalamin supplements at 2 months of age; however, the definitive diagnosis could only be established at 6 years of age when a genetic evaluation revealed homozygous nonsense variation in exon 8 of the TCN2 gene (chr22:g.31019043C>T).

Update on transcobalamin deficiency: clinical presentation, treatment and outcome.

Transcobalamin (TC) transports cobalamin from blood into cells. TC deficiency is a rare autosomal recessive disorder usually presenting in early infancy with failure to thrive, weakness, diarrhoea, pallor, anemia, and pancytopenia or agammaglobulinemia. It can sometimes resemble neonatal leukemia or severe combined immunodeficiency disease. Diagnosis of TC deficiency is suspected based on megaloblastic anemia, elevation of total plasma homocysteine, and blood or urine methylmalonic acid. It is confirmed by studying the synthesis of TC in cultured fibroblasts, or by molecular analysis of the TCN2 gene. TC deficiency is treatable with supplemental cobalamin, but the optimal type, route and frequency of cobalamin administration and long term patient outcomes are unknown. Here we present a series of 30 patients with TC deficiency, including an update on multiple previously published patients, in order to evaluate the different treatment strategies and provide information about long term outcome. Based on the data presented, current practice appears to favour treatment of individuals with TC deficiency by intramuscular injections of hydroxy- or cyanocobalamin. In most cases presented, at least weekly injections (1 mg IM) were necessary to ensure optimal treatment. Most centres adjusted the treatment regimen based on monitoring CBC, total plasma homocysteine, plasma and urine methylmalonic acid, as well as, clinical status. Finally, continuing IM treatment into adulthood appears to be beneficial.

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.

Transcobalamin (TC) deficiency (OMIM# 275350) is a rare, autosomal recessive disorder that presents in early infancy with a broad spectrum of symptoms, including failure to thrive, megaloblastic anemia, immunological deficiency, and neurological symptoms. Here we report a study of a family (parents and three children) with two children suffering from TC deficiency caused by two different mutations in the TCN2 gene. Initially, molecular genetic analysis of genomic DNA revealed a heterozygous mutation in the +1 position of exon 7 (c.1106+1 G > A) in the father and all three children. Bioinformatic analysis indicates that this mutation causes exon skipping, and further experiments supported this hypothesis and suggested that the mutant allele undergoes nonsense-mediated messenger RNA (mRNA) decay. We did not identify further mutations in genomic DNA that could explain TC deficiency in the two children. However, further efforts using complementary DNA (cDNA) derived from RNA from blood leukocytes identified a large deletion removing the entire exon 8, resulting in a frameshift and a premature stop codon (p.E371fsX372) in the mother and the two affected children. Our data indicate that if exon-by-exon DNA sequencing of genomic DNA does not uncover mutations corresponding to the phenotype, a systematic search for other mutations should be initiated by sequencing cDNA or using semiquantitative methods to detect large deletions in TCN2.

TC II deficiency: avoidance of false-negative molecular genetics by RNA-based investigations.

Transcobalamin II (TC II) is a plasma transport protein for cobalamin. TC II deficiency can lead to infant megaloblastic anemia, failure to thrive and to neurological complications. This report describes the genetic work-up of three patients who presented in early infancy. Initially, genomic investigations did not reveal the definite genetic diagnosis in the two index patients. However, analysis of cDNA from skin fibroblasts revealed a homozygous deletion of exon 7 of the TC II gene caused by the mutation c.940+303_c.1106+746del2152insCTGG (r.941_1105del; p.fs326X) in one patient. The other patients were siblings and both affected by an insertion of 87 bp on the transcript which was caused by the homozygous mutation c.580+624A>T (r.580ins87; p.fs209X). Additional experiments showed that cDNA from lymphocytes could have been used also for the genetic work-up. This report shows that the use of cDNA from skin fibroblasts or peripheral lymphocytes facilitates genetic investigations of suspected TC II deficiency and helps to avoid false-negative DNA analysis.

Hereditary partial transcobalamin II deficiency with neurologic, mental and hematologic abnormalities in children and adults.

BACKGROUND: Transcobalamin II is a serum transport protein for vitamin B12. Small variations in TC-II affinity were recently linked to a high homocysteine level and increased frequency of neural tube defects. Complete absence of TC-II or total functional abnormality causes tissue vitamin B12 deficiency resulting in a severe disease with megaloblastic anemia and immunologic and intestinal abnormalities in the first months of life. This condition was described in hereditary autosomal-recessive form. Low serum TC-II without any symptoms or clinical significance was noted in relatives of affected homozygotes. OBJECTIVES: To study 23 members of a four-generation family with hereditary vitamin B12 deficiency and neurologic disorders. METHODS: Thorough neurologic, hematologic and family studies were supplemented by transcobalamin studies in 20 family members. RESULTS: Partial TC-II deficiency was found in 19 subjects. Apo TC-II (free TC-II unbound to vitamin B12) and total unsaturated B12 binding capacity were low in all tested individuals but one, and holo TC-II (TC-II bound by vitamin B12) was low in all family members. The presentation of the disease was chronic rather than acute. Early signs in children and young adults were dyslexia, decreased IQ, vertigo, plantar clonus and personality disorders. Interestingly, affected children and young adults had normal or slightly decreased serum vitamin B12 levels but were not anemic. Low serum B12 levels were measured in early adulthood. In mid-late adulthood megaloblastic anemia and subacute combined degeneration of the spinal cord were diagnosed. Treatment with B12 injections resulted in a significant improvement. The pedigree is compatible with an autosomal-dominant transmission. This family study suggests a genetic heterogeneity of TC-II deficiency. CONCLUSIONS: We report the first family with a hereditary transmitted condition of low serum TC-II (partial TC-II deficiency) associated with neurologic and mental manifestations in childhood. Partial TC-II deficiency may decrease the amount of stored cobalamin, resulting in increased susceptibility to impaired intestinal delivery of cobalamin and predisposing to clinically expressed megaloblastic anemia at a later age. Partial TC-II deficiency should be suspected in families with megaloblastic anemia and in individuals with neurologic and mental disturbances--despite normal serum vitamin B12 levels. Low serum UBBC and apo TC-II should confirm the diagnosis. Early vitamin B12 therapy may prevent irreversible neurologic damage.

Cellular import of cobalamin (Vitamin B-12).

Recent studies have isolated and characterized human gastric intrinsic factor (IF) and transcobalamin II (TC II) genes, whose products mediate the import of cobalamin (Cbl; Vitamin B-12) across cellular plasma membranes. Analyses of cDNA and genomic clones of IF and TC II have provided some important insights into their sites of expression, structure and function. IF and TC II genes contain the same number, size and position of exons, and four of their eight intron-exon boundaries are identical. In addition, they share high homology in certain regions that are localized to different exons, indicating that IF and TC II may have evolved from a common ancestral gene. Both IF and TC II mediate transmembrane transport of Cbl via their respective receptors that function as oligomers in the plasma membrane. IF-mediated import of Cbl is limited to the apical membranes of epithelial cells; it occurs via a multipurpose receptor recently termed "cubilin," and the imported Cbl is usually exported out of these cells bound to endogenous TC II. On the other hand, TC II-mediated Cbl import occurs in all cells, including epithelial cells via a specific receptor, and the Cbl imported is usually retained, converted to its coenzyme forms, methyl-Cbl and 5'-deoxyadenosyl-Cbl, and utilized.

Homozygous transcobalamin II deficiency maintained on oral hydroxocobalamin.

A case of transcobalamin II (TCII) deficiency in which a total absence of TCII was demonstrated both functionally and immunologically is reported. Unlike previously described patients, this child has been maintained on oral hydroxocobalamin, 2 mg daily, without any parenteral supplementation for the last five years. At the age of six years her development is normal and her health is good. Plasma cobalamin levels are in the range of 3,000 ng/L and most of this appears to be bound to a molecule, which on gel filtration, elutes with albumin. In an extended family study, a clear separation of heterozygotes from both the propositus and from normal subjects suggests that the underlying defect in this condition is confined to a single gene.

Clinical chemistry of vitamin B12.

PIP: This monograph on the clinical chemistry of vitamin B12 reviews the literature on daily requirements, methods for measurement, the effects of drugs on vitamin B12 metabolism absorption, pregnancy, clinical conditions associated with vitamin B12 deficiency, errors of metabolism, and reactions to vitamin therapy. Although only very small quantities of vitamin B12 are required to satisfy the daily requirement, a sufficient supply is stored in the liver to meet normal requirements for at least a 3-year period. A number of drugs are known to affect the absorption of vitamin B12, including neomycin, potassium chloride, p-aminosalicylic acid, and colchicine. Significantly reduced serum concentrations of vitamin B12 have been noted in users of oral contraceptives (OCs), although concentrations still remain within the limits of normal. It appears that the vitamin B12 level in OC users reestablishes itself at a different and somewhat lower level. Vitamin B12 binding protein appears to remain unchanged. A vitamin B12 deficiency is unusual in pregnant women who consume a normal, varied diet. On the other hand, lactating women whose diets are low in animal protein and dairy products may have problems providing enough vitamin B12 to meet their own and their infant's needs; supplementary oral vitamins should be considered.^ieng

[Granulocyte dysfunction in transcobalamin II deficiency]. / Granulozytendysfunktion bei Transcobalamin-II-Mangel.

Granulocytes from a boy with congenital transcobalamin II (TC II) deficiency were found to have abnormally low antibacterial activity against Staphylococcus aureus. Transfusion of normal plasma supplemented with hydroxocobalamin temporarily restored granulocyte bactericidal activity to normal. Granulocyte function was also temporarily restored by oral leucovorin. The defect appears to be causally related to the patient's TC II deficiency and indirectly to an intracellular deficiency of cobalamin and folate coenzymes [1].