Congenital Deficiency of Transcobalamin II (TC II Deficiency)
What is Congenital Deficiency of Transcobalamin II (TC II Deficiency)?
Congenital deficiency of transcobalamin II (TC II deficiency) is a rare genetic disorder affecting the transport of vitamin B12 (cobalamin) into body cells. Transcobalamin II is a key protein that binds to vitamin B12 and facilitates its movement into cells for DNA synthesis and red blood cell production. Without this protein, individuals are unable to properly utilize vitamin B12, leading to severe anemia, developmental delays, and other health issues. Early diagnosis and intervention are critical for managing the condition and preventing long-term complications.
Synonyms
- TC II Deficiency
- Hereditary Transcobalamin Deficiency
- Congenital Transcobalamin II Deficiency
Congenital deficiency of transcobalamin II (TC II deficiency) is a rare genetic disorder affecting the transport of vitamin B12 (cobalamin) into body cells. Transcobalamin II is a key protein that binds to vitamin B12 and facilitates its movement into cells for DNA synthesis and red blood cell production. Without this protein, individuals are unable to properly utilize vitamin B12, leading to severe anemia, developmental delays, and other health issues. Early diagnosis and intervention are critical for managing the condition and preventing long-term complications.
TC II deficiency is extremely rare, with fewer than 100 cases reported globally. The disorder affects individuals of all ethnic backgrounds and occurs equally in males and females.
| Name | Abbreviation |
|---|---|
| TC II Deficiency | |
| Hereditary Transcobalamin Deficiency | |
| Congenital Transcobalamin II Deficiency |
The condition is caused by mutations in the TCN2 gene, located on chromosome 22. This gene encodes the transcobalamin II protein, responsible for transporting vitamin B12 from the bloodstream into cells. The mutations in the TCN2 gene lead to either a nonfunctional or completely absent transcobalamin II protein, disrupting B12 metabolism and leading to the characteristic symptoms of the disease.
The disease is inherited in an autosomal recessive pattern, where both parents must be carriers of the genetic mutation to have an affected child. Carriers are asymptomatic. There is a 25% chance of having an affected child if both parents are carriers (see RareShare Guide on Genetic Inheritance).
Symptoms usually appear in infancy but can vary in severity. The most common symptoms include:
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Failure to thrive and feeding difficulties
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Severe megaloblastic anemia (characterized by large, immature red blood cells)
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Recurrent infections due to low white blood cell counts (neutropenia)
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Developmental delays
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Neurological issues such as muscle weakness, cognitive impairment, irritability
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Gastrointestinal symptoms like vomiting and diarrhea
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Fatigue and general weakness
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Poor growth.
Without treatment, the condition can lead to life-threatening complications, including neurological damage and severe infections.
Diagnosis is based on a combination of clinical symptoms and laboratory tests:
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Blood tests: These may show low levels of transcobalamin-bound B12 (holotranscobalamin), elevated methylmalonic acid (MMA), and elevated homocysteine levels.
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Genetic testing: Confirms the presence of mutations in the *TCN2* gene.
Bone marrow biopsy: May reveal megaloblastic anemia in more severe cases.
The main treatment is lifelong vitamin B12 supplementation. Since oral vitamin B12 cannot be properly absorbed due to the transport defect, treatment requires lifelong parenteral (intramuscular) injections of hydroxocobalamin (a form of vitamin B12). Early and consistent administration of vitamin B12 can prevent many of the complications associated with the disease, including neurological damage and anemia.
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Infection management: Due to the risk of recurrent infections, patients may also need antibiotics or supportive care to manage infections.
Monitoring: Regular monitoring of vitamin B12 levels, MMA, and homocysteine is essential to ensure effective treatment.
With early diagnosis and treatment, many individuals with TC II deficiency can live normal, healthy lives. However, delays in diagnosis and treatment can result in permanent neurological damage, developmental delays, or death. Lifelong vitamin B12 supplementation is usually required to maintain health.
1. Orphanet: Congenital Transcobalamin II Deficiency. Orphanet Report Series, 2022.
2. Sharma, L. et al. "Congenital Transcobalamin II Deficiency: A Rare Cause of Megaloblastic Anemia in Infants." Pediatric Hematology-Oncology Journal, 2022.
3. Gordon, N. "Congenital Transcobalamin II Deficiency: Diagnostic and Treatment Guidelines." Journal of Rare Genetic Disorders, 2020.
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Clinical Trials
CoRDS, or the Coordination of Rare Diseases at Sanford, is based at Sanford Research in Sioux Falls, South Dakota. It provides researchers with a centralized, international patient registry for all rare diseases. This program allows patients and researchers to connect as easily as possible to help advance treatments and cures for rare diseases. The CoRDS team works with patient advocacy groups, individuals and researchers to help in the advancement of research in over 7,000 rare diseases. The registry is free for patients to enroll and researchers to access.
Enrolling is easy.
- Complete the screening form.
- Review the informed consent.
- Answer the permission and data sharing questions.
After these steps, the enrollment process is complete. All other questions are voluntary. However, these questions are important to patients and their families to create awareness as well as to researchers to study rare diseases. This is why we ask our participants to update their information annually or anytime changes to their information occur.
Researchers can contact CoRDS to determine if the registry contains participants with the rare disease they are researching. If the researcher determines there is a sufficient number of participants or data on the rare disease of interest within the registry, the researcher can apply for access. Upon approval from the CoRDS Scientific Advisory Board, CoRDS staff will reach out to participants on behalf of the researcher. It is then up to the participant to determine if they would like to join the study.
Visit sanfordresearch.org/CoRDS to enroll.
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