Transcobalamin II deficiency (TCII deficiency) is a genetic, metabolic condition caused by a defect in transporting cobalamin (vitamin B12) into cells. Vitamin B12 is found in many foods and is important for the body to make red blood cells and DNA (genetic material), and to support the body’s nervous system and overall function.¹ In TCII deficiency, the transcobalamin protein, which carries vitamin B12 in a form that gets transported into cells, does not work properly.^2,3 This prevents vitamin B12 from getting into cells. Decreased vitamin B12 in cells can also lead to increased homocysteine and methylmalonic acidaemia, which can be harmful to the body.

Symptoms of TCII deficiency that present early on in life may include failure to thrive (not growing and gaining weight as expected), lack of energy (lethargy), vomiting and diarrhea.^1-4 Individuals with TCII deficiency also often have a blood disorder called megaloblastic anaemia (where the body has abnormally large red blood cells and less healthy red blood cells) and pancytopenia (low levels of red blood cells, white blood cells and platelets) and are at risk of repeated, life-threatening infections.

In Australia, TCII deficiency may be detected shortly after birth via newborn bloodspot screening (NBS) programs. For individuals who are not screened at birth, TCII deficiency is often diagnosed after symptoms develop.

Synonyms:^2,4 Inherited deficiency of transcobalamin II; TC; TCN2D

Universal rare disease classifications provide a common language for recording, reporting and monitoring diseases. Please visit the Rare Disease Classifications page for more information about these internationally recognised classifications.

ORPHA:859 Transcobalamin II deficiency

ICD-11: 3A01.0 Hereditary vitamin B12 deficiency anaemia

Whilst symptoms of TCII deficiency are not present at birth, they often develop during the first few months of life.^1-4 Initial symptoms may include failure to thrive (not growing and gaining weight as expected), weight loss, lack of energy (lethargy), pallor (pale appearance), mouth ulcers, vomiting and diarrhea. They also often have a blood disorder called megaloblastic anaemia (where the body has abnormally large red blood cells and less healthy red blood cells) and pancytopenia (low levels of red blood cells, white blood cells and platelets) and have severe repeated infections, which can be life-threatening. If not diagnosed early and treated, individuals may develop developmental delay, intellectual disability, weakness, ataxia (loss of muscle coordination and control), and neuropathy.

TCII deficiency can be severe, life-threatening and symptoms can worsen quickly over time (rapidly progressing.¹ In rare cases, individuals may not have any symptoms (asymptomatic).

There may be other symptoms or complications that have not been listed here. Please speak to your medical team to learn more about the symptoms of this condition.

Rare diseases are often serious and progressive, exhibiting a high degree of symptom complexity, leading to significant disability. Majority of the estimated two million Australians living with a rare disease meet the Australian Government’s definition for disability (in accordance to the Australian Public Service Commission and Australian Bureau of Statistics), and many experience severe and permanent disability impacts. If you or someone you care for is experiencing disability-related impacts from a rare condition, please speak with a health or disability professional for advice. Information about relevant disability support can be found at the RARE Portal’s Disability Support Information page.

TCII deficiency is a genetic condition. It is caused by disease-causing genetic changes (variants) in the TCN2 gene on chromosome 22.^2,4 The TCN2 gene is responsible for producing the transcobalamin protein, which is a transport protein for cobalamin (vitamin B12).

All individuals have two copies (alleles) of the TCN2 gene – one copy inherited from each parent. TCII deficiency is an autosomal recessive condition, which means both copies of the TCN2 gene must have the disease-causing genetic variants. More information on autosomal recessive inheritance pattern can be found at Centre for Genetics Education: Autosomal recessive inheritance.

If you would like to learn more about the inheritance and impact of this condition, please ask your doctor for a referral to a genetic counsellor. Genetic counsellors are qualified allied health professionals who can provide information and support regarding genetic conditions and testing. More information about genetic counselling can be found at:

• Information on Genetic Services
• The National and State Services pages underneath the ‘Genetic Counselling’ sections listed

Newborn screening

In Australia, TCII deficiency may be detected via the newborn bloodspot screening (NBS) programs.  Shortly after birth and with parental consent, a nurse or midwife will collect the baby’s blood via a heel prick blood test. The healthcare provider will then send it to a specific laboratory to test for a range of rare conditions, including TCII deficiency. If the test results suggest that there is a risk of the baby having one of the screened conditions, laboratory staff will promptly get in touch with healthcare providers. The healthcare providers will then arrange for the baby to have further testing to confirm if the baby actually has the condition. The healthcare providers will also organise for the baby to receive urgent care if required. Depending on your state or territory, parents may or may not receive a notification if the test results are clear. You can find out more about NBS in your state or territory at Australian Government Department of Health, Disability and Ageing: Delivering newborn bloodspot screening programs.

Newborn bloodspot screening is a reliable way to check for certain rare conditions early in life. Although it’s extremely rare, cases can sometimes be missed. If you are concerned your baby may have a condition that they have already been screened for, you should contact a medical professional.

Diagnosis

A diagnosis of TCII deficiency may be suspected based on an abnormal result from NBS but additional tests or a clinical examination will be required to confirm a diagnosis. For individuals who are not screened at birth, TCII deficiency is often diagnosed after symptoms develop.

Diagnosis of TCII deficiency may be made based on clinical evaluation of symptoms, laboratory tests to detect pancytopenia (low levels of red blood cells, white blood cells, and platelets), elevated levels of homocysteine and methylmalonic acid, and reduced unsaturated vitamin B12-binding capacity, and confirmed by quantification of serum transcobalamin or genetic testing.^2,3 Serum cobalamin levels are usually not detected to be low.

As part of the diagnostic process, doctors may do a differential diagnosis, which is to rule out other conditions that have similar symptoms, such as inborn errors of cellular cobalamin metabolism such as methylmalonic acidaemia with homocystinuria, inherited disorders of intestinal cobalamin absorption (Gräsbeck-Imerslund disease and congenital intrinsic factor deficiency), pernicious anaemia and myelodysplastic syndrome (MDS).^2,5

Please speak to your medical team to learn more about the available pathways for diagnosis of this condition.

There is currently no curative treatment for TCII deficiency; however, early diagnosis and appropriate management can improve outcomes and reduce or prevent life-threatening and long-term complications.

Management of TCII deficiency may involve injections of hydroxocobalamin into the muscle (intramuscular injections) with regular monitoring.^2,3 Treatment with intramuscular injections of hydroxocobalamin is recommended over taking it orally or treatment with cyanocobalamin. Intravenous cobalamin is not recommended.³

Please speak to your medical team to learn more about the possible treatment or management options for your condition. Treatment will depend on an individual’s specific condition and symptoms. It is also important to stay connected to your medical team so that you can be made aware of any upcoming clinical trial opportunities. For many rare diseases, treatment options may be limited. Participation in a clinical trial may provide access to new or emerging therapies.

Healthcare professionals involved in the clinical care of individuals with TCII deficiency may include general practitioners (GP), paediatricians, geneticists, genetic counsellors, immunologists and haematologists.¹ The need for different healthcare professionals may change over a person’s lifetime and extend beyond those listed here. 

Clinical care for rare diseases often involves a multidisciplinary team of medical, care and support professionals. Please note that the information provided here is as a guide and that RVA does not necessarily monitor or endorse specific clinics or health experts.

This may not be applicable to all rare diseases but for many, palliative care services may be relevant and useful. Palliative care services are available for people (adults, children and their families) living with a life-limiting illness and is not only for end-of-life care. It can also help at any stage of illness from diagnosis onwards, and will look different for different people. Palliative care services provide assistance, support, resources and tools to help people manage their illness and the symptoms, ease pain, and improve comfort and quality of life. If this is relevant to you and you wish to find out more information about palliative care and how it can help you, please visit:

• Australian Institute of Health and Welfare: Palliative care Overview
• Australian Government Department of Health, Disability and Ageing: Palliative care
• Palliative Care Australia

If you know of any relevant clinical care guidelines, please let us know via the  Contribute page.

Individuals living with rare diseases may have complex medical issues and disabilities, which are not always visible. It is often useful to refer to their medical history as well as personal information such as a medical card, doctor’s letter, or if available, a rare disease passport, for relevant information.

In addition, individuals, their parents, families and carers often develop extensive expertise on their specific rare disease. It is important to recognise that they can contribute valuable knowledge about their rare condition. Rare diseases often impact individuals differently, so it’s important to consider a person’s lived experience.

If you know of any relevant emergency management guidelines or information relevant to emergency care, please let us know via the  Contribute page.

We are not aware of any rare disease organisations specifically for TCII deficiency in Australia. If you are aware of any relevant Australian organisations, please let us know via the Contribute page.

Genetics Alliance Australia (GAA) may be able to provide some support for families and individuals affected by an undiagnosed or rare genetic condition for which there is no disease specific organisation in Australia.

Please note that RVA does not monitor or endorse each group/organisation’s operational governance and activities. When engaging with a group, please consider the information on the RARE Portal’s Finding Helpful Peer and Community Supports page.

TCII deficiency varies between individuals, and each person’s experience is unique.

If you would like to share your personal story with RVA, please visit the Rare Voices Australia: Share Your Story page. RVA will consider your story for publishing on our website and inclusion on the RARE Portal.

For information on available government and social services that provide support for individuals with a rare disease, please visit the National and State Services pages.

People living with a rare disease often face unique challenges such as diagnostic delays, misdiagnoses, limited treatment options, and limited access to rare disease specialists and support. These challenges may impact people’s emotional wellbeing and quality of life. Many find it helpful to seek mental health and wellbeing support to cope with ongoing stress and uncertainty. Connecting with people who have shared experiences through a support group may also be helpful. Information about relevant mental health and wellbeing support can be found at:

• Mental Health and Wellbeing Support for Australians Living with a Rare Disease
• The National and State Services pages underneath the ‘Mental Health’ sections listed

Genetic and Rare Diseases (GARD) Information Center: Transcobalamin ii deficiency

MedlinePlus Genetics: Transcobalamin deficiency

Orphanet: Transcobalamin II deficiency

Online Mendelian Inheritance in Man, OMIM^®: #275350 – Transcobalamin II deficiency; TCN2D

This page has been developed by Rare Voices Australia (RVA)’s RARE Portal team.

If you are aware of any additional information that may benefit stakeholders with an interest in this page, or if you notice any broken links or inaccurate information, please let us know via the Contribute page.