Vitamin B12-responsive methylmalonic acidaemia is a genetic metabolic condition and a type of organic acid disorder. People with vitamin B12-responsive methylmalonic acidaemia cannot properly break down certain amino acids (which are building blocks of protein) and some types of fats. Vitamin B12-responsive methylmalonic acidaemia is caused by defects in producing a co-factor called adenosylcobalamin from cobalamin (vitamin B12).¹ Adenosylcobalamin helps the methylmalonyl-CoA mutase enzyme carry out its function. Without adenosylcobalamin, the methylmalonyl-CoA mutase enzyme cannot break down those amino acids and fats, leading to a build-up of methylmalonic acid and other products that are harmful to the body. This can lead to symptoms such as weak muscle tone (hypotonia), excessive tiredness and lack of energy (lethargy), difficulty feeding, dehydration, poor growth and low blood sugar (hypoglycaemia). If left untreated, this can lead to developmental delay, intellectual disability, and renal failure.

There are three different types of vitamin B12-responsive methylmalonic acidaemia, which are caused by genetic changes in different genes:^1,2

• type cblA involves the MMAA gene (on chromosome 4)
• type cblB involves the MMAB gene (on chromosome 12) and tends to be most severe
• type cblDv2 involves the MMADHC gene (on chromosome 2)

In Australia, vitamin B12-responsive methylmalonic acidaemia is often detected shortly after birth via newborn bloodspot screening (NBS) programs. Additional testing is required to confirm the diagnosis. For individuals who are not screened at birth, vitamin B12-responsive methylmalonic acidaemia is often diagnosed after symptoms develop. Vitamin B12-responsive methylmalonic acidaemia can be managed by a low protein diet and vitamin B12 supplementation.

Please note that Vitamin B12-responsive methylmalonic acidaemia differs from methylmalonyl-CoA mutase deficiency (vitamin B12-unresponsive methylmalonic acidaemia), which is caused by a defect in the methylmalonyl-CoA mutase enzyme itself and has different management strategies.

Synonyms:^2,3 Adenosylcobalamin deficiency; adenosylcobalamin synthesis defect; methylmalonic acidemia due to defects in adenosylcobalamin biosynthesis; methylmalonic aciduria, type ii; vitamin b12-responsive methylmalonic aciduria

Note: Vitamin B12-responsive methylmalonic acidaemia is a type of methylmalonic acidemia without homocystinuria [ORPHA:293355] or isolated methylmalonic acidemia (MMA). Other types of MMA include methylmalonyl-CoA mutase deficiency and methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency, which are separate conditions.¹

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:28 Vitamin B12-responsive methylmalonic acidemia

• ORPHA:79310 Vitamin B12-responsive methylmalonic acidemia type cblA
• ORPHA:79311 Vitamin B12-responsive methylmalonic acidemia type cblB
• ORPHA:308442 Vitamin B12-responsive methylmalonic acidemia, type cblDv2

ICD-11: 5C50.E0 Classical organic aciduria

Symptoms of vitamin B12-responsive methylmalonic acidaemia vary between individuals and between the different types. Individuals with type cblA have been reported to have milder symptoms than the other types, especially if the condition is diagnosed and managed early.^1,2

Symptoms often present within the first year or sometime in early childhood. Individuals are at risk of metabolic crisis, such as metabolic acidosis (high levels of acid in blood) and hyperammonaemia (toxic build-up of ammonia in blood). Babies may have low muscle tone (hypotonia), poor feeding, dehydration, vomiting, extreme tiredness and lack of energy (lethargy) and an enlarged liver (hepatomegaly). It may also progress to breathing difficulties and coma. Individuals may also have developmental delay and intellectual disability. Kidney-related complications, including kidney failure, may develop later in life, in teenage years or adulthood.^1,2

Early diagnosis and appropriate management can improve outcomes and reduce or prevent complications for some individuals, in particular those with type cblA.^1,2

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.

Vitamin B12-responsive methylmalonic acidaemia is a genetic condition. It is caused by disease-causing genetic changes (variants) in one of three genes involved in the producing adenosylcobalamin from vitamin B12.  There are three different types of vitamin B12-responsive methylmalonic acidaemia:^1,2

• type cblA involves the MMAA gene (on chromosome 4)
• type cblB involves the MMAB gene (on chromosome 12)
• type cblDv2 involves the MMADHC gene (on chromosome 2)

All individuals have two copies (alleles) of either of those genes – one copy inherited from each parent. Vitamin B12-responsive methylmalonic acidaemia is an autosomal recessive condition, which means both copies of the affected 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, vitamin B12-responsive methylmalonic acidaemia is usually 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 vitamin B12-responsive methylmalonic acidaemia. 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 vitamin B12-responsive methylmalonic acidaemia 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, vitamin B12-responsive methylmalonic acidaemia is often diagnosed after symptoms develop.

Diagnosis of vitamin B12-responsive methylmalonic acidaemia may be made based on clinical evaluation of symptoms, laboratory tests on blood and urine samples to detect for increased levels of proprionylcarnitine (in blood), methylmalonic acid (in blood and urine) as well as other organic acids (in urine) and confirmed by genetic testing.^1,2 Homocysteine levels in the blood are should be within the normal range.

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 methylmalonic acidaemia with homocystinuria (which is characterised by presence of megaloblastic anemia) and methylmalonyl-CoA mutase deficiency.²

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 vitamin B12-responsive methylmalonic acidaemia; however, early diagnosis and appropriate management can improve outcomes and reduce or prevent complications for some individuals, in particular those with type cblA.^1,2

Metabolic crises in vitamin B12-responsive methylmalonic acidaemia can include metabolic acidosis (high levels of acid in blood) and hyperammonaemia (toxic build-up of ammonia in blood), which are medical emergencies and require immediate treatment.

Long-term management of vitamin B12-responsive methylmalonic acidaemia may involve a low-protein diet (with a special nutritional supplement) and injections of vitamin B12 into the muscle (intramuscular injections).^1,2 The recommended amount of protein from food and supplement varies between individuals and may also change over time with age. Individuals with type cblA are generally responsive to the vitamin B12 treatment, whilst responsiveness to the treatment can vary for the other types.

Management strategies of symptoms and complications may include physiotherapy, occupational therapy, speech therapy and treatment of kidney-related complications, which could involve kidney transplantation.^1,4

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 methylmalonyl-CoA mutase deficiency may include general practitioners (GP), paediatricians, geneticists, metabolic physicians, genetic counsellors, metabolic dietitians, neurologists, nephrologists, cardiologists, gastroenterologists, ophthalmologists, physiotherapists, occupational therapists, speech therapists and others. The need for different healthcare professionals may change over a person’s lifetime and extend beyond those listed here. It is recommended that care be managed by a metabolic specialist team.¹

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

Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision was produced by a panel of 21 international healthcare professionals who work in the field of metabolic medicine; published in 2021 and is an update of the following:

Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia published in 2014 and intended for metabolic specialists, pediatricians, dietitians, neonatologists, intensive care specialists, adult physicians, obstetricians, nurses and psychologists involved in the care of MMA/PA patients.

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.

Below are some considerations for the emergency management of individuals living with methylmalonyl-CoA mutase deficiency, including when presenting to emergency departments:¹

• Prolonged fasting, stress and excessive protein intake should be avoided.
• Individuals are at risk of metabolic crises, particularly during times of illness, dehydration, vomiting and fasting. Emergency treatment will be required.
• metabolic specialist team or specialists with expertise in inherited metabolic disorders to be consulted

Australian Organisation:

Metabolic Dietary Disorders Association (MDDA)
Website: https://mdda.org.au/

Metabolic Dietary Disorders Association Inc (MDDA) is the national peak consumer body dedicated to supporting, educating, connecting, and representing all individuals their families and carers living with Inborn Errors of protein Metabolism (IEpM).

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.

Vitamin B12-responsive methylmalonic acidaemia 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

Further information relevant to Vitamin B12-responsive methylmalonic acidaemia can be found at:

• Government of Western Australia Department of Health: Methylmalonic aciduria
• Genetic and Rare Diseases (GARD) Information Center: Vitamin b12-responsive methylmalonic acidemia

Orphanet: Vitamin B12-responsive methylmalonic acidemia

• ORPHA:79310 Vitamin B12-responsive methylmalonic acidemia type cblA
• ORPHA:79311 Vitamin B12-responsive methylmalonic acidemia type cblB
• ORPHA:308442 Vitamin B12-responsive methylmalonic acidemia, type cblDv2

Online Mendelian Inheritance in Man, OMIM^®: #251100 – Methylmalonic aciduria, cblA TYPE; MACA

Online Mendelian Inheritance in Man, OMIM^®: #251110 – Methylmalonic aciduria, cb1B TYPE;MACB

Online Mendelian Inheritance in Man, OMIM^®: #620953 – Methylmalonic aciduria, cblD TYPE; MACD 

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