Methylmalonyl-CoA mutase deficiency, also known as Vitamin B12-unresponsive methylmalonic acidaemia, is a genetic, metabolic condition and a type of organic acid disorder. It is caused by genetic changes in the MUT gene that is responsible for producing the methylmalonyl-CoA mutase enzyme.^1,2 The methylmalonyl-CoA mutase enzyme is a mitochondrial enzyme involved in a multi-step process of breaking down certain amino acids (which are building blocks of protein) and some types of fats in the body.³ When the methylmalonyl-CoA mutase enzyme is not working properly, it affects how those amino acids and fats are broken down and leads to a build-up of methylmalonic acid and other products that are harmful to the body.

Methylmalonyl-CoA mutase deficiency can be caused by complete or partial loss of methylmalonyl-CoA mutase enzyme activity.^1,2 Individuals with genetic changes that cause complete loss of enzyme activity have more severe symptoms than those with partial loss of enzyme activity.^2-5 Symptoms may include weak muscle tone (hypotonia), excessive tiredness and lack of energy (lethargy), difficulty feeding, dehydration, poor growth and low blood sugar (hypoglycaemia).^1-4 If left untreated, this can lead to developmental delay, intellectual disability, and life-threatening complications that can result in coma and early death.

In Australia, methylmalonyl-CoA mutase deficiency is often detected shortly after birth via newborn bloodspot screening (NBS) programs. Additional testing is required for diagnosis. For individuals who are not screened at birth, methylmalonyl-CoA mutase deficiency is often diagnosed after symptoms develop.

Synonyms: Methylmalonyl-Coenzyme A mutase deficiency; Vitamin B12-unresponsive methylmalonic aciduria; Vitamin B12-unresponsive methylmalonic acidemia

Note: Methylmalonyl-CoA mutase deficiency is a type of methylmalonic acidemia without homocystinuria [ORPHA:293355] or isolated methylmalonic acidemia (MMA). Other types of MMA include vitamin B12-responsive methylmalonic acidaemia and methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency, which are separate conditions.²

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:27 Vitamin B12-unresponsive methylmalonic acidemia

•  ORPHA:79312 Vitamin B12-unresponsive methylmalonic acidemia type mut-
• ORPHA:289916 Vitamin B12-unresponsive methylmalonic acidemia type mut0

ICD-11: 5C50.E0 Classical organic aciduria

Symptoms of methylmalonyl-CoA mutase deficiency vary between individuals and often depend on the amount of remaining methylmalonyl-CoA mutase enzyme activity. Individuals with complete loss of enzyme activity (mut0) have more severe symptoms than those with partial loss of enzyme activity (mut-).^2-5

Symptoms are not observed at birth but in most cases (usually associated with mut0), symptoms present during early childhood and are often severe and life-threatening.^1-5 For some individuals (particularly those with mut-), symptoms may only present later, and usually during periods of illness. Symptoms tend to present as severe metabolic crisis with metabolic acidosis (high levels of acid in blood), build-up of ketones in the blood (ketosis) and urine (ketonuria), and hyperammonaemia (toxic build-up of ammonia in blood). Babies may have low muscle tone (hypotonia), poor feeding and extreme tiredness and lack of energy (lethargy). Symptoms may present in older children as poor growth. An enlarged liver (hepatomegaly) may be observed. If the metabolic crisis is left untreated, this can progress to encephalopathy (where brain function is affected), seizures, coma and early death. Repeated episodes of metabolic crises can also result in developmental delay, intellectual delay and movement disorders. Other long-term complications include kidney disease, inflammation of pancreas (pancreatitis) and optic atrophy (damage to the optic nerve which can affect vision). Other body systems may also be affected.

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.

Orphanet: Disability – ORPHA:289916 Vitamin B12-unresponsive methylmalonic acidemia type mut0  has information about the activity limitations that people with vitamin B12-unresponsive methylmalonic acidemia type mut0 may face; please note that this was last updated in 2022 and may not reflect the most current information.

Information about the activity limitations of people with vitamin B12-unresponsive methylmalonic acidemia type mut- is not currently available.

Methylmalonyl-CoA mutase deficiency is a genetic condition. It is caused by disease-causing genetic changes (variants) in the MUT gene on Chromosome 6.^1,2 The MUT gene is responsible for producing the methylmalonyl-CoA mutase enzyme. Methylmalonyl-CoA mutase deficiency can be caused by complete (mut0) or partial (mut-) loss of methylmalonyl-CoA mutase enzyme activity.

All individuals have two copies (alleles) of the MUT gene – one copy inherited from each parent. Methylmalonyl-CoA mutase deficiency is an autosomal recessive condition, which means both copies of the MUT 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, methylmalonyl-CoA mutase deficiency 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 methylmalonyl-CoA mutase 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 methylmalonyl-CoA mutase 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, methylmalonyl-CoA mutase deficiency is often diagnosed after symptoms develop.

Diagnosis of methylmalonyl-CoA mutase deficiency 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.⁶ 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, vitamin B12-responsive methylmalonic acidaemia as well as other types of isolated methylmalonic acidaemia.

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 methylmalonyl-CoA mutase deficiency; however, early diagnosis and appropriate management can reduce or prevent the risk of early death and long-term complications.^2-4,7

Metabolic crises in methylmalonyl-CoA mutase deficiency can include metabolic acidosis (high levels of acid in blood), build-up of ketones in the blood (ketosis) and urine (ketonuria), and hyperammonaemia (toxic build-up of ammonia in blood), which are medical emergencies and require immediate treatment.

Long-term management of methylmalonyl-CoA mutase deficiency may involve a low-protein diet and a special nutritional supplement, with monitoring and regular attendance at a metabolic clinic.^2,6,7 The recommended amount of protein from food and supplement varies between individuals and may also change over time with age. Prolonged fasting should be avoided. Carnitine supplementation may be considered for some individuals to help the body remove the toxic byproducts that build up. 

Methylmalonyl-CoA mutase deficiency, which is also known as vitamin B12-unresponsive methylmalonic acidaemia, does not respond to vitamin B12 supplementation as a treatment strategy, unlike for another type of methylmalonic acidaemia (vitamin B12-responsive methylmalonic acidaemia).

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.²

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:

• 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

Metabolic Dietary Disorders Association (MDDA): Latest Research Updates has information about key areas of ongoing research for various inborn errors of metabolism conditions, including organic acidaemias.

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.

Methylmalonyl-CoA mutase 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

Further information relevant to methylmalonyl-CoA mutase deficiency can be found at:

• Government of Western Australia Department of Health: Methylmalonic aciduria
• Genetic and Rare Diseases (GARD) Information Center: Methylmalonic aciduria due to methylmalonyl-coa mutase deficiency
• National Organization for Rare Disorders: methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Orphanet: Vitamin B12-unresponsive methylmalonic acidemia

Online Mendelian Inheritance in Man, OMIM^®: #251000 – Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency; MAMM

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

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