Methylmalonic acidaemia with homocystinuria is a genetic metabolic condition and a type of organic acid disorder. It is also known as combined adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) deficiency, as people with this condition are unable to convert cobalamin (vitamin B12) into its two active forms, adenosylcobalamin and methylcobalamin.¹ These active forms of vitamin B12 are needed for important processes in the body, such as the processing of certain amino acids (building blocks of protein). AdoCbl deficiency leads to build-up of methylmalonic acid (causing methylmalonic acidaemia), whilst MeCbl deficiency leads to build-up of homocysteine (causing homocystinuria).² High levels of methylmalonic acid and homocysteine can be harmful to the body.

 There are five different types of methylmalonic acidaemia with homocystinuria, which are caused by genetic changes in different genes:^3,4

• type CblC involves MMACHC gene on chromosome 1
• type CblD involves MMADHC gene on chromosome 2
• type CblF involves LMBRD1 gene on chromosome 6
• type CblJ involves ABCD4 gene on chromosome 14
• type CblX involves HCFC1 gene on the X chromosome

Type CblC is the most common and well understood out of all the types. As there are low number of cases reported for the other types, available information about the other types is limited and those types are less understood.

In Australia, methylmalonic acidaemia with homocystinuria 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, methylmalonic acidaemia with homocystinuria often diagnosed after symptoms develop.

Synonyms:^1,2 Combined defect in adenosylcobalamin and methylcobalamin synthesis; Methylmalonic aciduria with homocystinuria; Methylmalonic aciduria and homocystinuria; combined remethylation disorder

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:26 Methylmalonic acidemia with homocystinuria

• ORPHA:79282 Methylmalonic acidemia with homocystinuria, type cblC
• ORPHA:79283 Methylmalonic acidemia with homocystinuria, type cblD
• ORPHA:79284 Methylmalonic acidemia with homocystinuria type cblF
• ORPHA:369955 Methylmalonic acidemia with homocystinuria, type cblJ
• ORPHA:369962 Methylmalonic acidemia with homocystinuria, type cblX

ICD-11: 5C50.E0 Classical organic aciduria

Symptoms of methylmalonic acidaemia with homocystinuria vary widely between individuals and between the different types. Symptoms may begin early in life or, in some cases, during childhood or adulthood. Type CblC is the most frequently observed type with more information available. Fewer cases of the other types have been reported, and the available information is based on a small number of individuals.

Type CblC^1-3,5,6

Symptoms often begin during the first year of life and can be severe, but later onset cases have also been reported. Some babies are born with heart defects, facial differences and brain abnormalities. In the early-onset cases, there is a risk of metabolic acidosis (build-up of acid in the blood). Individuals may have feeding difficulties, low muscle tone (hypotonia), developmental delay, lack of energy (lethargy) and pallor (pale appearance). If left untreated, this can progress to seizures, coma and in some cases, early death. Long term complications include intellectual disability, pigmentary retinopathy (eye condition that affect the retina and can lead to vision issues and loss over time), kidney issues, liver issues, and cardiomyopathy (a heart muscle condition that makes it harder for the heart to pump blood effectively). Individuals may also have megaloblastic anaemia (a blood disorder in which the body’s bone marrow produces unusually large, immature red blood cells called megaloblasts that cannot properly transport oxygen around the body) and pancytopenia (low levels of red blood cells, white blood cells and platelets). Those with later-onset type CblC often have milder symptoms, but may develop other symptoms as well, such as confusion, psychosis, and decline in memory, thinking and other brain functions.

Type CblD^1,5,7

Some individuals have symptoms within the first year of life, whilst others develop symptoms during early childhood or the early teenage years. Individuals may have developmental delay, learning difficulties, behavioural issues, intellectual disability, loss of muscle coordination and control (ataxia), eye movement disorders and seizures. Some individuals also have megaloblastic anaemia.

Type CblF^1,5,8

Symptoms have been observed in the first year of life and include intrauterine growth restriction (slower growth in the womb, with babies born smaller than expected), feeding difficulties, failure to thrive (difficulty growing and gaining weight as expected) and developmental delay. Individuals may also have skin rashes and persistent stomatitis (ongoing inflammation of the mucous membranes of the mouth, causing painful sores). Some individuals were also born with heart defects and facial differences. They also may have megaloblastic anaemia, neutropenia (low count of neutrophils, a type of white blood cell) and thrombocytopenia (low levels of platelets in the blood).

Type CblJ^1,5,9

Symptoms have been described to be similar to that of type CblF. Some individuals had symptoms during the newborn period, whilst others developed symptoms later but still during childhood. Symptoms include feeding difficulties, weak muscle tone (hypotonia), lack of energy (lethargy), poor growth, developmental delay and skin conditions. Some individuals were born with heart defects. Individuals may also have bone marrow suppression (where there is a decrease in production of blood cells).

Type CblX¹⁰

Symptoms that have been observed in males include failure to thrive, developmental delay, intellectual disability and intractable epilepsy (seizures that do not respond well to anti-seizure medications).

There may be other symptoms and 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.

Methylmalonic acidaemia with homocystinuria is a genetic condition. It is caused by disease-causing genetic changes (variants) in one of five genes involved in the production of the two active forms of vitamin B12 (adenosylcobalamin and methylcobalamin).^3-4 There are several different types of methylmalonic acidaemia with homocystinuria:

• type CblC involves MMACHC gene (on chromosome 1)
• type CblD involves MMADHC gene (on chromosome 2)
• type CblF involves LMBRD1 gene (on chromosome 6)
• type CblJ involves ABCD4 gene (on chromosome 14)
• type CblX involves HCFC1 gene (on the X chromosome)

For types CblC, CblD, CblF and CblJ: All individuals have two copies (alleles) of each of the genes – one on each chromosome that is inherited from each parent. Methylmalonic acidaemia with homocystinuria is an autosomal recessive condition, which means both copies of the affected gene must have the disease-causing genetic variants.

Individuals with the genetic variant in only one copy are unaffected but will be a carrier and may pass on that variant to their children. If both parents are carriers (each have a copy of the disease-causing variant), there is a 25% chance the child will inherit both disease-causing variants and have methylmalonic acidaemia with homocystinuria. More information on autosomal recessive inheritance pattern can be found at Centre for Genetics Education: Autosomal recessive inheritance.

Type CblX is a X-linked condition.^3-5,10 As males only have one X chromosome, they have one copy of the HCFC1 gene, so if their HCFC1 gene has the disease-causing genetic variant, they will have type CblX. Females have two X chromosomes and two copies of the HCFC1 gene; females with the disease-causing variant in one of their HCFC1 gene have so far been reported to be unaffected or are not as affected as males. More information on X-linked inheritance pattern can be found at Centre for Genetics Education: X-linked 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, methylmalonic acidaemia with homocystinuria 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 methylmalonic acidaemia with homocystinuria.  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 methylmalonic acidaemia with homocystinuria may be suspected based on an abnormal result from NBS but additional tests and a clinical examination will be required to confirm a diagnosis. For individuals who are not screened at birth, methylmalonic acidaemia with homocystinuria is often diagnosed after symptoms develop.

Diagnosis of methylmalonic acidaemia with homocystinuria is typically made based on clinical examination, laboratory tests on blood and urine samples to measure levels of organic acids and amino acids, such as increased levels of total plasma homocysteine (tHcy) and methylmalonic acid, and confirmed by complementation analyses in skin fibroblasts or genetic testing.^1,3 

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 acquired vitamin B12 deficiency, vitamin B12-responsive methylmalonic acidaemia, and homocystinuria without methylmalonic aciduria.¹

There is currently no curative treatment for methylmalonic acidaemia with homocystinuria; however, early diagnosis and appropriate management can improve outcomes and reduce or prevent life-threatening complications. 

Management of methylmalonic acidaemia with homocystinuria often involve parenteral hydroxycobalamin, which is the administration of hydroxycobalamin through a route that does not involve the mouth, stomach or intestine.^1,3,5,11 Parenteral routes include intramuscular injections (into the muscle), subcutaneous injections (into fatty layer under the skin), and intravenous (directly into a vein). Intramuscular injection of hydroxocobalamin is typically used.^1,5 Oral hydroxycobalamin and use of cyanocobalamin have been shown to be ineffective.^3,5,11 Oral supplementation of betaine is also used together with the parenteral hydroxycobalamin.^1,3,5,11 Folate is also sometimes supplemented, but it is unclear if its use is beneficial.

It is recommended that individuals with methylmalonic acidaemia with homocystinuria avoid low protein diets (protein restriction) and nitrous oxide.^3,12 

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 care of individuals with methylmalonic acidaemia with homocystinuria may include general practitioners (GP), paediatricians, geneticists, genetic counsellors, neurologists, haematologists, ophthalmologists, occupational therapists, physiotherapists, speech therapists, psychiatrists and others. 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.

The following guidance is available from international experts outside Australia; however, there may be information that is not relevant or applicable to the Australian context:

• Guidelines for diagnosis and management of the cobalamin‐related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency was published in 2016/2017; development of the guidelines was part of the “European network and registry for homocystinurias and methylation defects” (E-HOD) project, an international consortium of metabolic centres (https://www.e-hod.org)
• First Revision of the Guidelines for the Diagnosis and Management of Remethylation Disorders was published in 2026 and is a revision of the 2017 guidelines.

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.

There may be special considerations for the emergency management of individuals living with methylmalonic aciduria with homocystinuria:^3,11

• it has been recommended that protein restriction and nitrous oxide be avoided

Australian Organisation:

HCU Network Australia
Website: https://www.hcunetworkaustralia.org.au/
HCU Network Australia is a health promotion charity established in 2014 that aims is to improve outcomes of individuals impacted by homocystinuria through education, research and support.

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.

Methylmalonic acidaemia with homocystinuria 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 methylmalonic acidaemia with homocystinuria can be found at:

• Genetic and Rare Diseases (GARD) Information Center: Methylmalonic aciduria and homocystinuria
• MedlinePlus Genetics: Methylmalonic acidemia with homocystinuria

GeneReviews®: Disorders of Intracellular Cobalamin Metabolism

Orphanet: Methylmalonic acidemia with homocystinuria

• ORPHA:79282 Methylmalonic acidemia with homocystinuria, type cblC
• ORPHA:79283 Methylmalonic acidemia with homocystinuria, type cblD
• ORPHA:79284 Methylmalonic acidemia with homocystinuria type cblF
• ORPHA:369955 Methylmalonic acidemia with homocystinuria, type cblJ
• ORPHA:369962 Methylmalonic acidemia with homocystinuria, type cblX

Online Mendelian Inheritance in Man, OMIM^®: #277380 – Methylmalonic aciduria and homocystinuria, cblF TYPE; MAHCF

Online Mendelian Inheritance in Man, OMIM^®: #277400 – Methylmalonic aciduria and homocystinuria, cblC TYPE; MAHCC

Online Mendelian Inheritance in Man, OMIM^®: #277410 – Methylmalonic aciduria and homocystinuria, cblD TYPE; MAHCD

Online Mendelian Inheritance in Man, OMIM^®: #614857 – Methylmalonic aciduria and homocystinuria, cblJ TYPE; MAHCJ

Online Mendelian Inheritance in Man, OMIM^®:#309541 -Methylmalonic aciduria and homocystinuria, cblX TYPE; MAHCX

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.