Homocystinuria without methylmalonic aciduria is a type of homocystinuria, which is a group of genetic metabolic conditions where the body is unable to properly break down homocysteine.¹ Homocysteine is an amino acid (protein building block) that is produced during the break down (metabolism) of another amino acid, methionine, obtained from foods. There are usually very low levels of homocysteine in the body, as it is recycled by the body by turning it back into methionine (through the remethylation pathway) or into another amino acid called cysteine (through the transsulfuration pathway).² High levels of homocysteine in the body can be toxic.

In homocystinuria without methylmalonic aciduria, the recycling of homocysteine into methionine (remethylation pathway) is disrupted. This is due to reduced activity of methionine synthase, the enzyme (a type of protein) responsible for converting homocysteine into methionine. There are three different types of homocystinuria without methylmalonic aciduria, caused by disease-causing genetic changes (variants) in a different gene:^3,4 

• type cblG – caused by variants in MTR gene that affects activity of methionine synthase itself
• type cblE – caused by variants in the MTRR gene that affects methionine synthase reductase, a protein that helps activate methionine synthase. When methionine synthase reductase not working properly, methionine synthase cannot function normally.
• type cblDv1 – caused by variants in the MMADHC gene that affects the supply of vitamin B12 (cobalamin), which is needed for methionine synthase to work properly

When methionine syntase activity is reduced, homocysteine cannot be efficiently converted back to methionine, leading to a build-up of homocysteine that can be toxic at high levels. There is also reduced levels of methionine. Methionine is important for DNA methylation processes that is required for normal growth, development and organ function.

In Australia, homocystinuria without methylmalonic aciduria 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, homocystinuriawithout methylmalonic aciduria is often diagnosed after symptoms develop.

Please note that there are other types of homocystinuria due to remethylation defects, such as homocystinuria due to MTHFR deficiency and methylamalonic aciduria and homocystinuria (combined defects). There is also another type of homocystinuria, called classical homocystinuria , which is caused by defect in the transsulfuration pathway.¹

Synonyms:⁴ Functional methionine synthase deficiency; Methylcobalamin deficiency

Homocystinuria without methylmalonic aciduria is also known as a type of homocystinuria due to remethylation defects, or a cobalamin 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:622 Homocystinuria without methylmalonic aciduria

ICD-11: 5C50.B Disorders of methionine cycle or sulphur amino acid metabolism

Symptoms of homocystinuria without methylmalonic aciduria varies widely between individuals. Early symptoms may include a smaller head size (microcephaly), poor feeding, vomiting and lethargy (extreme tiredness and lack of energy) during the first few months of life.⁴ Children may have failure to thrive (growing or gaining weight slower than expected), low muscle tone (hypotonia) and developmental delay. They may also have seizures and megaloblastic anaemia (a type of blood disorder where the body’s bone marrow produces unusually large, immature red blood cells called megaloblasts that cannot properly transport oxygen around the body).^3-5

There may also be other symptoms and complications, such as kidney issues and thromboembolic complications (when a blood clot, also known as a thrombus, breaks off and travel through the bloodstream to a different location, blocking the flow of blood).³ For the cblG type, symptoms may present later in the life, with milder or with other symptoms, such as neuropsychiatric illness and vision issues.^3,4 

Individuals also often have homocystinuria (increased levels of homocystine in their urine), hyperhomocysteinemia (increased levels of homocysteine in their blood) and in some cases hypomethioninemia (reduced levels of methionine in their blood) as well.^3-5 Unlike some other types of homocystinuria, there is no methylmalonic aciduria (high levels of methylmalonic acid that is toxic).

There may be other symptoms and complications that have not been covered here. Please speak to your medical team to learn more about the symptoms and complications 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.

Homocystinuria without methylmalonic aciduria is a genetic condition. It can be caused by disease-causing genetic changes in one of three different genes (MTR, MTRR and MMADHC).³ There are three different types of homocystinuria without methylmalonic aciduria:

• cblG involves the MTR gene
• cblE involves the MTRR gene
• cblDv1 involves the MMADHC gene

All individuals have two copies (alleles) of each of the genes – one on each chromosome that is inherited from each parent. Homocystinuria without methylmalonic aciduria is an autosomal recessive condition,^3,4 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 homocystinuria without methylmalonic aciduria. 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, homocystinuria without methylmalonic aciduria 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 homocystinuria without methylmalonic aciduria.  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 homocystinuria without methylmalonic aciduria 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, homocystinuria without methylmalonic aciduria is often diagnosed after symptoms develop.

Diagnosis of homocystinuria without methylmalonic aciduria is typically made based on clinical examination, laboratory tests on blood samples (to detect for increased levels of homocysteine or homocystine; there is usually low methionine levels as well) and urine samples (to detect for increased levels of homocystine), presence of megaloblastic anemia and genetic testing.^3,4 

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 classical homocystinuria (classical HCU),  homocystinuria due to methylene tetrahydrofolate reductase (MTHFR) deficiency, multiple sclerosis, folate deficiency or vitamin B₁₂ deficiency.^3,4

There is currently no curative treatment for homocystinuria without methylmalonic aciduria. Homocystinuria without methylmalonic aciduria is mainly treated with hydroxocobalamin (OHCbl), a form of vitamin B12, that appears best administered intramuscularly (injected into the muscle).^3-5 The dose and interval (time) between injections varies widely between individuals. The frequency of required dose often decreases over time as an individual’s condition stabilises.⁵ Individuals with increased levels of total plasma homocysteine (tHcy) are also treated with betaine and folate/folinic acid supplementation.^4,5 Such treatment is found to be beneficial for individuals with homocystinuria without methylmalonic aciduria,^4,5 but may not be able to result in improvement of all symptoms.⁴

It is recommended that individuals avoid fasting and protein restriction (diets with low protein) as it can result in hypomethioninemia (abnormally low levels of methionine).^3,5 Individuals should also avoid use of nitrous oxide, also known as laughing gas, as it can affect vitamin B12 and methionine synthase activity in the body.^3,5

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 homocystinuria without methylmalonic aciduria may include general practitioners (GP), paediatricians, geneticists, genetic counsellors, neurologists, haematologists, occupational therapists, physiotherapists, speech therapists 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.

There may be special considerations for the emergency management of individuals living with homocystinuria without methylmalonic aciduria:.^3,5

• individuals avoid fasting and protein restriction (diets with low protein) as it can result in hypomethioninemia (abnormally low levels of methionine)
• Individuals should also avoid use of nitrous oxide, also known as laughing gas, as it can affect vitamin B12 and methionine synthase activity in the body.

Australian Organisations:

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.

Homocystinuria without methylmalonic aciduria 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 on homocystinuria without methylmalonic aciduria can be found at:

• Genetic and Rare Diseases (GARD) Information Center: Homocystinuria without methylmalonic aciduria

Orphanet: Homocystinuria without methylmalonic aciduria

GeneReviews^®: Disorders of Intracellular Cobalamin Metabolism

Online Mendelian Inheritance in Man, OMIM^®: #620952 – Homocystinuria-megaloblastic anemia, cblD type; HMAD

Online Mendelian Inheritance in Man, OMIM^®: #236270 – Homocystinuria – megaloblastic anemia, cblE type; HMAE

Online Mendelian Inheritance in Man, OMIM^® #250940 – Homocystinuria-megaloblastic anemia, cblG type; HMAG

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.