Homocystinuria due to MTHFR deficiency 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 converted by the body back to methionine (through the remethylation pathway) or into another amino acid called cysteine (through the transsulfuration pathway).²

Homocystinuria due to MTHFR deficiency is caused by disease-causing genetic changes (variants) in the MTHFR gene.³ The MTHFR gene is involved in producing a protein called methylene tetrahydrofolate reductase that converts folate (vitamin B9) from one form (5,10-methylenetetrahydrofolate) to a different form (5-methyltetrahydrofolate).^4,5 The 5-methyltetrahydrofolate is important for the remethylation pathway to convert homocysteine back to methionine. When the methylene tetrahydrofolate reductase protein is not working properly, this re-conversion of homocysteine to methionine cannot occur, leading to a build-up of homocysteine, which can be toxic at high levels. There is also decreased concentration of methionine (which is important for DNA methylation processes in the body),⁵ resulting in neurological effects.

In Australia, homocystinuria due to MTHFR deficiency 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, homocystinuria due to MTHFR deficiency is often diagnosed after symptoms develop.

Please note that there are other types of homocystinuria that are caused by genetic variants in other genes that affect the transsulfuration pathway or other steps of the remethylation pathway. These include classical homocystinuria (affects transsulfuration pathway) and other types of homocystinuria due to remethylation defects, such as homocystinuria without methylmalonic aciduria and methylamalonic aciduria and homocystinuria (combined defects).¹

Synonyms: homocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase (MTHFR).

Homocystinuria due to MTHFR deficiency is also known as a type of homocystinuria due to remethylation defects.

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:395 Homocystinuria due to methylene tetrahydrofolate reductase deficiency

ICD-11: 5C63.1 Disorders of folate metabolism or transport

Symptoms of homocystinuria due to MTHFR deficiency varies between individuals. The symptoms can present soon after birth during the neonatal period, during adolescence or in adulthood. Symptoms that present during the neonatal period are often more severe and may include:^3,6

• postnatal microcephaly (small head size caused by child’s head not growing as expected after birth)
• developmental delay
• feeding difficulties and poor growth
• intellectual disability
• seizures
• neonatal apnea (condition where a person stops breathing temporarily during sleep) – this can range from brief episodes to severe episodes that requires medical intervention
• muscle weakness and poor motor coordination
• neurobehaviour and psychiatric symptoms such as anxiety, attention deficit hyperactivity disorder (ADHD) aggression, sleep disturbances and psychosis (delusions and hallucinations)
• stroke

Symptoms that present during adolescence or in adulthood may include:^3,6

• thromboembolic events (due to the formation of blood clots) such as strokes, which can result in serious or life-threatening complications
• dislocation of the eye lens (ectopia lentis)
• cognitive decline which affects memory, concentration and ability to plan, carry out and manage tasks
• neurobehaviour and psychiatric symptoms
• issues with muscle control and coordination

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 due to MTHFR deficiency is a genetic condition. It is caused by disease-causing genetic changes (variants) in the MTHFR gene on chromosome 1.^3,5

All individuals have two copies (alleles) of the MTHFR gene – one on each chromosome that is inherited from each parent. Homocystinuria due to methylene tetrahydrofolate reductase deficiency is an autosomal recessive condition, which means both copies of the MTHFR 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 due to MTHFR deficiency. 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 due to MTHFR 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 homocystinuria due to methylene tetrahydrofolate reductase deficiency. If the results of these tests suggest that the baby is at risk of having one of these conditions, laboratory staff will quickly get in touch with healthcare providers. The healthcare providers will then arrange for the baby to have further testing that will confirm whether the baby does indeed have 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 due to MTHFR deficiency 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 due to MTHFR deficiency is often diagnosed after symptoms develop.

Diagnosis of homocystinuria due to MTHFR deficiency is typically made based on clinical examination, blood tests that detect increased levels of total homocysteine and low levels of methyltetrahydrofolate, measurement of methylene tetrahydrofolate reductase enzyme activity and genetic testing.^3,4

Doctors may perform additional examinations or tests to rule out other conditions that have similar symptoms, such as other homocysteine remethylation disorders.⁴

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 homocystinuria due to MTHFR deficiency. The main treatment for homocystinuria due to MTHFR deficiency is betaine supplementation.^3,4 Betaine enables homocysteine to be converted to methionine through an alternative remethylation pathway and can reduce the high levels of homocysteine.¹ Additional therapies may include supplementation of methionine, vitamin B12 and L-5-MTHF (an active form of folate). Early diagnosis and treatment can prevent development of symptoms and life-threatening complications.

There are also strategies to manage the symptoms, which may involve a multidisciplinary care team. Management strategies may include respiratory support, use of feeding tubes, feeding therapy, seizure management, physiotherapy, occupational therapy, speech therapy, strategies to reduce risk of strokes, use of mobility aids and others.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 care of individuals with homocystinuria due to MTHFR deficiency may include general practitioners (GP), paediatricians, geneticists, genetic counsellors, neurologists, 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

We are not aware of any clinical care guidelines for homocystinuria due to MTHFR deficiency in Australia or internationally. If you know of any 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.

There may be special considerations for the emergency management of individuals living with homocystinuria due to MTHFR deficiency.

There are specific considerations around participating in rare disease research, including clinical trials. It is important to be mindful of issues such as data privacy, research ethics, consent and differences in research regulations between Australia and other countries. For more information, please visit the RARE Portal’s Considerations for Participating in Health and Medical Research page.

If you are interested in finding clinical trials for your condition, please visit the following websites; however, there may not be any clinical trials available:

• Australian Clinical Trials
• ClinicalTrials.gov

It is best to discuss your interest in research, including clinical trials,  with your medical team to determine suitability and eligibility.

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.

Homocystinuria due to MTHFR 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 on homocystinuria due to MTHFR deficiency can be found at:

• Genetic and Rare Diseases (GARD) Information Center: Homocystinuria due to methylene tetrahydrofolate reductase deficiency
• National Organization for Rare Disorders: Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Orphanet: Homocystinuria due to methylene tetrahydrofolate reductase deficiency

GeneReviews®: Homocystinuria due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity

Online Mendelian Inheritance in Man, OMIM®: #236250 – Homocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase activity

This page has been co-developed by Rare Voices Australia (RVA)’s RARE Portal team in consultation with HCU Network Australia.

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.