Classical homocystinuria (HCU) is the most common type of homocystinuria, which is a group of genetic metabolic conditions where the body is unable to properly break down homocysteine.^1,2 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 / reverse transsulfuration pathway).^3,4

Classical HCU is caused by a disease-causing genetic change (variant) in the CBS gene, which usually results in reduced activity of the cystathionine beta-synthase (CBS) protein.^5,6 The CBS protein is involved in the first step of the transsulfuration pathway.³ Deficiency of the CBS protein results in build-up of homocysteine and methionine, which are toxic to the body at high levels and can affect multiple organs, including the eyes, skeleton, blood vessels and the brain.^7,8 This can lead to a range of different symptoms, which can vary between individuals, as well as life-threatening complications.

In Australia, classical HCU 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, classical homocystinuria is often diagnosed after symptoms develop. Early diagnosis and treatment prevent life-threatening complications.

Please note that there are other types of homocystinuria that are caused by genetic variants in other genes that affect the remethylation pathway. These conditions are known as homocystinuria due to remethylation defects. They include homocystinuria due to methylene tetrahydrofolate reductase deficiency, homocystinuria without methylmalonic aciduria and methylmalonic aciduria and homocystinuria (combined defects).¹

Synonyms: Classical HCU; Cystathionine beta-synthase deficiency; Cystathionine beta-synthase-deficient homocystinuria; CBS-deficient HCU; Homocystinuria due to CBS deficiency.

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:394 Homocystinuria due to cystathionine beta-synthase deficiency

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

Symptoms of classical homocystinuria can vary widely between individuals, with some individuals having only mild symptoms whilst others may develop life-threatening complications. Early detection and treatment of classical homocystinuria can help reduce the risk or prevent these life-threatening complications.⁸

Classical homocystinuria can affect multiple body organs, with the most commonly affected being:^2,5

• eye – ectopia lentis (dislocation of the eye lens) and/or severe myopia (nearsightedness)
• skeleton – long limbs, scoliosis (abnormal sideways curvature of the spine), knock knees/genu valgum (where the knees turn inwards to each other), pes cavus (high arched foot), chest deformities such as pectus carinatum (protruding chest) and pectus excavatum (sunken chest), and osteoporosis
• vascular system – increased risk of thromboembolism (formation of blood clots in blood vessels that can dislodge and travel to another part of the body); this can cause life-threatening complications such as strokes and pulmonary embolism (clots in the lungs)
• central nervous system leading to developmental delay, intellectual disability, seizures, dystonia, as well as behavioural and psychiatric issues

Other features of classical homocystinuria may include discolouration of the skin and hair (hypopigmentation), malar flush (butterfly rash on the cheeks), inflammation of the pancreas (pancreatitis) and others.^2,5

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.

Classical homocystinuria is a genetic condition. It is caused by disease-causing genetic changes (variants) in the CBS gene on chromosome 21. ⁵

All individuals have two copies (alleles) of the CBS gene – one on each chromosome that is inherited from each parent. Classical homocystinuria is an autosomal recessive condition, which means both copies of the CBS 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 classical homocystinuria. 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, classical 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 classical homocystinuria. 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 classical 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, classical homocystinuria is often diagnosed after symptoms develop.

Diagnosis of classical homocystinuria is typically made based on clinical examination, blood tests that detect increased levels of total homocysteine and methionine, and confirmed by genetic testing.⁷ Pathology Tests Explained: Homocysteine has more information about testing for homocysteine.

As part of the diagnostic process, doctors may perform a differential diagnosis, which is to rule out other conditions that have similar symptoms , such as Marfan syndrome, several chronic renal failure, vitamin B12 or folate deficiency, as well as conditions caused by inborn errors of vitamin B12 or folate metabolism.⁷

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 classical HCU. Treatment of classical HCU is aimed at managing the concentration of homocysteine in the body to ensure it is at a safe level to prevent development of symptoms and complications.⁸ If classical HCU is diagnosed and treated early, this can help ensure normal growth and development.

The treatment strategy for classical HCU can vary between individuals.⁸ Diagnosed individuals are tested for pyridoxine-responsiveness, which is to see if they can respond to vitamin B6 (pyridoxine) supplements and whether that is sufficient to decrease homocysteine levels to a safe level in the body. Some individuals may respond well to the vitamin B6 supplementation (are pyridoxine responsive), whilst others may not respond at all (pyridoxine nonresponsive) or may respond partially which means their homocysteine levels can be controlled to a certain level but not fully by vitamin b supplementation (partially pyridoxine responsive). An individual’s treatment strategy depends on their pyridoxine responsiveness:⁸

• pyridoxine responsive – recommended treatment is vitamin B6 supplementation
• pyridoxine nonresponsive- recommended treatment is a life-long strict low protein (methionine-restricted) diet and a methionine free amino acid supplement.
• partially pyridoxine responsive – recommended treatment would be a life-long strict low protein (methionine-restricted) diet in combination with vitamin B6 supplements. Betaine treatment may sometimes also considered.

Folate supplementation is also recommended for all individuals as well as vitamin B12 supplementation if necessary.⁸ The recommended amounts of supplements and protein from food varies between individuals and may also change over time.

Regular monitoring of total homocysteine, plasma amino acid levels (including methionine levels), vitamin B12 and folate, as well as regular nutritional assessment is also recommended for all individuals.⁸

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 classical homocystinuria may include general practitioners (GP), paediatricians, geneticists, genetic counsellors, neurologists, ophthalmologists, 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

Guidelines for the diagnosis and management of cystathionine beta‐synthase deficiency was written as part of the European network and registry for homocystinurias and methylation defects (E-HOD) and published in 2017. It was developed by a Guideline Development Group (GDG), which included paediatricians, adult physicians, dietitians, biochemists, a clinical geneticist and a statistician, and was reviewed by a representative from Australian patient support group HCU Network Australia and two external reviewers.⁸

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 classical homocystinuria:

• Individuals with classical homocystinuria may require particular care after surgery as there may be increased risk of post-surgical thromboembolic complications.²

HCU Network Australia: Research has information about global research on classical homocystinuria, including available research grants.

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 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.

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.

Classical 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.

The ASIEM Low Protein Handbook for Homocystinuria

HCU Fruit and Veg Counting Lists

HCU General Protein Counting Lists

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 classical homocystinuria can be found at:

• HCU Network Australia: Homocystinuria Australia Community
• Metabolic Dietary Disorders Association (MDDA): Homocystinuria (HCU)
• Genetic and Rare Diseases (GARD) Information Center: Classic homocystinuria
• National Organization for Rare Disorders: Homocystinuria due to Cystathionine Beta-Synthase Deficiency

Orphanet: Homocystinuria due to cystathionine beta-synthase deficiency

GeneReviews®: Homocystinuria due to Cystathionine Beta-Synthase Deficiency

Online Mendelian Inheritance in Man, OMIM®: #236200 – Homocystinuria due to cysthathionine beta-synthase deficiency

HCU Network Australia: Homocystinuria Australia Community has information for health professionals

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.