Holocarboxylase synthetase deficiency is a genetic metabolic condition. It is a type of multiple carboxylase deficiency (MCD),^1,2 a group of conditions in which the body cannot properly use a vitamin called biotin. Biotin, also known as vitamin B7 or vitamin H, is needed to help the body to convert carbohydrates, fats and proteins to energy.

In holocarboxylase synthetase deficiency, a protein called holocarboxylase synthetase does not work properly. This protein is responsible for attaching biotin to several carboxylase enzymes.^1,3 Without biotin, these carboxylase enzymes cannot function properly, affecting the body’s ability to break down carbohydrates, fats and proteins into energy. This can lead to symptoms such as poor appetite, vomiting, lethargy, irritability, weak muscle tone (hypotonia), skin and hair issues.^1-3 If left untreated, this can lead to growth and developmental delays, as well as seizures, coma and early death.^1,4

In Australia, holocarboxylase synthetase 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, holocarboxylase synthetase deficiency is often diagnosed after symptoms develop. Early detection and management of holocarboxylase synthetase deficiency can help reduce the symptoms and risk of life-threatening complications.

Synonyms:^1,2 HCSLD; HCSD; biotin-(propionyl-CoA-carboxylase) ligase deficiency; early-onset multiple carboxylase deficiency; multiple carboxylase deficiency – neonatal onset; neonatal multiple carboxylase 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:79242 Holocarboxylase synthetase deficiency

ICD11: 5C50.E0 Classical organic aciduria

Symptoms of holocarboxylase synthetase deficiency usually appear soon after birth, but in some cases, may develop later in early childhood.^1,2 Symptoms may include poor appetite, vomiting, extreme tiredness and lack of energy (lethargy), weak muscle tone (hypotonia), irritability, skin issues, and hair loss (alopecia).^1-3 Babies may also be at risk of metabolic acidosis (a build-up of too much acid in the blood) as well as hyperammonemia (high ammonia levels).^1,3,4 These complications can lead to growth and developmental delays and, if left untreated, can be life-threatening, resulting in seizures, respiratory distress, coma and early death.^1,4

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.

Holocarboxylase synthetase deficiency is a genetic condition. It is caused by disease-causing genetic changes (variants) in the HLCS gene located on Chromosome 21.^1,3 These genetic changes result in the holocarboxylase synthetase enzyme not working properly and unable to attach biotin to carboxylase enzymes.

All individuals have two copies (alleles) of the HLCS gene – one on each chromosome that is inherited from each parent. Holocarboxylase synthetase deficiency is an autosomal recessive condition, which means both copies of the HLCS  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, holocarboxylase synthetase 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 holocarboxylase synthetase 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 holocarboxylase synthetase 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, holocarboxylase synthetase deficiency is often diagnosed after symptoms develop.

Diagnosis of holocarboxylase synthetase deficiency is typically made based on clinical examination, biochemical tests on blood and urine samples to detect increased levels of certain organic acids, and confirmed by genetic testing.¹ In some cases, a skin biopsy may also be performed to get samples for enzyme activity tests to detect if the holocarboxylase synthetase enzyme is working properly.

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 biotinidase deficiency and isolated carboxylase deficiencies, sepsis, urea cycle defects and other inborn errors of metabolism.¹

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 holocarboxylase synthetase deficiency. Treatment of holocarboxylase synthetase deficiency involves lifelong biotin supplementation to help reduce or prevent development of symptoms and complications.¹ The required amount of biotin varies between individuals and needs to be assessed individually by the medical team.⁴ The required dose may also need to be adjusted over time. Early diagnosis and prompt treatment with biotin can help manage or reduce symptoms, reduce the risk of developing symptoms and complications that can be life-threatening, as well as improve long-term outcomes.^1,4 Individuals with holocarboxylase synthetase deficiency should be monitored regularly for symptoms and complications, and to assess whether the biotin dose needs to be adjusted.¹

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 of holocarboxylase synthetase deficiency may include metabolic doctors, nurses, geneticists, and healthcare workers who are trained to look after people with metabolic disorders. 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 for holocarboxylase synthetase deficiency, 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.

If you know of any relevant emergency management guidelines or information relevant to emergency care, please let us know via the  Contribute page.

Australian Organisation:

We are not aware of any rare disease organisations specifically for holocarboxylase synthetase deficiency in Australia. If you are aware of any relevant Australian organisations, please let us know via the Contribute page.

Genetics Alliance Australia (GAA) may be able to provide some support for families and individuals affected by an undiagnosed or rare genetic condition for which there is no disease specific organisation in Australia.

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.

Holocarboxylase synthetase 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 holocarboxylase synthetase deficiency can be found at:

• Genetic and Rare Diseases (GARD) Information Center: Holocarboxylase synthetase deficiency
• MedlinePlus Genetics: Holocarboxylase synthetase deficiency

Orphanet: Holocarboxylase synthetase deficiency

Online Mendelian Inheritance in Man, OMIM^®: #253270 Holocarboxylase synthetase deficiency

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.