ORGANIC ACID DISORDER

Disorder name: Holocarboxylase synthetase deficiency
Also known as: Multiple carboxylase deficiency – neonatal form (MCD)
Acronym: HCSD
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• What is HCSD?
• What causes HCSD?
• If HCSD is not treated, what problems occur?
• What is the treatment for HCSD?
• What happens when HCSD is treated?
• What causes the HCS enzyme to be absent or not working correctly?
• How is HCSD inherited?
• Is genetic testing available?
• What other testing is available?
• Can you test during a future pregnancy?
• Can other members of the family have HCSD or be carriers?
• Can other family members be tested?
• How many people have HCSD?
• Does HCSD happen more often in a certain ethnic group?
• Does HCSD go by any other names?
• Where can I find more information?

This fact sheet contains general information about HCSD. Every child is different and some of these facts may not apply to your child specifically. Certain treatments may be recommended for some children but not others. All children with HCSD should be followed by a metabolic doctor in addition to their primary doctor.

WHAT IS HCSD?

HCSD stands for “holocarboxylase synthetase deficiency.” It is one type of organic acid disorder. People with HCSD have problems changing protein and carbohydrates from food into energy for the body.

Organic Acid DisordersThis is a group of rare inherited conditions. OA disorders are caused by one or more enzymes that do not work properly. People with these conditions cannot digest certain parts of protein from the food they eat. This causes harmful substances to build up in their blood and urine. This can cause serious effects on health, growth, and learning.: Organic acid disorders (OAs) are a group of rare inheritedAcquiring a trait from one’s parents. Most traits, such as eye color or hair color, are inherited from a parent through genes. conditions. They are caused by enzymes that do not work properly. A number of enzymesA molecule that helps chemical reactions take place. For example, enzymes in the stomach speed up the process of breaking down food. Each enzyme can participate in many chemical reactions without changing or being used up. are needed to process protein from the food we eat for use by the body. Problems with one or more of these enzymes can cause an organic acid disorder. People with organic acid disorders cannot break down proteinA molecule that makes up many parts of every cell in the body. Examples of proteins include hormones, enzymes, hair, and antibodies. Proteins are made up of 20 different types of individual units called amino acids. It is the order of these amino acids in a protein that determines what form and function a protein has. Each gene holds the instructions for making a single protein. properly. This causes harmful substances to build up in their blood and urine. These substances can affect health, growth, and learning. The symptoms and treatment vary between different organic acid disorders. They can also vary from person to person with the same organic acid disorder. See the fact sheets for each specific organic acid disorder. Organic acid disorders are inherited in an autosomal recessive manner and affect both males and females.

WHAT CAUSES HCSD?

HCSD is caused by problems with the enzyme “holocarboxylase synthetase” (HCS). In people with HCSD, the HCS enzyme is either missing or not working properly. This enzyme’s job is to add a vitamin called ‘biotin’ to other enzymes called ‘carboxylases’ so that they can change the food we eat into energy for the body. When the HCS enzyme is not working, certain harmful substances build up in the blood and urine. This can cause serious health problems.

Each child with HCSD is likely to experience slightly different effects. Many babies with this condition start to have symptoms within hours of birth or during the first few days or weeks of life. Other babies have their first symptoms sometime in infancy, usually before two years of age.

A small number of people with HCSD never show symptoms and are only diagnosed with HCSD after a brother or sister is diagnosed.

HCSD causes episodes of illness called metabolic crises. Some of the first symptoms of a metabolic crisisThis is a serious health condition caused by low blood sugar and the build-up of toxic substances in the blood. Symptoms of a metabolic crisis are poor appetite, nausea, vomiting, diarrhea, extreme sleepiness, irritable mood and behavior changes. If not treated, breathing problems, seizures, coma, and sometimes even death can occur.Metabolic crises happen more often in people with certain metabolic disorders (some fatty acid oxidation disorders, amino acid disorders, and organic acid disorders). They are often triggered by things like illness or infection, going without food for a long time, and, in some cases, heavy exercise. are:

• poor appetite
• vomiting
• extreme sleepiness or lack of energy
• irritability
• low muscle tone (floppy muscles and joints)
• severe peeling skin rash

Common lab findings are:

• low blood sugar, called hypoglycemiaThis happens when there is too little sugar (glucose) in the blood. It may cause a person to feel nervous, shaky, weak, or sweaty. It may also cause headache, blurred vision, and hunger. If left untreated, it can cause unconsciousness (coma) and sometimes even death.
• high levels of acidic substances in the blood, called metabolic acidosisThis happens when acidic substances build up in the blood. It can cause rapid breathing, confusion, and extreme sleepiness. If not treated, it may lead to shock, coma or death.
• slightly high levels of ammonia in the blood
• low plateletsThis is a type of blood cell that helps to clot the blood. Platelets help prevent or control bleeding.
• ketones in the urine
• high levels of substances called organic acids in the urine

If a metabolic crisis is not treated, a child with HCSD can develop:

• breathing problems
• seizuresThese are also called "convulsions" or "fits." During a seizure, a person loses consciousness and control of his or her muscles. It may also cause involuntary movements. Seizures can happen for many reasons. Some causes are metabolic disorders, a metabolic crisis, brain injury, and infection.
• swelling of the brain
• comaThis is a sleep-like condition from which a person cannot be awakened. People in a coma are unconscious. A coma can be caused by many things. Two causes are untreated low blood sugar (hypoglycemia) and a metabolic crisis., sometimes leading to death

Untreated children with HCSD often have other symptoms, whether or not they have metabolic crises. These can include:

• skin rashes or skin infections
• hair loss
• learning problems or intellectual disabilities
• delays in walking and motor skills
• problems coordinating movements, called ataxiaThis is the lack of ability to coordinate muscle movements. It causes balance problems and difficulty walking. People with ataxia often walk with jerky, unsteady movements. Ataxia has many different causes.
• rigid muscle toneIn order to hold our posture and control our movements, a certain amount of tension is needed in our muscles. This tension is called “muscle tone.” People with hypotonia have too little tension in their muscles and appear “floppy.” People with hypertonia have too much tension in their muscles and have problems with tight, rigid muscles and joints., called spasticityThis is rigidity of the muscles and increased reflexes. It is caused by increased muscle tone. It results in abnormal tightness or stiffness of the muscles and joints.
• poor growth
• seizures
• hearing loss
• vision loss

Without treatment, most babies with HCSD will die.

WHAT IS THE TREATMENT FOR HCSD?

Your baby’s primary doctor will work with a metabolic doctorThis is a doctor or medical geneticist who has special training in diagnosing and treating metabolic disorders. They often work in university hospitals or large medical centers. to provide care for your child.

The main treatment for HCSD is a type of B vitamin called biotinThis is one type of B vitamin. It helps break down fat, protein, and carbohydrates from food for use by the body. Biotin is found in chicken, salmon, cheese, eggs, and some vegetables. It can also be bought in pill form. Children with certain metabolic disorders may be treated with biotin supplements.. In babies found to have HCSD through newborn screeningThe process of testing for disease in a person who does not show signs of having the disease (nonsymptomatic or asymptomatic person). The goal of screening is to catch the disease in its early stages., biotin treatment can prevent symptoms from occurring. It can also reverse some of the health problems in children who have already shown symptoms. You will need a prescription from your doctor in order to purchase the amount of biotin your child will need.

Prompt treatment with biotin is needed to prevent intellectual disabilities and serious medical problems. You should start the treatment as soon as you know your child has HCSD. Your child will need to take biotin by mouth on a daily basis throughout life.

Biotin is usually the only medication needed to treat HCSD. Your child will not need to restrict any activities or change his or her diet.

WHAT HAPPENS WHEN HCSD IS TREATED?

Babies who receive prompt and ongoing treatment with biotin before they have a metabolic crisis are expected to have normal growth and development.

Even with treatment, a few children have developed life-long learning problems or intellectual disabilities. In children who have already shown delays in learning, or loss of hearing or eyesight, treatment can prevent additional problems but it may not be able to correct the effects that are already present.

WHAT CAUSES THE HCS ENZYME TO BE ABSENT OR NOT WORKING CORRECTLY?

Genes tell the body how to make enzymes. The HLCS gene instructs the body to make the HCS enzyme. Everyone has two copies of the HLCS gene. People with HCSD have changes, also called variantsA variant is a change or alteration in a person’s DNA sequence. Variants can happen in genes and affect how the gene functions. There are different types of variants – they can be non-problem causing (benign), disease-causing (pathogenic) or of unknown significance. The term variants is now used in place of the term mutation. in both copies of their HLCS genesA segment of DNA that contains the instructions to make a specific protein (or part of a protein). Genes are contained on chromosomes. Chromosomes, and the genes on those chromosomes, are passed on from parent to child. Errors in the DNA that make up a gene are called variants and can lead to diseases. that cause them to not work correctly.

HOW IS HCSD INHERITED?

HCSD is inherited in an autosomal recessive manner. It affects both boys and girls equally.

Everyone has two copies of the HLCS gene that make the HCS enzyme. In children with HCSD, neither of their HLCS genes works correctly. These children inherit one non-working gene for the condition from each parent.

Parents of children with HCSD rarely have the disorder. Instead, each parent has a single non-working HLCS gene. They are called carriersA person who has one copy of a gene mutation for a particular autosomal recessive disorder (remember genes come in pairs). Carriers are not affected by the disorder. However, they can pass on the gene variant to their children. Children who inherit two such gene variants will be affected by the disorder. The term variants is now used in place of the term mutation.. Carriers do not have HCSD because their other gene is working correctly.

When both parents are carriers, there is a 25% chance in each pregnancy for the child to have HCSD. There is a 50% chance for the child to be a carrier, just like the parents. And, there is a 25% chance for the child to have two working genes.

GeneticRelating to (or due to) genes and heredity or the field of studying genes and heredity. counseling is available to families who have children with HCSD. Genetic counselors can answer your questions about how HCSD is inherited, choices during future pregnancies, and how to test other family members. Ask your doctor about a referral to a genetic counselorThese are health care providers who have special training in genetic conditions. They help families understand genetic disorders and how they are passed down. Genetic counselors offer information and support to people who have genetic conditions in their families or are concerned that they may have a child with an inherited disorder..

IS GENETIC TESTING AVAILABLE?

Genetic testing for HCSD is available. Genetic testing, also called DNA testing, looks for changes (variants) in the HCLS genes that cause HCSD. Talk with your genetic counselor or metabolic doctor if you have questions about DNADeoxyribonucleic acid (DNA) is a molecule found in the chromosomes that carries genetic information. DNA is composed of four units (called bases) that are designated A, T, G, and C. The sequence of the bases spell out instructions for making all of the proteins needed by an organism. A gene is a section of DNA that holds the instructions for a specific protein. A change in one or more of the DNA bases making up a gene is called a mutation. Some mutations change the protein instructions and can lead to particular health problems or disorders. Each parent passes half of their chromosomes, and thus half of their DNA instructions, onto their children. It is these instructions that cause certain traits, such as eye or hair color, to be inherited. testing.

DNA testing is not necessary to diagnose your child. If available, it can be helpful for carrier testing or prenatal diagnosis, discussed below.

WHAT OTHER TESTING IS AVAILABLE?

Special tests on blood or skin samples can be done to confirm HCSD. Talk to your metabolic doctor or genetic counselor if you have questions about testing for HCSD.

CAN YOU TEST DURING A FUTURE PREGNANCY?

If both gene changes (variants) have been found in your child with HCSD, DNA testing can be done during future pregnancies. The sample needed for this test is obtained by either CVS or amniocentesisThis is a test done during pregnancy. A needle is used to remove a small sample of fluid from the sac around the fetus. The sample can be used to test for certain genetic disorders in the fetus. Amniocentesis to test for genetic conditions is usually done between 13 and 20 weeks of pregnancy..

Parents may either choose to have testing during pregnancy or wait until birth to have the baby tested. Parents may also choose to use assisted reproductive techniques to decrease the chance that their future children would have HCSD. A genetic counselor can talk to you about your choices and answer questions about prenatal testing or testing your baby after birth.

CAN OTHER MEMBERS OF THE FAMILY HAVE HCSD OR BE CARRIERS?

Having HCSD
Older brothers and sisters of a baby with HCSD have a small chance of being affected, even if they haven’t had symptoms. Finding out whether other children in the family have this condition is important because early treatment may prevent serious health problems. Talk to your metabolic doctor or genetic counselor about testing your other children.

HCSD carriers
Brothers and sisters who do not have HCSD still have a chance to be carriers like their parents. Except in special cases, carrier testing should only be done on people over 18 years of age.

If you are a parent of a child with HCSD, your brothers and sisters have a 50% chance to be an HCSD carrier. It is important for other family members to be told that they could be carriers. There is a small chance they are also at risk to have children with HCSD.

All states offer newborn screening for HCSD. However, when both parents are HCSD carriers, newborn screeningA screening test that looks for different disorders using a small sample of blood taken from a newborn’s heel. A positive or abnormal newborn screening result means that there are slight differences that were found in the baby’s blood, and further testing is needed to figure out if the baby has a metabolic disorder. results are not sufficient to rule out the condition in a newborn baby. In this case, special diagnostic testing should be done in addition to newborn screening.

CAN OTHER FAMILY MEMBERS BE TESTED?

Diagnostic testing
Diagnostic testing on blood or skin samples can be done for brothers or sisters of a child with HCSD. Talk to your doctor or genetic counselor if you have questions about testing for HCSD.

Carrier testing
Carrier testing for HCSD may be available. If you have questions about carrier testing, ask your genetic counselor or metabolic doctor.

HOW MANY PEOPLE HAVE HCSD?

Less than one in 100,000 babies in the United States is born with HCSD.

DOES HCSD HAPPEN MORE OFTEN IN A CERTAIN ETHNIC GROUP?

No, HCSD does not happen more often in any specific race, ethnic group, geographical area, or country.

DOES HCSD GO BY ANY OTHER NAMES?

HCSD is sometimes also called:

• Holocarboxylase deficiency
• HLCS deficiency
• Multiple carboxylase deficiency, early-onset
• Infant multiple carboxylase deficiency
• MCD, neonatal form
• Early onset combined carboxylase deficiency

WHERE CAN I FIND MORE INFORMATION?

Organic Acidemia Association
http://www.oaanews.org

Metabolic Support UK
https://www.metabolicsupportuk.org

MedlinePlus
https://medlineplus.gov/genetics/condition/holocarboxylase-synthetase-deficiency/

Baby’s First Test
http://www.babysfirsttest.org

DOCUMENT INFO:

Created by:	www.newbornscreening.info
Reviewed by:	HI, CA, OR, and WA metabolic specialists
Review date:	September 31, 2007 June 6, 2011 August 29, 2013 May 12, 2020 March 5, 2023
Update on:	March 5, 2023

DISCLAIMER:

THIS INFORMATION DOES NOT PROVIDE MEDICAL ADVICE. All content (“Content”), including text, graphics, images and information are for general informational purposes only. You are encouraged to confer with your doctor or other health care professional with regard to information contained on this information sheet. After reading this information sheet, you are encouraged to review the information carefully with your doctor or other healthcare provider. The Content is not intended to be a substitute for professional medical advice, diagnosis or treatment. NEVER DISREGARD PROFESSIONAL MEDICAL ADVICE, OR DELAY IN SEEKING IT, BECAUSE OF SOMETHING YOU HAVE READ ON THIS INFORMATION SHEET. This project is supported by a grant from the MaternalHaving to do with the mother. and Child Health Bureau, Health Resources and Service Administration, Genetic Services Branch, MCH Project #:UH7MC30774-01-00 http://mchb.hrsa.gov