ORGANIC ACID DISORDER

Disease name: Beta ketothiolase deficiency
Acronym: BKD
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• What is BKD?
• What causes BKD?
• If BKD is not treated, what problems occur?
• What is the treatment for BKD?
• What happens when BKD is treated?
• What causes the MAT enzyme to be absent or not working correctly?
• How is BKD inherited?
• Is genetic testing available?
• What other testing is available?
• Can you test during a future pregnancy?
• Can other members of the family have BKD or be carriers?
• Can other family members be tested?
• How many people have BKD?
• Does BKD happen more often in a certain ethnic group?
• Does BKD go by any other names?
• Where can I find more information?

This fact sheet has general information about BKD. 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 BKD should be followed by a metabolic doctor in addition to their primary doctor.

WHAT IS BKD?

BKD stands for “beta ketothiolase deficiency.” It is one type of organic acid disorder. People with BKD have problems breaking down an amino acid called isoleucine from the food they eat.

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 BKD?

In order for the body to use protein from the food we eat, it is broken down into smaller parts called amino acidsAmino acids are small molecules that make up proteins. There are over 100 different amino acids, but our body uses only 20 amino acids to make all of its proteins. Our genes determine the sequence of amino acids in a protein. This sequence determines what shape the protein takes, and what function that protein serves in the body.. Special enzymes then make changes to the amino acids so the body can use them.

BKD is caused by problems with the enzyme “mitochondrial acetoacetyl-CoA thiolase” (MAT). In people with BKD, the MAT enzyme is either missing or not working properly. This enzyme’s job is to help break down the amino acid isoleucineThis is one of 20 amino acids that make up protein. It is not made by the body and must be eaten in the diet. It is found in all foods that contain protein.. When a child with BKD eats food containing isoleucine, harmful substances called organic acids build up in the blood and cause problems. Isoleucine is found in all foods that contain protein.

IF BKD IS NOT TREATED, WHAT PROBLEMS OCCUR?

Each child with BKD has slightly different effects. The first symptoms often start around age one, although babies can show signs either earlier or later than this. Some people with BKD never develop symptoms.

BKD can cause 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:

• extreme sleepiness or lack of energy
• vomiting
• diarrhea
• fever
• poor appetite
• ketones in the urine (substances created during the breakdown of fatFat is one of the three main nutrients in food (carbohydrates, fat, protein). Some foods that contain fat are butter, margarine, oils, nuts, meats, poultry, fish and some dairy products. Extra calories from food are stored as body fat. Stored body fat provides the body with a reserve supply of energy.)

Other symptoms then follow:

• increased 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.
• 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.
• 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

Episodes of metabolic crisis can be triggered by:

• going too long without food
• illness or infection
• eating too much protein

Other long-term effects of untreated BKD can include:

• intellectual disabilities
• enlarged heart with irregular heart beat
• poor growth
• abnormal muscle tone (too floppy or too rigid)
• jerky uncoordinated movements
• low plateletsThis is a type of blood cell that helps to clot the blood. Platelets help prevent or control bleeding.
• low level of white blood cellsThe smallest living unit. Cells make up all organs and tissues in multi-cellular organisms, like humans. They can also live independently, as in bacteria and other microorganisms. At a minimum, a cell is surrounded by a membrane, contains DNA at some stage in its life, and is able to replicate itself into two equal parts. (increasing the risk of infection)

Some people with BKD never have symptoms and are only found to be affected after a brother or sister is diagnosed.

WHAT IS THE TREATMENT FOR BKD?

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. and a dietician to care for your child.

Prompt treatment is needed to prevent metabolic crises and the health effects that follow. When necessary, treatment is usually needed throughout life.

The following are treatments sometimes advised for babies and children with BKD:

1. Medication
Some children may be helped by taking L-carnitine by mouth. This is a safe and natural substance that helps body cells make energy. It also helps the body get rid of harmful wastes. Your doctor will decide whether or not your child needs L-carnitineThis is a natural substance found in muscle cells. It helps the body make energy from the fat in food and the fat stored in the body. It also helps the cells get rid of harmful wastes made during the breakdown of fat. Carnitine supplements may be used as a treatment for some metabolic disorders. supplements. Unless you are advised otherwise, use only L-carnitine prescribed by your doctor.  Do not use any medication without checking with your metabolic doctor.

Children with symptoms of a metabolic crisis need to be treated in the hospital. During a metabolic crisis, your child may be given medications such as bicarbonate by IV to help reduce the acid levels in the blood. In addition, glucose is often given by IVThis is a small tube placed into a vein, usually in the hand or arm. Medications and nutrients can be given through this tube directly into the blood. IV’s are often used in the hospital to give fluids, glucose and medication over a long period of time. to prevent the breakdown of body stores of protein.  Ask your metabolic doctor if you should carry a special travel letter with medical instructions for your child’s care.

2. Avoid going a long time without food
Some infants and young children with BKD need to eat frequently to prevent a metabolic crisis. Your metabolic doctor will tell you how often your child needs to be fed. Your doctor will also give you a ‘sick day’ plan, tailored to your child’s needs, for you to follow during illnesses or other times when your child will not eat.

Your metabolic doctor will continue to advise you on how often your child should eat as he or she gets older.  When they are well, many teens and adults with BKD can go without food for up to 12 hours without problems. The other treatments usually need to be continued throughout life.

3. Low-protein diet
Some children may be able to eat normal amounts of protein, but others will need to be on a low-protein diet.

Foods high in protein that may need to be limited include:

• milk and dairy products
• meat and poultry
• fish
• eggs
• dried beans
• nuts and  peanut butter

Eating large amounts of these foods can cause protein levels to become too high, causing illness. However, do not remove all protein from the diet. Children with BKD need a certain amount of protein to grow properly.

If it is necessary for your child to eat a low-protein diet, your dieticianThis is a person with special training in food and nutrition. A registered dietician (RD) has met the necessary educational requirements and has passed a national examination. If your child has a metabolic disorder, it is important for you to work with a registered dietician. They help create healthy food plans for people with metabolic disorders or other special needs. can help you create a food plan that meets your child’s needs. Any diet changes should be made under the guidance of a dietician.

4.  TrackingThe process of testing a disease for a person who does not appear to have the disease (non-symptomatic or asymptomatic). The goal of tracking is to find the disease in its earliest stages. ketone levels
Periodic urine tests to test the level of ketonesThese are substances made when the body breaks down fat (fatty acids) for energy. In people with certain metabolic disorders or diabetes, ketones can build up in the blood and spill over into the urine. If ketones build up in the blood, they can cause acidosis which can lead to serious health problems. may be necessary. This can be done at home or at the doctor’s office. Ketones are substances formed when body fat is broken down for energy. This happens after going without food for long periods of time, during illness, or during periods of heavy exercise. Ketones in the urine may signal the start of a metabolic crisis.

5.  Call your doctor at the start of any illness
In some children, even minor illnesses can lead to a metabolic crisis. In order to prevent problems, call your doctor right away when your child has any of the following:

• loss of appetite
• vomiting
• diarrhea
• infection or illness
• fever

When your child is ill, he or she needs extra fluids and carbohydratesThis is one of the three types of nutrients in food (carbohydrates, fats, proteins). Sugars and starches are the most important types of carbohydrates. They are broken down by the body into glucose, the main source of energy for the body. Carbohydrates are found in foods such as: bread, cereal, pasta, grains, fruits and vegetables. Milk and dairy products, fruit drinks, sugar, candy, and sweet desserts also contain carbohydrates. to prevent a metabolic crisis. Whenever your child becomes ill, it is important to restrict protein and give him or her extra starchy or sugary foods.

WHAT HAPPENS WHEN BKD IS TREATED?

If treatment is started early and metabolic crises do not occur, your child is likely to have normal growth and intelligence. Even with treatment, some children still have repeated episodes of metabolic crises, which can cause brain damage. This can result in learning problems, intellectual disabilities, or other problems.

Between episodes of metabolic crisis, people with BKD are usually healthy. Metabolic crises tend to happen less often as a child gets older. They are rare in children older than 10.

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

Genes tell the body how to make enzymes. The ACAT1 gene instructs the body to make the MAT enzyme. Everyone has two copies of the ACAT1 gene. People with BKD 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 ACAT1 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.. Because of the variants in the ACAT1 genes, the MAT enzyme either does not work properly or is not made at all.

HOW IS BKD INHERITED?

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

Everyone has two copies of the ACAT1 gene that makes the MAT enzyme. In children with BKD, neither of their ACAT1 genes works correctly. These children inherit one non-working ACAT1 gene for the condition from each parent.

Parents of children with BKD rarely have the condition themselves. Instead, each parent has a single non-working ACAT1 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 BKD 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 BKD. 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 BKD. Genetic counselors can answer your questions about how the condition 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 BKD is available. Genetic testing, also called DNA testing, looks for changes (variants) in the ACAT1 genes that causes BKD. 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. It can be helpful for carrier testing or prenatal diagnosis, discussed below.

WHAT OTHER TESTING IS AVAILABLE?

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

CAN YOU TEST DURING A FUTURE PREGNANCY?

If both gene changes have been found in your child, 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 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 BKD. 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 BKD OR BE CARRIERS?

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

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

If you are a parent of a child with BKD, your brothers and sisters have a 50% chance to be a 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 BKD.

All states offer newborn screening for BKD. However, when both parents are 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 BKD in a newborn baby. In this case, special diagnostic testing should be done in addition to 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..

CAN OTHER FAMILY MEMBERS BE TESTED?

Diagnostic testing
Brothers and sisters of a child with BKD can be tested using blood, urine, or skin samples.

Carrier testing
If both gene changes (variants) have been found in your child, other family members can have DNA testing to see if they are carriers.

If DNA testing is not possible or is not helpful, other methods of carrier testing may be available. Your metabolic doctor or genetic counselor can answer your questions about carrier testing.

HOW MANY PEOPLE HAVE BKD?

BKD is thought to be rare. The actual incidence is unknown.

DOES BKD HAPPEN MORE OFTEN IN A CERTAIN ETHNIC GROUP?

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

DOES BKD GO BY ANY OTHER NAMES?

BKD is also sometimes called:

• Ketone utilization disorder
• Alpha-methylacetoacetic aciduria
• 2-methyl-3-hydroxybutyric acidemia
• Mitochondrial acetoacetyl-CoA thiolase deficiency
• MAT deficiency
• T2 deficiency
• 3-oxothiolase deficiency
• 3-ketothiolase deficiency
• 3-KTD 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/beta-ketothiolase-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 May 1, 2011 August 26, 2013 May 20, 2020 March 8, 2023
Update on:	March 8, 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