ORGANIC ACID DISORDER

Disorder name: 3-hydroxy-3-methylglutaryl-CoA lyase deficiency
Acronym: HMG lyase deficiency
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• What is HMG lyase deficiency?
• What causes HMG lyase deficiency?
• If HMG lyase deficiency is not treated, what problems occur?
• What is the treatment for HMG lyase deficiency?
• What happens when HMG lyase deficiency is treated?
• What causes the HMG CoA lyase enzyme to be absent or not working correctly?
• How is HMG lyase deficiency inherited?
• Is genetic testing available?
• What other testing is available?
• Can you test during a future pregnancy?
• Can other members of the family have HMG lyase deficiency or be carriers?
• Can other family members be tested?
• How many people have HMG lyase deficiency?
• Does HMG lyase deficiency happen more often in a certain ethnic group?
• Does HMG lyase deficiency go by any other names?
• Where can I find more information?

This fact sheet contains general information about HMG lyase deficiency. 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 this condition should be followed by a metabolic doctor in addition to their primary doctor.

WHAT IS HMG LYASE DEFICIENCY?

HMG lyase deficiency is one type of organic acid disorder.  People with this condition have problems breaking down an amino acid called leucine 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 HMG LYASE DEFICIENCY?

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.

In order for the body to use fat for energy, enzymes break down fatty acids into ketone bodies. Normally, during long periods without eating, 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. are made by the body and used for fuel.

HMG lyase deficiency is caused by problems with the enzyme “HMG CoA lyase.” In people with HMG lyase deficiency, the HMG CoA lyase enzyme is either missing or not working properly. This enzyme has two jobs. The first is to help break down leucineThis 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.. Leucine is found in all foods that contain protein. The second job is to help the body make ketone bodies from stored 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..

When children with this condition eat food containing leucine, harmful substances build up in the blood. In addition, children with HMG lyase deficiency can’t make ketone bodies from stored fat like most people. So, when they don’t eat for a long period of time, they can develop low blood sugar (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.) and serious health problems.

 

IF HMG LYASE DEFICIENCY IS NOT TREATED, WHAT PROBLEMS OCCUR?

Each child with HMG lyase deficiency will have somewhat different effects. Babies with this condition are usually healthy at birth. Most babies start to have symptoms between 3 months and two years of age. A few babies, though, have had their first symptoms just a few days after birth.

HMG lyase deficiency 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
• extreme sleepiness or lack of energy
• behavior changes
• irritable mood
• muscle weakness

Some or all of these symptoms may also occur:

• fever
• nausea
• diarrhea
• vomiting
• hypoglycemia
• 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.
• high levels of ammonia in the blood
• enlarged liver

If a metabolic crisis is not treated, a child with HMG lyase deficiency 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.
• 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

If not treated, many babies with HMG lyase deficiency die during their first metabolic crisis. In surviving babies, repeated episodes of metabolic crisis can cause brain damage. This can result in life-long learning problems or intellectual disabilities.

Episodes of metabolic crisis can be triggered by:

• illness or infection
• going without food for long periods of time
• eating large amounts of protein

When a child is ill or goes without food for too long, the body breaks down its own protein and fat to use for energy. In people with HMG lyase deficiency, this can trigger a metabolic crisis, as described above.

Between episodes of metabolic crisis, children with this condition are usually healthy.

Long-term effects can happen in some children. These may include:

• enlarged heart
• inflammation of the pancreasThis is a large organ behind the stomach. One of its jobs is to make digestive enzymes and release them into the small intestine. The digestive enzymes are essential for food (carbohydrates, proteins and fats) to be broken down into small enough nutrients to get into the blood. Without them, people cannot absorb enough nutrients and will develop malnutrition and poor growth. The pancreas also makes the hormone insulin which is needed for glucose (sugar) to leave the blood and get into body cells., called pancreatitisThis happens when the pancreas, an organ near the stomach, becomes inflamed. It causes severe abdominal pain. It can be caused by some metabolic disorders, gallstones or too much alcohol.
• hearing loss
• vision loss
• learning problems or intellectual disabilities

Some people with HMG lyase deficiency never have symptoms and are only found to be affected after a brother or sister is diagnosed. A few individuals have been diagnosed after developing heart conditions in their teens and early twenties.

WHAT IS THE TREATMENT FOR HMG LYASE DEFICIENCY?

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. You need to start treatment as soon as you know your child has HMG lyase deficiency. Certain treatments may be advised for some children but not others. Treatment is usually needed throughout life.

The following are treatments often recommended for babies and children with this condition:

1.  Avoid going a long time without food
Infants and young children with HMG lyase deficiency need to eat frequently to prevent a metabolic crisis. Your metabolic doctor will tell you how often your child needs to be fed.  In general, it is often suggested that infants be fed every four to six hours. Some babies need to eat even more frequently than this. It is important that infants be fed during the night. They may need to be woken up to eat if they do not wake up on their own. Your metabolic doctor and 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. will give you an appropriate feeding plan for your infant. 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.

2. Low-leucine diet, including medical foods and formula
A food plan low in leucine with limited amounts of fat and protein is often recommended. Most foods in the diet will be carbohydrates (bread, cereal, pasta, fruit, vegetables, etc.). 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. give the body many types of sugar that can be used as energy. Eating a diet high in carbohydrates and low in protein and fat can help prevent low blood sugar and metabolic crises.

Foods high in protein and fat that your child may need to avoid or limit:

• milk and dairy products
• meat and poultry
• fish
• eggs
• dried beans and legumes
• nuts and peanut butter
• butter, margarine, oil, lard, and foods made with these fats

Many vegetables and fruits have only small amounts of protein and fat and can be eaten in carefully measured amounts. Do not remove all protein and fat from the diet. Your child needs a certain amount of each to grow properly.

Your dietician will create a food plan that contains the right amount of protein, fat, nutrients, and energy to keep your child healthy. Your child may need to be on a special food plan throughout life.
           
Medical foods and formula
There are medical foods such as special low-protein flours, pastas, and rice that are made especially for people with organic acid disorders. Your dietician will tell you how to use these foods as part of your child’s diet.

Some children are also given a special leucine-free medical formula. Your metabolic doctor and dietician will decide whether your child needs this formula. Some states offer help with payment for this special formula, and others require private insurance to pay for the formula and other special medical foods.

3.  Medications
Some children may benefit by taking 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.. 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-carnitine. Unless you are advised otherwise, use only L-carnitine prescribed by your doctor.  Do not use any medication without checking with your doctor.

Children with symptoms of a metabolic crisis need medical treatment right away. They often need to be treated in the hospital. During a metabolic crisis, children may be given glucoseThis is a type of sugar made from the carbohydrates in food. Glucose is found in the blood. It is the main source of energy for the body and brain., bicarbonateThis is a substance that lowers the amount of acid in the blood. It is sometimes used as part of the treatment for children with certain organic acid disorders., and other medications by IV to treat hypoglycemia and other symptoms of a metabolic crisis.  Ask your metabolic doctor if you should carry a special travel letter with medical instructions for your child’s care.

4.  Call your doctor at the start of any illness
In some children, even minor illnesses such as a cold or the flu 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

Children with HMG lyase deficiency need to eat more carbohydrates and drink more fluids when they are ill – even if they’re not hungry – or they could have a metabolic crisis. Also, they need to avoid eating protein and fat during any illness.

Children who are ill often don’t want to eat. If they can’t eat, or if they show signs of a metabolic crisis, they may need to be treated in the hospital.

WHAT HAPPENS WHEN HMG LYASE DEFICIENCY IS TREATED?

With prompt and careful treatment, children with HMG lyase deficiency have a good chance to live healthy lives with typical growth and development.

Even with treatment, some children still have repeated bouts of hypoglycemia or metabolic crises. This can cause brain damage and may lead to life-long learning problems or intellectual disabilities.

WHAT CAUSES THE HMG COA LYASE ENZYME TO BE ABSENT OR NOT WORKING CORRECTLY?

Genes tell the body how to make enzymes. The HMGCL gene instructs the body to make the HMG-CoA lyase enzyme. Everyone has two copies of the HMGCL gene. People with HMG lyase deficiency 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 HMGCL 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 HMGCL genes, the HMG-CoA lyase enzyme either does not work properly or is not made at all.

HOW IS HMG LYASE DEFICIENCY INHERITED?

HMG lyase deficiency is inherited in an autosomal recessive manner. It affects both boys and girls equally.

Everyone has two copies of the HMGCL gene that make the HMG CoA lyase enzyme. In children with HMG lyase deficiency, neither of their HMGCL genes works correctly. These children inherit one non-working HMGCL gene for the condition from each parent.

Parents of children with HMG lyase deficiency rarely have the disorder. Instead, each parent has a single non-working HMGCL gene for HMG lyase deficiency. 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 HMG lyase deficiency because their other HMGCL gene is working correctly.

When both parents are carriers, there is a 25% chance in each pregnancy for the child to have HMG lyase deficiency. 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 HMG lyase deficiency. 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 this condition is available. Genetic testing, also called DNA testing, looks for changes (variants) in the HMGCL genes that cause HMG lyase deficiency. 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, urine, or skin samples can be done to help confirm if your child has HMG lyase deficiency. Talk to your metabolic doctor or genetic counselor if you have questions about testing for this condition.

CAN YOU TEST DURING A FUTURE PREGNANCY?

If both gene changes (variants) 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..

It may also be possible to do an enzyme test using 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. from the fetus. The sample needed for this test is obtained by either CVSThis is a special test done early in pregnancy. During CVS, a small sample of the placenta is removed for testing. This sample can be used to test for certain genetic disorders in the fetus. CVS is usually done between 10 and 12 weeks of pregnancy. or amniocentesis. Testing has also been done in late pregnancy (after 23 weeks) using a urine sample from the mother.

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 HMG lyase deficiency. 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 HMG LYASE DEFICIENCY OR BE CARRIERS?

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

HMG lyase deficiency carriers
Brothers and sisters who do not have HMG lyase deficiency 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 HMG lyase deficiency, 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 HMG lyase deficiency.

All states offer newborn screening for HMG lyase deficiency. However, when both parents are carriers for HMG lyase deficiency, 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 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 HMG lyase deficiency can be tested using blood, urine, or skin samples to see if they also have HMG lyase deficiency.

Carrier testing
If both gene changes (variants) have been found in the child with HMG lyase deficiency, 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 HMG LYASE DEFICIENCY?

This condition is very rare. The actual incidence is unknown.

DOES HMG LYASE DEFICIENCY HAPPEN MORE OFTEN IN A CERTAIN ETHNIC GROUP?

HMG lyase deficiency happens in all ethnic groups throughout the world. It happens more often in people from Saudi Arabia, Portugal, and Spain.

DOES HMG LYASE DEFICIENCY GO BY ANY OTHER NAMES?

This condition is sometimes also called:

• HMG-CoA lyase deficiency
• hydroxymethylglutaric aciduria
• HMGCL deficiency
• HL deficiency
• HMG
• 3-OH 3-CH3 glutaric aciduria
• 3-OH 3-methyl glutaric aciduria

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/3-hydroxy-3-methylglutaryl-coa-lyase-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 2011 August 29, 2013 May 19, 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