FATTY AND ORGANIC ACID DISORDER

Disorder name: Glutaric acidemia, type 2
Acronym: GA-2
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• What is GA-2?
• What causes GA-2?
• If GA-2 is not treated, what problems occur?
• What is the treatment for GA-2?
• What happens when GA-2 is treated?
• What causes the enzyme to be absent or not working correctly?
• How is GA-2 inherited?
• Is genetic testing available?
• What other testing is available?
• Can you test during a future pregnancy?
• Can other members of the family have GA-2 or be carriers?
• Can other family members be tested?
• How many people have GA-2?
• Does GA-2 happen more often in a certain ethnic group?
• Does GA-2 go by any other names?
• Where can I find more information?

This fact sheet contains general information about GA-2. 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 GA-2 should be followed by a metabolic doctor in addition to their primary doctor.

WHAT IS GA-2?

GA-2 stands for “glutaric acidemia, type 2.” People with GA-2 have problems breaking down fat and protein into energy for the body. GA-2 has symptoms that are part of two different groups of disorders: fatty acid oxidationThis is the process used by the body to change fatty acids, the building blocks of fat, into energy. It happens in the mitochondria – the small energy-producing parts found in each cell of the body. disorders and 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..

Fatty Acid Oxidation Disorders: Fatty acid oxidation disorders (FAODs)This is a group of rare inherited conditions. FAODs are caused by missing or non-working enzymes. Normally, many enzymes are used by the body to break down fat into energy. In people with FAODs, one of these enzymes is not working and fat cannot be used for energy. If these conditions are not treated, they can lead to serious health problems. 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 break down fats in the body (a process called fatty acid oxidation). Problems with any of these enzymes can cause a fatty acid oxidation disorder. People with FAODs cannot properly break down 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. from either the food they eat or from fat stored in their bodies. The symptoms and treatment vary between different FAODs. They can also vary from person to person with the same FAOD. See the fact sheets for each specific FAOD. FAODs are inherited in an autosomal recessive manner and affect both males and females.

 

Organic Acid Disorders: Organic acid disorders (OAs) are a group of rare inherited conditions. They are caused by enzymes that do not work properly. A number of enzymes 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 GA-2?

GA-2 occurs when one of two different enzymes is either missing or not working properly. The enzymes responsible for GA-2 are called “electron transfer flavoprotein” (ETF) and “electron transfer flavoprotein dehydrogenase” (ETFDH). The job of these enzymes is to help make energy for the body by breaking down certain fats and proteins from the food we eat. They also break down fat and protein already stored in the body.

Energy from fat and protein keeps us going whenever our body runs low of its main source of energy, a type of sugar called 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.. Our bodies rely mainly on fat when we don’t eat for a stretch of time – like when we miss a meal or when we sleep.

When either one of these two enzymes is missing, the body cannot break down protein and fat for energy, and must rely on glucose. While glucose is a good source of energy, there is a limited amount available. Once the glucose has been used up, the body tries to use fat and protein with limited success. This leads to the build up of glutaric acid and other harmful substances in the blood. It also causes 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..

IF GA-2 IS NOT TREATED, WHAT PROBLEMS OCCUR?

GA-2 can cause bouts 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
• behavior changes
• irritable mood
• muscle weakness
• poor appetite

Other symptoms then follow:

• 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.

If a metabolic crisis is not treated, a child with GA-2 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

Symptoms can first show up in the newborn period or later in childhood or sometimes even adulthood.

GA-2 in newborns
Some babies have their first symptoms shortly after birth. Rapid breathing and weak muscle tone often happen one to two days after birth. Episodes of metabolic crisis often show up at this time, too.

Many babies with GA-2 have an odor that smells like “sweaty feet.” In addition, they often have serious heart and liver problems.

Without treatment, most babies die within the first few weeks of life. Even with treatment, many babies with GA-2 die of severe heart problems within a few months.

Some newborns with GA-2 also have birth defects. If this is the case, treatment is usually not helpful. Babies with GA-2 and birth defects usually die within the first weeks of life.

GA-2 in childhood
The symptoms of GA-2 can be very different from person to person. If symptoms do not happen in the newborn period, they may begin anytime from early childhood through adulthood.

Symptoms in childhood can include:

• nausea
• vomiting
• muscle weakness
• periods of hypoglycemia
• full metabolic crisis (described above)

Hypoglycemia, or low blood sugar, can cause a child to feel weak, shaky, or dizzy with clammy, cold skin. Hypoglycemia can occur:

• after strenuous exercise
• after eating too much protein
• after going too long without food
• during illness or infection

Episodes of metabolic crisis can happen for the same reasons.

Other symptoms of GA-2 happen in some people:

• liver problems
• heart problems
• low levels of carnitine, a substance that helps the body use fat for energy
• involuntary movements

Some people with GA-2 never have symptoms and are only found to be affected after a brother or sister is diagnosed.

WHAT IS THE TREATMENT FOR GA-2?

Your child’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 dietician familiar with GA-2 to provide your child with medical care.

Certain treatments may be advised for some children but not others. When necessary, treatment is usually needed throughout life. The following are treatments often recommended for children with GA-2:

1. Avoid going a long time without food
Infants and young children with GA-2 need to eat frequently to prevent hypoglycemia or 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.  When they are well, many teens and adults with GA-2 can go without food for up to 12 hours without problems. They may need to continue the other treatments throughout life.

2. Diet
A diet low in fat, low in protein and high in carbohydrates is often advised. 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. In fact, for children needing this treatment, most food in the diet should be carbohydrates (bread, cereal, pasta, fruit, vegetables, etc.). Do not remove all fat and protein from the diet. Children with GA-2 need a certain amount of each to grow properly.

Your dietician 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 experienced with GA-2.

3. RiboflavinThis is a one type of B vitamin (vitamin B2). It helps change carbohydrates, protein, and fat into energy for the body. Some foods high in riboflavin are dairy products, yogurt, cheese, meats, poultry, whole and enriched grains, and green vegetables. Some children with metabolic disorders may be helped by taking riboflavin supplements., 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., and Coenzyme Q₁₀
Some children and adults with GA-2 are helped by taking daily riboflavin supplements. Check with your doctor to see whether your child should take riboflavin.

Some children may be helped by taking L-carnitine. 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 supplements.  Unless you are advised otherwise, use only L-carnitine prescribed by your doctor.

Supplementation with Coenzyme Q₁₀ may also be beneficial. Coenzyme Q₁₀ is a substance this is found in every cellThe 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. in the body and it helps convert food into energy and it is a powerful antioxidant. Some people with GA-2 may benefit from taking Coenzyme Q_10.

Do not use any of these supplements without checking with your doctor.

4. Call your doctor at the start of any illness
Always call your health care provider when your child has any of the following:

• poor appetite
• low energy or extreme sleepiness
• vomiting
• diarrhea
• an infection
• a fever

During illness or infection, children with GA-2 have a much higher chance of developing hypoglycemia or a metabolic crisis. They need to drink fluids and eat extra carbohydrates when they are ill – even if they aren’t hungry – or they could have a metabolic crisis.

Children who are sick often don’t want to eat. If they can’t eat, or if they show signs of hypoglycemia or a metabolic crisis, they may need to be treated in the hospital.  Ask your metabolic doctor if you should carry a special travel letter with medical instructions for your child’s care.

WHAT HAPPENS WHEN GA-2 IS TREATED?

GA-2 in newborns
A small number of newborns with symptoms of GA-2 have shown benefit from treatment. But, in most cases, treatment has not been helpful. Many newborns with GA-2 die from heart problems within the first few months of life.

GA-2 in children
With prompt and careful treatment, children and adults with GA-2 usually live healthy lives with normal growth and development.

The goal of treatment is to prevent long-term problems. However, children who have repeated metabolic crises may develop life-long learning problems.

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

Genes tell the body how to make enzymes. Three different 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. – ETFA, ETFB, and ETFDH – provide the instructions to make electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase enzymes. Everyone has two copies of each of these three genes. People with GA-2 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 either their ETFA, ETFB, or ETFDH genes. Because of the variants in the ETFA, ETFB, or ETFDH genes, the electron transfer flavoprotein or electron transfer flavoprotein dehydrogenase enzyme either does not work properly or is not made at all.

HOW IS GA-2 INHERITED?

GA-2 is inherited in an autosomal recessive manner. It affects both boys and girls equally.

Everyone has two copies of the ETFA and ETFB genes that make the ETF enzyme, and two copies of the ETFHD genes that makes the ETFDH enzyme. In children with GA-2, the pair of genes for one of these enzymes does not work correctly. These children inherit one non-working gene for the condition from each parent.

Parents of children with GA-2 rarely have the disorder. Instead, each parent has a single non-working gene for GA-2. 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 GA-2 deficiency 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 GA-2. 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 GA-2. 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 GA-2 can be done on a blood sample. Genetic testing, also called DNA testing, looks for the changes (variants) in the pair of genes that cause GA-2. 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. However, it can be helpful for carrier or prenatal testing, discussed below.

WHAT OTHER TESTING IS AVAILABLE?

GA-2 can be confirmed by tests done on urine, blood, or skin samples. Ask your metabolic doctor or genetic counselor about testing for GA-2.

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 GA-2. 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 GA-2 OR BE CARRIERS?

Having GA-2
The brothers and sisters of a baby with GA-2 have a chance of being affected, even if they haven’t shown symptoms. Finding out if other children in the family have GA-2 is important because early treatment may prevent serious health problems. Talk to your metabolic doctor or genetic counselor about testing your other children for GA-2.

GA-2 carriers
Brothers and sisters who do not have GA-2 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 GA-2, your brothers and sisters have a 50% chance to be a GA-2 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 GA-2.

Some states do not provide newborn screening for GA-2. However, expanded 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. through private labs is available for babies born in states that do not screen for this condition. Your healthcare provider or genetic counselor can help you obtain expanded 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..

When both parents are carriers, newborn screening results are not sufficient to rule out GA-2 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
GA-2 can be confirmed by special tests using urine, blood, or skin samples.

Carrier testing
Carrier testing for GA-2 may be available. Ask your genetic counselor or metabolic doctor whether carrier testing is possible for your family.

HOW MANY PEOPLE HAVE GA-2?

GA-2 is very rare. The actual incidence is unknown.

DOES GA-2 HAPPEN MORE OFTEN IN A CERTAIN ETHNIC GROUP?

GA-2 does not happen more often in any specific race, ethnic group, geographical area, or country.

DOES GA-2 GO BY ANY OTHER NAMES?

GA-2 is sometimes also called:

• glutaric acidemia-II
• glutaric aciduria-II
• multiple acyl-CoA dehydrogenase deficiency (MADD)
• electron transfer flavoprotein dehydrogenase deficiency
• ETF/ETF QO deficiency

WHERE CAN I FIND MORE INFORMATION?

Fatty Oxidation Disorders (FOD) Family Support Group
http://www.fodsupport.org

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

United Mitochondrial Disease Foundation
http://www.umdf.org

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

MedlinePlus
https://medlineplus.gov/genetics/condition/glutaric-acidemia-type-ii/

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 26, 2013 May 19, 2020 March 1, 2023
Update on:	March 1, 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