Conditions 3-Methylglutaconic Aciduria
3-methylglutaconic aciduria (3MGA) is the name for a group of five different conditions. All of these conditions affect the body’s mitochondria, the part of a human cell that produces energy. The causes, symptoms, and treatment of the five different types of 3MGA vary. However, all types of 3MGA are classified as organic acid conditions because they can result in a build-up of harmful amounts of organic acids and toxins in the body.
Organic Acid Conditions
3-methylglutaconic aciduria (3-MGA) is considered a rare condition. Less than 20 cases of MGA type I have been reported. 3MGA type II is estimated to affect one out of every 200,000 males. MGA type III is extremely rare in most populations. It is more common in the Iraqi-Jewish population where it affects approximately one in every 10,000 individuals. Exact numbers of affected individuals with MGA type IV and MGA type V are currently not available. MGA type V has only been reported in the Hutterite population of North America and Canada.
Also known as
- Barth syndrome (Type II only)
- Costeff optic atrophy syndrome (Type III only)
- Dilated cardiomyopathy with ataxia (Type V only)
- 3-methylglutaconyl CoA hydratase deficiency
Your baby’s doctor may ask you if your baby is showing any of the signs of 3MGA (see Early Signs, below). If your baby has certain signs, your baby’s doctor may suggest starting immediate treatment.
If your baby’s newborn screening result for 3-methylglutaconic aciduria (3MGA) was out of the normal range, your baby’s doctor or the state screening program will contact you to arrange for your baby to have additional testing. It is important to remember that an out-of-range screening result does not necessarily mean that your child has the condition. An out-of-range result may occur because the initial blood sample was too small or the test was performed too early. However, a few babies do have the condition, so it is very important that you go to your follow-up appointment for a confirmatory test. Because the harmful effects of untreated 3MGA can occur within days after birth, follow-up testing must be completed as soon as possible to determine whether or not your baby has the condition.
Follow-up testing will involve checking your baby’s urine and blood samples for harmful levels of acids and toxins. Certain acids and toxins build up in the body when a child has an organic acid condition, so studying the amounts of these substances in your baby’s body can help doctors determine if your baby has a condition. High levels of C5-OH acylcarnitine in the blood and organic acids in the urine may indicate that your baby has 3MGA. Sometimes follow-up testing may include testing a very small sample of skin.
About 3-Methylglutaconic Aciduria
The signs of 3-methylglutaconic aciduria (3MGA) differ depending on type, but they all begin in utero or at birth.
3MGA type I signs include:
- Delays in reaching developmental milestones (such as speech or motor skills)
- Irregular, uncontrolled muscle movements (called dystonia)
- Muscle spasms and weakness in the arms and legs (called spastic quadriparesis)
3MGA type II (Barth syndrome) signs include:
- Frequent infections
- Weak muscles
- Delayed growth
3MGA type III (Costeff optic atrophy syndrome) signs include:
- Vision loss
- Trouble with balance
- Weak muscle tone (called hypotonia)
- Involuntary and irregular movements
3MGA type IV signs vary from individual to individual. Type IV has signs similar to types I, II, and III.
3MGA type V (dilated cardiomyopathy with ataxia) signs include:
- Difficulty coordinating voluntary muscle movements (called ataxia)
- Delayed growth
- Undescended testes or an opening in the urethra on the underside of the penis
The best way to care for your baby is to monitor your baby’s heart for any cardiac complications by regularly visiting a cardiologist. A cardiologist can identify changes in your baby’s heart and decide if any additional treatments are necessary. Each baby with 3-methylglutaconic aciduria (3MGA) experiences unique signs and symptoms, so it is important to talk to your baby’s doctor to decide which treatment is right for your baby.
Other than following up with a cardiologist as necessary, there are no specific treatments available for 3MGA.
It is also important to immediately treat infections.
3-methylglutaconic aciduria (3MGA) types II, III, and V can cause an enlarged, weak heart (also called cardiomyopathy). Heart treatments improve the life span of children with 3MGA, but there is still a high risk of early death.
Even with treatment, some children with 3MGA type V may develop intellectual disabilities.
If heart problems are not treated, children with 3MGA can die during infancy.
When we eat food, enzymes help break it down. Some enzymes help break down proteins into their building blocks, called amino acids. Other enzymes break down the amino acids further into their base molecules.
The enzyme 3-methylglutaconyl-CoA hydratase is an enzyme that helps break down the amino acid leucine. When your baby has 3MGA type I, their body does not make enough or makes non-working 3-methylglutaconyl-CoA hydratase. When this happens, your baby’s body cannot break down leucine, which causes a build up of harmful substances in the body.
When your baby has 3MGA type II, their body is not making enough of a protein called tafazzin. Tafazzin helps balance the levels of a type of fat called cardiolipin, which helps cells make energy. When your baby’s body does not have tafazzin, the cells have trouble making energy.
When your baby has 3MGA type III, their body does not make enough of a protein known as the OPA3 protein. We do not yet know what the role of this protein is in the body.
Currently, we do not understand what causes 3MGA type IV.
When your baby has 3MGA type V, their body does not make enough of a protein known as the DNAJC19 protein. Currently, we do not know what this protein does, but some researchers think that it might help make, move, and break down other proteins in the cells.
All types of 3MGA are genetic conditions, but they are not all passed down in the same way.
Types I, III, and V are autosomal recessive genetic conditions. This means that a child must inherit two copies of the non-working gene for that type of 3MGA, one from each parent, in order to have the condition. The parents of a child with an autosomal recessive condition each carry one copy of the non-working gene, but they typically do not show signs and symptoms of the condition. While having a child with 3MGA is rare, when both parents are carriers, they can have more than one child with the condition.
Type II is an X-linked recessive genetic condition. This means that a male must inherit one copy of the non-working gene from his mother to have the condition. A female must inherit two copies of the non-working gene, one from each parent, in order to have the condition. In X-linked conditions, the gene is carried on the X sex chromosome, and the condition affects males more than females. While having a child with 3MGA is rare, when one or both parents carry the non-working gene for 3MGA type II, they can have more than one child with the condition. Learn more about autosomal recessive inheritance and X-linked recessive inheritance.
Support for 3-Methylglutaconic Aciduria
Support groups can help connect families who have a child or other family member affected by 3-methylglutaconic aciduria (3MGA) with a supportive community of people who have experience and expertise in living with the condition. These organizations offer resources for families, affected individuals, health care providers, and advocates.
At this time, we have not located support groups for each particular type of 3MGA. However, there are groups for many of the condition's most common symptoms. These groups may have useful resources for families affected by certain types of 3MGA. For example, families affected by cardiomyopathy as a result of 3MGA or vision loss as a result of 3MGA type III may be interested in symptom-specific support.
Work with your baby’s doctor to determine the next steps for your baby’s care. Your child's health care provider will help you coordinate care with other medical resources in the community. Care depends on what type of 3-methylglutaconic aciduria(3MGA) your child has and on your child’s symptoms. Some children will need specialized care from a cardiologist, a metabolic specialist, a dietician, and/or an optometrist. Some children with 3MGA have developmental delays. If you think that your baby is not meeting their developmental milestones, ask your child's health care provider about the next steps in accessing a developmental evaluation and care.
Because 3MGA is a genetic condition, you may want to speak with a genetics specialist. A genetic counselor or geneticist can help you understand the causes of the condition, discuss genetic testing for 3MGA, and understand what this diagnosis means for other family members and future pregnancies. Speak with your baby’s doctor about getting a referral. The Clinic Services Search Engine offered by the American College of Medical Genetics and Genomics and the Find a Genetic Counselor tool on the National Society of Genetic Counselors website are two good resources for you or your health care provider to use to identify local specialists.
Ben Thorpe is a sixteen-year-old boy from South Africa with Barth syndrome (3MGA type II). He shared his story at the 2010 International Barth Syndrome Foundation Conference. Watch him talk about his experience in this video of his speech, which is available on YouTube.
Through the kindness of an organ donation and a supportive community, Miloh Kalapashez has a chance at life. Miloh was born with Barth syndrome (3MGA type II). Read his family’s story in this news article published on www.wcpo.com.
Ben Johnson is a teenager living with cardiomyopathy. Ben’s cardiomyopathy is probably not caused by 3MGA. However, many children with certain types of 3MGA suffer from cardiomyopathy. Ben’s story is an inspiring story of growing up with a heart condition. You can read his story on page 11 of the Children’s Cardiomyopathy Foundation’s newsletter.
References & Sources
Read this fact sheet prepared by the Texas Department of State Health Services for more information
Visit Genetics Home Reference from the National Library of Medicine for more condition information
Vreken P, Valianpour F, Nijtmans L, et al. Defective Remodeling of Cardiolipin and Phosphatidylglycerol in Barth Syndrome. Biochemical and Biophysical Research Communications. 2000; 279(2): 378-382.