3-methylglutaconic aciduria, type III

Some genetic conditions are more frequently found in certain populations. This is known as the "founder effect", which means that a "founding" gene change/mutation happened in someone in a particular group and then spread throughout that group. "Founding" genetic changes (mutations) stay within that specific group when people tend to only have children with other members of the same community for social and cultural reasons.
The Iraqi Jewish population was founded by a small number (about 120,000) of Jews who were exiled to Babylon 586 B.C. This group was very cut off from the rest of the world for about 2,500 years. This meant that people of this group were having children only with other people in the same group, and so the same genes were being passed around the entire population.

Individuals who should be tested for 3-methylglutaconic aciduria type 3 include siblings of the person in the family identified with the condition.

Parents of the person diagnosed with 3-methylglutaconic aciduria type 3 are obligate carriers – they will have one OPA3 gene that has a mutation/change that causes 3-methylglutaconic aciduria type 3. They may want to have testing to inform their family members (blood relatives) who are also at risk of being a carrier for this condition. This can help for their future family planning in addition to their relative’s family planning.

The Organic Acidemia Association has a "Parent Connection" service where you can fill out a questionnaire and have your information shared with the OAA Family Roster. You can then connect with other parents in similar situations.
[link url="” target=”_blank”>http://www.oaanews.org/connection.htm

A doctor might suspect 3-methylglutaconic aciduria type 3 in a child who was growing and developing normally in early childhood but is now showing symptoms of optic atrophy (breakdown of the nerves that send signals from the eyes to the brain) in both eye and who is having trouble moving properly.

Symptoms of 3-methylglutaconic aciduria type 3 usually appear in childhood, by around 10 years old. Some of the symptoms may occur in early childhood, like decreased vision.

There are a few tests may be recommended after a person is diagnosed with 3-methylglutaconic aciduria type 3, including:

People with 3-methylglutaconic aciduria type 3 typically see a team of different doctors to help manage their condition, including:

The oldest person reported with 3-methylglutaconic aciduria type 3 is in their 40s. Because the syndrome is so rare, there aren’t any people known to have the syndrome who are older than this. Therefore, we don’t know if there are any problems associated with 3-methylglutaconic aciduria type 3 that happen later in life (after age 50) that may be serious or life-threatening.

3-methylglutaconic aciduria type 3 is a metabolic condition caused by genetic changes (mutations) to the OPA3 gene. Metabolic conditions affect the way our bodies break down and process the molecules our cells need to function. In 3-methylglutaconic aciduria type 3, the protein OPA3 does not work properly. It is not fully known what this protein normally does, but it is thought that it helps our cells to produce energy. The symptoms of 3-methylglutaconic aciduria type 3 include vision problems, movement problems, and mild to moderate intellectual disability. It is inherited in an autosomal recessive manner, which means a person needs a change/mutation in both copies of the OPA3 genes to have the condition. It is almost always seen in people with Iraqi Jewish ancestry.

The health problems that can occur in 3-methylglutaconic aciduria type 3 are:

When there are changes (mutations) to the OPA3 gene, not enough OPA3 protein is made or OPA3 protein is made but does not work. Cells that don’t have enough OPA3 have changes to their mitochondria (the energy-making factories in the cell). These altered mitochondria are not the right shape. This probably makes it difficult for the mitochondria to make enough energy for the cell, the cell then dies earlier than it is supposed to. This also could decrease the amount of energy available to our body, which might explain the problems with muscles that people with 3-methylglutaconic aciduria type 3 have. It is not known how to OPA3 protein works in the optic nerves or the brain.

3-methylglutaconic aciduria type 3 is caused by genetic changes (mutations) to the OPA3 gene. This gene is found on chromosome 19.

The OPA3 gene makes a protein called OPA3. The function of this protein is not quite understood yet. We do know that OPA3 is found inside the mitochondria, which are structures inside the cell that produce energy for the cell to use. The OPA3 protein may therefore help the body with energy production.

Everyone has spelling differences in their genes. That’s what makes us all different! A "variant" is a genetic spelling difference that has never been seen before or is not understood very well. If you have inherited a "variant" in OPA3, it means that there is a difference in how your OPA3 gene is spelled, but that we don’t yet know if this difference makes the gene work less or if it is just the way your OPA3 gene is normally spelled.
Since the 3-methylglutaconic aciduria type 3 is caused by spelling changes in both of a person’s OPA3 genes, it is possible to see someone who has one variant and one known mutation, or even someone with 2 variants. If this person is having symptoms of 3-methylglutaconic aciduria type 3, it more likely that the variants are spelling differences that make the gene work less. If they are not having symptoms, it makes it more likely that this is just a normal spelling difference.

The main symptoms of 3-methylglutaconic aciduria type 3 are:

If you already have a child with 3-methylglutaconic aciduria type 3, this means that both parents are "carriers" for a change in OPA3. A "carrier" is someone who has a change in 1 of the 2 copies of OPA3. Since they still have 1 working copy, they don’t have the disease but they can pass on the genetic change to their child. The chance of 2 carriers having a child with 3-methylglutaconic aciduria type 3 is 1 in 4, or 25%. There is a 1 in 2, or 50%, chance that their child will be a carrier like them. Finally, there is a 1 in 4, or 25%, chance that the child will have both working copies of OPA3.

3-methylglutaconic aciduria type 3 has complete penetrance, meaning that everyone will have some symptoms of the disease. However, 3-methylglutaconic aciduria type 3 has variable expression, meaning that not everyone with 3-methylglutaconic aciduria type 3 will have the same symptoms. Some people with 3-methylglutaconic aciduria type 3 will have severe movement problems requiring a wheelchair for getting around while others will not have any problems with movement. These symptoms can be highly variable even within the same family.

Prenatal testing for 3-methylglutaconic aciduria type 3 is available to families where the couple are known to be carriers of the condition and the OPA3 gene changes are known.

Prenatal testing can be done between 11 and 13 weeks gestation by means of chorionic villus sampling (a sample of the placenta is taken out with a needle) or by amniocentesis (a sample of the fluid around the baby is taken out with the needle) The baby’s (fetal) cells can then be tested for genetic changes (mutations) in the OPA3 gene.

As of April 2019, there is routine newborn screening for 3-methylglutaconic aciduria type 3 in some states. If you live in a state where this testing is performed at birth and your newborn screens positive, your baby will need further testing to find out if he/she actually has 3-methylglutaconic aciduria type 3. See www.babysfirsttest.org to see if you live in a state that tests for this condition in newborns. If you do not live in a state with 3-methylglutaconic aciduria type 3 on the screening panel and if the baby is known to be at risk for 3-methylglutaconic aciduria type 3, the parents might request testing for the baby at birth.

There are a few tests that can be used in the diagnosis of 3-methylglutaconic aciduria type 3. First is the urine test to see if the person has high levels of 3-methlyglutaconic acid and 3-methlyglutaric acid. Then there is the genetic testing. For genetic testing, there are a few ways that this can be done. First, the genetic test can be targeted to look for a single genetic change (called c.143-1G>C) that has been found in all Iraqi Jewish people with 3-methylglutaconic aciduria type 3. This is called "targeted mutation analysis". Second, the OPA3 gene could be read letter by letter from start to finish to look at any change in the gene. This is called "sequencing". Finally, a test can look for big pieces of extra of missing genetic material in and around the OPA3 gene. This is called "deletion/duplication" testing.

There is no cure for 3-methylglutaconic aciduria type 3. Treatment is available to assist with symptoms of the condition. Vision loss and movement problems are treated in the same ways they would be in a person without 3-methylglutaconic aciduria type 3. For individuals with vision problems, a referral to an ophthalmologist would be suggested. Individuals with movement symptoms may be referred to see a neurologist, physiotherapist, occupational therapist, and physiatrists. Individuals may also consult a pulmonologist if they are having problems with sleep apnea and difficulty breathing. The assessments by the various specialists would then recommend treatment to assist with the symptoms of 3-methylglutaconic acuduria type 3.

As of April 2019, there were not any clinical research studies ongoing for 3-methylglutaconic aciduria type 3. That does not mean that there will not be research in the future. You can visit [link url="” target=”_blank”>Clinicaltrials.gov to learn about whether there is currently clinical research on 3-methylglutaconic aciduria type 3.

If you have 3-methylglutaconic aciduria type 3, your chance to have a child with the same condition is dependent on your partner’s carrier status.

Since both of your OPA3 genes have mutations (changes) that cause the gene to be non-functional, you will always pass on a non-functional OPA3 gene to your child.

If your partner also has 3-methylglutaconic aciduria type 3, you will have a child with the condition 100% of the time. This is because your partner will also have 2 non-functional OPA3 genes.

However, if your partner does not have 3-methylglutaconic aciduria type 3, he/she could have testing of their OPA3 genes to see if there are any changes in the OPA3 genes. If they do NOT have any changes in the OPA3 genes, the chance for you to have a child with 3-methylglutaconic aciduria type 3 is less than 1%. Since genetic testing may not be able to identify all changes in the OPA3 gene that would cause 3-methylglutaconic aciduria type 3, there would still be a very small risk to have a child with the same condition as you. In this case, all your children would be carriers for 3-methylglutaconic aciduria type 3.

If your partner is identified as a carrier for 3-methylglutaconic aciduria type 3, the chance for you to have a child with the condition would be 50%. This is because you will always pass on a non-functional copy of the OPA3 gene and your partner will pass on a non-functional copy of the OPA3 gene 50% of the time, since he/she would have one functional copy of the OPA3 gene. The other 50% of the time, your child would only be a carrier for 3-methylglutaconic aciduria type 3.

If you have a child with 3-methylglutaconic aciduria type 3, both of the child’s parents must be "carriers" for the condition. This means that both parents carry one gene change (also known as a mutation) in the OPA3 gene. With every pregnancy, each parent has a 50% chance of passing on the changed gene and a 50% chance of passing on the unchanged gene. This means that there is a 25% chance that each future child will have the same disorder. To understand more about your chances to have a child with 3-methylglutaconic aciduria type 3 and testing that is available, you can meet with a genetic counselor. Genetic counselors in your area can be found on the National Society of Genetic Counselors website.

In studies of people with 3-methylglutaconic aciduria type 3, over half did not have any intellectual disability (IG greater than or equal to 71). About 36% had mild intellectual disability (IQ between 55 and 71). The remaining 11% had moderate intellectual disability (IQ between 40 and 54).

People with 3-methylglutaconic aciduria type 3 do not completely lose their vision. In studies of people with 3-methylglutaconic aciduria type 3, young children (less than 2 years old) appeared to have normal vision. By age 21, vision was 6/21 or less. This means that a person with 3-methylglutaconic aciduria type 3, 6 feet (or less, in some cases) away from an eye test chart can see what a person with normal vision can see at 21 feet away.

In studies on people with 3-methylglutaconic aciduria type 3, about half of people with the condition had severe enough problems with their movements that they needed a wheelchair. About 19% of people with 3-methylglutaconic aciduria type 3 had no movement problems, or movement symptoms that were so mild that they did not cause any problems to the person. The other 30% of people had mild movement symptoms that caused minor problems to the person.

We each typically have 2 copies of the OPA3 gene, one from our mother and one from our father. We only need 1 copy of the OPA3 gene to work in order for our cells to work properly. In order to have 3-methylglutaconic aciduria type 3, both copies of the OPA3 gene need to have changes or mutations that make the gene not work properly. This is called "autosomal recessive" inheritance. The changes in the two copies of the OPA3 gene can be the same change or different. As long as both changes make the gene work less or not at all, the person will have 3-methylglutaconic aciduria type 3. Someone who only has 1 change is known as a "carrier". Therefore, the parents of a person with 3-methylglutaconic aciduria type 3 are both carriers of a change in the OPA3 gene.

Some people choose to donate a support group like the Organic Acidemia Association ([link url="” target=”_blank”>www.oaanews.org) or the Jewish Genetic Disease Consortium ([link url="” target=”_blank”>http://www.jewishgeneticdiseases.org). Support groups will use their funds differently. Some will help to raise awareness, assist people with Triple X syndrome, or donate to medical research.

First, your doctor may order a test on your urine (pee) to look for 2 molecules called 3-methylglutaconic acid and 3-methylglutaric acid. These molecules are high in the urine of people with 3-methylglutaconic aciduria type 3. If these molecules are high in your urine, your doctor can then order genetic testing to look at the OPA3 gene. If a change is found in both of your copies of OPA3, you will be diagnosed with 3-methylglutaconic aciduria type 3. If the molecules are not high in your urine but your doctor still thinks it is 3-methylglutaconic aciduria type 3, he/she might order genetic testing anyways.

[link url="” target=”_blank”>Clinicaltrials.gov is a good place to start looking for clinical research on 3-methylglutaconic aciduria type 3. You can also look at the Organic Acidemia Association website ([link url="” target=”_blank”>www.oaanews.org) for information on current research into 3-methylglutaconic aciduria type 3.

Since 3-methylglutaconic aciduria type 3 is so rare, it can be difficult to find doctors who have experience treating the condition. There are a few different places you can look to find a doctor/center with experience treating 3-methylglutaconic aciduria type 3:

In the general population, it is very rare to be a carrier of 3-methylglutaconic aciduria type 3. In the Iraqi Jewish population, it is estimated that 1 in 10 people are carriers for 3-methylglutaconic aciduria type 3.

In the general population, 3-methylglutaconic aciduria type 3 is very rare and only a small number of people have been reported with the disease. However, 3-methylglutaconic aciduria type 3 is more common in the Iraqi Jewish population. In this group, about 1 in 10,000 people are born with 3-methylglutaconic aciduria type 3. In total, over 40 cases of the syndrome have been described in this group.

Carrier testing for 3-methylglutaconic aciduria type 3 is done by genetic testing. Your relatives can be tested for the same change/mutation in OPA3 that you have. Urine testing for 3-methylgluconic acid and 3-methlyglutaric acid is not helpful because carriers of 3-methylglutaconic aciduria type 3 will have normal levels of these molecules. Genetic testing can typically be arranged by your relative’s family physician or general practitioner. They may also wish to meet with a genetic counselor or geneticist to discuss the option of genetic testing.

While it is possible for people to have different changes/mutations in the OPA3 gene causing 3-methylglutaconic aciduria type 3, all Iraqi Jewish people who have 3-methylglutaconic aciduria type 3 have been found to have the same genetic change. This change is called a "c.143-1G>C" variant. This means that usually, at the position before #143, there is a G. In these individuals with 3-methylglutaconic aciduria type 3, this G is changed to a C. This can prevent the normal function of this gene.

Other substances that affect the mitochondria (the energy factories of the cell) can make 3-methylglutaconic aciduria type 3 worse. Tobacco, alcohol, and certain medicines are known to prevent the mitochondria form working properly. Therefore, people with 3-methylglutaconic aciduria type 3 should avoid these products.

Generally, 3-methylglutaconic aciduria type 3 is a stable disorder, meaning that the symptoms stay the same. In early childhood (by age 10), the person with 3-methylglutaconic aciduria type 3 will start to lose some of their vision and develop problems moving. The vision problems do not tend to get worse over the course of the person’s life. In their teenage years, movement problems may become worse and there could be mild intellectual disability. However, by adulthood, the symptoms do not typically change.

Some people with 3-methylglutaconic aciduria type 3 will have severe problems with movement and will need a wheelchair to help them get around. A wheelchair may be needed as soon as early childhood for some people.

There have been reports of 2 changes in the OPA3 gene ("pGly93Ser" and "p.Gln105Glu") that cause autosomal dominant optic atrophy and cataract.

There have been reports of at least one person with 3-methylglutaconic aciduria type 3 of Turkish-Kurdish descent and another with Indian descent. However, these reports are very rare incidents.

Other names you might hear to refer to 3-methylglutaconic aciduria type 3 are:

[link url="www.oaanews.org” target=”_blank”>There are support groups for people with 3-methylglutaconic aciduria type 3:

Optic atrophy is a relatively common symptom of many disorders.
Behr syndrome is the most similar condition to 3-methylglutaconic aciduria type 3. It is a childhood-onset syndrome with symptoms that include optic atrophy, movement problems, intellectual disability, and sensory loss. The best way to tell the difference between Behr syndrome and 3-methylglutaconic aciduria type 3 is to do urine testing for high levels of 3-methylglutaconic acid and 3-methylglutaric acid, which are high in 3-methylglutaconic aciduria type 3 but not in Behr syndrome.
Cerebral palsy can also look like 3-methylglutaconic aciduria type 3 because the neurologic symptoms (those having to do with the brain and movement problems) can look very similar to cerebral palsy. This is especially true if the vision loss is not noticed.

High levels of 3-methylglutaconic acid can be seen in many other inborn errors of metabolism, which are conditions that affect the way our body processes certain substances. These include conditions that cause organic aciduria, defective phospholipid remodeling, and mitochondrial membrane disorders. Other syndromes can cause high levels of this molecule in urine, like Barth syndrome (TAZ defect) and DMCA syndrome (DNAJC19 defect).