3-methylglutaconic aciduria, type III

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How common is 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.

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Do people with 3-methylglutaconic aciduria type 3 need a wheelchair?

I have a child with 3-methylglutaconic aciduria type 3. If I have more children, will they have the same disorder too?

If I have 3-methylglutaconic aciduria type 3, will my children have the same disorder?

When does a doctor suspect that a child has 3-methylglutaconic aciduria type 3?

Does everyone with 3-methylglutaconic aciduria type 3 have the same change/mutation in the OPA3 gene?

Does 3-methylglutaconic aciduria type 3 get worse as the person gets older?

How severe are the vision problems associated with 3-methylglutaconic aciduria type 3?

How severe are the movement problems associated with 3-methylglutaconic aciduria type 3?

How severe is the intellectual disability in 3-methylglutaconic aciduria type 3?

What is the life expectancy of people with 3-methylglutaconic aciduria type 3?

How common is it to be a carrier of 3-methylglutaconic aciduria type 3?

How can my relatives be tested for 3-methylglutaconic aciduria type 3?

Why is 3-methylglutaconic aciduria type 3 almost only seen in people of Iraqi Jewish ancestry?

Are there reports of 3-methylglutaconic aciduria type 3 in people from racial background other than Iraqi Jewish?

Do people with 3-methylglutaconic aciduria type 3 need a wheelchair?

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.

References
I have a child with 3-methylglutaconic aciduria type 3. If I have more children, will they have the same disorder too?

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.

References
If I have 3-methylglutaconic aciduria type 3, will my children have the same disorder?

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.

References
When does a doctor suspect that a child has 3-methylglutaconic aciduria type 3?

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.

References
Does everyone with 3-methylglutaconic aciduria type 3 have the same change/mutation in the OPA3 gene?

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.

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Does 3-methylglutaconic aciduria type 3 get worse as the person gets older?

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.

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How severe are the vision problems associated with 3-methylglutaconic aciduria type 3?

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.

References
How severe are the movement problems associated with 3-methylglutaconic aciduria type 3?

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.

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How severe is the intellectual disability in 3-methylglutaconic aciduria type 3?

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).

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What is the life expectancy of people with 3-methylglutaconic aciduria type 3?

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.

References
How common is it to be a carrier of 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.

References
How can my relatives be tested for 3-methylglutaconic aciduria type 3?

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.

References
Why is 3-methylglutaconic aciduria type 3 almost only seen in people of Iraqi Jewish ancestry?

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.

References
  • Anikster Y., Kleta, R., Shaag, A., Gahl, W.A. and Elpeleg, O. (2001) Type III 3-Methylglutaconic Aciduria (Optic Atrophy Plus Syndrome, or Costeff Optic Atrophy Syndrome): Identification of the OPA3 Gene and Its Founder Mutation in Iraqi Jews. AJHG 69(6):1218-1224. http://www.cell.com/ajhg/fulltext/S0002-9297(07)61251-8
Are there reports of 3-methylglutaconic aciduria type 3 in people from racial background other than Iraqi Jewish?

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.

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