Portuguese Study Links Extra Copies of Mitochondrial DNA to Earlier Development of FAP

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by Alice Melao |

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DNA copies and FAP

Extra copies of DNA in energy-producing cell components known as mitochondria play a role in the development of the Val30Met-mutation form of familial amyloid polyneuropathy, a Portuguese study suggests.

Mutations of the TTR gene cause transthyretin-related familial amyloid polyneuropathy, or TTR-FAP, by producing faulty versions of the transthyretin protein.

More than 100 genetic variations have been associated with TTR gene dysfunction. The most common is the Val30Met mutation, which gets its name from an amino acid change in position 30 of the gene.

The first signs of FAP commonly appear between the ages of 25 and 35. But studies have reported huge differences in the age at which people with Val30Met mutations develop the disease. That range is from 19 years old all the way to 82.

Researchers have also found gender differences in the age at which the disease appears, with women generally showing symptoms later than men.

Another trend has been a decrease in age of onset from one generation to the next. This is particularly true among people who have inherited their disease from their mothers — a condition know as inherited  mitochondrial DNA, or mtDNA.

Researchers have found a link between cells’ energy needs and the number of copies of a person’s mtDNA: The more energy needed, the more copies.

The problem is that increases or decreases in mtDNA can lead to the development of any number of neurodegenerative diseases such as FAP.

Researchers at the University of Porto and the University of Coimbra in Portugal wondered if the number of mtDNA copies could affect the age at which a person develops TTR-FAP and its prevalence in families with Val30Met mutations.

Their study, “mtDNA copy number associated with age of onset in familial amyloid polyneuropathy,” appeared in the Journal of Neurology, Neurosurgery, &Psychiatry.

The team checked the number of mtDNA copies in 175 people with Val30Met mutations, in 30 of their relatives who did not have the mutations, and in 57 healthy volunteers.

Fifty-six of the 175 people with the mutation had early-onset TTR-FAP —  that is, they developed it before the age of 40. Fifty-two had a late-onset disease, and 67 showed no symptoms of it.

Those with the mutation had more copies of mtDNA than the healthy volunteers, researchers discovered. And the highest number of copies was in the early-onset group.

When the team looked at inheritance patterns, they discovered that the early-onset group’s children had more copies of mtDNA than children of late-onset parents.

Researchers found no significant correlations between number of mtDNA copies and gender or the age at which a person developed the disease.

The team concluded there was a link between the number of mtDNA copies and the development of TTR-FAP. They also concluded there was a link between parents’ age of onset and the number of mtDNA copies that their children had.

“The present study is a step forward and opens a new possibility for elucidating the mechanisms underlying TTR-FAP Val30Met,” the team wrote. “The present findings suggest, for the first time, that mtDNA copy number may be associated with earlier [disease] events and may therefore be further explored as a potential biomarker for follow-up of TTR-FAP Val30Met carriers.”