Mutations marking rare brain disease not seen as Parkinson’s risk factor

Mutations associated with a rare genetic neurological disorder called neurodegeneration with brain iron accumulation (NBIA) do not appear to be risk factors for Parkinson’s disease, a study reported.

NBIA refers to a group of extremely rare genetic conditions characterized by a buildup of iron in the brain, damaging and killing cells in ways that can be similar to Parkinson’s. Mutations in 13 different genes have been linked to NBIA to date.

“In Parkinson’s Disease (PD), iron accumulation is a cardinal feature of degenerating regions in the brain and seems to be a key player in mechanisms that precipitate cell death,” its researchers noted. “We examined whether a genetic burden of NBIA variants contributes to PD risk.”

The study, “Exploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for Parkinson’s disease,” was published in npj Parkinson’s Disease. 

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Iron plays an important role in many processes that brain cells use to remain healthy, ranging from generating energy to manufacturing signaling molecules. Excessive levels of iron, however, can be toxic to the brain.

Some studies suggest that iron at such levels contributes to the brain cell death and damage that causes Parkinson’s. This implies that the disease-driving processes behind NBIA and Parkinson’s might share common features.

Scientists in the U.S. and Spain tested this idea by investigating whether mutations in any of the NBIA-associated genes might influence Parkinson’s.

Using genetic data from two large databases, the team conducted a comprehensive assessment comparing the frequency of NBIA-associated mutations in a total of 4,481 people with Parkinson’s and a control group of 10,253 people without the disease.

Researchers identified 29 NIBA-associated mutations across seven genes that were numerically more common among Parkinson’s patients than controls. However, the difference was only statistically significant for four of these mutations, in the genes ATP13A2, FA2H, C19orf12, and PANK2.

All four of these mutations were found in one Parkinson’s patient, and none were in any of the controls. Technically, the difference was statistically significant. But overall, these results suggest that NIBA-associated mutations are not likely to play a role in the development of the vast majority of Parkinson’s cases, the researchers said.

“Only four out of the 29 variants of interest [mutations linked to NIBA] … had a statistically significant difference in frequency between cases and controls,” and they were found “always in only one case,” they wrote.

“These data suggest that [NIBA-causing mutations] are not frequently associated with risk” of Parkinson’s, the scientists concluded.

Additional analyses looking at the cumulative effects of different NIBA mutations also suggested no association with Parkinson’s risk.

Altogether, these findings are inconsistent with the idea that NBIA and Parkinson’s might share common disease-driving mechanisms.

“We suggest that even though NBIA and PD [Parkinson’s disease] share similar symptoms, they could be molecularly different entities supporting the notion that the mechanisms underpinning iron accumulation in PD are not shared with NBIA,” the scientists wrote.