Large normal alleles of ATXN2 decrease age at onset in transthyretin familial amyloid polyneuropathy Val30Met...

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Transthyretin (TTR)-related familial amyloid polyneuropathy (FAP) is a progressive, autosomal dominant neurological disorder.
• The Val30Met (Val50Met) substitution in TTR is the most common cause of TTR-FAP, with significant variability in age of onset (AO) between generations.
• Unstable oligonucleotide repeats in various genes are known to modify neurological disease phenotypes.

Purpose of the Study:

• To investigate the potential modifier effect of large normal repeat alleles in 10 genes on the AO in Portuguese TTR-FAP Val30Met families.
• To determine if specific repeat lengths in genes like ATXN2 influence disease progression.

Main Methods:

• Analysis of 329 Portuguese patients from 123 families with TTR-FAP Val30Met.
• Assessment of repeat length in ATXN1, ATXN2, ATXN3, ATXN7, TBP, ATN1, HTT, JPH3, AR, and DMPK using polymerase chain reaction and capillary electrophoresis.
• Application of a family-centered approach with generalized estimating equations to account for intrafamilial correlation in AO.

Main Results:

• The presence of at least one ATXN2 allele with more than 22 CAG repeats was significantly associated with an earlier AO in TTR-FAP Val30Met patients.
• This association resulted in a mean decrease in AO of 6 years (95% CI: -8.81 to -2.19, p=0.001).
• No significant associations were found for the remaining repeat loci investigated.

Conclusions:

• Normal repeat length in the ATXN2 gene may act as a modifier and risk factor for AO in TTR-FAP Val30Met.
• The role of ATXN2 in RNA metabolism and cellular processes, including mitochondrial stress, may underlie this observed effect.
• These findings have potential implications for the prognosis and follow-up of presymptomatic TTR-FAP carriers.