Transthyretin (TTR) related familial amyloid polyneuropathy (FAP) is an autosomal dominant neurological disease, caused most frequently by a Val30Met (now classified as Val50Met) substitution in TTR. Age‐at‐onset (AO) ranges 19‐82 years and variability exists mostly between generations. Unstable oligonucleotide repeats in various genes are the mechanism behind several neurological diseases, found also to act as modifiers for other disorders. Our aim was to investigate whether large normal repeat alleles of ten genes, had a possible modifier effect in AO in Portuguese TTR‐FAP Val30Met families.
We analysed 329 Portuguese patients, from 123 families. Repeat length (at ATXN1, ATXN2, ATXN3, ATXN7, TBP, ATN1, HTT, JPH3, AR and DMPK) was assessed by single and multiplex PCR, using fluorescently‐labelled primers, followed by capillary electrophoresis. We used a family‐centred approach and generalized estimating equations (GEE) were used to account for AO correlation between family members.
For ATXN2, the presence of at least one allele longer than 22 CAGs was significantly associated with an earlier onset in TTR‐FAP Val30Met, decreasing mean AO by 6 years (95% CI: [‐8.81; ‐2.19], p=0.001). No association was found for the remaining repeat loci.
Length of normal repeats at ATXN2 may modify AO in TTR‐FAP Val30Met and may function as a risk factor. This can be due to ATXN2 role in RNA metabolism and as a modulator of various cellular processes, including mitochondrial stress. This may have relevant implications for prognosis and the follow‐up of presymptomatic carriers.
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