Investigation into thiol conjugation of transthyretin in hereditary transthyretin amyloidosis

Background For all forms of amyloidosis, the amyloid‐generating mechanism is unknown. Familial amyloidotic polyneuropathy type I is caused by a variant transthyretin (TTR Met‐30). As electrospray ionization mass spectrometry (ESI‐MS) discloses both thiol‐conjugated and ‐unconjugated forms of wild‐type and variant TTR, we wanted to investigate the relationship between TTR conjugation and clinically overt amyloid disease. Methods Plasma from 35 individuals (12 symptomatic TTR Met‐30 carriers, nine asymptomatic and 14 healthy control subjects) were analysed using ESI‐MS. Results The total TTR concentration was significantly lower in symptomatic TTR Met‐30 carriers than in control subjects. An increased percentage of conjugated TTR Met‐30 was found in symptomatic carriers compared with asymptomatic, whereas the percentage conjugated wild‐type TTR was similar for control subjects, asymptomatic and symptomatic TTR Met‐30 carriers. Conclusion The finding of a decreased ratio of unconjugated to conjugated TTR Met‐30 in plasma samples from symptomatic TTR Met‐30 carriers indicates that thiol conjugation of TTR could be involved in amyloid formation.