Transthyretin gene analysis in European patients with suspected familial amyloid polyneuropathy

We investigated 99 patients from 64 European families (51 French, 11 British, one Italian and one Spanish) with suspected familial amyloid polyneuropathy (FAP) for transthyretin (TTR) gene mutations. Thirty-nine families were found to have point mutations causing the following amino acid substitutions: Met30 (28 families), Tyr77 (five), Arg 50 (one), Ala49 (one), Gln89 (one), Ala60 (one) and one each with previously undescribed mutations at Asn35 and Gys54. The clinical picture in the patients with new and known mutations were typical of FAP, without any specific features for a particular mutation. Onset of symptoms was late (over 50 years) in many French and British patients with the Met30 and Tyr77 mutations, and only 30% of all index cases had affected relatives. We propose an approach to molecular diagnosis in European patients with FAP, apart from members of families with known mutations, based on the frequency of TTR mutations observed in this and and other studies of FAP in Europe. It is logical to screen for the Met30 and Tyr77 mutations and Ala60 in the UK, using restriction enzyme analysis. If these are absent, the TTR gene should be sequenced directly to detect less common or unknown mutations.