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Genotypic-phenotypic variations in a series of 65 patients with familial amyloid polyneuropathy

From the Service de Neurologie (Drs. Planté-Bordeneuve, Lalu, Adams, Lacroxic, and Said) and Laboratoire d'Hormonologie et Biologie Moléculaire (Dr. Misrahi), Centre Hospitalier de Bicêtre(Université Paris-Sud); and the University Department of Clinical Neurology (Dr. Reilly), Institute of Neurology, London, UK.

Address correspondence and reprint requests to Dr. V. Planté-Bordeneuve, Service de Neurologie, Centre Hospitalier Universitaire de Bicêtre, 94275 Le Kremlin Bicêtre, France.

Objective: To investigate the genotypic-phenotypic variations in a series of patients with familial amyloid polyneuropathy (FAP).

Background: Progress in molecular genetics has led to the identification of point mutations in the transthyretin (TTR) gene in FAP-a dominantly inherited neuropathy with a fatal outcome. These findings have modified the management of patients with small-fiber neuropathy and allow genetic counseling.

Methods: We performed a clinical and molecular genetic study with screening of the TTR gene mutations and associated haplotypes in 65 patients from 29 unrelated families of French ancestry.

Results: We detected nine heterozygous point mutations segregating with FAP. Fourteen families (48%) carried the common methionine (Met) 30 substitution. Seven kindreds (24%) had previously unreported TTR variants, namely asparagine 35, serine (Ser) 91, phenylanine (Phe) 77, and Ser 116. At least two different haplotypes were associated with each of the following: Met 30, Phe 77, and valine 107, suggesting that multiple founders occurred for each variant. Only 35% the index patients had affected relatives. Other patients had a sporadic presentation. All progressed to a severe sensorimotor and autonomic neuropathy with frequent cardiac involvement (80%). On average, a late age at onset (54.3 ± 13.3 years) and a disease duration shorter than 10 years were observed for virtually all variants.

Conclusion: The heterogeneity of the TTR variants, the late age at onset, and the short duration of the disease found in our patients contrast with the presentation of FAP in Portugal. These findings must be taken into account in the management of both patients and asymptomatic carriers.

Supported by grants from the Association Franaise Contre la Myopathie, the Association "Paulette Ghiron-Bistagne" Contre l'Amylose, and the Assistance Publique des Hôpitaux de Paris.

Received January 30, 1998. Accepted in final form May 22, 1998.

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