A European family with histidine 58 transthyretin mutation in familial amyloid polyneuropathy

Abstract

1. IntroductionMore than 50 mutations of the transthyretin (TTR) [1]molecule resulting in different clinical forms of amyloidosisincluding familial amyloid polyneuropathy (FAP) havebeen reported to date. Within this FAP spectrum severaltransthyretin mutations are more frequent, others are rare.One mutation, the codon 58 histidine for leucine has pre-viously been recorded only in American subjects (Mary-land/German type), originally reported in a large kinship[2,3] and in another family from Ohio [4]. In the originaldescription of the Maryland/German type of amyloidosis[2], it was stated that the early immigrants in this pedigreewere from the Rhine river area, nearly all of them from theleft Rhine side southward of (p. 15).We now report an identification of the codon 58 histidinefor leucine mutation in autosomal-dominant FAP from afamily that has always lived south of Mainz on the leftside of the Rhine river, suggesting that this family is geneti-cally related to the 58 histidine for leucine mutation patientsin the US. This paper, thus, does not give a lengthy accountof FAP type II, the Maryland/German type, because this hasbeen described exhaustively before [2] and is now commontextbook knowledge; instead, this paper aims to highlight,the somewhat historic aspect, where the US founder of thisHis 58 FAP originated from—documented by modernmolecular techniques.2. Patients’ report2.1. Patient 1This 59-year-old man had experienced stiffness andimpaired sensation in both hands and later in both legs forthe past 10 years. Clinical examination revealed bilateralimpaired hearing suspected by his clinicians to have devel-oped due to excessive noise, decreased deep tendon reflexesin both legs, mild afferent type ataxia, atrophy of small footmuscles, not hand muscles, distal hypesthesia and hypalge-sia in both hands and feet, reduced sense of vibration in bothhands and both legs. Electroneurographically (Table 1), hehad markedly reduced conduction velocities of his motormedian and tibial nerves and no potentials in his sensorymedian nerves in the carpal tunnel region. Sural nervebiopsy revealed chronic neuropathy and focal amyloiddeposits which reacted with an antibody against anti-trans-thyretin amyloid. He died suddenly, while abroad, 5 yearslater of cardiac failure.2.2. Patient 2 (son of patient 1)This 45-year-old man complained of occasional repeti-tive, later of frequent numbness of his right hand. Hedescribed mild dysesthesia in his right hand due to compres-sion of his right carpal tunnel. Data of his electrophysiolo-gical examination are listed in Table 1. Operation of bothcarpal tunnels showed deposits of amyloid within the con-nective tissue.2.3. DNA analysesDirect DNA sequencing analysis of the TTR gene ofpatient 2 showed both thymine and adenine at the secondbase of codon 58 of TTR. Thus patient 2 was heterozygouswith a normal allele and a mutant allele encoding histidinefor leucine at codon 58. Restriction fragment length poly-morphisms (RFLP) analysis based on the polymerase chainreaction [5] revealed three mutant His 58 gene carriers ofseven family members at risk that were tested. DNA haplo-type analysis of the TTR gene of this German family, i.e.patient 2, his mother but not his father who had previously