A Japanese patient with frontotemporal dementia and parkinsonism by a tau P301S mutation

Abstract

The authors report a patient carrying a missense mutation in exon 10 of tau that causes a substitution at codon 301 (P301S). Although the patient shares the rapidly progressive frontotemporal dementia of the other reported pedigrees with P301S, the clinical phenotype is unique in that parkinsonism was a major symptom in the early stage and because behavioral symptoms with dementia became prominent 2 years after the onset of the disease. This study substantiates the notion that tau mutations at codon 301 can show various phenotypes.

Frontotemporal dementia and parkinsonism with the P301S tau gene mutation in a Jewish family

“…These clinical features strongly reflect the reported P301S phenotype with a few notable exceptions (Table 2). In contrast to previous reports, we did not observe myoclonus or seizures, reported in the European families [3,28], and parkinsonism did not dominate early stages of the disease, as in the patient from Japan [35]. In addition, the age of onset was older and the disease duration was shorter in our patients than in the European pedigrees [3,28] and were more like the patient from Japan [35].…”

“…In contrast to previous reports, we did not observe myoclonus or seizures, reported in the European families [3,28], and parkinsonism did not dominate early stages of the disease, as in the patient from Japan [35]. In addition, the age of onset was older and the disease duration was shorter in our patients than in the European pedigrees [3,28] and were more like the patient from Japan [35]. Significant inter-and intrafamilial heterogeneity is known in FTDP-17 kindred with the same molecular defect, suggesting that other genetic and environmental factors modify phenotypic expression of the disease [2,26,30,31].…”

“…Asymmetric limb dystonia and apraxia as in subject III-2 is observed in CBD, whereas supranuclear gaze impairment as in subjects II-5, II-7 and III-1, but more pronounced in the vertical plane, is typical for progressive supranuclear palsy. Similar findings were also noted in the other P301S pedigrees (Table 2) further adding to a considerFamily 1 Family 2 Family 3 Family 4 Clinical characteristic II-1 III-2 V-4 IV-4 III-3 III-1 II-5 II-7 Origin (reference) Italy [3] German [28] Japan [35] NR not reported; FT frontotemporal; * age at onset of symptoms; ** duration until death or last follow up (+ alive at the time of report) Table 2 Clinical features in the present and reported patients with FTDP-17 with the P301S tau mutation able phenotypic overlap between these classical nosologic entities [17]. Diagnosis of FTDP-17 is currently based on the combination of clinical, genetic and pathological findings.…”

“…The P301S tau gene mutation has been previously identified in only four families. Two families of European and one of Japanese origin were described in detail [3,28,35],and one family was briefly mentioned [22]. Independent observation of P301S in different ethnic groups, together with the occurrence of a more common P301L, suggests that codon 301 may be a hot spot for pathogenic mutations [35].…”

“…These mutations may alter tau function or gene regulation and therefore may explain in part the observed phenotypic heterogeneity of the disorder [26].Among others, codon 301 in the alternatively spliced exon 10 is affected by three kinds of base transition resulting in two missense (P301L and P301S) and one silent (P301P) mutations [3,4,21,22,28,35]. P301L is apparently the most prevalent mutation [12,25,27] whereas P301S has been previously identified in only four families [3,22,28,35] and both are implicated in highly diverse clinical phenotypes.We present a new report of FTDP-17 with the P301S tau gene mutation.…”