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Mutations in the gene encoding the microtubule-associated protein tau (MAPT) cause frontotemporal dementia and parkinsonism linked to chromosome 17. Clinical variability is seen not only among families with different mutations, but also among family members with the same mutation. We investigated a newly identified familial frontotemporal dementia and parkinsonism family. The disease was of early onset and was inherited as an autosomal dominant trait. Clinically, parkinsonism was the prominent and often early feature, and it preceded dementia. Three autopsied cases shared involvement predominantly in the frontal and temporal lobes and also in the subcortical nuclei, including substantia nigra, globus pallidus, and subthalamic nucleus, that microscopically consisted of neuronal loss, microvacuolation, and astrocytic fibrosis. Immunohistochemistry demonstrated neuropil threads, ballooned cells, and glial fibrillary tangles. Sequencing analysis of the MAPT gene showed an alteration in one allele, resulting in a P301S substitution. These findings suggest that the MAPT P301S mutation can cause pathologically subcortical-predominant, neuropil thread-rich, tau-containing lesions, which could result in consistent parkinsonism. Our study confirms the notion that the phenotype observed in affected individuals from P301S MAPT mutation families is heterogeneous and is broader than the phenotypes seen to date in affected family members carrying other MAPT mutations.

The clinical phenotype of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) varies. This variability is seen not only between kindreds with different mutations but also in families sharing the same mutation. Inheritance of tau haplotype (H1) and genotype (H1/H1) has been established as a risk factor for some neurodegenerative disorders with parkinsonism. We assessed the effect of tau polymorphism on the clinical features of FTDP-17 in 61 cases from 30 separately ascertained families with four different tau mutations, including P301L, +16, N279K, and P301S. There were no significant differences of age at symptomatic onset and disease duration between H1/H1 and H1/H2 genotypes. The comparison between tau genotype and type of initial clinical sign showed an association between the H1/H1 genotype and parkinsonian phenotype and between the H1/H2 genotype and frontotemporal dementia phenotype (OR=11.7; 95% confidence interval, 1.4-98.7; P=0.008). Our results suggest that tau genotype does not influence the disease course. However, it may predispose to a specific clinical sign in the early stage of FTDP-17.

Since the original description of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) during the Consensus Conference held in Ann Arbor, Michigan in 1996, it has become apparent that this syndrome has worldwide distribution. More than 70 families have been described in North America, Europe, Australia and Asia. The molecular genetic studies have identified 29 mutations outside and on exon 10 of tau gene. Here, we report the progress in clinical, genetic and pathological studies of FTDP-17 in Japan. There have been 15-separetely ascertained families described in Japan. These kindreds harbor following tau mutations: exon 10, exonic mutations, N 279 K, N 296 H, P 301 L and P 301 S; exon 10 5' splice-site mutations, S 305 N (-2), +11, and +12; exon 1, R 5 H mutation; exon 9, L 266 V mutation; and exon 13, R 406 W mutation. The phenotype of FTDP-17 kindreds varies significantly between families with different mutations and among the families carrying the same mutation. This variability is also seen in Japanese kindreds. Exon 10, P 301 L, +16 and N 279 K mutations are the most common but only P 301 L and N 279 K mutations have been described so far in Japan. On the other hand, R 5 H, N 296 H, +11, and +12 mutations have not been identified outside of Japan. Comparison of phenotypes of Japanese and non-Japanese families with P 301 S, P 301 L and R 406 W mutations uncovers significant differences in clinical presentations. It is difficult to compare pathology of Japanese and non-Japanese families on the basis of available medical literature but no apparent differences can be seen. Autopsies demonstrate the presence of neuronal and glial tau inclusions and ballooned neurons, frequently in the distribution seen in other sporadic tauopathies. A search for the common founder in Japanese families may be successfully performed. FTDP-17 families have been identified with increasing frequency in Japan. The discovery of tau mutations and the fact that they are responsible for the disease processes in the brain lead to the major advancement of our understanding of neurodegeneration. It is hoped that future studies of these families will also lead to finding the curative treatments for the tauopathies.

Early onset familial Alzheimer disease (FAD) has been associated with mutations in three genes, of which presenilin 1 (PSEN1) mutations are the most frequent. We reported previously a variant form of FAD, due to deletion of exon 9 of PSEN1, with spastic paralysis and rigidity. We describe a novel PSEN1 mutation in a family of Japanese origin with six affected individuals of both genders in two generations. The disease is characterized by presenile dementia, which is preceded by spastic paraparesis and apraxia. This mutation, which is predicted to cause a missense substitution of serine for glycine, occurred at codon 266 in exon 8 of PSEN1. The mutation was not found in 200 controls and 200 sporadic AD patients. On this basis alone, it seems this mutation is pathogenic. Our findings provide a new clue to the etiology of the familial early onset dementia., (Copyright 2002 Wiley-Liss, Inc.)

Presents a letter to the editor commenting about an unusual case with frontotemporal dementia and Parkinsonism with four-repeat tau-positive Pick body-like inclusions published in the October 2005 issue of the article "Acta Neuropathologica."

The article presents the authors' comment on an article by researcher P. Soliveri and colleagues on Italian kindred with frontotemporal dementia and Parkinsonism linked to chromosome 17, namely, FTDP-17 with the N279K mutation. The observation that personality change preceded parkinsonism in the patient described by Soliveri and colleagues is of interest because isolated personality changes at symptom onset occur in only a few previously described patients with the N279K mutation. The earlier age at symptom onset and longer disease duration are notable in patients with the H1/H2 genotype. These early neuropsychiatric changes parallel findings of neuropsychological dysfunction in carriers of the N279K mutation prior to the onset of motor symptoms.