Contrasting genotypes of the tau gene in two phenotypically distinct patients with P301L mutation of frontotemporal dementia and parkinsonism linked to chromosome 17

Abstract

Association between clinical characteristics and types of the tau gene mutation has been observed in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). P301L mutation seldom causes parkinsonism as a leading symptom; instead it usually causes personality changes with aggressiveness and disinhibition. We experienced two patients of FTDP-17 from separate families (designated as patient 1 from family 1 and patient 2 from family 2). They had P301L mutation in common. However, their phenotypes were distinct from each other. Aggressive behaviors and disinhibition were the main symptoms in patient 1, whereas parkinsonism was the most prominent feature in patient 2. Their genotypes of the tau gene were different at three sites, i. e. in exon 6, in intron segment before exon 10, and in exon 13, though they do not bring amino acid change. Patient 1 had more prevalent C/C, C/C, and rare T/C respectively. Patient 2 had less prevalent T/T, A/A, and more prevalent T/T respectively. These findings suggest two things. Firstly, they do not share a common founder for P301L mutation. Secondly, either of the two less prevalent genotypes observed in patient 2 may be the factor to modify the phenotype of P301L mutation into those unusual clinical features with prominent parkinsonism. Accumulation of information as to phenotype-genotype association will settle this hypothesis.

Clinicopathologic heterogeneity in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17) due to microtubule‐associated protein tau (MAPT) p.P301L mutation, including a patient with globular glial tauopathy

“…Our series confirmed frequent degeneration of the substantia nigra in FTDP-17 due to p.P301L mutation ( Table 2) [21]. Despite degeneration, most p.P301L carriers do not have prominent parkinsonian features, at least early in the disease [20,21,25,30,31]. In our series, parkinsonism was observed only in two patients and gaze palsy was absent.…”

Severe amygdala dysfunction in a MAPT transgenic mouse model of frontotemporal dementia

“…Thus, the amygdala is an important brain structure that contributes to several behavioral phenotypes in multiple species. Disinhibition is one of the earliest symptoms to arise in FTDP-17 (Baker et al 1997; van Swieten et al 1999; Kobayashi et al 2002), and our work here demonstrates that this disinhibition is also a prominent and early feature of the rTg4510 mouse model, likely due to severe amygdala pathology. These findings have important implications when assessing the effects of genetic or pharmacologic manipulations of this model.…”

Familial aggregation of parkinsonism in progressive supranuclear palsy

“…4 Frontotemporal dementia is the most common clinical presentation occurring in affected family members of the patient with PSP with a P301L mutation, although PSP has occasionally been reported. 24,34,35 Whether this intrafamilial variation is due to genetic or environmental factors is unknown, although parkinsonism within MAPT mutations has been associated with homozygosity for the tau H1 haplotype. 36 In another family of the present study, FTD occurred in three third-degree relatives in the absence of mutations in one of the other candidate genes, suggesting another genetic factor.…”