Progressive supranuclear palsy as a disease phenotype caused by the S305S tau gene mutation

Stanford and colleagues add a new kindred to the literature on parkinsonism linked to chromosome 17 (Stanford et al. , 2000). They identified a novel silent mutation (S305S) in exon 10 of the tau gene and suggest that this mutation causes progressive supranuclear palsy (PSP) pathology. We believe that this kindred should be considered to have frontotemporal dementia with parkinsonism (FTDP-17) rather than PSP.The S305S mutation leads to an increase in the splicing of exon 10 and excessive production of tau isoforms containing four microtubule-binding repeats. A similar pathogenetic mechanism is observed in pallido-ponto-nigral degeneration (PPND), which is caused by an N279K mutation in the tau gene. We have studied a kindred with PPND for the last 14 years (Wszolek et al. , 1992). Of the 311 family members, 39 individuals were affected by the disease; detailed clinical information is available on 30. On the basis of our knowledge of PPND, we do not find it surprising that patients with the S305S mutation exhibit parkinsonian signs and supranuclear gaze palsy. The majority of the patients with PPND also had parkinsonism as a predominant clinical feature, and 20 out of 30 (67%) had a cardinal feature of parkinsonism as the initial neurological finding (Table 1). Eye movement abnormalities, including supranuclear gaze palsies, occur in the second and third stages of the disease (Wszolek et al. , 1992; Wszolek and Pfeiffer, 1993). Additional clinical signs, including frontotemporal dementia, personality changes, dystonia, dysphagia and frontal lobe and pyramidal signs, are found in patients with the N279K mutation as well as in those with the S305S mutation. One of the patients with the S305S mutation reported by Stanford and colleagues had an episode of coma (Stanford et al. , 2000). Although none of our patients with PPND experienced episodic loss of consciousness, …