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

Letters to the Editor Brain (2001), 124, 1666–1670 Progressive supranuclear palsy as a disease phenotype caused by the S305S tau gene mutation Zbigniew K. Wszolek1, Yoshio Tsuboi1, Ryan J. Uitti1, Lee Reed2, Michael L. Hutton1 and Dennis W. Dickson1 1Mayo Clinic, Jacksonville, Florida and 2University of Minnesota, Minneapolis, Minnesota, USA Correspondence to: Z. K. Wszolek, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA E-mail: Abbreviations: FTDP-17 ⫽ frontotemporal dementia with parkinsonism; PPND ⫽ pallido-ponto-nigral degeneration; PSP ⫽ progressive supranuclear palsy 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, they had other signs, such as perseverative vocalizations, dysarthria leading to mutism, eyelid-opening and eyelid-closing apraxia, fixed joint contractures, cachexia and urinary incontinence. Phenotypic variations appear to occur more commonly with the S305S mutation than with the N279K mutation. Stanford and colleagues found different clinical presentations © Oxford University Press 2001 in the S305S kindred they studied (Stanford et al., 2000), and we have identified a second family with the S305S mutation (Dickson et al., 2000) in which the presenting features are behavioural changes and frontal lobe dementia, but not parkinsonism. The pathology associated with the S305S mutation appears similar to that of the N279K mutation. Both mutations result in neuronal loss in the substantia nigra, cortical neuronal loss with ballooned neurones and tau-positive neuronal and glial inclusions in cortical and subcortical structures. Tufted astrocytes, a feature seen in the case reported by Stanford and colleagues (Stanford et al., 2000), are not a feature in PPND (Reed et al., 1998), and are also not a prominent feature in our patient with the S305S mutation. In that patient, double immunolabelling studies with tau and glial fibrillary acidic protein indicated that almost all the glial inclusions were in oligodendroglia. Tau-positive astrocytic inclusions were rare, and those that were present did not resemble the tufted astrocytes typical of PSP. Because Stanford and colleagues did not do double immunostaining, it is difficult to know what proportion of the tau-positive glia in their patient with S305S were astrocytic. On the basis of the available information, it is difficult to know whether the pathology in the S305S kindred described by Stanford and colleagues is actually that of PSP (Stanford et al., 2000). One of their patients had atrophy of the medial temporal lobe. Because PSP is not associated with medial temporal lobe atrophy, this finding would suggest a diagnosis other than PSP. Ballooned neurones were found in the same patient throughout the frontal lobe and the atrophic regions. Such a finding occurs only rarely in PSP and suggests a diagnosis of Pick’s disease, corticobasal degeneration or FTDP-17. The finding that the cerebellum of this patient had no pathology also indicates a diagnosis other than PSP, which virtually always entails some pathology in the cerebellum in the form of tau-positive oligodendroglia in white matter, taupositive neuronal and glial inclusions and grumose degeneration in the dentate nucleus. Finally, electron microscopic analysis showed that the intracellular filament Letters to the Editor 1667 Table 1 Initial symptoms and signs in a family with pallido-ponto-nigral degeneration (PPND) Pedigree number Sex Age at symptom onset (years) Initial symptoms and signs Category of initial symptoms IV-4 IV-10 IV-12 IV-14 IV-15 V-2 V-3 V-4 V-5 V-6 V-9 V-21 V-23 V-25* V-26* V-29* V-36* V-37* V-38* V-40* V-43* VI-5* VI-9* VI-12* VI-16* VI-19* VI-27* F M F M F F M F M F M F F F M M F F M F F M M M M F F 36 42 58 45 47 41 41 39 39 43 41 47 46 52 56 45 44 41 42 43 46 41 41 41 32 44 46 PC P P, D P PC PC, D P D P D D P P P P P P P, PC P P P P P D PC D P, D VI-28* VI-29* VI-53* F M M 44 39 41 Emotional change Bradykinesia, gait difficulty Bradykinesia, dementia Slow walking Abnormal behaviour Irritability, forgetfulness Micrographia, walking on toes Memory disturbance Tremor, rigidity Forgetfulness Forgetfulness Bradykinesia, clumsiness Tremor, falling backward Bradykinesia Tremor, stooped posture Hand tremor, speech difficulty Bradykinesia Bradykinesia, personality change Bradykinesia Slowness of movement Bradykinesia Tremor, clumsiness Gait difficulty, loss of arm swing Memory disturbance Personality change Forgetfulness Slowness of movement, memory disturbance Balance and walking difficulties Mood change Micrographia, gait disturbance P PC P For pedigree designation, see Wszolek et al. (1992). D ⫽ dementia; F ⫽ female; M ⫽ male; P ⫽ parkinsonism; PC ⫽ personality change. *Examined by Z.K.W. bundles contained twisted filaments, which we also found in our patient with the S305S mutation. This twisted ribbon structure is not consistent with the filamentous inclusions seen in PSP, which are straight filaments. Thus, although the clinical and pathological signs found in the kindred with the S305S mutation resemble PSP in some respects, we believe that the differences outweigh the similarities (...truncated)