Brain, Vol. 124, No. 8, 1666-1670,
August 2001
© 2001 Oxford University Press
Letter to the Editor |
Progressive supranuclear palsy as a disease phenotype caused by the S305S tau gene mutation
1 Mayo Clinic, Jacksonville, Florida and 2 University of Minnesota, Minneapolis, Minnesota, USA
Correspondence to:
Z. K. Wszolek, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA E-mail: wszolek.zbignrew{at}mayo.edu
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.
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Phenotypic variations appear to occur more commonly with the S305S mutation than with the N279K mutation. Stanford and colleagues found different clinical presentations 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, tau-positive neuronal and glial inclusions and grumose degeneration in the dentate nucleus. Finally, electron microscopic analysis showed that the intracellular filament 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 and that it is misleading to imply that the S305S mutation may be a genetic cause of PSP. Our contention is that this kindred has a form of FTDP-17, not PSP. FTDP-17 kindreds have various clinical presentations (Reed et al., 2001) including parkinsonism, supranuclear gaze palsy, dementia, personality changes and a constellation of other signs occurring in different combinations and at different stages of the disease in each kindred.
The molecular genetic basis of the disorder outlined by Stanford and colleagues reflects a disorder of tau exon 10 alternative splicing and is similar to the effects of other well-characterized mutations close to the 5' splice site of exon 10, all of which lead to increased expression of 4-repeat tau (Stanford et al., 2000). Although the molecular pathogenesis of PSP is still poorly understood, there is no evidence that PSP is associated with increased expression of 4-repeat tau.
The report by Stanford et al. (2000) reflects a tendency to assign a relatively common diagnostic term—in this case PSP—to a rare disorder with which it shares only a few clinical and pathological features, but which may have a very different aetiology. For the sake of clarity, defined research criteria should be followed to enable a more consistent definition of such conditions.
Received November 6, 2000. Accepted January 14, 2001.
References
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Progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17 and familial tauopathies
1 Garvan Institute of Medical Research, Sydney, 2 Prince of Wales Medical Research Institute, Randwick and 3 Centre for Education and Research on Ageing, University of Sydney, Concord Hospital, Concord, Sydney, Australia.
Correspondence to:
Professor Petter Schofield, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney NSW 2001, Australia E-mail: p.schofield{at}garvan.unsw.edu.au
FTDP-17 = frontotemporal dementia with parkinsonism linked to chromosome 17; PSP = progressive supranuclear palsy
In their letter to the editor above, Wszolek and colleagues consider that an individual with a clinicopathological description of progressive supranuclear palsy (PSP) from a pedigree with an S305S tau gene mutation (Stanford et al., 2000), may have frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) rather than PSP (Wszolek et al., 2001). An international consensus conference concluded that, although highly variable, numerous pedigrees with frontotemporal dementia, behavioural disturbances and parkinsonism linked to chromosome 17 were best defined as having FTDP-17 (Foster et al., 1997). PSP-like pathology is seen in a number of FTDP-17 pedigrees including the pedigree studied by Wszolek and colleagues (Wszolek et al., 2001) (see Table 3 in Stanford et al., 2000). Since we document an individual with a clinicopathological diagnosis of PSP, we believe that the descriptor FTDP-17, for our S305S pedigree, may be misleading. A more appropriate descriptor may be `familial tauopathy' (Spillantini et al., 1998a; Lee and Trojanowski, 1999; van Slegtenhorst et al., 2000) as this would encompass both frontotemporal dementia and PSP.
Mutations that cause PSP have been suspected from the association of a polymorphic dinucleotide marker and an extended haplotype within the tau gene in individuals with the disorder (Conrad et al., 1997; Bennett et al., 1998; Higgins et al., 1998, 2000; Oliva et al., 1998; Baker et al., 1999; Morris et al., 1999, 2000). Rojo and colleagues highlighted the familial nature of PSP and the clinical heterogeneity observed within such kindreds (Rojo et al., 1999). It was therefore not unexpected that our pedigree with a S305S tau gene mutation has similar heterogeneity (Stanford et al., 2000). PSP clinical features and PSP-like pathology have been observed in other pedigrees with tau gene mutations (Reed et al., 1997; see Table 3 in Stanford et al., 2000).
The pathological criteria for PSP are a high density of neurofibrillary tangles and neuropil threads in the basal ganglia and brainstem. In our subject, more than six tangles were observed per high power field in these regions (see Table 2, Stanford et al., 2000), while cortical tangles were less frequent. Recent studies have found that tufted astrocytes in the motor cortex and striatum distinguish PSP from corticobasal degeneration (Bergeron et al., 1997; Komori et al., 1998; Matsusaka et al., 1998; Dickson, 1999). As can be seen from our quantitative pathology, tufted astrocytes were numerous in the motor cortex (more than two per high-power field; see Table 2 in Stanford et al., 2000). Although we did not perform double labelling for glial fibrillary acidic protein, tufted astrocytes are easily distinguished from other glial types, as evidenced in other studies (Bergeron et al., 1997; Komori et al., 1998; Matsusaka et al., 1998) (see Figs 5 and 6 in Stanford et al., 2000). The quantity and distribution of this pathology in our patient is indicative of PSP. Both twisted and straight filaments have been documented in PSP (Tellez-Nagel and Wisniewski, 1973; Tomonaga, 1977). The electron microscopy we presented of our patient showed both twisted and straight filaments within the cortical tangles (see Fig. 6 in Stanford et al., 2000).
While our case had some atrophy of the medial temporal lobe (mainly amygdala and entorhinal cortex), we showed the imaging and external brain features so that readers could see the lack of considerable atrophy in our kindred (see Figs 3 and 4 in Stanford et al., 2000). This lack of considerable atrophy is consistent with a diagnosis of PSP. Ballooned neurones were only found in the frontal regions sampled (see Table 2 in Stanford et al., 2000). As demonstrated by others, the use of neurofilament immunohistochemistry greatly facilitates the detection of such neurones in most PSP cases (Mackenzie and Hudson, 1995; Mori et al., 1996). The presence of these neurones does not exclude the diagnosis of PSP. Our case reflects the clinical and pathological criteria for the diagnosis of PSP as established by Hauw et al. (1994) and Litvan et al. (1996).
Wszolek and colleagues suggest there is no evidence that PSP is associated with increased expression of 4-repeat tau (Wszolek et al., 2001). However, many other studies disagree with this and have shown that the filaments in PSP consist of only 4-repeat tau (Flament et al., 1991; Sergeant et al., 1999; Arai et al., 2001). Sergeant and colleagues used antibodies specific for the different tau isoforms to demonstrate that the intraneuronal inclusions of PSP were composed exclusively of tau isoforms containing exon 10 (Sergeant et al., 1999). This is consistent with our exon trapping experiments which showed increased splicing of exon 10 (Stanford et al., 2000).
Single mutations within the tau gene can give rise to a wide spectrum of clinical presentations and neuropathology, both within (Bugiani et al., 1999; Stanford et al., 2000) and between families (Bird et al., 1999) demonstrating that tau gene mutations are pleiotropic. The clinical and pathological heterogeneity associated with tau gene mutations has been expanded beyond FTDP-17 to now include PSP (Stanford et al., 2000), corticobasal degeneration (Bugiani et al., 1999) and possibly even Pick's disease (Spillantini et al., 1998b; Murrell et al., 1999; Rizzini et al., 2000). Wszolek and colleagues suggest that all kindreds, including our S305S pedigree with a PSP individual, should be broadly grouped under the highly descriptive nomenclature of FTDP-17 (Wszolek et al., 2001). However, in view of the expanding knowledge of tau gene mutations, we consider that this detracts from the genuine clinical and pathological differences seen in disease phenotypes. Therefore, if they are to be considered as a whole, tau gene disorders should more accurately be referred to as familial tauopathies.
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Wszolek ZK, Tsuboi Y, Uitti RJ, Reed L, Hutton ML, Dickson DW. Progressive supranuclear palsy as a disease phenotype caused by the S305S tau gene mutation [letter]. Brain 2001; 124: 1666–8.
Received December 18, 2000. Accepted March 20, 2001.
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