Tau exon 10 +16 mutation FTDP-17 presenting clinically as sporadic young onset PSP

Methods.

DNA was extracted from whole blood after informed consent and tau was sequenced as previously described.4 The pathogenic mutation was confirmed using both direct sequencing and restriction enzyme digestion. Tissue sections from representative brain areas were stained with routine methods and used for immunohistochemistry with antibodies to tau (A024 and AT8 antibodies), αB-crystallin, α-synuclein, and ubiquitin.

Pathologic examination.

Whole brain weight was 1400 g. Macroscopic examination showed severe atrophy involving globus pallidus and subthalamic nucleus with relative preservation of brainstem structures such as substantia nigra and locus coeruleus. Histologic examination showed mild neuronal loss in the frontal and temporal cortices, but cortical spongiosis was not a prominent feature. In the affected cortical areas, a proportion of neurons were positive with anti-tau antibodies (figure, A). Such positively stained neurons often had a diffuse or globular staining pattern, which was different from the neurofibrillary tangles seen in AD. In addition, neuropil threads and oligodendroglial cytoplasmic inclusions (coiled bodies) were seen in cortex and white matter (figure, B). The mediotemporal region as well as the temporal neocortex was most affected, while the frontal and parietal areas showed less severe changes. In the mediotemporal region, in addition to neurofibrillary tangles, neuropil threads, and coiled bodies, a large number of tau and αB-crystallin-positive ballooned neurons were also found, which were sparse in the temporal neocortex (figure, C). Senile plaques were not seen. In the atrophied globus pallidus and subthalamic nucleus, a significant proportion of the remaining nerve cells contained tau-positive inclusions, and oligodendroglial coiled bodies were also numerous. The thalamus was also severely affected by tau pathology, while the putamen, basal nucleus of Meynert, hypothalamus, and amygdala were only moderately affected (figure, D). In the putamen, occasional tau-positive astrocytes were seen (figure, E). Many of the neurons in the midbrain tectum and tegmentum, including the periaqueductal gray and third nerve nucleus, contained tau-positive inclusions, and in these areas a large number of tau-positive oligodendroglial inclusions were present. The substantia nigra showed severe neuronal depletion and pronounced gliosis. Many of the remaining pigmented neurons contained globose neurofibrillary tangles (figure, F). The pontine tegmentum was severely affected and tau-positive inclusions were seen in the neurons of the basis pontis. In the medulla, tau-positive neurofibrillary tangles were numerous in the inferior olive as well as in the midline dorsal and lateral nuclei. The cerebellar dentate nucleus showed pronounced grumose degeneration, neuronal depletion, and numerous tau-positive nerve cells. The cerebellar white matter contained frequent tau-positive coiled bodies in oligodendroglial cells.

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Figure. Photomicrographs show extensive tau-positive neurofibrillary pathology in the temporal neocortex (A), oligodendroglial filamentous inclusions in the internal capsule (B), and αB-crystallin positive ballooned neurons in the medial temporal cortex (C). In the putamen there were neurofibrillary tangles, oligodendroglial inclusions (D), and occasional tau-positive astrocytes (E). Globose neurofibrillary tangles were found in the substantia nigra (F). (A, B, D through F: AT8 immunohistochemistry; C: αB-crystallin immunohistochemistry. Scale bar represents 25 μm on F; 50 μm on A, B, C, and D; and 75 μm on E.)

Discussion.

Our patient presented with lethargy and micrographia and then developed disturbances of gait, eye movement, and bulbar dysfunction, typical of PSP. His age at onset did not preclude a diagnosis of NINDS-SPSP probable PSP. However, as the median age at onset of PSP is 63, and the two youngest cases of pathologically proven PSP reported in the literature were aged 43 and 45 at onset, this would have been a uniquely young presentation.6,7⇓ The absence of falls in the first year of life precluded a diagnosis of probable PSP according to NINDS-SPSP clinical research criteria. Neuropsychological evaluation revealed a decline in verbal memory at an advanced disease stage, but also evidence of decreased word fluency and cognitive slowing, consistent with PSP. The pathologic findings in this case supported the genetic diagnosis of FTDP-17.8 In FTDP-17 cases with exon 10 mutations, there is usually involvement of the frontal and temporal cortices, whereas cortical pathology in PSP predominantly involves premotor frontal cortex. The extent and distribution of tau-positive neuronal inclusions, in combination with a large number of neuropil threads and oligodendroglial tau-positive inclusions in both gray and white matter, seen in the current case would be atypical for PSP. Although tufted astrocytes, which are characteristic of PSP, were present in some brain areas, these are not specific for PSP and have also been described in FTDP-17. The large number of oligodendroglial coiled bodies is more in keeping with FTDP-17, where such inclusions have been found to be numerous, especially in cases with intronic mutations.9 In addition, the presence of ballooned neurons in the medial temporal cortex supports a diagnosis of FTDP-17. An interesting aspect of this case is the severity of the involvement of subcortical structures such as the subthalamic nucleus and pallidum as well as brainstem nuclei including the substantia nigra, which is comparable with PSP, and may account for the clinical overlap.

Despite the genetic association between PSP and the tau common haplotype and similarities between the pathology of FTDP-17 and PSP, in general, clinically and pathologically diagnosed familial and sporadic patients with PSP do not have tau mutations.10 Existing clinical, pathologic, and genetic evidence suggests that PSP and FTDP-17 are different but closely related diseases. The case presented here suggests that the combination of a young age at onset with the absence of falls in the first year is a red flag that may possibly suggest FTDP-17 in a patient whose clinical presentation is otherwise consistent with PSP, even in the absence of a positive family history.