Neuropathology in the S305S tau gene mutation

Sir,We reported in Brain a novel, silent (S305S) mutation in the tau gene in two siblings and a history of presenile dementia in their mother (Stanford et al ., 2000). One sibling (III-15) had pathologically-proven progressive supranuclear palsy. The second affected individual (proband: III-14) has recently died at 63 years of age following 7 years of clinical symptoms, and the family consented to an autopsy for research purposes. Because of the controversy regarding the final neuropathological diagnosis in this family (Stanford et al ., 2001; Wszolek et al ., 2001) and the question raised regarding the overexpression of soluble 4R tau (Spillantini and Goedert, 2000), we would like to document the neuropathology of this second family member. The family history, initial clinical features and neuroimaging have been previously published (Stanford et al ., 2000).At the time of our previous publication (Stanford et al ., 2000) the patient was 58 years old and was living at home with her husband. She scored 27/30 on MMSE but had deficits on neuropsychological testing and minor neurological signs. She subsequently developed obsessional behaviours such as frequent washing and was admitted to a hostel. At age 60 she scored 16/30 on MMSE; her gait was normal; she had a staring look and restricted upgaze; her speech was adynamic and dysarthric. At 61 she had a dramatic functional decline with episodes of unresponsiveness and was admitted to hospital, where a lung scan showed pulmonary emboli and she was treated with heparin and warfarin. Despite some functional improvement, she continued to have episodes of unresponsiveness, which were considered possibly epileptic in nature, although EEG was normal. Similar episodes were reported in her mother in the 2 years before she died. III-14 was discharged to a nursing home; 2 months later she was still …