Unclassified four-repeat tauopathy associated with familial parkinsonism and progressive respiratory failure
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CASE REPORT
Unclassified four‑repeat tauopathy associated with familial parkinsonism and progressive respiratory failure Masayoshi Nakano1†, Yuichi Riku2,6†, Kenya Nishioka3, Masato Hasegawa4, Yukihiko Washimi1, Yutaka Arahata1, Akinori Takeda1, Kentaro Horibe1, Akiko Yamaoka1, Keisuke Suzuki1, Masashi Tsujimoto1, Yuanzhe Li3, Hiroyo Yoshino5, Nobutaka Hattori3,5, Akio Akagi2, Hiroaki Miyahara2, Yasushi Iwasaki2 and Mari Yoshida2*
Abstract We describe an autopsied patient with familial parkinsonism and unclassified four repeat-tau (4R-tau) aggregation. She presented with bradykinesia, truncal dystonia, and mild amnesia at the age of 61 and then exhibited body weight loss (15 kg over 8 months), sleep disturbances, and progressive respiratory failure with C O2 narcosis. She died of respiratory failure at the age of 62, 14 months after disease onset. Her brother also showed parkinsonism at the age of 58 and suddenly died 6 months later. Postmortem examination revealed 4R-tau aggregation, which was characterized by neuronal globose-type tangles or pretangles, bush-like or miscellaneous astrocytic inclusions, and coiled bodies. The temporal tip, the striatum, the substantia nigra, the tegmentum of the midbrain, the medullary reticular formation, and the spinal cord were severely involved with tau aggregation. Argyrophilic grains and ballooned neurons were also found in the medial temporal structures, however, extensions of the 4R-aggregations in the case were clearly broader than those of the argyrophilic grains. Western blot analysis of sarkosyl-insoluble fractions from brain lysates revealed prominent bands of tau at both 33 kDa and 37 kDa. Genetic examinations did not reveal any known pathogenic mutations in MAPT, DCTN-1, PSEN-1, or familial or young-onset parkinsonism-related genes. The clinical manifestations, pathologic findings, and biochemical properties of aggregated tau in our patient cannot be explained by argyrophilic grain disease or other known 4R-tauopathies alone. Our results further extend the clinical and neuropathologic spectra of 4R-tauopathy. Keywords: Four-repeat tau aggregation, Familial parkinsonism, Respiratory failure, Autopsy, Postmortem study Introduction Neuronal and glial aggregation of tau protein is known to cause neurodegenerative diseases. Tau protein is classified into three-repeat tau (3R-tau) and four-repeat tau (4R-tau), which are determined by alternative mRNA splicing of exon 10 [1, 10]. Aggregations of 4R-tau are *Correspondence: myoshida@aichi‑med‑u.ac.jp † Masayoshi Nakano and Yuichi Riku contributed to this publication equally 2 Institute for Medical Science of Aging, Aichi Medical University, 1‑1 Yazakokarimata, Nagakute, Aichi 480‑1195, Japan Full list of author information is available at the end of the article
pathologic hallmarks of corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), argyrophilic grain dementia (AGD), globular glial tauopathy (GGT), agingrelated tau astrogliopathy (ARTAG), and microtubuleassociated protein tau (MAPT)
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