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Frontotemporal dementia (FTD) is one of the most common dementia syndromes and represents a collection of neurodegenerative diseases of frontal and temporal brain regions. About 14% of FTD cases show features of parkinsonism (FTDP).

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Epidemiliogy, Genetics, and Pathophysiology

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Sporadic or autosomal-dominant familial forms of FTDP have long been associated with mutations in the microtubule-associated protein tau (MAPT).1 The identification of loss-of-function mutations in progranulin (PGRN) fully resolves a 10-year-old conundrum,2 namely the genetic basis of FTDP linked to chromosome 17q21, and explains why multiple families linked to this region lack MAPT mutations (60–90%).3 The facts that PGRN is located 1.7 Mb centromeric of MAPT and that mutations in both genes independently yield indistinguishable clinical phenotypes are presumably an extraordinary coincidence. The main function of MAPT is to stabilize and promote microtubuli assembly by binding to tubulin, which is likely to regulate transport of vesicles and organelles as well as the cell shape and cell motility. Over 100 families with 45 different pathogenic mutations in the gene have been identified worldwide,4 with the most common mutations accounting for approximately 60% of known cases, being P301L, N279K, and a splice site mutation (exon 10+16). The pathogenetic mechanisms are thought to be related to the altered proportion of tau isoforms (with three amino acid repeats to those with four amino acid repeats) or to the ability of tau to bind microtubules and to promote microtubule assembly.5 PGRN encodes a widely expressed secreted precursor protein that is cleaved into seven nonidentical cysteine-rich granulin peptides A–G. PGRN and the granulin peptides have mitogenic functions in the regulation of cell growth and cell cycle progression and are involved in multiple physiological processes such as cellular proliferation, survival, and tissue repair and pathological processes including inflammation and tumorogenesis. At least 35 different pathogenic mutations (mostly in exons 2, 10, and 11) have been found, resulting in haploinsufficiency of the PGRN protein by nonsense-mediated transcript decay.4

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Neuropathology

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The brains of FTDP-17 patients are characterized by an atrophy of the frontotemporal cortex and basal ganglia and by a depigmentation of the substantia nigra. Neuronal loss and gliosis are found in affected brain regions. The histopathology of patients with defined mutations is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau in neurons and glial cells in the cortex, basal ganglia, brain stem nuclei, and white matter (FTDP-17T).6 In contrast, patients with PGRN mutations have ubiquitin-positive cytoplasmic and intranuclear inclusions in neurons in the frontotemporal cortex, striatum, and hippocampus (FTDP-17U).7 In both, Pick or Lewy bodies, tangles or plaques are usually not found.

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Clinical Presentation

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It was estimated that there have been reports of about 50–600 FTDP-17T patients, with fewer than 70 individuals still living in 2006.5 The mean age of disease onset ranges between 25 and 65 years for FTDP-17T and between 45 and 85 years ...

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