Frontotemporal dementia with parkinsonism

In 1996, an international consensus conference was held in order to define the cognitive, behavioural, and motor disturbances of families with FTD with parkinsonism linked to chromosome 17 (FTDP-17) [82]. The group discussed 25 families with similar symptoms of familial adult- onset behavioural disturbances, frontal lobe dementia, and parkinsonism, and identified 13 kindreds with sufficient evidence for linkage of this phenotype to chromosome 17 [82]. These families shared common, although heterogeneous, clinical features, with symptoms starting typically in the fifth decade, patients developing behavioural (disinhibition, loss of personal awareness, apathy, mental rigidity, defective judgement, stereotyped behaviours, and hyperoral- ity with hyperphagia) and cognitive disturbances (speech disturbances with non-fluent aphasia, echolalia, palilalia, mutism, executive dysfunction, relative preservation of memory, orientation, and visuospatial functions) typical of frontotemporal lobar degeneration. Either early or during the course of the disease, patients also presented parkinsonian symptoms with early postural instability, absence of resting tremor, poor response to levodopa, and, occasionally, supranuclear ophthalmoplegia or apraxia of eyelid opening [82-85]. At that point, participants in the consensus conference decided to classify all these patients under the term FTDP-17, and stressed the need to identify the gene or genes responsible for this disorder [82].

In the past 5 years, advances in immunocytochemistry and molecular genetics have expanded our knowledge about the different disorders that can manifest as FTDP-17. In many kindreds with FTDP-17, mutations in the gene encoding the microtubule-associated protein tau (MAPT) on chromosome 17 have been found, with patients showing tau-positive inclusions on neuropathology [86]. In several other kindreds with FTDP-17, ubiquitin-positive inclusions were described, but no associated tau pathology or mutations in the MAPT gene were observed. In 2006, this group of patients was better defined by the identification of mutations in the gene encoding pro- granulin (PGRN), which is only 1.7 Mb centromeric to MAPT on chromosome 17. Symptoms of patients with MAPT and PGRN mutations are almost identical to those previously described in FTDP-17, although some clinical features may help to differentiate patients with MAPT or PGRN mutations [87]. In FTDP with MAPT mutations, the syndromes of mild cognitive impairment, probable AD, semantic dementia, or corticobasal syndrome have been rarely described, a few cases have been diagnosed with amyotrophic lateral sclerosis, and no cases have been reported with symptoms of posterior cortical atrophy or suggestive of dementia with Lewy bodies. In FTDP with PRGN mutations the syndromic diagnoses have been more variable, with patients presenting with predominant memory impairment, limb apraxia, parkinsonism, or visuospatial dysfunction; the development of a corticobasal syndrome has been frequent in the cases reported thus far [88].

In summary, the nosological entity previously called FTDP-17 is now known to include patients with different mutations and different neuropathological features. With the possible discovery of new mutations to come, current terminology for patients developing symptoms of FTDP should indicate if those patients are carrying mutations in either the MAPT or the PRGN gene.

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