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Frontotemporal dementia and parkinsonism (FTDP) is a major neurodegenerative syndrome, particularly for those with symptoms beginning before age 65. A spectrum of degenerative disorders can present as sporadic or familial FTDP. Mutations in the gene encoding the microtubule associated protein tau (MAPT) on chromosome 17 have been found in many kindreds with familial FTDP. Several other kindreds with FTDP had been linked to chromosome 17, but they had ubiquitin-positive inclusions rather than tauopathy pathology, and no mutations in MAPT. This conundrum was solved over this past year with the identification of mutations in the gene encoding progranulin (PGRN), which is only 1.7 Mb centromeric to MAPT on chromosome 17. In this review, we compare and contrast the demographic, clinical, radiologic, neuropathologic, genetic, and pathophysiologic features in patients with FTDP linked to mutations in MAPT and PGRN, highlighting the many similarities but also a few important differences. The findings provide an intriguing oddity of nature in which two genes can cause a similar phenotype through apparently different mechanisms yet reside so near to each other on the same chromosome.
Frontotemporal dementia and parkinsonism (FTDP) is one of the major degenerative dementia syndromes (Table 1), particularly for those who begin experiencing cognitive, behavioral, or motor changes before age 65. Advances in immunocytochemistry and molecular genetics have greatly expanded our knowledge of the disorders (and their associated dysfunctional proteins) that can manifest as dementia +/- parkinsonism (Table 2). No disease altering treatment has been identified as yet for any of the neurodegenerative disorders that can manifest clinically as FTDP (see Table 2). The development of potential therapies requires knowledge about the pathophysiology of the varying disorders. The identification of causative genes offers opportunities to quickly learn about the pathophysiologic processes involved in neurodegeneration, and drug testing can proceed relatively quickly using transgenic mouse models that are designed to mimic the human disease. Several groups of investigators have focused their efforts on the families who have the misfortune of carrying mutations that cause FTDP.
The hunt for causative genes in FTDP was largely spearheaded by the first FTDP conference in Ann Arbor in 1996, in which FTDP linked to chromosome 17 (FTDP-17) was the major focus of attention.1 Soon thereafter in 1998, mutations in the microtubule-associated protein tau (MAPT) were identified.2 Over the eight years since this discovery, 41 mutations in MAPT have been found3 and many other issues relating to FTDP-17 due to mutations in MAPT have been characterized [data summarized from data and references in 4, 5] (Table 3) . No gender predilection has been identified. The typical age of onset varies between 25 and 65. Penetrance appears to be close to 100%, although individuals living into old age without symptoms have been observed in families with at least one mutation (exon 10 +16).2 The duration of symptoms from onset to death is typically 3-10 years. Symptomatology usually involves executive dysfunction and altered personality and behavior, with aphasia and parkinsonism evolving in many. Memory impairment occurs less frequently as the primary presenting feature, and visuospatial impairment and limb apraxia are quite rare. Motor neuron disease is also infrequent, although several cases have been reported. Most patients carry one or more of the syndromic diagnoses listed in Table 1, particularly FTD with or without parkinsonism, PNFA, or primary progressive aphasia. Rarely, the syndromes of MCI, AD, SD, or CBS are manifested. Few have been diagnosed with amyotrophic lateral sclerosis (ALS), and there are no reports of patients with mutations in MAPT who were diagnosed with posterior cortical atrophy (PCA) or dementia with Lewy bodies (DLB). Over time, most patients develop other clinical features such that two or more syndromes can be applied, reflecting the progressively expanding involvement of other brain regions.6
Structural neuroimaging studies show frontal and/or temporal atrophy, either symmetric or asymmetric,7 and parenchymal signal changes on magnetic resonance imaging (MRI) are either absent or very mild.8 A similar topography of abnormalities is typically seen on SPECT and PET scans, often with basal ganglia and/or thalamic hypoperfusion or hypometabolism. Pathologically, cortical atrophy is as indicated on imaging studies, with the maximally affected cortical gyri sometimes described as “knife edge” in appearance. Tau-positive inclusions in neurons (eg, neurofibrillary tangles, neuronal threads, Pick bodies) and/or glia (eg, astrocytic plaques, oligodendroglial coiled bodies) are always present on histologic examination, sometimes accompanied by argyrophilic grains. These tau-positive inclusions are often in a distribution such that patients would be pathologically diagnosed as CBD, PSP, AGD, or Pick’s disease if the presence of a MAPT mutation was not known.
The mutations presumably cause disease either through disrupting the alternative splicing of MAPT exon 10 and thereby altering the relative levels of tau isoforms with four or three microtubule binding repeats, or they directly decrease the ability of tau to bind to and to promote microtubule assembly and/or increase tau filament formation. No disease-altering treatments exist yet for the tauopathies, although kinase inhibitors and microtubule-tau stabilizers have shown promise in in vitro and animal model studies.9, 10
A significant minority of patients with FTDP linked to chromosome 17—many of whom were the focus of discussion in Ann Arbor in 1996—had no identifiable mutations in MAPT, nor did they have any tau-positive inclusions at autopsy.11-14 The recent identification of mutations in progranulin (PGRN) in all of these remaining chromosome 17-linked families and in many other kindreds (example shown in Figure),15-28 has now solved this decade-long conundrum, a few atypical FTDP phenotypes have been redefined, and an amazing freak of nature has been realized. The PGRN gene is only 1.7 Mb centromeric to MAPT on chromosome 17, demonstrating an intriguing example of how two apparently different genes can cause a very similar phenotype and reside so near to each other on the same chromosome.28
With closer inspection, how similar are the clinical phenotypes associated with mutations in MAPT and PGRN? While our knowledge of the full spectrum of clinical, radiologic, and pathologic issues in FTDP associated with mutations in PGRN is still evolving, interesting findings have already emerged that allow comparisons between MAPT and PGRN mutation-associated characteristics (based on published findings to date and unpublished data from our group) (Table 3). The frequency of mutations in PGRN in FTD series is similar to that in MAPT.19 With at least 35 mutations now identified to date,3 almost as many mutations in PGRN have been discovered in less than one year than in the eight years since the initial identification of mutations in MAPT. The mode of inheritance follows an autosomal dominant pattern but with reduced penetrance (only 90% of carriers develop symptoms by age 70).19 There are multiple known PGRN mutation carriers who are asymptomatic in their 70’s, and at least one known affected individual developed symptoms after age 80. The clinical features and particularly the syndromic diagnoses have been more variable than in MAPT mutation carriers, with not only behavioral and cognitive features commonly present, but also memory impairment, limb apraxia, parkinsonism, and visuospatial dysfunction, leading to cases being diagnosed with MCI, AD, PD, PDD, and DLB in addition to FTD +/- parkinsonism and one of the progressive aphasia syndromes. The CBS has also been particularly frequent in the cases reported thus far. While there is a positive family history of ALS in the newly described PGRN sequence variation R433W,26 it is not yet clear if this variation is pathogenic or not, and thus no patient with a definite pathogenic PGRN mutation has been reported to date with an ALS phenotype.
As one would expect based on the clinical features of apraxia and visuospatial dysfunction, greater parietal involvement is clearly present in many PGRN+ cases, which is also reflected on imaging and pathologic studies. In some cases, rather striking signal changes on MRI are present, which is rarely seen in MAPT mutation carriers. Another curious observation is the tendency in some kindreds for the same cerebral hemisphere to be maximally involved in most or all affected members of a family, such as a progressive aphasia syndrome with maximal left hemisphere involvement 23, 27, 29 and the CBS +/- FTD features with maximal right hemisphere involvement30; this tendency has not been noted among any kindreds with MAPT mutations to our knowledge.
Upon histologic exam, the consistent finding is FTLD-U with neuronal intranuclear inclusions.15, 17-19, 21-27 Immunostaining directed against progranulin stain normal structures within neurons and activated microglia. However, the ubiquitinated inclusions are not progranulin immunoreactive; rather, TAR DNA- binding protein 43 (TDP-43) was very recently discovered to be a major ubiquitinated protein in both neuronal cytoplasmic and intranuclear inclusions in PGRN mutation cases.31 Moreover, TDP-43 is also present in neuronal ubiquitin-positive inclusions in FTLD-U, FTLD with MND, and in idiopathic ALS.32
Also contrasting with MAPT is the mechanism of disease — all PGRN mutations identified thus far create functional null alleles that cause a partial reduction in progranulin production, or haploinsufficiency.15, 17, 19 This disease mechanism may allow a more straight-forward approach for treatment by either replacing progranulin or using drugs to increase production or secretion of progranulin from the remaining normal PGRN allele.
The net effect of two genes linked not only by proximity but also by the bulk of overlapping and expanding features requires refinements in our conceptual framework and nomenclature in FTDP. An obvious solution to this problem is to simply refine the term by including reference to the genetic cause of the disease in each case, and thus FTDP-17 could be sub-divided into FTDP-17(MAPT) and FTDP-17(PGRN). This approach has the advantage of utilizing a now widely used, if not always completely appropriate, clinical terminology but refining it to reflect the fact that ultimately these conditions are defined by their genetics rather than clinical or pathological phenotype. The scientific community has clearly just begun to expand the characterization and refine the nomenclature of familial disorders linked to chromosome 17.
We thank our many collaborators within and outside of the Mayo Foundation, particularly Rosa Rademakers, PhD, for her critical review of this paper, and her and Matt Baker’s assistance in providing the sequence chromatograms for Figure 1. Our MAPT- and PGRN-related research is supported by grants AG06786, AG16574, AG11378, and AG07216 from the National Institute on Aging, the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program of the Mayo Foundation, and the Fund for Scientific Research Flanders (FWO-F). We thank the staff of the Mayo Clinic Alzheimer’s Disease Research Center for their assistance in characterizing subjects, and we particularly thank the members of the many kindreds with MAPT and PGRN mutations for participating in neurodegenerative disease research.