 |
|
Refining Frontotemporal Dementia With Parkinsonism Linked to Chromosome 17Introducing FTDP-17 (MAPT) and FTDP-17 (PGRN)
Bradley F. Boeve, MD;
Mike Hutton, PhD
Arch Neurol. 2008;65(4):460-464.
ABSTRACT
| |
Frontotemporal dementia with parkinsonism (FTDP) is a major neurodegenerative syndrome, particularly for those with symptoms beginning before age 65 years. A spectrum of degenerative disorders can present as sporadic or familial FTDP. Mutations in the gene encoding the microtubule-associated protein tau (MAPT; OMIM +157140) 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 in 2006 with the identification of mutations in the gene encoding progranulin (PGRN; OMIM *138945), 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. Our findings describe an intriguing oddity of nature in which 2 genes can cause a similar phenotype through apparently different mechanisms yet reside so near to each other on the same chromosome.
INTRODUCTION
Frontotemporal dementia with parkinsonism is one of the major degenerative dementia syndromes (Table 1), particularly for those who begin experiencing cognitive, behavioral, or motor changes before age 65 years. Advances in immunocytochemistry and molecular genetics have greatly expanded our knowledge of the disorders (and their associated dysfunctional proteins) that can manifest as dementia with or without parkinsonism (Table 2). No disease-altering treatment has been identified as yet for any of the neurodegenerative disorders that can manifest clinically as FTDP (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 on families carrying mutations that cause FTDP.
|
|
|
|
Table 1. Major Cognitive Impairment and Dementia Syndromes
|
|
|
|
|
|
|
Table 2. Specific Neurodegenerative Disorders Manifesting as Dementia With or Without Parkinsonism and Their Associated Dysfunctional Proteins
|
|
|
The hunt for causative genes in FTDP was largely spearheaded by the first Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 Consensus Conference in Ann Arbor in 1996, for which FTDP linked to chromosome 17 (FTDP-17) was the major focus.1 Soon thereafter in 1998, mutations in MAPT were identified.2 During the 8 years since this discovery, 41 mutations in MAPT have been found,3 and many other issues relating to FTDP-17 due to mutations in MAPT have been characterized (Table 3).4 No sex predilection has been identified. The typical age of onset varies between 25 and 65 years. Penetrance appears to be close to 100%, though individuals living into old age without symptoms have been observed in families with at least 1 mutation (exon 10 + 16).2 The duration of symptoms from onset to death is typically 3 to 10 years. Symptomatology usually involves executive dysfunction and altered personality and behavior, with aphasia and parkinsonism evolving in many individuals. 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, though several cases have been reported. Most patients carry 1 or more of the syndromic diagnoses listed in Table 1, particularly frontotemporal dementia (FTD) with or without parkinsonism, progressive nonfluent aphasia, or primary progressive aphasia. Rarely, the syndromes of mild cognitive impairment, probable Alzheimer disease, semantic dementia, or corticobasal syndrome are manifested. Few cases 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 or dementia with Lewy bodies. Over time, most patients develop other clinical features such that 2 or more syndromes can be applied, reflecting the progressively expanding involvement of other brain regions.5
|
|
|
|
Table 3. Comparison Between Neurodegenerative Characteristics Associated With Mutations in MAPT and PGRN Genes
|
|
|
Structural neuroimaging studies show frontal and/or temporal atrophy, either symmetric or asymmetric6; parenchymal signal changes on magnetic resonance imaging are either absent or very mild.7 A similar topography of abnormalities is typically seen on single-photon emission computed tomography and positron emission tomography 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 having a "knife edge" appearance. Tau-positive inclusions in neurons (eg, neurofibrillary tangles, neuronal threads, and Pick bodies) and/or glia (eg, astrocytic plaques and 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 identified as having corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease, or Pick disease if the presence of an 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 4 or 3 microtubule binding repeats, or they directly decrease the ability of tau to bind to and promote microtubule assembly and/or increase tau-filament formation. No disease-altering treatments exist yet for the tauopathies, though kinase inhibitors and microtubule tau stabilizers have shown promise in in vitro and animal model studies.8-9
A significant minority of patients with FTDP-17—many of whom were the focus of discussion at the meeting in Ann Arbor in 1996—had no identifiable mutations in MAPT, nor did they have any tau-positive inclusions at autopsy.10-13 The recent identification of mutations in PGRN in all of these remaining chromosome 17–linked families and in many other kindreds (Figure)14-27 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 2 apparently different genes can cause a very similar phenotype and reside so near to each other on the same chromosome.27
|
|
|
|
Figure. Sequence chromatograms of exon 11 of the progranulin gene (PGRN) from a control individual (A) and a patient with frontotemporal dementia carrying the common c.1477C>T mutation (B). Below each chromatogram is the predicted amino acid sequence of progranulin including codon numbering. The arrow denotes the position of the mutation in the chromatogram. The PGRN c.1477C>T mutation results in a premature termination of the coding sequence at codon 493, inducing the degradation of mutant PGRN RNA by nonsense-mediated decay and loss of progranulin (haploinsufficiency).
|
|
|
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 comparisonsbetween MAPT's and PGRN's 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.18 With at least 35 mutations identified to date,3 almost as many mutations in PGRN have been discovered in less than 1 year than in the 8 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 years).18 There are multiple known PGRN mutation carriers who are asymptomatic in their 70s, and at least 1 known affected individual developed symptoms after age 80 years. 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 mild cognitive impairment, Alzheimer disease, Parkinson disease, Parkinson disease with dementia, and dementia with Lewy bodies in addition to FTD with or without parkinsonism and 1 of the progressive aphasia syndromes.25 The diagnosis of corticobasal syndrome has also been particularly frequent in the cases reported thus far, while 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 mutation cases, which is also reflected on imaging and pathologic studies. In some cases, rather striking signal changes on magnetic resonance imaging are present,25 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 involvement22, 26, 28 and the corticobasal syndrome with or without FTD features with maximal right hemisphere involvement25, 29; to our knowledge, this tendency has not been noted among any kindreds with MAPT mutations.
On histologic examination, the consistent finding is FTLD with ubiquitin-positive inclusions with neuronal intranuclear inclusions.14, 16-18,20-26 Immunostaining directed against progranulin stain normal structures within neurons and activated microglia. However, the ubiquitinated inclusions are not progranulin immunoreactive; rather, transactive response DNA–binding protein 43 was very recently discovered to be a major ubiquitinated protein in both neuronal cytoplasmic and intranuclear inclusions in PGRN mutation cases.30 Moreover, transactive response DNA–binding protein 43 is also present in neuronal ubiquitin-positive inclusions in FTLD with ubiquitin-positive inclusions, FTLD with motor neuron disease, and idiopathic ALS.31
Also contrasting with MAPT is the mechanism of disease with PGRN mutations—all PGRN mutations identified thus far create functional null alleles that cause a partial reduction in progranulin production or haploinsufficiency.14, 16, 18 This disease mechanism may allow a more straightforward 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 2 genes linked not only by proximity but also by most 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 subdivided into FTDP-17 (MAPT) and FTDP-17 (PGRN). This approach has the advantage of employing a now widely used, if not always completely appropriate, clinical terminology, refining it to reflect that ultimately these conditions are defined by their genetics rather than their clinical or pathological phenotypes. The scientific community has clearly just begun to expand the characterization and refine the nomenclature of familial disorders linked to chromosome 17.
AUTHOR INFORMATION
Correspondence: Bradley F. Boeve, MD, Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (bboeve{at}mayo.edu).
Accepted for Publication: January 14, 2007.
Author Contributions: Study concept and design: Boeve and Hutton. Acquisition of data: Boeve and Hutton. Analysis and interpretation of data: Boeve and Hutton. Drafting of the manuscript: Boeve and Hutton. Administrative, technical, and material support: Boeve and Hutton.
Financial Disclosure: None reported.
Funding/Support: This study was supported by grants AG06786, AG16574, AG11378, and AG07216 from the National Institute on Aging; by the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation; and by the Fund for Scientific Research–Flanders.
Additional Contributions: We thank our many collaborators within and outside 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. We thank the staff of the Mayo Clinic Alzheimer's Disease Research Center for their assistance in characterizing participants, and we particularly thank the members of the many kindreds with MAPT and PGRN mutations for participating in neurodegenerative disease research.
Author Affiliations: Divisions of Behavioral Neurology and Movement Disorders, Department of Neurology, Mayo Clinic, Rochester, Minnesota (Dr Boeve); Mayo Alzheimer's Disease Research Center, and Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation, Rochester, Minnesota, and Jacksonville, Florida (Drs Boeve and Hutton); and Neurogenetics Laboratory, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida (Dr Hutton).
REFERENCES
| |
1. Foster NL, Wilhelmsen K, Sima A, Jones MZ, D'Amato CJ, Gilman S. Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Ann Neurol. 1997;41(6):706-715.
FULL TEXT
|
ISI
| PUBMED
2. Hutton M, Lendon CL, Rizzu P; et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998;393(6686):702-705.
FULL TEXT
| PUBMED
3. Alzheimer Disease & Frontotemporal Dementia Mutation Database. http://www.molgen.ua.ac.be/FTDmutations/. Accessed February 14, 2007.4. Poorkaj P, Grossman M, Steinbart E; et al. Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia. Arch Neurol. 2001;58(3):383-387.
FREE FULL TEXT
5. Kertesz A. Pick's complex and FTDP-17. Mov Disord. 2003;18(suppl 6):S57-S62.
FULL TEXT
|
ISI
| PUBMED
6. Boeve BF, Tremont-Lukats I, Waclawik A; et al. Longitudinal characterization of two siblings with frontotemporal dementia and parkinsonism linked to chromosome 17 associated with the S305N tau mutation. Brain. 2005;128(pt 4):752-772.
FREE FULL TEXT
7. Frank AR, Wszolek ZK, Jack CR Jr, Boeve BF. Distinctive MRI findings in pallidopontonigral degeneration (PPND). Neurology. 2007;68(8):620-621.
FREE FULL TEXT
8. Noble W, Planel E, Zehr C; et al. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci U S A. 2005;102(19):6990-6995.
FREE FULL TEXT
9. Zhang B, Maiti A, Shively S; et al. Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. Proc Natl Acad Sci U S A. 2005;102(1):227-231.
FREE FULL TEXT
10. Lendon CL, Lynch T, Norton J; et al. Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22. Neurology. 1998;50(6):1546-1555.
ABSTRACT
11. Rademakers R, Cruts M, Dermaut B; et al. Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval. Mol Psychiatry. 2002;7(10):1064-1074.
FULL TEXT
|
ISI
| PUBMED
12. van der Zee J, Rademakers R, Engelborghs S; et al. A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD. Brain. 2006;129(pt 4):841-852.
FREE FULL TEXT
13. Mackenzie IR, Baker M, West G; et al. A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17. Brain. 2006;129(pt 4):853-867.
FREE FULL TEXT
14. Baker M, Mackenzie I, Pickering-Brown S; et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006;442(7105):916-919.
FULL TEXT
| PUBMED
15. Benussi L, Binetti G, Sina E; et al. A novel deletion in progranulin gene is associated with FTDP-17 and CBS [published online ahead of print December 5, 2006]. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2006.10.028. 2008;29(3):427-435.
FULL TEXT
|
ISI
| PUBMED
16. Boeve BF, Baker M, Dickson D; et al. Frontotemporal dementia and parkinsonism associated with the IVS1+1G->A mutation in progranulin: a clinicopathologic study. Brain. 2006;129(pt 11):3103-3114.
FREE FULL TEXT
17. Cruts M, Gijselinck I, van der Zee J; et al. Null mutations in progranulin cause ubiquitin positive frontotemporal dementia linked to chromosome 17q21. Nature. 2006;442(7105):920-924.
FULL TEXT
| PUBMED
18. Gass J, Cannon A, Mackenzie I; et al. Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet. 2006;15(20):2988-3001.
FREE FULL TEXT
19. Huey ED, Grafman J, Wassermann EM; et al. Characteristics of frontotemporal dementia patients with a Progranulin mutation. Ann Neurol. 2006;60(3):374-380.
FULL TEXT
|
ISI
| PUBMED
20. Mackenzie IR, Baker M, Pickering-Brown S; et al. The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain. 2006;129(pt 11):3081-3090.
FREE FULL TEXT
21. Masellis M, Momeni P, Meschino W; et al. Novel splicing mutation in the progranulin gene causing familial corticobasal syndrome. Brain. 2006;129(pt 11):3115-3123.
FREE FULL TEXT
22. Mukherjee O, Pastor P, Cairns NJ; et al. HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin. Ann Neurol. 2006;60(3):314-322.
FULL TEXT
|
ISI
| PUBMED
23. Pickering-Brown SM, Baker M, Gass J; et al. Mutations in progranulin explain atypical phenotypes with variants in MAPT. Brain. 2006;129(pt 11):3124-3126.
FREE FULL TEXT
24. Snowden JS, Pickering-Brown S, Mackenzie I; et al. Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia. Brain. 2006;129(pt 11):3091-3102.
FREE FULL TEXT
25. Kelley BJ, Haidar W, Boeve BF; et al. Prominent phenotypic variability associated with mutations in Progranulin [published online ahead of print October 18, 2007]. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2007.08.022.
PUBMED
26. Mesulam M, Johnson N, Krefft T; et al. Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families. Arch Neurol. 2007;64(1):43-47.
FREE FULL TEXT
27. Rosenberg RN. Progranulin and tau gene mutations both as cause for dementia: 17q21 finally defined. Arch Neurol. 2007;64(1):18-19.
FREE FULL TEXT
28. Krefft TA, Graff-Radford N, Dickson D; et al. Familial primary progressive aphasia. Alzheimer Dis Assoc Disord. 2003;17(2):106-112.
FULL TEXT
|
ISI
| PUBMED
29. Boeve BF, Maraganore DM, Parisi JE; et al. Corticobasal degeneration and frontotemporal dementia presentations in a kindred with nonspecific histopathology. Dement Geriatr Cogn Disord. 2002;13(2):80-90.
FULL TEXT
|
ISI
| PUBMED
30. Josephs KA, Ahmed Z, Katsuse O; et al. Neuropathologic features of frontotemporal lobar degeneration with ubiquitin-positive inclusions with progranulin gene (PGRN) mutations. J Neuropathol Exp Neurol. 2007;66(2):142-151.
PUBMED
31. Neumann M, Sampathu D, Kwong L; et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130-133.
FREE FULL TEXT
SECTION EDITOR: DAVID E. PLEASURE, MD
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati
What's this?
|
