NEUROLOGICAL REVIEW Refining Frontotemporal Dementia With Parkinsonism Linked to Chromosome 17 Introducing FTDP-17 (MAPT) and FTDP-17 (PGRN) Bradley F. Boeve, MD; Mike Hutton, PhD rontotemporal dementia with parkinsonism (FTDP) is a major neurodegenerative syn- drome, particularly for those with symptoms beginning before age 65 years. A spec- trum of degenerative disorders can present as sporadic or familial FTDP. Mutations in the gene encoding the microtubule-associated protein tau (MAPT; OMIM ϩ157140) onF 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. Arch Neurol. 2008;65(4):460-464 Frontotemporal dementia with parkin- ology of the varying disorders. The iden- sonism is one of the major degenerative tification of causative genes offers dementia syndromes (Table 1), particu- opportunities to quickly learn about the larly for those who begin experiencing pathophysiologic processes involved in cognitive, behavioral, or motor changes be- neurodegeneration, and drug testing can fore age 65 years. Advances in immuno- proceed relatively quickly using trans- cytochemistry and molecular genetics have genic mouse models that are designed to greatly expanded our knowledge of the dis- mimic the human disease. Several groups orders (and their associated dysfunc- of investigators have focused on families tional proteins) that can manifest as de- carrying mutations that cause FTDP. mentia with or without parkinsonism The hunt for causative genes in FTDP (Table 2). No disease-altering treat- was largely spearheaded by the first Fron- ment has been identified as yet for any of totemporal Dementia and Parkinsonism the neurodegenerative disorders that can Linked to Chromosome 17 Consensus manifest clinically as FTDP (Table 2). The Conference in Ann Arbor in 1996, for development of potential therapies re- which FTDP linked to chromosome 17 quires knowledge about the pathophysi- (FTDP-17) was the major focus.1 Soon thereafter in 1998, mutations in MAPT Author Affiliations: Divisions of Behavioral Neurology and Movement Disorders, were identified.2 During the 8 years since Department of Neurology, Mayo Clinic, Rochester, Minnesota (Dr Boeve); Mayo this discovery, 41 mutations in MAPT have Alzheimer’s Disease Research Center, and Robert H. and Clarice Smith and Abigail 3 Van Buren Alzheimer’s Disease Research Program of the Mayo Foundation, been found, and many other issues relat- Rochester, Minnesota, and Jacksonville, Florida (Drs Boeve and Hutton); and ing to FTDP-17 due to mutations in MAPT Neurogenetics Laboratory, Department of Neuroscience, Mayo Clinic, Jacksonville, have been characterized (Table 3).4 No Florida (Dr Hutton). sex predilection has been identified. The (REPRINTED) ARCH NEUROL / VOL 65 (NO. 4), APR 2008 WWW.ARCHNEUROL.COM 460 ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 1. Major Cognitive Impairment Table 3. Comparison Between Neurodegenerative and Dementia Syndromes Characteristics Associated With Mutations in MAPT and PGRN Genes Mild cognitive impairment Clinically probable Alzheimer disease Gene Dementia with Lewy bodies Parkinson disease with dementia Characteristic MAPT PGRN Frontotemporal dementia Frequency among individuals 65 Frontotemporal dementia with parkinsonism with FTD, % Progressive nonfluent aphasia Mode of inheritance AD AD Semantic dementia Penetrance, % Ͼ 95 90 by age 70 y Corticobasal syndrome Sex M=F M=F Posterior cortical atrophy Onset age, y 25-65 45-85 Duration of illness, y 3-10 1-15 Clinical features Personality/behavior changes ϩϩϩϩ ϩϩϩϩ Executive dysfunction ϩϩϩϩ ϩϩϩϩ Table 2. Specific Neurodegenerative Disorders Manifesting Language impairment ϩϩϩϩ ϩϩϩϩ as Dementia With or Without Parkinsonism and Their Memory impairment ϩϩ ϩϩ Associated Dysfunctional Proteins Visuospatial impairment ϩϩϩ Limb apraxia ϩϩϩ Parkinsonism ϩϩ ϩϩϩ Neurodegenerative Disorder (Dysfunctional Protein) Motor neuron disease ϩ 0 Amyloidopathies (Amyloid) Clinical syndromes Alzheimer diseasea FTD with or without ϩϩϩϩ ϩϩϩϩ Alzheimer disease associated with mutations in the genes encoding parkinsonism amyloid precursor protein (APP ), presenilin 1 (PSEN1), or Progressive nonfluent aphasia ϩϩ ϩϩϩ a presenilin 2 (PSEN2 ) Semantic dementia ϩϩ Down syndrome Amnestic mild cognitive ϩϩ Familial British dementia with mutations in the gene encoding the impairment integral membrane protein 2B (ITMP2B/BRI/FBD) Probable AD ϩϩϩ Familial Danish dementia with mutations in the gene encoding the Corticobasal syndrome ϩ ϩϩϩ integral membrane protein 2B (ITMP2B/BRI/FDD) Posterior cortical atrophy 0 0 Tauopathies (Tau) Parkinson disease 0 ϩ Pick diseasea Parkinson disease plus dementia 0 ϩ Corticobasal degenerationa Dementia with Lewy bodies 0 ϩ Progressive supranuclear palsya Amyotrophic lateral sclerosis ϩϩ 0 Argyrophilic grain diseasea Magnetic resonance imaging findings Multisystem tauopathya Frontal atrophy ϩϩϩϩ ϩϩϩϩ Frontotemporal dementia and parkinsonism linked to chromosome 17 Temporal atrophy ϩϩϩ ϩϩϩ associated with mutations in the gene encoding microtubule Parietal atrophy ϩϩϩ associated protein tau (MAPT)a Occipital atrophy 0 0 Alzheimer diseasea Parenchymal signal changes ϩϩϩ Pathologic findings Tardopathies (TDP-43) Tau-positive inclusions ϩϩϩϩ ϩ Frontotemporal lobar degeneration with ubiquitin-positive inclusionsa Ubiquitin-positive inclusions ϩ ϩϩϩϩ Frontotemporal lobar degeneration with motor neuron diseasea Mechanism of neurodegeneration Altered tau Loss of Frontotemporal dementia and parkinsonism linked to chromosome 17 progranulin with mutations in the gene encoding progranulin (PGRN )a Potential treatments Alter Replace or Inclusion body myopathy with early-onset Paget disease and protein-protein increase frontotemporal dementia associated with mutations in the gene interactions progranulin encoding valosin-containing protein (VCP )a Synucleinopathies (␣-Synuclein) Abbreviations: AD, Alzheimer disease; FTD, frontotemporal dementia; Lewy body disease manifesting as the syndromes of Parkinson M = F, men and women inherit mutation equally; 0, no definite cases reported disease, dementia with Lewy bodies, or Parkinson disease with to date; ϩ, extremely rare; ϩϩ, infrequently reported; ϩϩϩ, frequently dementiaa reported; ϩϩϩϩ, very frequently reported. Lewy body disease associated with mutations or duplications in the gene encoding ␣-synuclein (SNCA) Multiple system atrophy; rarely associated with dementia typical age of onset varies between 25 and 65 years. ␣-Internexinopathy (␣-Internexin) Penetrance appears to be close to 100%, though indi- Neurofilament inclusion body dementia,a also known as neuronal viduals living into old age without symptoms have been intermediate filament inclusion disease observed in families with at least 1 mutation (exon Unknown Dysfunctional Protein 10ϩ16).2 The duration of symptoms from onset to death Dementia lacking distinctive histopathologya is typically 3 to 10 years. Symptomatology usually in- Frontotemporal dementia associated with mutations in the gene a volves executive dysfunction and altered personality and encoding chromatin-modifying protein 2B (CHMP2B ) behavior, with aphasia and parkinsonism evolving in many Abbreviation: TDP-43, transactive response DNA–binding protein 43. individuals. Memory impairment occurs less frequently a Disorder that can manifest as frontotemporal dementia with or without as the primary presenting feature, and visuospatial im- parkinsonism. pairment and limb apraxia are quite rare. Motor neuron (REPRINTED) ARCH NEUROL / VOL 65 (NO. 4), APR 2008 WWW.ARCHNEUROL.COM 461 ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 A DNA A A C G T G A A G G C T C G A T C C T G C G A G A A G G A A G T G G T C T C T Protein N V K A R S C E K E V V S Codon 489 490 491 492 493 494 495 496 497 498 499 500 501 B DNA A A C G T G A A G G C T Y G A T C C T G C G A G A A G G A A G T G G T C T C T Protein N V K A X Codon 489 490 491 492 493 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.1477CϾT 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.1477CϾT 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). disease is also infrequent, though several cases have been sive supranuclear palsy, argyrophilic grain disease, or