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Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17: a Consensus Conference

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Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17: a Consensus Conference SPECIAL REPORT Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17: A Consensus Conference Norman L. Foster, MD,* Kirk Wilhelmsen, MD, PhD,? Anders A. F. Sima, MD, PhD,ts Margaret Z. Jones, MD," Constance J. D'Amato, BS,$ Sid Gilman, MD,* and Conference Participants7 We held an international consensus conference on frontotemporal dementia, behavioral disturbances, and parkinsonism linked to chromosome 17 to determine whether these are homogeneous or heterogeneous disorders, to agree on termi- nology, and to develop strategies for further research. The group identified 13 kindreds with sufficient evidence for linkage, finding in common to all a critical 2 CM between markers D17S791 and D17S800. There was agreement that (I) despite previous descriptions that have emphasized one or another clinical or neuropathological feature, the kindreds share clinical and neuropathological features; (2) until more specific information about the genetic defects becomes available, this disorder is best termed frontotemporal dementia and parkinsonism linked to chromosome 17; and (3) hrther research will be enhanced by identifying the gene or genes responsible for this disorder, detecting additional cases within known families and, in new families, correlating mutations with phenotypes and more fully delineating the clinical, neuropsychological, and neuropathological characteristics of this disorder. Foster NL, Wilhelmsen K, Sima AAF, Jones MZ, D'Amato CJ, Gilman S, Conference Participants. Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Ann Neurol 1997;41:706-715 _- Most dementia in late life is caused by Alzheimer's dis- 17 [ 1 I]. Subsequently, several other families have had ease (AD), but neuropathological examinations some- difficult-to-classif, progressive neurodegenerative dis- times disclose other neurodegenerative disorders. In ap- orders that have been linked to the same region of proximately 3 to 10% of these patients, autopsy fails to chromosome 17. Because these families have been con- reveal the characteristic neuropathological features of sidered in isolation, their disorders have received vari- the common causes of dementia, including AD, stroke, ous names that emphasize particular clinical or neuro- structural lesions, Parkinson's disease, diffuse Ley pathological features. This has made the disorders body disease, or Picks disease [ 1, 21. The terminology appear disparate when they in fact may have much in to describe such cases varies and many names have common. been used. Nonspecific dementia is the most com- To extend our knowledge about chromosome 17- monly used term, but dementia lacking distinctive his- linked dementia, a forum was needed to bring together tology, Pick's disease without Pick bodies, and fronto- investigators who could compare the clinical and neu- temporal dementia [2-61 are terms that have also been ropathological features of the disorders in identified used. These dementias have been difficult to study be- kindreds, determine whether they share common ele- cause the clinical variability makes it unclear whether ments, develop a consensus about these issues, and for- they represent a distinct clinical syndrome. Many pa- mulate strategies for further research. tients later found to have one of these dementias were erroneously thought to have AD, but in some cases Methods atypical features were recognized [7,81. An international consensus conference was held in Ann Ar- Many patients with nonspecific neuropathology or bor, Michigan, October 4 through 6, 1996. Before the meet- frontotemporal dementia have a disease that is heredi- ing, the organizing committee searched the medical literature tary, up to 60% in one series [l, 31, 9, lo]. Recently, to identify all known kindreds with a neurodegenerative dis- dementia in 1 such family was linked to chromosome ease linked to chromosome 17. We contacted investigators From the Departments of *Neurology and $Pathology, University Received Nov 7, 1996, and in revised form Feh 4 and Mar 6, 1997. of Michigan, Ann Arbor, $Departments of Parhology and Neurol- Accepted for puhlication Mar 7, 1997. ogy, Wayne State University, Detroit, and "Department of Pathol- ogy, Michigan State University, East laxing, MI; and tDepart- Address correspondence to Dr Foster, Department of Neurology, ment of Neurology, Univcrsity of California, San Francisco, San University of Michigan Medical Center, 1920 Taubman Center, Francisco, CA. Box 0316, Ann Arbor, MI 48109-0316. YScc page 714 for conference participants 706 Copyright 0 1997 by the American Neurological Association who were familiar with each kindred and invited them to The conference-organizing committee provided a draft attend the meeting and to present clinical, genetic, and neu- consensus statement in advance of the meeting to guide the ropathological data. They were also asked to identify any discussions. The participants reviewed the statement and other kindreds that have been linked to chromosome 17. We modified both the statement and the tables summarizing in- gave the investigators a list of publications related to their formation presented at the meeting. Members of the orga- kindreds that they checked for accuracy and completeness. nizing committee served as moderators of the discipline- We distributed a list of key published references to all par- specific sessions and recorded the results of the consensus. ticipants for review before the meeting. The conference in- cluded clinicians, geneticists, and neuropathologists associ- Results ated with each kindred and an independent panel of senior Kindreds with Frontotemporal Dementia and commentators with expertise in dementia and neurodegen- Parkinsonism Linked to Chromosome I7 erative disorders. These commentators provided perspective The participants discussed 25 families they had identi- and a summary of each day's deliberations. At the beginning of the meeting, the organizing commit- fied. They agreed that 8 families have disease that is tee instructed participants on procedures for achieving con- definitely linked to the critical region of chromosome sensus, and the moderators used previously described meth- 17 because of multipoint affected-only LOD scores ods to encourage consensus among all participants [l2]. In a greater than 3, and they classified 5 families as having plenary session on the first day, the invited participants pre- disease that is probably linked because of LOD scores sented the clinical, laboratory, neuropathological, and genetic between 1 and 3 (Table I). The remaining 12 kindreds features of each kindred showing linkage to chromosome 17 had similar clinical and neuropathological features but and cases of sporadic and familial neurodegenerative disor- had only a small number of available tissue samples for ders that clinically and neuropathologically resemble the de- DNA testing. In these kindreds where LOD scores scribed kindreds but are not known to be linked to chromo- were less than 1, there was no indication of a genetic some 17. On the second day, clinicians, neuropathologists, mutation at another location, but linkage to chromo- and geneticists held three discipline-specific sessions to present and discuss in detail the characteristics of the kin- some 17 had to be classified as uncertain. Information dreds and to address a list of predetermined questions. In a about these kindreds was tabulated, but they were oth- final plenary session on the third day, the conclusions of the erwise not considered further in the deliberations. discipline-specific sessions were presented and discussed and The 13 families with definitely and probably linked the participants agreed on a final consensus statement. disease have been analyzed by a subset of markers that Table 1. Kindreds with Newodegenerative Disease Linked to Cbromosome 17 Affected Only Multipoint Number in Pedigree LOD Score Flanking Markers Rcferences Definitely linked Irish family 1 (family Mo) 13 of 33 in 3 generations >3 D 17S798-Dl7S808 11, 20-22 Pallido-ponto-nigral de- 35 of 303 in 8 generations 6.8 D 17S250-D 17S943 23-29 generation (PPND) Familial multiple system 41 of 383 in 6 generations >3 THRA-D 17S79 1 None 7-opathy with presenile dementia (FMST) Seattle family A or BK 18 of -60 in 3 generations >3 No obligate recombinants 30, 31 Dutch family I 49 of 162 in 6 generations >3 D 17S800-D 17S790 32 Duke University family 16 of 41 in 5 generations >5 D 17S800-D 17S806 33 1684 Hereditary dyphasic disin- 21 of 475 in 8 generations 3.7 No obligate recombinants 34 hibition dementia (HDDD) family 2 Australian family 26 of 172 in 5 generations >3 No obligate recombinants 35, 36 Probably linked Dutch family I1 34 of 144 in 7 generations 1.6 No obligate recombinants 15, 37-40 Dutch family I11 30 of 169 in 5 generations 2.6 D 17S953"-D 17S79 1 32 Karolinska family 12 of 35 in 5 generations 2.7 No obligate recombinants None Familial progressive subcor- 17 of 67 in 5 generations 1.6 No obligate recombinants 19, 41 tical gliosis (FPSG), fam- ily A Seattle family B 7 of 30 in 3 generations 1.1 No obligate recombinants None "Nonrecornbinant marker. Special Report: Foster et al: FTDP-17 Consensus Conference 707 have been ordered in publicly available meiotic segre- common among affected individuals in the kindreds in gation maps (http://www.genethon.fr/genethon-en. which linkage to chromosome 17 has been demon- html, http://www.chlc.org/) allowing direct compari- strated. The disease commonly begins insidiously with son of linkage data. The presence of disease in these behavioral or motor manifestations, typically in the families segregates with markers in the 17q21-22 re- fifth decade and occasionally in the third, fourth, or gion, which includes, in all kindreds, a critical 2 cM sixth decade. The duration of the disease is variable, between markers D17S731 and D17S800 (Fig). Link- usually extending 10 years, but it can be as short as 3 age analysis used to classify kindreds was based on an years and as long as 30 years. Patients may first seek “affected-only model” because the age-adjusted pen- medical attention because of cognitive impairment pro- etrance varies between families.
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