BACKGROUND: Frontotemporal dementia (FTD) is a neurodegenerative disease with early symptoms of personality change and/or language disorder. Approximately 40% of individuals with FTD have a family history of dementia; however, in our experience, less than 10% have clear autosomal dominant inheritance. Mutations in the microtubule-associated protein tau (MAPT) gene have been reported in up to 50% of hereditary cases, but are unusual except in families with more than 3 individuals with FTD. The genetics of FTD is complicated by clinical heterogeneity, variable expression, phenocopies, misdiagnoses, and lost family histories. The objective of this paper is to enable physicians to recognize hereditary patterns and genetic concerns of FTD families and to understand genetic counseling strategies. REVIEW SUMMARY: The complexity of FTD genetics and genetic counseling are illustrated using 4 case histories. Case 1 demonstrates the difficulty obtaining a reliable FTD family history. Case 2 illustrates how psychiatric phenocopies can make family linkage studies difficult. The lack of genotype and phenotype correlation and issues of predictive genetic testing within FTD families are the subject of case 3, and case 4 shows how normal aging language difficulties and cognitive changes can be misinterpreted when a family history of dementia is present. CONCLUSIONS: Physicians seeing patients with possible FTD should be aware of the risk of a genetic etiology. A 3-generation family history should be obtained with attention to neurologic, psychiatric, and behavioral symptoms. Variable expression and phenocopies are confounding factors when assessing a possible genetic etiology. Referral of the patient and family for genetic counseling is recommended.
BACKGROUND: Frontotemporal dementia (FTD) is a neurodegenerative disease with early symptoms of personality change and/or language disorder. Approximately 40% of individuals with FTD have a family history of dementia; however, in our experience, less than 10% have clear autosomal dominant inheritance. Mutations in the microtubule-associated protein tau (MAPT) gene have been reported in up to 50% of hereditary cases, but are unusual except in families with more than 3 individuals with FTD. The genetics of FTD is complicated by clinical heterogeneity, variable expression, phenocopies, misdiagnoses, and lost family histories. The objective of this paper is to enable physicians to recognize hereditary patterns and genetic concerns of FTD families and to understand genetic counseling strategies. REVIEW SUMMARY: The complexity of FTD genetics and genetic counseling are illustrated using 4 case histories. Case 1 demonstrates the difficulty obtaining a reliable FTD family history. Case 2 illustrates how psychiatric phenocopies can make family linkage studies difficult. The lack of genotype and phenotype correlation and issues of predictive genetic testing within FTD families are the subject of case 3, and case 4 shows how normal aging language difficulties and cognitive changes can be misinterpreted when a family history of dementia is present. CONCLUSIONS: Physicians seeing patients with possible FTD should be aware of the risk of a genetic etiology. A 3-generation family history should be obtained with attention to neurologic, psychiatric, and behavioral symptoms. Variable expression and phenocopies are confounding factors when assessing a possible genetic etiology. Referral of the patient and family for genetic counseling is recommended.
Authors: Yi Xiao Jiang; Qin Cao; Michael R Sawaya; Romany Abskharon; Peng Ge; Michael DeTure; Dennis W Dickson; Janine Y Fu; Rachel R Ogorzalek Loo; Joseph A Loo; David S Eisenberg Journal: Nature Date: 2022-03-28 Impact factor: 69.504
Authors: Vivianna M Van Deerlin; Patrick M A Sleiman; Maria Martinez-Lage; Alice Chen-Plotkin; Li-San Wang; Neill R Graff-Radford; Dennis W Dickson; Rosa Rademakers; Bradley F Boeve; Murray Grossman; Steven E Arnold; David M A Mann; Stuart M Pickering-Brown; Harro Seelaar; Peter Heutink; John C van Swieten; Jill R Murrell; Bernardino Ghetti; Salvatore Spina; Jordan Grafman; John Hodges; Maria Grazia Spillantini; Sid Gilman; Andrew P Lieberman; Jeffrey A Kaye; Randall L Woltjer; Eileen H Bigio; Marsel Mesulam; Safa Al-Sarraj; Claire Troakes; Roger N Rosenberg; Charles L White; Isidro Ferrer; Albert Lladó; Manuela Neumann; Hans A Kretzschmar; Christine Marie Hulette; Kathleen A Welsh-Bohmer; Bruce L Miller; Ainhoa Alzualde; Adolfo Lopez de Munain; Ann C McKee; Marla Gearing; Allan I Levey; James J Lah; John Hardy; Jonathan D Rohrer; Tammaryn Lashley; Ian R A Mackenzie; Howard H Feldman; Ronald L Hamilton; Steven T Dekosky; Julie van der Zee; Samir Kumar-Singh; Christine Van Broeckhoven; Richard Mayeux; Jean Paul G Vonsattel; Juan C Troncoso; Jillian J Kril; John B J Kwok; Glenda M Halliday; Thomas D Bird; Paul G Ince; Pamela J Shaw; Nigel J Cairns; John C Morris; Catriona Ann McLean; Charles DeCarli; William G Ellis; Stefanie H Freeman; Matthew P Frosch; John H Growdon; Daniel P Perl; Mary Sano; David A Bennett; Julie A Schneider; Thomas G Beach; Eric M Reiman; Bryan K Woodruff; Jeffrey Cummings; Harry V Vinters; Carol A Miller; Helena C Chui; Irina Alafuzoff; Päivi Hartikainen; Danielle Seilhean; Douglas Galasko; Eliezer Masliah; Carl W Cotman; M Teresa Tuñón; M Cristina Caballero Martínez; David G Munoz; Steven L Carroll; Daniel Marson; Peter F Riederer; Nenad Bogdanovic; Gerard D Schellenberg; Hakon Hakonarson; John Q Trojanowski; Virginia M-Y Lee Journal: Nat Genet Date: 2010-02-14 Impact factor: 38.330
Authors: Elisabeth M Wood; Dana Falcone; Eunran Suh; David J Irwin; Alice S Chen-Plotkin; Edward B Lee; Sharon X Xie; Vivianna M Van Deerlin; Murray Grossman Journal: JAMA Neurol Date: 2013-11 Impact factor: 18.302