Longitudinal characterization of two siblings with frontotemporal dementia and parkinsonism linked to chromosome 17 associated with the S305N tau mutation

Bradley F. Boeve, Ivo W. Tremont-Lukats, Andrew J. Waclawik, Jill R. Murrell, Bruce Hermann, Clifford R. Jack, Maria M. Shiung, Glenn E. Smith, Anil R. Nair, Noralane Lindor, Vinaya Koppikar, Bernardino Ghetti

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

The background to this study began with the reporting of two Japanese kindreds with the S305N tau mutation. Although the pathological findings in the autopsied cases were well characterized, only limited antemortem data were presented. In this study, longitudinal characterization was carried out in two siblings of European ancestry found to have frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) through comprehensive neurobehavioural examinations and other scales at approximate 6-month intervals. Scales included the Mini-Mental State Examination, Short Test of Mental Status, modified motor subtest of the Unified Parkinson's Disease Rating Scale, detailed neuropsychological testing, and the Neuropsychiatric Inventory. Changes in whole-brain volume and ventricular volume were measured from serial MRI studies. All members of the kindred underwent molecular genetic analyses to elucidate the mechanism of inheritance. The missense mutation in tau, S305N, was detected in the proband (onset age 30), who has undergone serial evaluations for almost 4 years. Her older sister (onset age 36) was subsequently found to have the same mutation, and has undergone serial evaluations for 2 years. This mutation is absent in both parents and the only other sibling, and non-paternity was excluded by additional analyses. The siblings have exhibited cognitive and behavioural features typical of FTDP-17, which have proved challenging to manage despite aggressive pharmacological and behavioural therapies. The proband's sister has demonstrated an atypical profile of impairment on neuropsychological testing. Both siblings have developed striking atrophy of the anterior part of temporal lobes and moderate atrophy of the dorsolateral and orbitofrontal cortical regions, which in both cases is relatively symmetrical. The annualized changes in whole-brain volume and ventricular volume, respectively, were -35.2 ml/year (3.23% decrease per year) and +20.75 ml/year (16.93% increase per year) for the proband, and -30.75 ml/year (2.77% decrease per year) and +5.01 ml/year (3.11% increase per year) for the proband's sister. In conclusion, the mutation in these siblings may have arisen during oogenesis in the mother and probably represents germline mosaicism. Although both patients have exhibited the typical cognitive and behavioural features of FTDP-17, one patient is exhibiting an atypical neuropsychological profile. Also, despite a similar topographic pattern of progressive atrophy on MRI, the rates of change in whole-brain volume and ventricular volume between the two patients are quite different. These findings have implications for future drug trial development in FTDP-17 and the sporadic tauopathies.

Original languageEnglish
Pages (from-to)752-772
Number of pages21
JournalBrain
Volume128
Issue number4
DOIs
StatePublished - Apr 2005

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Frontotemporal Dementia
Chromosomes, Human, Pair 17
Siblings
Mutation
Parkinsonian Disorders
Atrophy
Age of Onset
Brain
Tauopathies
Oogenesis
Intelligence Tests
Mosaicism
Missense Mutation
Temporal Lobe
Prefrontal Cortex
Parkinson Disease
Molecular Biology
Parents
Mothers
Pharmacology

Keywords

  • Frontotemporal dementia
  • Magnetic resonance imaging
  • MAPT
  • Neuropsychology
  • Tau

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Longitudinal characterization of two siblings with frontotemporal dementia and parkinsonism linked to chromosome 17 associated with the S305N tau mutation. / Boeve, Bradley F.; Tremont-Lukats, Ivo W.; Waclawik, Andrew J.; Murrell, Jill R.; Hermann, Bruce; Jack, Clifford R.; Shiung, Maria M.; Smith, Glenn E.; Nair, Anil R.; Lindor, Noralane; Koppikar, Vinaya; Ghetti, Bernardino.

In: Brain, Vol. 128, No. 4, 04.2005, p. 752-772.

Research output: Contribution to journalArticle

Boeve, BF, Tremont-Lukats, IW, Waclawik, AJ, Murrell, JR, Hermann, B, Jack, CR, Shiung, MM, Smith, GE, Nair, AR, Lindor, N, Koppikar, V & Ghetti, B 2005, 'Longitudinal characterization of two siblings with frontotemporal dementia and parkinsonism linked to chromosome 17 associated with the S305N tau mutation', Brain, vol. 128, no. 4, pp. 752-772. https://doi.org/10.1093/brain/awh356
Boeve, Bradley F. ; Tremont-Lukats, Ivo W. ; Waclawik, Andrew J. ; Murrell, Jill R. ; Hermann, Bruce ; Jack, Clifford R. ; Shiung, Maria M. ; Smith, Glenn E. ; Nair, Anil R. ; Lindor, Noralane ; Koppikar, Vinaya ; Ghetti, Bernardino. / Longitudinal characterization of two siblings with frontotemporal dementia and parkinsonism linked to chromosome 17 associated with the S305N tau mutation. In: Brain. 2005 ; Vol. 128, No. 4. pp. 752-772.
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abstract = "The background to this study began with the reporting of two Japanese kindreds with the S305N tau mutation. Although the pathological findings in the autopsied cases were well characterized, only limited antemortem data were presented. In this study, longitudinal characterization was carried out in two siblings of European ancestry found to have frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) through comprehensive neurobehavioural examinations and other scales at approximate 6-month intervals. Scales included the Mini-Mental State Examination, Short Test of Mental Status, modified motor subtest of the Unified Parkinson's Disease Rating Scale, detailed neuropsychological testing, and the Neuropsychiatric Inventory. Changes in whole-brain volume and ventricular volume were measured from serial MRI studies. All members of the kindred underwent molecular genetic analyses to elucidate the mechanism of inheritance. The missense mutation in tau, S305N, was detected in the proband (onset age 30), who has undergone serial evaluations for almost 4 years. Her older sister (onset age 36) was subsequently found to have the same mutation, and has undergone serial evaluations for 2 years. This mutation is absent in both parents and the only other sibling, and non-paternity was excluded by additional analyses. The siblings have exhibited cognitive and behavioural features typical of FTDP-17, which have proved challenging to manage despite aggressive pharmacological and behavioural therapies. The proband's sister has demonstrated an atypical profile of impairment on neuropsychological testing. Both siblings have developed striking atrophy of the anterior part of temporal lobes and moderate atrophy of the dorsolateral and orbitofrontal cortical regions, which in both cases is relatively symmetrical. The annualized changes in whole-brain volume and ventricular volume, respectively, were -35.2 ml/year (3.23{\%} decrease per year) and +20.75 ml/year (16.93{\%} increase per year) for the proband, and -30.75 ml/year (2.77{\%} decrease per year) and +5.01 ml/year (3.11{\%} increase per year) for the proband's sister. In conclusion, the mutation in these siblings may have arisen during oogenesis in the mother and probably represents germline mosaicism. Although both patients have exhibited the typical cognitive and behavioural features of FTDP-17, one patient is exhibiting an atypical neuropsychological profile. Also, despite a similar topographic pattern of progressive atrophy on MRI, the rates of change in whole-brain volume and ventricular volume between the two patients are quite different. These findings have implications for future drug trial development in FTDP-17 and the sporadic tauopathies.",
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AU - Boeve, Bradley F.

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AU - Waclawik, Andrew J.

AU - Murrell, Jill R.

AU - Hermann, Bruce

AU - Jack, Clifford R.

AU - Shiung, Maria M.

AU - Smith, Glenn E.

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AU - Lindor, Noralane

AU - Koppikar, Vinaya

AU - Ghetti, Bernardino

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N2 - The background to this study began with the reporting of two Japanese kindreds with the S305N tau mutation. Although the pathological findings in the autopsied cases were well characterized, only limited antemortem data were presented. In this study, longitudinal characterization was carried out in two siblings of European ancestry found to have frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) through comprehensive neurobehavioural examinations and other scales at approximate 6-month intervals. Scales included the Mini-Mental State Examination, Short Test of Mental Status, modified motor subtest of the Unified Parkinson's Disease Rating Scale, detailed neuropsychological testing, and the Neuropsychiatric Inventory. Changes in whole-brain volume and ventricular volume were measured from serial MRI studies. All members of the kindred underwent molecular genetic analyses to elucidate the mechanism of inheritance. The missense mutation in tau, S305N, was detected in the proband (onset age 30), who has undergone serial evaluations for almost 4 years. Her older sister (onset age 36) was subsequently found to have the same mutation, and has undergone serial evaluations for 2 years. This mutation is absent in both parents and the only other sibling, and non-paternity was excluded by additional analyses. The siblings have exhibited cognitive and behavioural features typical of FTDP-17, which have proved challenging to manage despite aggressive pharmacological and behavioural therapies. The proband's sister has demonstrated an atypical profile of impairment on neuropsychological testing. Both siblings have developed striking atrophy of the anterior part of temporal lobes and moderate atrophy of the dorsolateral and orbitofrontal cortical regions, which in both cases is relatively symmetrical. The annualized changes in whole-brain volume and ventricular volume, respectively, were -35.2 ml/year (3.23% decrease per year) and +20.75 ml/year (16.93% increase per year) for the proband, and -30.75 ml/year (2.77% decrease per year) and +5.01 ml/year (3.11% increase per year) for the proband's sister. In conclusion, the mutation in these siblings may have arisen during oogenesis in the mother and probably represents germline mosaicism. Although both patients have exhibited the typical cognitive and behavioural features of FTDP-17, one patient is exhibiting an atypical neuropsychological profile. Also, despite a similar topographic pattern of progressive atrophy on MRI, the rates of change in whole-brain volume and ventricular volume between the two patients are quite different. These findings have implications for future drug trial development in FTDP-17 and the sporadic tauopathies.

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