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

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 ante-mortem 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.

Atrophy patterns in IVS10+16, IVS10+3, N279K, S305N, P301L, and V337M MAPT mutations

“…These included 4 subjects with the P301L mutation in exon 10 (c.1907CϾT; p.Pro301Leu) from 2 families, 4 subjects with a mutation at position ϩ16 in intron 10 (referred to as IVS10ϩ16) (c.1920ϩ16CϾT; IVS10ϩ16CϾT) from 1 family, 3 subjects with a mutation at position ϩ3 in intron 10 (referred to as IVS10ϩ3) (c.1920ϩ3GϾA; IVS10ϩ3GϾA) from 1 family, 3 subjects with the N279K mutation (c.1842TϾG; p.Asn279Lys) from 1 family, 3 subjects with the V337M (c.2014GϾA; Val337Met) mutation from 1 family, 2 subjects with the S305N mutation (c.1919GϾA; p.Ser305Asn) from 1 family, 10 1 subject with the G389R mutation (c.2170GϾA; p.Gly389Arg), 1 subject with the R406W (c.2221CϾT; p.Arg406Trp) mutation, and 1 subject with a mutation at position Ϫ10 in intron 9 (referred to as IVS9-10) (c.1827-10GϾT; IVS9-10GϾT). 11 These cases had been prospectively studied in our Alzheimer's Disease Research Center (ADRC) or Alzheimer's Disease Patient Registry (ADPR) between 1991 and 2008.…”

Prominent phenotypic variability associated with mutations in Progranulin

“…The MRI findings in FTD linked to charged multivesicular body protein 2B (CHMP2B) on chromosome 3 (Brown et al 2004;Skibinski et al 2005), to the valosin-containing protein (VCP) on chromosome 9 (Vance et al 2006) and to MAPT on chromosome 17 have been frontotemporal cortical abnormalities varying from symmetric to markedly asymmetric atrophy (Basun et al 1997;Rosso et al 2001;Boeve et al 2005). Most descriptions of MRI findings in sporadic and familial FTD have not reported subcortical white matter signal changes.…”

An algorithm for genetic testing of frontotemporal lobar degeneration

“…34,40 In one small kindred with FTD with parkinsonism, the mother of multiple affected offspring lacked a somatic mutation in MAPT, suggesting a spontaneous germline mutation in MAPT. 41 PGRN carrier phenotype. More than 60 mutations in the PGRN gene have been described (www.molgen.ua.ac.be/FTDMutations).…”