Dement Geriatr Cogn Disord 2004;17:274–276

DOI: 10.1159/000077153

Frontotemporal Dementia Linked to

Chromosome 3
Jerry Brown a Susanne Gydesen c Peter Johannsen d Anders Gade e
Gaia Skibinski b Lisa Chakrabarti b Arne Brun g Maria Spillantini a
Despina Yancopoulou a Tove Thusgaard f Asger Sorensen f
Elizabeth Fisher b John Collinge b FReJA (Frontotemporal Dementia
Research in Jutland Association)
a Department of Neurology, Addenbrooke’s Hospital, Cambridge, b MRC Prion Unit, Institute of Neurology, London,
UK; c Department of Psychiatry, Central Hospital, Holbaek, d PET Centre, Department of Neurology,
Aarhus University Hospitals, Aarhus, e Department of Psychology, University of Copenhagen, Rigshospitalet,
f Institute of Medical Genetics, Panum Institute, Copenhagen, Denmark; g Department of Pathology,

University Hospital of Lund, Lund, Sweden

Key Words family has been studied for over 15 years by Dr. Susanne
Frontotemporal dementia W Chromosome 3 Gydesen and more recently by our collaboration – FreJA
(Frontotemporal Dementia Research in Jutland Associa-
tion). The family was first described by Dr. Gydesen et al.
Abstract in 1987 [1]. Information about the linkage to chromo-
A large pedigree with autosomal dominant frontotempo- some 3 was published in 1995 [2] and full clinical and
ral dementia has been identified. Positional cloning has pathological details and references to all earlier works on
linked the disease gene to the pericentromeric region of this topic issued in Neurology were published in 2002 [3]
chromosome 3. Clinical, neuropsychological, imaging, (with a supplement on the journal web site).
pathological and molecular genetic data are presented.
The genetic mutation responsible for the disease has not
been identified. The Family
Copyright © 2004 S. Karger AG, Basel

The proband was a farmer’s wife who was born in

1876. She had 12 children who survived to adulthood.
Introduction She developed dementia at the age of 56 years and died in
1948 at the age of 68 years. Eight of her children devel-
We report on the results of a multinational, multidisci- oped dementia and 1 further individual died in a traffic
plinary study of a novel form of frontotemporal dementia accident at the typical age of onset of this disease. He had
(FTD) defined by its clinical, neuropsychological, imag- passed the disease onto his children. Therefore, he must
ing and pathological features and its linkage to the peri- have carried the disease gene. It is possible that his acci-
centromeric region of chromosome 3 (FTD-3). dent was related to early dementia.
FTD-3 has been described in a single pedigree, which Twenty-six individuals in 4 generations developed de-
originates and resides in western Jutland, Denmark. The mentia. There was male to male transmission and the pat-

© 2004 S. Karger AG, Basel Dr. J.M. Brown

ABC 1420–8008/04/0174–0274$21.00/0 Department of Neurology, Addenbrooke’s Hospital
Fax + 41 61 306 12 34 Hills Road, Cambridge CB2 2QQ (UK)
E-Mail karger@karger.ch Accessible online at: Tel. +44 1223 217909, Fax +44 1223 217554
www.karger.com www.karger.com/dem E-Mail jmb75@medschl.cam.ac.uk
tern of inheritance was autosomal dominant. The age of Nineteen affected individuals have had a CT brain
onset varied between 46 and 65 years and the duration of scan. Four out of 5 with symptoms at the time of scanning
the disease between 3 and 21 years. The mean age at dis- showed global atrophy. One of the 14 without symptoms
ease onset was 57 years. In 1995 [2], we published evi- had atrophy; she developed symptoms of the disease 15
dence that there was anticipation of the age of onset with years later. On CT brain scans, the atrophy has a general-
paternal transmission. However, recent paternally inher- ized pattern with both cortical and central atrophy having
ited cases have had a later onset than their father, casting secondary enlargement of the lateral ventricles. There is
doubt on our earlier observation. no clear frontal preponderance. MRI scans have been per-
There is a trend to increasing age of onset in more formed in 2 cases showing a similar pattern of atrophy
recent decades, suggesting the possibility of a protective with some frontal preponderance and some white matter
factor, which is likely to be environmental. However, the changes in 1 individual.
trend is not statistically significant [FReJA, unpubl. Positron emission tomography (PET) scanning mea-
obs.]. suring quantitative regional cerebral blood flow (rCBF)
with 0–15 water has been performed in 4 affected individ-
uals and 6 first-degree ‘at risk’ individuals. PET CBF
Clinical Characteristics scans of first-degree relatives were all considered to be
within normal limits at the time of scanning. One of the
The clinical phenotype has been uniform, when the healthy first-degree relatives was rescanned 6 years later
large number of cases is considered. The disease starts after she had developed the disease. The new scan showed
with a change in behaviour and personality. Affected indi- no significant changes in either the absolute CBF values
viduals may become disinhibited or may withdraw and or in the regional distribution of the flow. In the affected
become apathetic. Ritualized behaviour, loss of emotion individuals, PET scanning showed a reduction in the per-
and change in eating habits are common. Some individu- fusion of the frontal, temporal and parietal lobes, without
als develop dyscalculia, suggesting a parietal lobe involve- clear frontal preponderance. Normal flow measurements
ment, but no individuals have early features such as were obtained in the primary visual cortex, thalami, basal
route-finding problems or visuospatial problems. The dis- ganglia and cerebellum. A visual comparison of the scans
ease is generally slowly progressive and the patient devel- between the 4 patients indicates more pronounced defi-
ops dynamic aphasia, which typically progresses to abbre- cits with lower rCBF values in the more severely affected
viated words and then mutism. patients.
Physical signs are absent in the early stages of the dis-
ease. After 4 or more years into the illness, several indi-
viduals have developed a striking motor syndrome. Many Pathology and Genetics
of these individuals have been exposed to neuroleptic
drugs, but the syndrome continues to progress years after Pathological examination of the brain has been per-
the neuroleptic drugs have been stopped. They develop an formed in 6 individuals, but only 3 of these brains are still
asymmetric akinetic rigid syndrome with arm and gait available for study. On external examination and slices,
dystonia and pyramidal signs. there is mild generalized, but mainly frontal, cortical atro-
A retrospective structured interview of carers shows phy with neuronal loss and gliosis, affecting particularly
close similarity in symptoms to other cases of FTD [4] the upper half of the cortex. Some brains show mainly
and clear differences to Alzheimer’s disease. The results frontal white matter attenuation with mild gliosis and loss
of these interviews indicate early behavioural and person- of myelin. There are no inclusion bodies and staining for
ality change with preservation of episodic memory and beta amyloid and prion protein is negative. There is some
topographical orientation, as well as a lack of insight and tau deposition, more marked in individual 11,12 who had
empathy. a very protracted disease course.
More detailed recent studies on affected individuals Molecular genetic studies published in 1995 [2] dem-
show very widespread cognitive deficits with preservation onstrated a linkage of the disease gene in this family to the
of memory and visuospatial skills. Monitoring of individ- pericentromeric region of chromosome 3. Repeat analyses
uals using serial Mini-Mental State Examinations reveals of newly affected individuals have confirmed the linkage
relatively good scores early in the illness and then a sharp to this region. Extensive sequencing of candidate genes in
decline with worsening dynamic aphasia. the region has not revealed a pathogenic mutation. Earlier

Frontotemporal Dementia Linked to Dement Geriatr Cogn Disord 2004;17:274–276 275

Chromosome 3
studies suggested that there was anticipation of the age of Southern blot analysis is being used to look for large
onset with paternal inheritance, which led to an extensive genetic deletions and fluorescent in situ hybridization
search for a trinucleotide expansion mutation; however, technology is being employed to identify larger chromo-
none has been located. somal rearrangements.

References 1 Gydesen S, Hagen S, Klinken L, Abelskov J, 3 Gydesen S, Brown J, Brun A, Chakrabarti L,

Sorensen SA: Neuropsychiatric studies in a Gade A, Johannsen P, Rossor M, Thusgaard T,
family with presenile dementia different from Grove A, Yancopoulou D, Spillantini MG,
Alzheimer and Pick disease. Acta Psychiatr Fisher E, Collinge J, Sorensen SA: Chromo-
Scand 1987;76:276–284. some 3 linked frontotemporal dementia (FTD-
2 Brown J, Ashworth A, Gydesen S, Sorensen A, 3). Neurology 2002;59:1585–1594.
Rossor M, Hardy J, Collinge J: Familial non- 4 Brun A, Englund B, Gustafson L, Passant U,
specific dementia maps to chromosome 3. Mann DMA, Neary D, Snowden JS: Consensus
Hum Mol Genet 1995;4:1625–1628. statement – Clinical and neuropathological cri-
teria for frontotemporal dementia. J Neurol
Neurosurg Psychiatry 1994;57:416–418.

276 Dement Geriatr Cogn Disord 2004;17:274–276 Brown et al.

Copyright: S. Karger AG, Basel 2004. Reproduced with the permission of S. Karger AG, Basel. Further
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