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Autopsy-Confirmed Familial Early-Onset Alzheimer Disease Caused by the L153V Presenilin 1 Mutation
John C. Janssen, MRCP;
Peter L. Lantos, MD, PhD, DSc, FRCPath;
Nicholas C. Fox, MRCP;
Richard J. Harvey, MD, MRCPsych;
Jonathan Beck, BSc;
Andrew Dickinson, BSc;
Tracey A. Campbell, BSc;
John Collinge, MD, FRCP, FRCPath;
Diane P. Hanger, PhD;
Lisa Cipolotti, PhD;
John M. Stevens, FRCR;
Martin N. Rossor, MD, FRCP
Arch Neurol. 2001;58:953-958.
ABSTRACT
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Background Three affected individuals are described from a small English kindred
with early-onset autosomal dominant familial Alzheimer disease (FAD) caused
by a leucine-to-valine change at codon 153 (L153V) of the presenilin 1 (PSEN1) gene.
Methods Clinical information on the pedigree was collected directly from family
members and from hospital records. Samples of DNA were screened by means of
direct sequencing of all coding exons of PSEN1. One
patient underwent neuropathological examination.
Results Mean age at onset of symptoms was 35.3 years (95% confidence interval
[CI], 34.6-36.0 years); at death, 44.0 years (95% CI, 39.1-48.9 years). Mean
duration of illness was 8.3 years (95% CI, 4.7-11.9 years). Myoclonus was
a late feature in 1 patient; seizures were not reported in any subjects. Spastic
paraparesis and extrapyramidal signs were absent. The neuropsychometric profile
of 1 patient showed relatively preserved naming skills in the setting of global
cognitive deficits. Results of neuropathological examination demonstrated
the signature lesions of Alzheimer disease and the presence of occasional
cortical Lewy bodies.
Conclusions The PSEN1 L153V mutation lies in the main mutation
cluster of PSEN1 in the second transmembrane domain.
It causes early-onset FAD with clinical features similar to those of other
reported FAD pedigrees.
INTRODUCTION
TO DATE, the following 3 causative genes have been identified in autosomal
dominant familial Alzheimer disease (FAD): amyloid precursor protein (APP), presenilin 1 (PSEN1), and
presenilin 2.1 Approximately 55% of early-onset
FAD cases are associated with PSEN1 mutations.2 More than 80 PSEN1 mutations
have now been reported, and although an intronic mutation has been identified,3 most are missense point mutations, about half of which
occur in exons 5 and 8.1 Recently, a leucine-to-valine
change at codon 153 (L153V), another mutation in exon 5, was identified in
a French pedigree without neuropathological confirmation.4
We report the clinical and neuropathological features of members of family
177 in whom we have demonstrated the L153V mutation.
SUBJECTS AND METHODS
Family 177 (Figure 1) is British.
Information was collected from hospital records and family members. Age at
onset (AAO) was defined as the age at which an individual first demonstrated
signs of memory loss or personality change. Patients III:2 and III:3 underwent
clinical assessment. Informed consent for genetic screening was obtained.
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Figure 1. Family 177 pedigree. To preserve
confidentiality, the pedigree has been altered to maintain anonymity, and
the current generation has been omitted. Affected family members are represented
with solid shapes; slashes indicate deceased.
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Patient III:3 underwent neuropathological examination. Blocks were taken
from the frontal, temporal, parietal, and occipital lobes; the basal ganglia;
the thalamus with the subthalamic nucleus; the midbrain; the pons; the medulla
oblongata; and the cerebellar hemisphere and vermis. Sections were stained
with hematoxylin-eosin and impregnated with silver according to the modified
Bielschowsky method and with Luxol fast blue and cresyl violet (only on selected
sections). Antibodies were used to immunostain beta amyloid, glial fibrillary
acidic protein, tau protein (DAKO, Ely, England), and  -synuclein (D.P.H.).
The DNA was extracted from frozen brain tissue, and all coding exons of PSEN1 were screened by means of direct sequencing. In addition,
100 healthy, unrelated white control subjects also underwent sequencing.
RESULTS
The clinical findings are summarized in Table 1. Mean AAO of symptoms was 35.3 years (95% confidence interval
[CI], 34.6-36.0 years); mean age at death, 44.0 years (95% CI, 39.1-48.9 years);
and mean duration of illness, 8.3 years (95% CI, 4.7-11.9 years).
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Table 1. Clinical Features of Family 177*
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PATIENT II:5
A right-handed factory worker presented at 40 years of age with a 5-year
history of progressive memory problems. Results of neurologic examination
and baseline dementia screening blood tests were normal. A ventriculogram
showed good filling of the ventricular system without evidence of a space-occupying
lesion. A diagnosis of presenile dementia was established. He died of bronchopneumonia
2 years later without undergoing neuropathological examination.
PATIENT III:2
A draughtsman was referred at 38 years of age with a 3-year history
of personality change, progressive memory impairment, and difficulties at
work. A full-scale IQ of 71 was obtained on the Revised Wechsler Adult Intelligence
Scale (WAIS-R)5 and a premorbid IQ estimate
of 106 was obtained on the National Adult Reading Test (NART).6
Deficits were also recorded in memory, spelling, writing, and reading. He
had a brisk pout and positive grasp reflex. Results of dementia screening
blood tests were normal. Computed tomographic brain scan, electroencephalography,
electromyography, and cerebrospinal fluid examinations showed no abnormalities.
He deteriorated progressively and died without undergoing neuropathological
examination.
PATIENT III:3
A left-handed bookkeeper presented at 37 years of age with a 1-year
history of memory impairment and anxiety symptoms. She complained of difficulty
with mental arithmetic and impaired episodic memory. Her medical history was
unremarkable. Results of verbal and performance IQ measures were average,
in keeping with her optimal level of functioning as estimated using the NART
(Table 2). Results of the Recognition
Memory Test (RMT)7 showed a mild global weakness
in memory functions. Nominal skills were preserved. She performed flawlessly
on the Unusual Views Test10 and the fragmented
letters subtest of the Visual Object and Space Perception Battery (VOSP).11 Results of an unenhanced computed tomographic brain
scan were interpreted as being normal. During the next 18 months, she was
downgraded at work and reported further deterioration of her episodic memory.
A second computed tomographic brain scan showed cortical atrophy, but she
failed to attend follow-up until she underwent reassessment at 41 years of
age, when her Mini-Mental State Examination12
score was 12/30. Examination demonstrated evidence of dyspraxia, with impaired
copying of gestures and limb substitution.
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Table 2. Neuropsychometry Results in Patient III:3*
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Repeated neuropsychometry (Table 2) showed a borderline defective verbal IQ and a defective performance
IQ. Performance on the RMT for words was at chance; for faces, below the first
percentile. Nominal skills were relatively well preserved on the Oldfield
Picture Naming Test.9 Visuoperceptual functions
had deteriorated; she scored below the fifth percentile on the silhouettes
subtest of the VOSP. There was no evidence of frontal executive dysfunction
(Weigl Sorting Test13). She performed poorly
on a letter cancellation task. Results of dementia screening blood tests and
cerebrospinal fluid examination were normal. A magnetic resonance brain scan
(Figure 2) showed marked atrophy
of the parietal lobes and posterior parts of the frontal lobes. The temporal
lobes were relatively spared, although the amygdalae were slightly atrophied.
There was no white matter disease. The ventricles were enlarged. The following
year, myoclonus developed, which was treated with carbamazepine. She died
of bronchopneumonia at the age of 49 years. The brain weighed 930 g; the brainstem
and cerebellum, 128 g. The leptomeninges were thickened. Severe, generalized
atrophy affecting all lobes of the brain was seen. Results of histological
examination showed features of severe AD, ie, neurofibrillary tangles, neuritic
plaques, and neuropil threads were abundant in the hippocampus and cerebral
cortex (Figure 3). In the hippocampus,
severe neuronal loss was accompanied by astrocytosis. Superficial status spongiosis
and astrocytosis were noted focally in the cerebral cortex, indicating severe
neuronal loss. Neurofibrillary tangles occurred also in the deep gray matter,
including the nucleus basalis of Meynert, the lentiform nucleus, the substantia
nigra, the locus ceruleus, the periaqueductal gray matter, and the raphe nuclei.
Immunohistochemical analysis for -synuclein revealed an occasional
Lewy body in the transentorhinal, cingulate, insular, and parietal cortexes,
and in the nucleus basalis of Meynert (Figure
4). There was extensive deposition of beta amyloid in the cerebral
parenchyma and in the blood vessels (Figure
5).
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Figure 2. Axial T2-weighted magnetic resonance
image of patient III:3 showing biparietal atrophy.
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Figure 3. Senile plaques, neurofibrillary
tangles, and neuropil threads in the temporal cortex. Immunostaining of tau
protein (original magnification x70).
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Figure 4. Lewy bodies in the amygdala. Immunostaining
of -synuclein (original magnification x120).
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Figure 5. Immunostaining of beta amyloid
in the cerebral parenchyma and the leptomeningeal and cerebral blood vessels
(original magnification x30).
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The L153V mutation was demonstrated in patient III:3 and was absent
in 100 unrelated healthy controls from the same ethnic background.
COMMENT
The PSEN1 gene consists of 13 exons, of which
exons 3 through 12 code for a 467-amino acid–length protein.14, 15 This serpentine protein is believed
to consist of 6 to 8 transmembrane domains, where mutations tend to be concentrated.
The L153V mutation is part of and extends a previously described mutation
cluster on the second transmembrane domain (Table 3). The mutations in this cluster occur every third or fourth
amino acid. Consequently, it has been suggested that they line up on the same
side of an helix, disrupting the structure and function of PSEN1.1 The other major mutation cluster
is in exon 8, near the PSEN1 cleavage site.2 Together, these major mutation clusters account for
more than 50% of PSEN1 mutations.32
Most PSEN1 mutations have been missense mutations,
leading to the hypothesis that mutant proteins result in disease by means
of toxic gain of function.33 In common with APP mutations, they mediate their pathogenic effect by
means of increased beta amyloid 42(43) formation.33, 34, 35
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Table 3. Mutation Cluster in Transmembrane Domain of PSEN1*
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Unlike other PSEN1 mutation pedigrees, myoclonus
was a feature in only 1 patient.36, 37, 38, 39
Seizures are a well-recognized feature of younger-onset FAD,36, 37, 38, 40, 41
but were absent in family 177 as in FAD due to PSEN1
leucine-to-serine change at codon 250 (L250S).42
Spastic paraparesis was absent in our patients, and there was no neuropathological
evidence of the "fluffy cotton wool" plaques reported in association with
mutations causing paraparesis.43 The French
family with the L153V mutation has not been described in detail, but myoclonus,
seizures, and spastic paraparesis were not reported.4
The main phenotypic difference between the families with the L153V mutation
and most PSEN1 kindreds appears to be a very early
AAO. In a review of 38 published pedigrees with 22 different PSEN1 mutations, only 7 pedigrees had a mean AAO in the fourth decade
of life.2 There appears to be no clear correlation
between AAO and the site of the mutation. Even for the second transmembrane
domain mutation cluster, where the 12 known mutations are in close juxtaposition,
there is a 23-year range in AAO. Data for this cluster are available for 25
of the 29 published pedigrees (Table 3); 11 families had a mean AAO in the fourth decade of life, and 13 families in
the fifth decade. For 1 family, the mean AAO was in the sixth decade of life.
The nature of individual mutations may account for a degree of this variation
as illustrated by the 2 mutations at codon 143: a nonconservative change (isoleucine
to threonine) has a mean AAO of 35 years, whereas a semiconservative change
(isoleucine to phenylalanine) has a mean AAO of 55 years. However, this would
not account for the variation in AAO seen within some families. For families
with an APP mutation, the dose of apolipoprotein
E  4 alleles has been shown to reduce the AAO,44
but in families with PSEN1 mutations, this effect
is absent.45 Further unidentified genetic factors
have been proposed for these families.41, 46
It is generally agreed that the neuropathological changes of FAD are
indistinguishable from those of sporadic AD,47
but our patient undergoing neuropathological evaluation also has sufficient
Lewy bodies to consider a secondary diagnosis of dementia with Lewy bodies
(transitional or limbic type).48 Although the
coexistence of Lewy body and Alzheimer lesions is recognized in sporadic AD,
it is more common in FAD. In a neuropathological series of 74 patients with
FAD, Lewy bodies were demonstrated in 22%, when -synuclein immunostaining
was used to define them.49 The Lewy body abnormalities
in our patient are negligible compared with the AD changes, and there were
no clinical Lewy body symptoms to support the diagnosis in this family. The
original Newcastle criteria could not be maintained in the light of -synuclein
immunostaining and have been revised.50 For
these reasons, we believe that a secondary diagnosis of dementia with Lewy
bodies cannot be justified.
AUTHOR INFORMATION
Accepted for publication November 26, 2000.
This study was supported by program grant G9626876 from the Medical
Research Council (UK), London, England.
The authors thank the family members and their attendant physicians,
especially Jeffrey Gawler, MD, FRCP, consultant neurologist, St Bartholomew's
hospital, London; Christine Garrett, FRCP, consultant clinical geneticist,
Kennedy-Galton Centre, Northwick Park Hospital, Harrow, London; and Angus
Kennedy, MD, MRCP, and Penelope Roques, Dementia Research Group, Institute
of Neurology, London. Members of the Medical Research Council supported the
London Neurodegenerative Diseases Brain Bank; in particular, Heidi Barnes
provided technical assistance.
From the Dementia Research Group, Institute of Neurology (Drs Janssen,
Fox, Harvey, and Rossor), the Departments of Neuropathology (Dr Lantos) and
Neuroscience (Dr Hanger), Institute of Psychiatry, the Medical Research Council
Prion Unit, Department of Neurogenetics, Imperial College School of Medicine
(Messrs Beck and Dickinson, Ms Campbell, and Dr Collinge), and the Departments
of Clinical Neuropsychology (Dr Cipolotti) and Neuroradiology (Dr Stevens),
National Hospital for Neurology and Neurosurgery, London, England.
Corresponding author and reprints: M. N. Rossor, Dementia Research
Group, Institute of Neurology, Queen Square, London WC1N 3BG, England (e-mail: m.rossor{at}dementia.ion.ucl.ac.uk).
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