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Codon 618 variant of alzheimer amyloid gene associated with inherited cerebral hemorrhage.

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1. Maire FW,Patton HD. Neural structures involved in the gene2.
sis of “preoptic pulmonary edema,” gastric erosions and behavior changes. Am J Physiol 1956;184:345-350
Duker TB. Increased intracranial pressure and pulmonary
edema. Part 1: clinical study of 11 patients. J Neurosurg 1968;
28: 1 12-1 17.
HoffJT, Reis DJ. Localization of regions mediaring the Cushing
response in brain and spinal cord of cat. Arch Neurol 1970;
Giroud M, Guard 0, Dumas R. Anomahes cardio-respiratoires
dans la sclerose en plaques. Rev Neurol (Paris) 7988;144:
Nathan MA, Reis DJ. Fulminating arterial hypertension with
pulmonary edema from release of adrenomedullary catecholamines after lesions of the anterior hypothalamus in the rat. Circ
Res 1975;37:226-235
Minnear FL, Connell RS. Increased permeability of the
capillary-alveolar barriers in neurogenic pulmonary edema
(NPE). Microvasc Res 1981;22:345-366.
Schlesinger B. Neurogenic pulmonary edema due to puncture
wound of the medulla oblongata J Nerv Ment Dis 1945;
Harari A, Rapin M, Regnier B, et al. Normal pulmonarycapillary pressures in the late phase of the neurogenic pulmonary
edema. Lancet 1976;1:494
Yarnout BJ, Sridharan MR, Rice JF, et al. Electrocardiographic
changes in cerebrovascular hemorrhage. Am Heart J 1980;
99:294-3 00
Baker AB. Poliomyelitis: a study of pulmonary edema. Neurology 1957;7:743-751
DHooghe MB, Warshawski F. Ebers GC. Neurogenic pulmonary edema: brainstem localization of responsible lesions. Neurology 1989;39(suppl 1):244
Brown R H Jr, Beyerl BD, Iseke R, Lavyne MH. Medulla oblongata edema associated with neurogenic pulmonary edema J
Neurosurg 1986;64:494-500
Ariens-Kappers CU, Huber GC, Crosby EC. The compararive
anatomy of the nervous system of vertebrates, including man,
vol 1. New York: Macmillan, 1936:335-432
Mitchell RA, Berger AJ. Neural regulation of respiration. Am
Rev Respir Dis 1975;111:206-224
C o d e MK. Degeneration studies of primary afferents of IXth
and Xth cranial nerves in the cat. J Comp Neurol 1964;122:
Torvik A. The spinal projection from the nucleus of the solitary
tract. An experimental study in the cat. J Anat 1957;91:314322
Reis DJ. The brain and arterial hypertension: evidence for
neural-imbalance hypothesis. In: Abboud SM, Fozzard HA, Gilmore JP, Reis DJ (eds). Disturbances in neurogenic control of
circulation (clinical series-neurogenic). Bethesda, MD: American Physiologic Society, 1981:87-204
U S solitarius lesions eleDarragh TM, Simon RP.N U C ~ ~tractus
vate pulmonary arterial pressure and lymph flow. Ann Neurol
McClellan MD, Dauber IM, Wed JV. Elevated intracranial pressure increased pulmonary vascular permeability ro protein. J
Appl Physiol 1989;67:1185-1191
Codon 618 Variant of
Alzheimer Amyloid Gene
Associated with Inherited
Cerebral Hemorrhage
Ivan Fernandez-Madrid,BA,” Efrat Levy, PhD,”
Karen Marder, MD, MPH,t and
Blas Frangione, MD, PhD”
Hereditary cerebral hemorrhage with amyloidosis,
Dutch type (HCHWA-D) is an autosomal dominant form
of severe cerebrovascular amyloid angiopathy causing
recurrent strokes during the fifth and sixth decades of
life. The major constituent of the amyloid deposits in
HCHWA-D is the amyloid P-protein (AD), also found
in Alzheimer’s disease. A point mutation in the DNA
sequence encoding AD has been found in 2 unrelated
patients with HCHWA-D, and an assay detecting the
single base change was developed for diagnostic purposes. We describe the detection of the point mutation
in a patient living in the United States, suffering from
recurring cerebral hemorrhages, who only recently was
diagnosed with HCHWA-D. In addition, we tested a
number of family members, and found the mutation in 2
additional individuals, one of them too young to exhibit
clinical manifestations. This study combined with the
study of two other families in Holland indicates that the
codon 618 variant in the amyloid precursor protein gene
segregates with HCHWA-D.
Fernandez-Madrid I, Levy E, Marder K, Frangione B.
Codon 618 variant of Alzheimer amyloid gene
associated with inherited cerebral hemorrhage.
Ann Neurol 1991;30:730-733
An autosomal dominant form of cerebral amyloid angiopathy, designated hereditary cerebral hemorrhage
with amyloidosis, Dutch type (HCHWA-D) has been
described, in which apparently healthy and normotensive individuals develop intracerebral hemorrhages
between the ages of 45 and 65 [l). The amyloid deposition is primarily vascular; however, parenchymal
deposits that resemble immature plaques and preamyloid lesions exist, but are generally not surrounded by
From the *Department of Pathology, New York University Medical
Center, and tDeparunent of Neurology, College of Physicians and
Surgeons of Columbia University, The Presbyterian Hospital, New
York, NY.
Received Mar 25, 1991, and in revised form May 15. Accepted for
publication May 27, 1991.
Address correspondence to Dr Frangione, Department of Pathology,
New York University Medical Center, 550 First Avenue, TH 427,
New York, N Y 10016.
730 Copyright 0 1991 by the American Neurological Association
dystrophic neurites as they are in Alzheimer’s disease
(AD), and neurofibrillary tangles are absent [2).
The amyloid fibrils in HCHWA-D are composed
of the amyloid P-protein (AP), the major constituent
of parenchymal and vascular amyloid deposits in AD
and Down’s syndrome, and of the vascular deposits of
sporadic cerebral amyloid mgiopathy 13, 41. AP isolated from vascular amyloid is a 39 residue peptide
derived from an amyloid precursor protein (APP) by
proteolytic processing [3, 53. Two unrelated patients
with HCHWA-D were found to have a point mutation
(G to C) in one allele of the APP gene, causing an
amino acid substitution (Rlutamine for glutamic acid)
at position 22 of AP, corresponding to codon 618 of
the APP,,, complementary D N A (cDNA) [S-73. A
diagnostic assay has been developed to test high-risk
populations and for prenatal evaluation based on the
existence of the mutation {73.
We report the case history of a patient with multiple
cerebral hemorrhages, currently residing in the United
States, who was misdiagnosed for several years. The
diagnosis of HCHWA-D, based on clinical and familial
evidence, was confirmed through use of the slot-blot
hybridization assay. In addition the diagnostic assay was
used to screen this patient’s family members.
Case History
A 63-year-old normotensive, right-handed woman originally
from Katwijk, Holland, was completely well until the age of
47, when she had her first “syncopal” episode. She had a
repeat episode 1 1 years later, in 1986, and has had similar
episodes approximately every 2 weeks since that time. The
attacks were believed to be anxiety-related and treated with
alprazolam and desipramine.
In early 1989, a magnetic resonance image (MRI) revealed
bilateral, multiple confluent areas of increased signal in the
white matter (Fig 1). Electroencephalogram (EEG), 24 hour
ambulatory EEG, and transcranial and duplex Doppler scan
df the carotid arteries were normal. Several months later,
after complaining of dizziness and severe left-sided headache,
an MRI showed a right-sided occipital hemorrhage. Shortly
thereafter, the patient developed a tremor in the right arm. A
computed tomography (CT) scan revealed a new left parietal
hemorrhage. To date, there is no evidence of dementia on
neuropsychological testing, and no clinical evidence of new
hemorrhages, though the episodes persist. Several episodes
were recorded during continuous video EEG monitoring and
no electrographic seizure activity was evident.
Materials ahd Methods
Isokztion and Amplification of Genomic
DNA Sequences
Genomic DNA was isolated from peripheral blood cells by
the phenolichloroform extraction method [S}. The polymerase chain reaction (PCR) [9] was utilized to amplify exon 15
of APPb9, [lo], using intronal flanking primers in concentrations and cycling conditions, as previously described {G, 71.
Fig 1. A horizontal T2-weighted M R I showing multiple ureas
of signal intensity, mojtly in the white matter.
Slot-Blot Hybridization Assay
Equal amounts of amplified D N A from each individual were
blotted in duplicate onto nitrocellulose and hybridized to an
oligonucleotide containing the sequence complementary to
the point mutation [GI. The blots were washed in 2 x saline
sodium chloride, 0.1% sodium dodecyl sulfate (1 x SSC =
0.15 M sodium chloride, 0.015 M sodium citrate, p H 7.5) at
low-stringency temperature (48”C), then one of the duplicate
blots was washed at high stringency (68°C). The blots were
exposed to film overnight at - 70°C.
The pedigree chart shows the extensive history of
stroke in the patient’s family (Fig 2) and indicates the
individuals tested for the mutation. At high stringency,
the oligonucleotide hybridized only to amplified sequences from the patient (Patient l), from the patient’s
sister (Subject 8) (blot not shown), and from one of
the sister’s five children (Subject 6), indicating the presence of the mutation in these individuals. The patient’s
husband was also tested (blot not shown), and did not
have the mutation. The patient’s sister (Subject 8)
shows symptoms of HCHWA-D, having had an occipital bleed at 59 years old. Her children ranged in age
from 24 to 39 and as yet are too young to show symptoms of the disease. N o additional neurological or clinical data are available for Subjects 2 through 8.
Brief Communication: Fernandez-Madrid et al: Codon 618 Variant of APP Gene
Fig 2. Pedzgree of patient’s family, with the slot-blot analysis
shown below those family members tested. Females are denoted by
circles and males by squares. Triangles are used to represent the
present generation, t o preJerve anonymity. Oblique lines indicate
deceased individuals, and symbols representing symptomtic individuals are shaded. Line A shows the blots washed at low
stringency (48”C), and liBe B shows blots washed at high stringency (68°C).
Severe cerebral amyloid angiopathy has been implicated as the probable cause of normotensive intracerebra1 hemorrhage in 5 to 10% of strokes [1I}. Vascular
amyloid has been shown to be the cause of stroke in
HCHWA-D [I) and in another form of inherited cerebral amyloid angiopathy, hereditary cerebral hemor-.
rhage with amyloidosis, Icelandic type (HCHWA-I), in
which the amyloid subunit is derived from degradation
of a variant of cystatin C, an inhibitor of cysteine proteases [123. In HCHWA-I, the variant gene contains a
point mutation that results in a single amino acid substitution in the amyloid protein 1131. The role of the
amyloid deposits in causing the hemorrhages is unknown, though it has been postulated that the amyloid
deposits may make the vessels “brittle” and subject to
breaks or leaks { 1I]. This hypothesis is supported by
reports of head trauma precipitating a hemorrhage in
patients with HCHWA-D and in those with cerebral
amyloid angiopathy [Id, 15). Strokes in patients with
HCHWA-D have been shown to be primarily hemorrhagic in nature, though infarction does occur {16].
In the case presented here, the patient was diagnosed for 13 years as having psychiatric problems. A
diagnosis of HCHWA-D was only recently made after
the patient had documented hemorrhages and the extensive family history of stroke was uncovered. The
diagnosis was konfirmed, without need for a biopsy, on
detection of the codon 618 variant using the slot-blot
hybridization assay. The mutation was probably transmitted to the prftient and her sister (Subject 8) by their
father, who died during World War I1 at the age of 5 5 ,
prior to developing symptoms of the disease. Screening of high-risk individuals revealed the variant allele
in another family member before the symptoms of the
disease appeared. The study presented here, combined
with a similar analysis of two other families with
HCHWA-I3f {17], suggests that the codon 618 variant
causing a glutamine for glutamic acid substitution in
the APP segregates with HCHWA-D.
HCHWA-D is the first familial type of cerebrovascular amyloidosis related to a point mutation in the
gene encoding the AD amyloid precursor protein {6].
It has been suggested that the mutation may account
for the accelerated and tissue-specific arnyloid deposition found in HCHWA-D [G, 7}. Subsequently, another mutation was found in the APP gene in affected
members of two pedigrees with early-onset familial
AD { 18). It is as yet unclear what role these mutations
have in amyloidogenesis. While deposition of A@ is
found in individuals with a normal APP gene, it seems
likely that genetic defects in the precursor protein can
not only initiate and/or accelerate amyloid formation,
but also specify the tissue localization of the deposits.
This work was supported by the National Institutes of Health grants
AG05891, AM8721 (to B. F.), M 0 1 RR 00645-1931 (to K. M.),
and the Alzheimer’s Disease and Related Disorders Association,
grant llRG-89-112 (to E. L.).
We thank Fran Hitchcock for manuscript preparation.
Annals of Neurology Vol 30 No 5 November 1991
1. Luyendijk W, Bots GThAM, Vegtrr-van der Vlis M, Went LN,
Frangione B. Hereditary cerebral haemorrhage caused by o r t i cal amyloid angioparhy. J Neurol Sci 1988;85:266-280
2. Timmers W, Tagliavini F, Haan J, Frangione B. Parenchymal
preamyloid and amyloid deposits in the brains of patients with
hereditary cerebral hemorrhage with amyloidosis-Dutch type.
Neurosci Lett 1990;118:223-226
3. Van Duinen SG, Castaiio EM, Prelli F, Bots GThAM, Luyendijk W, Frangione B. Hereditary cerebral hemorrhage with m y loidasis in patients of Dutch origin is related to Alzheimer disease. Proc Natl Acad Sci USA 1987;84:5991-5994
4. Coria F, CastaAo EM, Frangione B. Brain amyloid in normal
aging and cerebral amyloid angiopathy is antigenically related to
Alzheimer’s disease beta-protein. Am J Pathol 1987;129:422-
5. Kang j, Lemaire HG, Unterbeck A, et al. The precursor of
Alzheimer’s disease amyloid A4 protein resembles cell surface
receptor. Nature 1987;325 :733- 7 36
6. Levy E, Carman MD, Fernandez-Madrid I, et al. Mutation of
the Alzheimer’s disease amyloid gene in hereditary cerebral
hemorrhage, Dutch type. Science 1990;248:1124-1 126
7. Prelli F, Levy E, van Duinen SG, Bots GThAM, Luyendijk W,
Frangione B. Expression of a normal and variant Alzheimer’s
beta-protein gene in amyloid of hereditary cerebral hemorrhage,
Dutch type, DNA and protein diagnostic assays. Biochem Biophys Res Commun 1990;170:301-307
Blin N, Stafford DW. A general method for isolation of high
molecular weight DNA from eukaryotes. Nucleic Acids Res
Saiki RK, Gelfand D H , Stoffel S, et al. Primer-directed enzymatic amplificationof DNA with a thermostable DNA polymerase. Science 1988;239:487-491
Lemaire HG, SalbaumJM, Multhaup G, et al. The PreA4 (695)
precursor protein of Alzheimer’s disease A4 amyloid is encoded
by 16 exons. Nucleic Acids Res 1987;17:517-522
Vinters HV. Cerebral amyloid angioparhy: a critical review.
Stroke 1987;18:311-324
Ghiso J, Jensson 0, Frangione B. Amyloid fibrils in hereditary
cerebral hemorrhage with amyloidosis of Icelandic type is a variant of gamma-trace basic protein (cystatin C ) . Proc Natl Acad
Sci USA 1986;83:2974-2978
Levy E, Lopez-Orin C , Ghiso J, Geltner D, Frangione B. Stroke
in Icelandic patients with hereditary amyloid angiopathy is related to a mutation in the cystatin C gene, an inhibitor of cysreine proteases. J Exp Med 1989;169:1771-1778
Haan J, Roos RAC, Brier PE, Herpers MJHM, Luyendijk W,
Dots GThAM. Hereditary cerebral hemorrhage wlth amyloidosis-Dutch type. Clin Neurol Neurosurg 1989;91:285290
Kalyan-Raman UP, Kalyan-Raman K. Cerebral amyloid angiopathy causing intracranial hemorrhage. Ann Neurol 1984;
Haan J, Alga PR, Roos RAC. Hereditary cerebral hemorrhage
with amyloidosis-Dutch type. Arch Neurol 1990;47:649-653
Bakker E, van Broeckhoven C , Haan J, et al. DNA diagnosis
for hereditary cerebral hemorrhage with amyloidosis (Dutch
type). Am J Hum Genet 1991 (in press)
Goate A, Chartier-Harlin M-C, Mullan M, et al. Segregation of
a missense mutation in the amyloid precursor protein gene with
familial Alzheimer’s disease. Nature 1991;349:704-706
Brief Communication: Fernandez-Madrid et al: C o d o n 618 Variant of APP G e n e
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