Clinid
Ne_udo,q~ cmclNeuro.wrgery,
@ 1992
Elsevier Science Publishers B.V. All rights reserved 0303-8467/92/s 05.00
94 (1992) 3 17.-318
317
CLINEU 00214
Case report
Progressive dementia, without cerebral hemorrhage, in a patient with hereditary cerebral amyloid angiopathy J. HaarPd,‘, E . Bakker’,‘, A. Jennekens-Schinkel’ Departments
of’ “Nwrology,
hHumun
dDepurtment
and R.A.C. ROOF’
Genetics, and ‘h’europ,v~‘~hnl(~g~~, L%ziwrsit~~ Hospital
qf‘ Newdog>: St. Elisaheth
Hospitd.
Leiderdorp,
Leiden.
Leiden.
The Nrtlrrrlmds.
cm/
The Netherl~mu”;
(Received I2 June. 1992) (Revised version received 22 June, 1992) (Accepted 22 June, 1992) Key
words:
Hereditary heimer’s
cerebral
hemorrhage
with amyloidosis,
Dutch
type:
Amyloid
angiopathy:
Dementia;
Alz-
disease
Summary A now 58-year-old female patient, causes hereditary cerebral hemorrhage
carrier of the point-mutation in the fl-amyloid gene on chromosome 21 which with amyloidosis - Dutch type, developed progressive dementia after the age of
55 years. She never suffered from a cerebral hemorrhage. Dementia has been described as a feature of hereditary amyloid angiopathy before, but only in patients who also suffer from strokes. The clinical manifestation of the patient described here underlines the relation between the Dutch type of hereditary amyloid angiopathy and (familial) Alzheimer’s disease.
Introduction The autosomal
Until recently, the diagnosis of HCHWA-D could only be posed with certainty histologically, the diagnosis dominant
disorder
called
hereditary
cerebral hemorrhage with amyloidosis - Dutch type (SCHWA-D} is characterized by recurrent strokes. caused
by widespread
severe amyloid
angiopathy
[l-2].
being probable in a patient from a HCHWA-D family, who suffered from a stroke at a relatively young age. The disease is caused by a point-mutation in the ~-amyIoid gene on chromosome 21 [4,5], which led to the develop-
In addition to the focal neurological abnormalities, many patients become demented in a stepwise fashion [3]. Some patients, however, also show a slowly progres-
ment of a diagnostic test [6]. Persons who are 50% at risk can now be detected as carriers of the point-mutation, and can be followed-up. Here, we describe the clinical
sive cognitive deterioration between the strokes [3]. The question remained whether the dementia was caused by multiple strokes or by another effect of amyloid angio-
history of a carrier of HCHWA-D the disease, unreported before.
with a presentation
of
pathy on the brain. Patient ‘Members of the Research Group on HCHWA-D. Correspon&ncc to: R.A.C. Roos, MD. PhD, Department of Neurology. Academic Hospital, P.O. Box 9600. 2300 RC Leiden, The Netherlands. Tel.: (71) 262117: Fax: (71) 154537.
In 1989 a 58-year-old patient was referred to the outpatient clinic because of a slowly progressive cognitive
deterioration that had started at the age of 55. She had been suffering from psychotic periods since her youth, treated with several antipsychotics. She had agorophobia, was unable to keep the household, and became dizzy when lying on her left side. According to her husband she showed gradual impairment of memory since several years, making her unable to go shopping, to find the way back home and, occasionally, to remember the names of her children. She had never been suffering from hypertension. No acute focal neurological signs were ever noticed. Her mother died at the age of 45 from recurrent cerebral hemorrhages caused by HCHWA-D. making our patient 50% at risk for the disease. Neurological examination showed no abnormalities. Extensive laboratory investigation including a search for thyroid dysfunction, vitamin-deficiencies and veneral diseases was unremarkable. Neuropsychological examination (in 1989) revealed impaired memory (a memory quotient of 74 on the Wechsler memory scale, with an estimated premorbid memory quotient of 90- 100) and intelligence (Wechsler adult intelligence scale intelligence quotient 65, against an estimated previously low average intelligences. CT-scan of the brain showed cortical atrophy and hypodensity of the white matter (‘leukoaraiosis’). The patient was followed-up in the out-patient clinic and on each visit her husband complained of further deterioration of memory. A second neuropsychoiogical investigation (1991) confirmed this: although her overall intelligence was almost unchanged (WAIS IQ 68) her memory clearly had further deteriorated (Wechsler memory scale memory quotient of 64). A repeat CT-scan showed no unequivocal progression of changes. The presence of the point-mutation in the ~-amyloid gene on chromosome 21 (investigated with informed consent of the patient and her husband) was proven, making it most likely that all her symptoms are caused by cerebral amyloid angiopathy.
Discussion The history of this patient is remarkable because firstly, it is the first carrier of the HCHWA-D point-mutation who was prospectively followed up for several years, and secondly, progressive dementia could be documented, without any other cause for this dementia. Slowly progressive dementia and white matter hypodensity have been described as features of HCHWA-D, but only in the presence of strokes [l-3]. Although in our
case the presence of amyloid angiopathy can only be proven post-mortem. all manifestations point at the prcsence of amyloid angiopathy. Consequently, the clinical spectrum of HCHWA-D can be enlarged: also slowly progressive dementia, without strokes. can be present. In Alzheimer’s disease the deposition of p-protein in the form of amyloid probably also plays an important role [7]. Recently, a point-mutation was found in familial Alzheimer’s disease in the region of the @-amyloid gene on chromosome 21 where the HCHWA-D mutation is also present [g]. The history of our patient confirms that an altered gene-product of the p-amyloid gene can lead to slowly progressive presenile dementia, It confirms that HCHWA-D is not only a possible model for presumed abnormal proteolytic processes occurring in Alzheimer’s disease. but in some cases probably also for the clinical and radiological features of the disease 191.
References Haan, J., Algra, P.R. and Roos, R.A.C. (I 990) Hereditary cerebral hemorrhage with amyloidosis - Dutch type: clinical and CT analysis of 24 cases. Arch. Neural., 47: 649-653. Haan, J., Roos, R.A.C., AJgra, P.R., Lanser, J.B.K., Bets. G.T.A.M. and Vegter-van der Vlis, M. (1990) Hereditary cerebral hemorrhage with amyloidosis - Dutch type: magnetic resonance imaging findings of seven cases. Brain, 113: 1251-1267. Haan, J., Lanser, J.B.K., Zijderveld, I.. van der Does, I.G.F. and Roos, R.A.C. (1990) Dementia in hereditary cerebral hemorrhage with amyloidosis - Dutch type. Arch. Neurol. 47: 965-967. van Broeckhoven, C., Haan, J., Bakker, E. et al. ( 1990) The genetic defect in hereditary cerebra1 hemorrhage with amyloidosis of Dutch type is tightly iinked to thee-amyloid gene on chromosome 21. Science, 248: 1120-i 122. Levy, E., Carman, M.D., Fernandez-Madrid. I.J. et al. (1990) Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science, 248: t124~1126. Bakker, E., Van Broeckhoven, C., Haan, J. et ai (1992) DNA-diagnosis for hereditary cerebral hemorrhage with amyloidosis (Dutch). Am. J. Hum. Genet., in press. Selkoe. D.J. (1989) Biochemistry of altered brain proteins in Alzheimer’s disease. Annu. Rev. Neurosci., 12: 463490. Goate, A., Chartier-Harhn, M.C. and Mullan, M. et aI. (1991) Segregation of a missense mutation in the amyioid precursor protein gene with familial Alzheimer’s disease. Nature, 349: 704-706. Haan, J.. Hardy, J.A. and Roos, R.A.C. (1991) Hereditary cerebral hemorrhage with amyloidosis - Dutch type: its importance for Alzheimer research. Trends Neurosci.. 14: 23 I-- 234.
Ne_udo,q~ cmclNeuro.wrgery,
@ 1992
Elsevier Science Publishers B.V. All rights reserved 0303-8467/92/s 05.00
94 (1992) 3 17.-318
317
CLINEU 00214
Case report
Progressive dementia, without cerebral hemorrhage, in a patient with hereditary cerebral amyloid angiopathy J. HaarPd,‘, E . Bakker’,‘, A. Jennekens-Schinkel’ Departments
of’ “Nwrology,
hHumun
dDepurtment
and R.A.C. ROOF’
Genetics, and ‘h’europ,v~‘~hnl(~g~~, L%ziwrsit~~ Hospital
qf‘ Newdog>: St. Elisaheth
Hospitd.
Leiderdorp,
Leiden.
Leiden.
The Nrtlrrrlmds.
cm/
The Netherl~mu”;
(Received I2 June. 1992) (Revised version received 22 June, 1992) (Accepted 22 June, 1992) Key
words:
Hereditary heimer’s
cerebral
hemorrhage
with amyloidosis,
Dutch
type:
Amyloid
angiopathy:
Dementia;
Alz-
disease
Summary A now 58-year-old female patient, causes hereditary cerebral hemorrhage
carrier of the point-mutation in the fl-amyloid gene on chromosome 21 which with amyloidosis - Dutch type, developed progressive dementia after the age of
55 years. She never suffered from a cerebral hemorrhage. Dementia has been described as a feature of hereditary amyloid angiopathy before, but only in patients who also suffer from strokes. The clinical manifestation of the patient described here underlines the relation between the Dutch type of hereditary amyloid angiopathy and (familial) Alzheimer’s disease.
Introduction The autosomal
Until recently, the diagnosis of HCHWA-D could only be posed with certainty histologically, the diagnosis dominant
disorder
called
hereditary
cerebral hemorrhage with amyloidosis - Dutch type (SCHWA-D} is characterized by recurrent strokes. caused
by widespread
severe amyloid
angiopathy
[l-2].
being probable in a patient from a HCHWA-D family, who suffered from a stroke at a relatively young age. The disease is caused by a point-mutation in the ~-amyIoid gene on chromosome 21 [4,5], which led to the develop-
In addition to the focal neurological abnormalities, many patients become demented in a stepwise fashion [3]. Some patients, however, also show a slowly progres-
ment of a diagnostic test [6]. Persons who are 50% at risk can now be detected as carriers of the point-mutation, and can be followed-up. Here, we describe the clinical
sive cognitive deterioration between the strokes [3]. The question remained whether the dementia was caused by multiple strokes or by another effect of amyloid angio-
history of a carrier of HCHWA-D the disease, unreported before.
with a presentation
of
pathy on the brain. Patient ‘Members of the Research Group on HCHWA-D. Correspon&ncc to: R.A.C. Roos, MD. PhD, Department of Neurology. Academic Hospital, P.O. Box 9600. 2300 RC Leiden, The Netherlands. Tel.: (71) 262117: Fax: (71) 154537.
In 1989 a 58-year-old patient was referred to the outpatient clinic because of a slowly progressive cognitive
deterioration that had started at the age of 55. She had been suffering from psychotic periods since her youth, treated with several antipsychotics. She had agorophobia, was unable to keep the household, and became dizzy when lying on her left side. According to her husband she showed gradual impairment of memory since several years, making her unable to go shopping, to find the way back home and, occasionally, to remember the names of her children. She had never been suffering from hypertension. No acute focal neurological signs were ever noticed. Her mother died at the age of 45 from recurrent cerebral hemorrhages caused by HCHWA-D. making our patient 50% at risk for the disease. Neurological examination showed no abnormalities. Extensive laboratory investigation including a search for thyroid dysfunction, vitamin-deficiencies and veneral diseases was unremarkable. Neuropsychological examination (in 1989) revealed impaired memory (a memory quotient of 74 on the Wechsler memory scale, with an estimated premorbid memory quotient of 90- 100) and intelligence (Wechsler adult intelligence scale intelligence quotient 65, against an estimated previously low average intelligences. CT-scan of the brain showed cortical atrophy and hypodensity of the white matter (‘leukoaraiosis’). The patient was followed-up in the out-patient clinic and on each visit her husband complained of further deterioration of memory. A second neuropsychoiogical investigation (1991) confirmed this: although her overall intelligence was almost unchanged (WAIS IQ 68) her memory clearly had further deteriorated (Wechsler memory scale memory quotient of 64). A repeat CT-scan showed no unequivocal progression of changes. The presence of the point-mutation in the ~-amyloid gene on chromosome 21 (investigated with informed consent of the patient and her husband) was proven, making it most likely that all her symptoms are caused by cerebral amyloid angiopathy.
Discussion The history of this patient is remarkable because firstly, it is the first carrier of the HCHWA-D point-mutation who was prospectively followed up for several years, and secondly, progressive dementia could be documented, without any other cause for this dementia. Slowly progressive dementia and white matter hypodensity have been described as features of HCHWA-D, but only in the presence of strokes [l-3]. Although in our
case the presence of amyloid angiopathy can only be proven post-mortem. all manifestations point at the prcsence of amyloid angiopathy. Consequently, the clinical spectrum of HCHWA-D can be enlarged: also slowly progressive dementia, without strokes. can be present. In Alzheimer’s disease the deposition of p-protein in the form of amyloid probably also plays an important role [7]. Recently, a point-mutation was found in familial Alzheimer’s disease in the region of the @-amyloid gene on chromosome 21 where the HCHWA-D mutation is also present [g]. The history of our patient confirms that an altered gene-product of the p-amyloid gene can lead to slowly progressive presenile dementia, It confirms that HCHWA-D is not only a possible model for presumed abnormal proteolytic processes occurring in Alzheimer’s disease. but in some cases probably also for the clinical and radiological features of the disease 191.
References Haan, J., Algra, P.R. and Roos, R.A.C. (I 990) Hereditary cerebral hemorrhage with amyloidosis - Dutch type: clinical and CT analysis of 24 cases. Arch. Neural., 47: 649-653. Haan, J., Roos, R.A.C., AJgra, P.R., Lanser, J.B.K., Bets. G.T.A.M. and Vegter-van der Vlis, M. (1990) Hereditary cerebral hemorrhage with amyloidosis - Dutch type: magnetic resonance imaging findings of seven cases. Brain, 113: 1251-1267. Haan, J., Lanser, J.B.K., Zijderveld, I.. van der Does, I.G.F. and Roos, R.A.C. (1990) Dementia in hereditary cerebral hemorrhage with amyloidosis - Dutch type. Arch. Neurol. 47: 965-967. van Broeckhoven, C., Haan, J., Bakker, E. et al. ( 1990) The genetic defect in hereditary cerebra1 hemorrhage with amyloidosis of Dutch type is tightly iinked to thee-amyloid gene on chromosome 21. Science, 248: 1120-i 122. Levy, E., Carman, M.D., Fernandez-Madrid. I.J. et al. (1990) Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science, 248: t124~1126. Bakker, E., Van Broeckhoven, C., Haan, J. et ai (1992) DNA-diagnosis for hereditary cerebral hemorrhage with amyloidosis (Dutch). Am. J. Hum. Genet., in press. Selkoe. D.J. (1989) Biochemistry of altered brain proteins in Alzheimer’s disease. Annu. Rev. Neurosci., 12: 463490. Goate, A., Chartier-Harhn, M.C. and Mullan, M. et aI. (1991) Segregation of a missense mutation in the amyioid precursor protein gene with familial Alzheimer’s disease. Nature, 349: 704-706. Haan, J.. Hardy, J.A. and Roos, R.A.C. (1991) Hereditary cerebral hemorrhage with amyloidosis - Dutch type: its importance for Alzheimer research. Trends Neurosci.. 14: 23 I-- 234.
