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(Stroke. 2001;32:1767.)
© 2001 American Heart Association, Inc.

Original Contributions

Phenotype of a Homozygous CADASIL Patient in Comparison to 9 Age-Matched Heterozygous Patients With the Same R133C Notch3 Mutation

Susanna Tuominen, MD; Vesa Juvonen, MSc; Kaarina Amberla, MSc; Tapani Jolma, MD; Juha O. Rinne, MD, PhD; Seppo Tuisku, MD; Timo Kurki, MD, PhD; Reijo Marttila, MD, PhD; Minna Pöyhönen, MD, PhD; Marja-Liisa Savontaus, PhD; Matti Viitanen, MD, PhD Hannu Kalimo, MD, PhD

From the Departments of Neurology (S.T., R.M.), Radiology (T.K.), and Pathology (H.K.), Turku University Hospital and University of Turku (Finland); Department of Medical Genetics, University of Turku (Finland) (V.J., M-L.S.); Division of Geriatric Medicine, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden (K.A., M.V.); Department of Neurology, Satakunta Central Hospital, Pori, Finland (T.J.); Turku PET Center (Finland) (J.O.R.); Department of Neurology, Keski-Pohjanmaa Central Hospital, Kokkola, Finland (S.T.); and Department of Medical Genetics, Family Federation of Finland, Helsinki (M.P.). Drs Tuominen and Juvonen have contributed equally to this study.

Correspondence to Hannu Kalimo, MD, Turku University Hospital and University of Turku, Department of Pathology, FIN-20520 Turku, Finland. E-mail hkalimo{at}utu.fi

Background and Purpose—— CADASIL is an autosomal dominant arteriopathy, characterized by multiple brain infarcts, cognitive decline, and finally dementia, which is caused by mutations in Notch3 gene encoding a Notch3 receptor protein. We describe the clinical, neuropsychological, imaging, genetic, and skin biopsy findings in a CADASIL patient homozygous for the C475T mutation resulting in R133C amino acid substitution, in comparison to 9 age-matched heterozygous patients with the same mutation.

Methods—— The patients were examined clinically and neuropsychologically and with MRI and positron emission tomography for assessment of cerebral blood flow. The gene defect was analyzed by sequencing the products of polymerase chain reaction of exons 3 and 4 of the Notch3 gene. Dermal arteries were analyzed electron microscopically.

Results—— The homozygous patient had his first-ever stroke at age 28 years. This is markedly earlier than the average, but the patient’s heterozygous son had his first transient ischemic attack–like episode at the same age and another heterozygous patient had his first-ever stroke when only 2 years older. He was neuropsychologically more severely deteriorated than all but 1 of the heterozygous patients. These 2 patients had the most severe (confluent grade D) white matter MRI changes. Positron emission tomography showed markedly reduced cerebral blood flow. Skin biopsy revealed profuse deposits of granular osmiophilic material. The progression of disease in the homozygous case was, however, slower than in the most severely affected heterozygous patient.

Conclusions—— Our homozygous patient’s phenotype is within the clinical spectrum of CADASIL, although at its severe end. Thus, CADASIL may follow the classic definition of a dominant disease, according to which the heterozygous and homozygous patients are clinically indistinguishable.

Key Words: CADASIL • dementia, vascular • homozygote • magnetic resonance imaging • neuropsychological tests • tomography, emission computed

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