Phenotype of a homozygous CADASIL patient in comparison to 9 age-matched heterozygous patients with the same R133C Notch3 mutation.
OBJECTIVE
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.
Tuominen
S
S
Department of Neurology, Turku University Hospital and University of Turku, Finland.
Juvonen
V
V
Amberla
K
K
Jolma
T
T
Rinne
J O
JO
Tuisku
S
S
Kurki
T
T
Marttila
R
R
Pöyhönen
M
M
Savontaus
M L
ML
Viitanen
M
M
Kalimo
H
H
D000328:Adult; D001158:Arteries / Q000473:pathology / Q000648:ultrastructure; D001706:Biopsy; D001783:Blood Flow Velocity / Q000235:genetics; D001921:Brain / Q000098:blood supply / Q000000981:diagnostic imaging / Q000473:pathology; D004252:DNA Mutational Analysis; D015161:Dementia, Multi-Infarct / Q000175:diagnosis* / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005387:Finland; D005799:Genes, Dominant; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009483:Neuropsychological Tests; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D012720:Severity of Illness Index; D012867:Skin / Q000098:blood supply / Q000473:pathology; D014055:Tomography, Emission-Computed
C499374:NOTCH3 protein, human; D011518:Proto-Oncogene Proteins; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface; D051880:Receptors, Notch