Incipient CADASIL.
BACKGROUND
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene. Knowledge of disease expression in young adult NOTCH3 mutation carriers (MCs) is limited.


OBJECTIVE
To characterize clinical, neuropsychological, and radiological status in NOTCH3 MCs younger than 35 years.


METHODS
Clinical characterization and blinded survey comparing MCs with non-MCs.


METHODS
Referral center.


METHODS
Individuals younger than 35 years who were at a 50% risk of a NOTCH3 mutation, from our CADASIL database. Thirteen individuals, from 8 families, met the criteria.


METHODS
Comprehensive clinical, genetic, neuropsychological, and radiological investigations. Magnetic resonance images were scored according to a standardized white matter hyperintensities rating scale.


RESULTS
Six individuals, from 5 families, were MCs. Clinical symptoms consisted of migraine (with aura), stroke, and stroke-like episodes. We did not find evidence for psychiatric disturbances, functional disability, or cognitive dysfunction, compared with non-MCs. Radiologically, a characteristic magnetic resonance imaging lesion pattern emerged for all MCs. This comprised white matter hyperintensities in the anterior temporal lobes, the frontal lobes, and the periventricular frontal caps.


CONCLUSIONS
Migraine (with aura) and stroke can present in NOTCH3 MCs younger than 35 years; however, more importantly, physical function and cognition are intact. Possible subtle cognitive dysfunction needs to be assessed in a larger study. White matter hyperintensities on magnetic resonance imaging are characteristic, and are consistently visualized from the age of 21 years and onward. Awareness of the clinical and radiological features of CADASIL in those younger than 35 years should increase early diagnosis and allow for customized counseling of young adults from families with CADASIL.
Lesnik Oberstein
Saskia A J
SA
Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. S.A.M.J.Lesnik_Oberstein@lumc.nl
van den Boom
Rivka
R
Middelkoop
Huub A M
HA
Ferrari
Michel D
MD
Knaap
Yvette M
YM
van Houwelingen
Hans C
HC
Breuning
Martijn H
MH
van Buchem
Mark A
MA
Haan
Joost
J
D000328:Adult; D015161:Dementia, Multi-Infarct / Q000000981:diagnostic imaging* / Q000453:epidemiology / Q000235:genetics; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D020325:Migraine with Aura / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics; D009483:Neuropsychological Tests; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011859:Radiography; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D012307:Risk Factors; D020521:Stroke / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics
C499374:NOTCH3 protein, human; D011518:Proto-Oncogene Proteins; D000071656:Receptor, Notch3; D011956:Receptors, Cell Surface; D051880:Receptors, Notch