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Incipient CADASIL
Saskia A. J. Lesnik Oberstein, MD;
Rivka van den Boom, MD;
Huub A. M. Middelkoop, PhD;
Michel D. Ferrari, MD, PhD;
Yvette M. Knaap, MSc;
Hans C. van Houwelingen, PhD;
Martijn H. Breuning, MD, PhD;
Mark A. van Buchem, MD, PhD;
Joost Haan, MD, PhD
Arch Neurol. 2003;60:707-712.
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.
Design Clinical characterization and blinded survey comparing MCs with non-MCs.
Setting Referral center.
Participants 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 strokelike 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.
From the Departments of Human and Clinical Genetics (Drs Lesnik Oberstein and Breuning), Radiology (Drs van den Boom and van Buchem), Neuropsychology (Dr Middelkoop and Ms Knaap), Neurology (Drs Ferrari and Haan), and Medical Statistics (Dr van Houwelingen), Leiden University Medical Center, Leiden, and the Department of Neurology, Rijnland Hospital, Leiderdorp (Dr Haan), the Netherlands.
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