Comparison of clinical, familial, and MRI features of CADASIL and NOTCH3-negative patients.
OBJECTIVE
To report the characteristics of patients suspected to have cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) but in whom no NOTCH3 gene pathogenic mutation was found.


METHODS
Between 2002 and 2008, we performed NOTCH3 gene analysis (exons 2-23) in 81 probands because CADASIL was clinically suspected. A retrospective analysis and comparison of clinical, familial, and neuroimaging features of patients with and without pathogenic mutations was performed.


RESULTS
CADASIL was diagnosed in 16/81 (20%) probands by finding a mutation leading to a cysteine substitution within the epidermal growth factor (EGF)-like repeats of the NOTCH3 receptor. In the remaining 65 patients, no pathogenic mutation was found. Some features were significantly (Fisher exact test p < 0.05) more frequent in CADASIL than in NOTCH3-negative patients: history of migraine (73 vs 39%), stroke before the age of 60 among relatives (71 vs 32%), severe leukoencephalopathy (94 vs 62%), white matter changes extended to the anterior temporal lobes (93 vs 45%), external capsule involvement (100 vs 50%), and presence of lacunar infarcts (100 vs 65%). The frequency of vascular risk factors was balanced between the 2 groups. No feature was peculiar to either group.


CONCLUSIONS
Although certain clinical and neuroimaging features are more frequent in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) than in NOTCH3-negative patients, none is pathognomonic. Clinicians should be aware that when diagnosing CADASIL, a number of patients with a cerebral disease phenotypically similar to CADASIL emerge. The genetic profile of these diseases and the full phenotypic difference with CADASIL remain to be further defined.
Pantoni
L
L
Department of Neurological and Psychiatric Sciences, University of Florence, Viale Morgagni 85, 50134 Florence, Italy. pantoni@unifi.it
Pescini
F
F
Nannucci
S
S
Sarti
C
C
Bianchi
S
S
Dotti
M T
MT
Federico
A
A
Inzitari
D
D
D000328:Adult; D000368:Aged; D020520:Brain Infarction / Q000473:pathology; D046589:CADASIL / Q000150:complications / Q000235:genetics / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology / Q000473:pathology; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*; D012189:Retrospective Studies; D012307:Risk Factors; D020521:Stroke / Q000473:pathology
C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch