Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (
CADASIL) is a genetically transmitted small vessel disease clinically characterized by
migraine, recurrent subcortical
strokes, and cognitive and
mood disorders. Pathogenic mutations are located on any of the exons of the NOTCH3 gene coding for
epidermal-growth factor (
EGF)-like repeats of the extracellular domain of the
NOTCH3 receptor. Because the gene is large and the mutations cluster on some exons, many laboratories restrict the analysis to these exons. We report the first missense mutation involving exon 24 and causing
CADASIL in a 64-year-old man. The patient was admitted to the hospital for a
loss of consciousness accompanied by profuse sweating. On examination, some parkinsonian features were present. Over the last 4 years, he had developed postural instability and gait disturbances with repeated falls, behavioral disorders, and
cognitive impairment. A diagnostic hypothesis of atypical
parkinsonism had been advanced. The presence of multiple subcortical
lacunar infarcts and
leukoencephalopathy extended to the external capsule on cerebral MRI suggested the presence of
CADASIL. The diagnosis was confirmed by finding a heterozygous mutation leading to a
cysteine substitution on exon 24 of the NOTCH3 gene. One proband's brother, who had progressive gait disturbances, unilateral
action tremor and
bradykinesia, and an asymptomatic niece also resulted affected. This report underlines that when
CADASIL is suspected the genetic analysis should be performed on all the NOTCH3 exons coding for
EGF-like repeats including exon 24 and confirms that
CADASIL may have heterogeneous phenotypes.