LAUSR

Dear Editor, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary vascular disease characterized by five main neurological manifestations: migraine with aura, recurrent subcortical ischemic infarctions, mood disturbances, apathy, and cognitive impairment, usually in absence of vascular risk factors. Subcortical signal abnormalities on magnetic resonance imaging (MRI) are the hallmarks of the pathology, detectable as early as 20 and always present after 35 years of age in affected people. Diagnosis of CADASIL is confirmed through the identification of mutations in the NOTCH3 gene (exons 2/24) affecting the number of cysteine residues. The disorder is inherited in an autosomal dominant fashion with wide expressivity within families [1]. Here, we describe an Italian family with a new variant identified in exon 6 of NOTCH3 gene and affected by a CADASIL form characterized by a mild symptomatology. A 41-year-old female patient presented to the emergency room because of severe pulsating right-sided headache that disappeared in 48 h after painkilling therapy. Seven years before, she reported a similar attack characterized bymoderate continuous diffuse pressing headache for about 1 month. Later, she referred with a monthly frequency of a tensiontype headache attack lasting about 12 hours, responsive to painkilling therapy. She had neither history of hypertension or smoking, nor a family history for stroke, dementia, or headache; the 68-year-old father and the 62-year-old mother were healthy, as well as her two younger sisters. Clinical, neurological, and neuropsychological examinations on the proband were normal. Brain CT showed multiple areas of hypodensity in the cerebral bilateral white matter. Brain MRI showed in long TR-weighted images multiple hyperintensities with a nearly symmetrical involvement in the periventricular and subcortical white matter, more evident in the subcortical anterior temporal white matter and in the external capsule (Fig. 1a, b); GRE-T2-weighted images showed one microbleed in the right pallidus nucleus (Fig. 1c). A diagnosis of CADASILwas suspected and the molecular analysis of exons 2/24 of the NOTCH3 gene was performed. The genetic test was offered during genetic counseling and after the signing of the informed consent approved by the local Ethics Committee. Direct Sanger sequencing was performed on both strands on an automated 3730 DNA Analyzer (Applied Biosystems). DNA sequences were analyzed by Sequencing Analysis V5.2 and SeqScape V2.5 softwares (Applied Biosystems). Direct sequencing identified in exon 6 the presence in the heterozygous state of the variant c.971_973delinsGTGCCACACCTGTGGCAG (p.Phe324_His325delinsCysAlaThrProValAlaAsp) (Fig. 2) which causes a gain of a cysteine residue in the EGF-like 8 domain of the protein and the insertion of other six amino acid residues. The presence of the mutation in the proband was confirmed on a second DNA sample. The variant is novel, since it is not reported in various public genetic databases (Human Genome Mutation Database, Leiden Open Variation Database, ExAC browser), and follows the stereotypical nature of most NOTCH3 causative mutations. Silvana Penco died before publication of this work was completed.