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First evidence of a pathogenic insertion in the NOTCH3 gene causing CADASIL
  1. R Mazzei1,
  2. D Guidetti2,
  3. C Ungaro1,
  4. F L Conforti1,
  5. M Muglia1,
  6. G Cenacchi3,
  7. P L Lanza1,
  8. A Patitucci1,
  9. T Sprovieri1,
  10. P Riguzzi4,
  11. A Magariello1,
  12. A L Gabriele1,
  13. L Citrigno1,
  14. P Preda5,
  15. A Quattrone1,6
  1. 1
    Institute of Neurological Sciences, National Research Council, Piano Lago di Mangone, Cosenza, Italy
  2. 2
    UOC di Neurologia, Ospedale Guglielmo da Saliceto di Piacenza, Italy
  3. 3
    Department of Radiological and Istocytopathological Sciences, Section of Pathology, University of Bologna, Italy
  4. 4
    Unitè Operativa di Neurologia, Ospedale Belluria di Bologna, Italy
  5. 5
    UO di Anatomia ed Istologia Patologica, Ospedale Sant’Orsola di Bologna, Italy
  6. 6
    Institute of Neurology, University Magna Graecia, Catanzaro, Italy
  1. Dr Rosalucia Mazzei, Istituto di Scienze Neurologiche CNR, Loc. Burga-87050 Piano Lago di Mangone (CS), Italy; r.mazzei{at}isn.cnr.it

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CADASIL (OMIM 125310) is an increasingly recognised adult-onset autosomal-dominant vascular disease that is characterised by recurrent transient ischaemic attacks and strokes (43% of patients), vascular dementia (6%), migraine with aura (40% of patients) and psychiatric disturbances (9% of patients); epilepsy has been reported in 2–10% of subjects.1 All patients revealed prominent signal abnormalities on brain magnetic resonance imaging (MRI)—leukoencephalopathy on T2- and small subcortical infarcts on T1-weighted images.2

The pathological hallmark of CADASIL is a non-amyloid and non-arteriosclerotic angiopathy, which predominantly affects the small penetrating brain arteries. Vascular lesions are characterised by degeneration and loss of smooth-muscle cells and by the presence of granular osmiophilic material (GOM) accumulating within the smooth-muscle-cell basement membrane and the surrounding extracellular matrix. Examination of several peripheral organs revealed vessel changes, including the presence of GOM deposits, providing evidence that CADASIL is a systemic arteriopathy.3

It has been reported that CADASIL is caused by single missense mutations, small in-frame deletions or splice-site mutations in the NOTCH3 gene encoding a transmembrane receptor (http://www.hgmd.cf.ac.uk/ac/gene.php?gene = NOTCH3). Almost all previously reported mutations resulted in an odd number of cysteine residues within one of the 34 epidermal growth factor (EGF)-like repeats in the …

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