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CADASIL in central Italy: a retrospective clinical and genetic study in 229 patients

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Abstract

The objective of the study is to detail clinical and NOTCH3 gene mutational spectrum in a large group of Italian CADASIL patients. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial cerebral small vessels disease caused by mutations in the NOTCH3 gene on 19p13 usually presenting in young or middle adulthood. Characteristic features include migraine, recurrent lacunar stroke, subcortical dementia, mood disturbances and leukoencephalopathy. The disorder is often overlooked and misdiagnosed. CADASIL prevalence and disease burden is still undetermined. We retrospectively reviewed demographic, clinical, and mutational characteristic of all CADASIL patients diagnosed from January 2002 to December 2012 in three referral centers for neurogenetic and cerebrovascular diseases in central Italy. 229 NOTCH3 positive subjects were identified. Mean age at diagnosis was 57.8 ± 14.7 years, and 48.6 ± 17.1 years at first symptom onset. Most frequent clinical symptoms were ischemic events (59 %) and psychiatric disturbances (48 %). The highest percentage of mutations were found on exons 4 and 19 (20.6 and 17.6 % respectively), the remaining being dispersed over the entire EGF-like region of the NOTCH3 gene. 209 patients resided in a circumscribed geographic area which included three regions of the central Italy, yielding a minimum prevalence of 4.1 per 100.000 adult inhabitants. This is the most extensive study on CADASIL in Italy. Clinical phenotype showed several peculiarities in frequency and presentation of the main disease manifestations. Our study enlarges the number of pathogenic NOTCH3 mutations and due to the heterogeneous mutational spectrum observed suggests that full sequencing of exons 2–24 is mandatory for CADASIL screening in the Italian population.

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Acknowledgments

Pianese L, MD (Molecular Medicine Laboratory, Mazzoni Hospital, ASUR Marche AV5, Ascoli Piceno, Italy); Cozzolino V, MD (Division of Neurology, Mazzoni Hospital, Azienda Sanitaria Unica Regionale, Zona Territoriale 13, Ascoli Piceno, Italy); Donnini I, MD, Rinnoci V, MD (Stroke Unit and Neurology, Azienda Ospedaliero Universitaria Careggi, Florence, Italy); Amato MP, MD, Hakiki B, MD, Sorbi S, MD (Neurologia 1, Azienda Ospedaliero Universitaria Careggi, Florence, Italy); Carlucci G, MD, Massacesi L, MD, (Neurologia 2, Azienda Ospedaliero Universitaria Careggi, Florence, Italy); Buzzi G, MD (Neurologia, Presidio Ospedaliero S. Maria alla Gruccia, Montevarchi, Arezzo, Italy); Rocchi R, MD, Rossi A, MD (UOC Neurologia- Neurofisiologia Clinica, Azienda Ospedaliera Universitaria Santa Maria alle Scotte, Siena, Italy); Orrico A, MD (UO Genetica Medica, Az. USL 9 Grosseto, Italy); Bartalucci M, MD, Pieri S, MD, Plewnia K, MD (UOC Neurologia, Az. USL 9 Grosseto, Italy); Biasi G, MD (DSA Reumatologia, Azienda Ospedaliera Universitaria Santa Maria alle Scotte, Siena, Italy); Mancuso M, MD, Orsucci D, MD, Siciliano G, MD (UO Neurologia- Neurofisiopatologia, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy); Berti C, MD, Bonuccelli U, MD, Salvetti S, MD, Vista M, MD (UOC Neurologia, Az. USL 12 Viareggio, Lucca, Italy); Zolo P, MD (DH Neurologia, Az. ASL 8, Arezzo, Italy); Cei M, MD (UO Medicina Interna 1, Az. USL 6 Livorno, Italy; Donti E, MD, Prontera P, MD (Centro Riferimento Regionale Genetica Medica, Azienda Ospedaliera Universitaria Perugia, Italy); Brunori P, MD, Cantisani T, MD (UOC Neurofisiopatologia, Azienda Ospedaliera Universitaria Perugia, Italy); Nichelli P, MD, Zini A, MD (Neurologia, Nuovo Osp. Civile S. Agostino Estense, Az. USL Modena, Italy); Amabile G, MD, Pirro C, BSc (UOC Neurologia C, Università degli Studi la Sapienza, Roma, Italy); Bomprezzi C, MD, Morresi S, MD, Passarin MG, MD (UO Neurologia, Osp. Bufalini Cesena, Forlì-Cesena, Italy; Montella A, MD, Ulgheri L, MD (Servizio Genetica Clinica, Azienda Ospedaliera Universitaria Sassari, Italy); Minervini L, MD (Servizio Psichiatrico, Az. USL 16 Padova, Italy); Basile AM, MD, Squarzanti F, MD (Cl. Neurologica II, Azienda Ospedaliera Universitaria Padova, Italy); Pugliese N, MD, Toriello A, MD (UOC Neurologia a Indirizzo Riabilitativo, Azienda Ospedaliera Universitaria Ospedali Riuniti S. Giovanni di Dio e Ruggi D’Aragona, Salerno, Italy); De Michele G, MD (Dip. Sc. Neurologiche, Azienda Ospedaliera Universitaria Federico II, Napoli, Italy); Reggio E, MD, Zappia M, MD (Neurologia, Azienda Ospedaliera Universitaria Policlinico Vittorio Emanuele, Catania, Italy). Research in part supported by a grant from MIUR (prot. 20095JPSNA_005), from the Ministry of Health and from Regione Toscana (Regional Health Research Program 2009) and from B.I.M. (Bacino Imbrifero Montano) Tronto (ref. no. 125/AV5; 07/02/2013).

Conflicts of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

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On behalf of all the authors, the corresponding author states that we acted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

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Authors and Affiliations

  1. Department of Medical, Surgical and Neurological Sciences Medical School, University of Siena, Viale Bracci 2, Siena, Italy

    Silvia Bianchi, Enza Zicari, Alessandra Carluccio, Ilaria Di Donato, Antonio Federico & Maria Teresa Dotti

  2. NEUROFARBA Department, Neuroscience Section, University of Florence, Florence, Italy

    Francesca Pescini, Serena Nannucci, Raffaella Valenti, Domenico Inzitari & Leonardo Pantoni

  3. Division of Neurology, Mazzoni Hospital, Azienda Sanitaria Unica Regionale, Zona Territoriale 13, Ascoli Piceno, Italy

    Michele Ragno

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  1. Silvia Bianchi
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  2. Enza Zicari
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  3. Alessandra Carluccio
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  11. Antonio Federico
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  12. Maria Teresa Dotti
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Correspondence to Maria Teresa Dotti.

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Bianchi, S., Zicari, E., Carluccio, A. et al. CADASIL in central Italy: a retrospective clinical and genetic study in 229 patients. J Neurol 262, 134–141 (2015). https://doi.org/10.1007/s00415-014-7533-2

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