Ruggiero, Lucia (2017) INVESTIGATION OF GENETIC AND CLINICAL COMPLEXITY OF FACIOSCAPULOHUMERAL DYSTROPHY: EXPERIENCE OF THE FSHD ITALIAN NATIONAL REGISTRY. [Tesi di dottorato]

Anteprima

Testo Ruggiero_Lucia_30.pdf Download (13MB) | Anteprima

[error in script] [error in script]

Tipologia del documento:	Tesi di dottorato
Lingua:	English
Titolo:	INVESTIGATION OF GENETIC AND CLINICAL COMPLEXITY OF FACIOSCAPULOHUMERAL DYSTROPHY: EXPERIENCE OF THE FSHD ITALIAN NATIONAL REGISTRY
Autori:	Autore Email Ruggiero, Lucia ruggilucia@gmail.com
Data:	10 Dicembre 2017
Numero di pagine:	86
Istituzione:	Università degli Studi di Napoli Federico II
Dipartimento:	dep16
Dottorato:	phd058
Ciclo di dottorato:	30
Coordinatore del Corso di dottorato:	nome email Annunziato, Lucio lannunzi@unina.it
Tutor:	nome email Santoro, Lucio [non definito]
Data:	10 Dicembre 2017
Numero di pagine:	86
Parole chiave:	FSHD, genotype-phenotype correletion, clinical tool, allele size
Settori scientifico-disciplinari del MIUR:	Area 06 - Scienze mediche > MED/26 - Neurologia
Depositato il:	08 Gen 2018 11:22
Ultima modifica:	26 Mar 2019 10:02
URI:	http://www.fedoa.unina.it/id/eprint/12139

Abstract

FSHD, an autosomal dominant disease, has been associated with reduced numbers (<11, alleles ≤41 kb) of D4Z4 repeats at 4q35. However, in the our previuos genetic studies, we observed that 3% of healthy individuals carry D4Z4 reduced alleles (DRA). Moreover, through a large genotype-phenotype study on a cohort of FSHD patients and families, we confirmed that DRAs correspond to several phenotypes with variable severity of the disease. We, also, observed that penetrance is incomplete and that the pattern of inheritance is not always autosomal dominant. The aim of the present study is to test the predictive significance of molecular variations in FSHD. For this, an accurate clinical research has been conducted in collaboration with the Italian Clinical Network for Facioscapulohmeral Muscular Dystrophy (FSHD). A detailed clinical characterization of probands and relatives, the analysis of disease penetrance and the study of inheritance mode in FSHD families from the Italian National Registry for FSHD (INRF) has been personally performed. Initially we investigated patients with 1-3 D4Z4 repeats, which represent the lower extreme of the molecular diagnostic spectrum with the most relavant clinical expression. Notably, our detailed analysis highlighted clinical variability also in this subgroup of patients. These observations have emphasized the concept that the molecular mechanisms leading to disease are still not clear and that the molecular markers proposed for FSHD diagnosis are not predictive of disease precense and/or severity. To dissect these clinical complexity, we designed a new Comprehensive Clinical Evaluation Form (CCEF), a clinical tool useful in describing in a harmonized manner the phenotypic spectrum observed among FSHD families. The CCEF permit to quantify the motor disability and defines clinical categories by the combination of different features: 1) subjects with typical FSHD phenotype (category A), 2) subjects with muscle weakness limited to scapular girdle or facial muscles (category B), 3) asymptomatic/healthy subjects (category C) and 4) subjects presenting clinical features not consistent with the FSHD (category D). Through the use of CCEF we decided to reevaluate the clinical spectrum of 154 proband and 306 relatives carriers of 33-35 kb (7-8 rps) D4Z4 reduced alleles, which represent the higher extreme of the molecular diagnostic spectrum with a wide disease variability This study showed two main aspects: first, the majority of probands carrying 33-35 DRA (53%) had moderate phenotype with partial or mild facial involvement; in contrast about 40% showed a prevalent shoulder girdle impairment or atypical phenotype. Therefore this clinical variability could be confounding for the differential diagnosis between the FSHD and a myopathy presenting with FHSD-like features. Second, the majority of relatives were non penetrant carriers. This result highlighted the necessity of additional parameters to evaluate the risk to develop the desease in relatives and the importance of an accurate genetic counselling. In conclusion in dissecting FSHD clinical complexity it is mandatory to associate clinical scales for the evaluation of the disability degree and a tool for the precise phenotypic classification.

Downloads

Actions (login required)

Modifica documento