Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1–3 D4Z4 reduced alleles: experience of the FSHD Italian National Registry
Objectives Facioscapulohumeral muscular dystrophy type 1 (FSHD1) has been genetically linked to reduced numbers (≤8) of D4Z4 repeats at 4q35. Particularly severe FSHD cases, characterised by an infantile onset and presence of additional extra-muscular features, have been associated with the shortest...
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2016-01-01
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| author | Antonio Di Muzio Corrado Angelini Tiziana Mongini Liliana Vercelli Lucia Morandi Giovanni Antonini Gabriele Siciliano Lucio Santoro Maurizio Moggio Giacomo Brisca Luisa Villa Giuliano Tomelleri Francesco Sera Carmelo Rodolico Lorenzo Maggi Giulia Ricci Angela Berardinelli Elena Pegoraro Sabrina Ravaglia Chiara Fiorillo Michelangelo Cao Rossella Tupler Ana Nikolic Elisabetta Bucci Monica Govi Fabiano Mele Marta Rossi Lucia Ruggiero Maria Chiara D'Amico Maria Grazia D'Angelo Claudio Bruno |
| author_facet | Antonio Di Muzio Corrado Angelini Tiziana Mongini Liliana Vercelli Lucia Morandi Giovanni Antonini Gabriele Siciliano Lucio Santoro Maurizio Moggio Giacomo Brisca Luisa Villa Giuliano Tomelleri Francesco Sera Carmelo Rodolico Lorenzo Maggi Giulia Ricci Angela Berardinelli Elena Pegoraro Sabrina Ravaglia Chiara Fiorillo Michelangelo Cao Rossella Tupler Ana Nikolic Elisabetta Bucci Monica Govi Fabiano Mele Marta Rossi Lucia Ruggiero Maria Chiara D'Amico Maria Grazia D'Angelo Claudio Bruno |
| author_sort | Antonio Di Muzio |
| collection | DOAJ |
| description | Objectives Facioscapulohumeral muscular dystrophy type 1 (FSHD1) has been genetically linked to reduced numbers (≤8) of D4Z4 repeats at 4q35. Particularly severe FSHD cases, characterised by an infantile onset and presence of additional extra-muscular features, have been associated with the shortest D4Z4 reduced alleles with 1–3 repeats (1–3 DRA). We searched for signs of perinatal onset and evaluated disease outcome through the systematic collection of clinical and anamnestic records of de novo and familial index cases and their relatives, carrying 1–3 DRA.Setting Italy.Participants 66 index cases and 33 relatives carrying 1–3 DRA.Outcomes The clinical examination was performed using the standardised FSHD evaluation form with validated inter-rater reliability. To investigate the earliest signs of disease, we designed the Infantile Anamnestic Questionnaire (IAQ). Comparison of age at onset was performed using the non-parametric Wilcoxon rank-sum or Kruskal-Wallis test. Comparison of the FSHD score was performed using a general linear model and Wald test. Kaplan-Meier survival analysis was used to estimate the age-specific cumulative motor impairment risk.Results No patients had perinatal onset. Among index cases, 36 (54.5%) showed the first signs by 10 years of age. The large majority of patients with early disease onset (26 out of 36, 72.2%) were de novo; whereas the majority of patients with disease onset after 10 years of age were familial (16, 53.3%). Comparison of the disease severity outcome between index cases with age at onset before and over 10 years of age, failed to detect statistical significance (Wald test p value=0.064). Of 61 index cases, only 17 (27.9%) presented extra-muscular conditions. Relatives carrying 1–3 DRA showed a large clinical variability ranging from healthy subjects, to patients with severe motor impairment.Conclusions The size of the D4Z4 allele is not always predictive of severe clinical outcome. The high degree of clinical variability suggests that additional factors contribute to the phenotype complexity. |
| format | Article |
| id | doaj-art-3ecd41d69cac4927bcaa1a83ca575fd1 |
| institution | Kabale University |
| issn | 2044-6055 |
| language | English |
| publishDate | 2016-01-01 |
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| spelling | doaj-art-3ecd41d69cac4927bcaa1a83ca575fd12025-02-01T19:10:10ZengBMJ Publishing GroupBMJ Open2044-60552016-01-016110.1136/bmjopen-2015-007798Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1–3 D4Z4 reduced alleles: experience of the FSHD Italian National RegistryAntonio Di Muzio0Corrado Angelini1Tiziana Mongini2Liliana Vercelli3Lucia Morandi4Giovanni Antonini5Gabriele Siciliano6Lucio Santoro7Maurizio Moggio8Giacomo Brisca9Luisa Villa10Giuliano Tomelleri11Francesco Sera12Carmelo Rodolico13Lorenzo Maggi14Giulia Ricci15Angela Berardinelli16Elena Pegoraro17Sabrina Ravaglia18Chiara Fiorillo19Michelangelo Cao20Rossella Tupler21Ana Nikolic22Elisabetta Bucci23Monica Govi24Fabiano Mele25Marta Rossi26Lucia Ruggiero27Maria Chiara D'Amico28Maria Grazia D'Angelo29Claudio Bruno3014Center for Neuromuscular Disease, University ‘G d`Annunzio’, Chieti, Italy15IRCCS S Camillo, Lido di Venezia, Italy10 Department of Neurosciences Rita Levi Montalcini, Università degli Studi di Torino, Torino, Piemonte, Italy7Department of Neurosciences “Rita Levi Montalcini”, University of Turin, Turin, Italy12IRCCS Foundation, C Besta Neurological Institute, Milan, ItalyUnit of Neuromuscular Diseases, Department of Neurology Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, `Sapienza` University of Rome, Sant`Andrea Hospital, Rome, Italy2Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa, Pisa, ItalyDipartimento di Neuroscienze, Scienze Riproduttive ed Odontostomatologiche, Università Federico II di Napoli, Napoli, Italy5 Neuromuscular and Rare Disease Unit, Department of Neuroscience, IRCCS Foundation Ca` Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy8 Pediatric Emergency Department, Giannina Gaslini Children’s Hospital, Genoa, Italy4Universidade de São Paulo and Instituto do Cancer do Estado de São Paulo, Faculdade De Medicina, São Paulo, Brazil17Department of Neurological and Movement Sciences, University of Verona, Verona, Italyassociate professor16Department of Neurosciences, University of Messina, Messina, Italy1 Neuroimmunology and Neuromuscular Disease Unit, Foundation IRCCS Carlo Besta Neurological Institute, Milano, Italy4 Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy21 Department of Child Neuropsychiatry, Fondazione Istituto Neurologico Nazionale C Mondino Istituto di Ricovero e Cura a Carattere Scientifico, Pavia, Lombardia, ItalyDepartment of Neurosciences, University of Padova, Padova, Italy8Department of Public Health and Neurosciences, University of Pavia, Pavia, Italy10Department of Molecular Medicine and Neuromuscular Disorders, IRCCS Institute Stella Maris, Pisa, Italy13Department of Neurosciences, University of Padua, Padua, Italy1Department of Science of Life, Institute of Biology, University of Modena and Reggio Emilia, Modena, Italy1Department of Science of Life, Institute of Biology, University of Modena and Reggio Emilia, Modena, Italy4Department of Neurology, S Andrea Hospital, Mental Health and Sensory Organs (NESMOS), University of Rome ‘Sapienza’, Rome, Italy1Department of Science of Life, Institute of Biology, University of Modena and Reggio Emilia, Modena, Italy1Department of Science of Life, Institute of Biology, University of Modena and Reggio Emilia, Modena, Italy5Department of Child Neurology and Psychiatry, IRCCS Institute ‘C Mondino’ Foundation, Pavia, Italy6Department of Neurosciences and Reproductive and Odontostomatologic Sciences, University Federico II, Naples, Italy14Center for Neuromuscular Disease, University ‘G d`Annunzio’, Chieti, Italy18Department of Neurorehabilitation, IRCCS Institute Eugenio Medea Ca’ Granada Ospedale Maggiore, Bosisio Parini, ItalyCenter of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Genoa, ItalyObjectives Facioscapulohumeral muscular dystrophy type 1 (FSHD1) has been genetically linked to reduced numbers (≤8) of D4Z4 repeats at 4q35. Particularly severe FSHD cases, characterised by an infantile onset and presence of additional extra-muscular features, have been associated with the shortest D4Z4 reduced alleles with 1–3 repeats (1–3 DRA). We searched for signs of perinatal onset and evaluated disease outcome through the systematic collection of clinical and anamnestic records of de novo and familial index cases and their relatives, carrying 1–3 DRA.Setting Italy.Participants 66 index cases and 33 relatives carrying 1–3 DRA.Outcomes The clinical examination was performed using the standardised FSHD evaluation form with validated inter-rater reliability. To investigate the earliest signs of disease, we designed the Infantile Anamnestic Questionnaire (IAQ). Comparison of age at onset was performed using the non-parametric Wilcoxon rank-sum or Kruskal-Wallis test. Comparison of the FSHD score was performed using a general linear model and Wald test. Kaplan-Meier survival analysis was used to estimate the age-specific cumulative motor impairment risk.Results No patients had perinatal onset. Among index cases, 36 (54.5%) showed the first signs by 10 years of age. The large majority of patients with early disease onset (26 out of 36, 72.2%) were de novo; whereas the majority of patients with disease onset after 10 years of age were familial (16, 53.3%). Comparison of the disease severity outcome between index cases with age at onset before and over 10 years of age, failed to detect statistical significance (Wald test p value=0.064). Of 61 index cases, only 17 (27.9%) presented extra-muscular conditions. Relatives carrying 1–3 DRA showed a large clinical variability ranging from healthy subjects, to patients with severe motor impairment.Conclusions The size of the D4Z4 allele is not always predictive of severe clinical outcome. The high degree of clinical variability suggests that additional factors contribute to the phenotype complexity.https://bmjopen.bmj.com/content/6/1/e007798.full |
| spellingShingle | Antonio Di Muzio Corrado Angelini Tiziana Mongini Liliana Vercelli Lucia Morandi Giovanni Antonini Gabriele Siciliano Lucio Santoro Maurizio Moggio Giacomo Brisca Luisa Villa Giuliano Tomelleri Francesco Sera Carmelo Rodolico Lorenzo Maggi Giulia Ricci Angela Berardinelli Elena Pegoraro Sabrina Ravaglia Chiara Fiorillo Michelangelo Cao Rossella Tupler Ana Nikolic Elisabetta Bucci Monica Govi Fabiano Mele Marta Rossi Lucia Ruggiero Maria Chiara D'Amico Maria Grazia D'Angelo Claudio Bruno Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1–3 D4Z4 reduced alleles: experience of the FSHD Italian National Registry BMJ Open |
| title | Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1–3 D4Z4 reduced alleles: experience of the FSHD Italian National Registry |
| title_full | Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1–3 D4Z4 reduced alleles: experience of the FSHD Italian National Registry |
| title_fullStr | Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1–3 D4Z4 reduced alleles: experience of the FSHD Italian National Registry |
| title_full_unstemmed | Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1–3 D4Z4 reduced alleles: experience of the FSHD Italian National Registry |
| title_short | Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1–3 D4Z4 reduced alleles: experience of the FSHD Italian National Registry |
| title_sort | clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1 3 d4z4 reduced alleles experience of the fshd italian national registry |
| url | https://bmjopen.bmj.com/content/6/1/e007798.full |
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