1. Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1-3 D4Z4 reduced alleles: experience of the FSHD Italian National Registry
- Author
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Francesco Sera, Marta Rossi, Corrado Angelini, Giuliano Tomelleri, Ana Nikolic, Antonio Di Muzio, Elisabetta Bucci, Michelangelo Cao, Luisa Villa, Giovanni Antonini, Giacomo Brisca, Monica Govi, Tiziana Mongini, Sabrina Ravaglia, Angela Berardinelli, Fabiano Mele, Lucia Ruggiero, Claudio Bruno, Lorenzo Maggi, Gabriele Siciliano, Chiara Fiorillo, Liliana Vercelli, Maria Chiara D’Amico, Carmelo Rodolico, Maria Grazia D'Angelo, Lucio Santoro, Elena Pegoraro, Giulia Ricci, Maurizio Moggio, Rossella Tupler, Lucia Morandi, Nikolic, Ana, Ricci, Giulia, Sera, Francesco, Bucci, Elisabetta, Govi, Monica, Mele, Fabiano, Rossi, Marta, Ruggiero, Lucia, Vercelli, Liliana, Ravaglia, Sabrina, Brisca, Giacomo, Fiorillo, Chiara, Villa, Luisa, Maggi, Lorenzo, Cao, Michelangelo, D'Amico, Maria Chiara, Siciliano, Gabriele, Antonini, Giovanni, Santoro, Lucio, Mongini, Tiziana, Moggio, Maurizio, Morandi, Lucia, Pegoraro, Elena, Angelini, Corrado, Di Muzio, Antonio, Rodolico, Carmelo, Tomelleri, Giuliano, D'Angelo, Maria Grazia, Bruno, Claudio, Berardinelli, Angela, and Tupler, Rossella
- Subjects
0301 basic medicine ,Male ,Facioscapulohumeral ,Disease ,Kaplan-Meier Estimate ,Severity of Illness Index ,0302 clinical medicine ,Medicine ,Facioscapulohumeral muscular dystrophy ,genetics ,Muscular Dystrophy ,Registries ,Young adult ,Age of Onset ,Child ,medicine.diagnostic_test ,Medicine (all) ,Microfilament Proteins ,RNA-Binding Proteins ,Nuclear Proteins ,General Medicine ,Middle Aged ,Penetrance ,Muscular Dystrophy, Facioscapulohumeral ,Phenotype ,Neurology ,Italy ,Child, Preschool ,Female ,1-3 D4-Z4 reduced alleles ,Adult ,medicine.medical_specialty ,Adolescent ,Genotype ,Physical examination ,FSHD, D4Z4 repetitive elements, genotype-phenotype correlation, infantile FSHD ,03 medical and health sciences ,Young Adult ,Internal medicine ,Severity of illness ,Humans ,Preschool ,Survival analysis ,Alleles ,FSHD ,Infant ,Infant, Newborn ,business.industry ,Research ,medicine.disease ,Newborn ,030104 developmental biology ,Physical therapy ,Age of onset ,business ,030217 neurology & neurosurgery - Abstract
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.
- Published
- 2016