title: Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1-3 D4Z4 reduced alleles: experience of the FSHD Italian National Registry.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Italy.
  
  
  METHODS
  66 index cases and 33 relatives carrying 1-3 DRA.
  
  
  RESULTS
  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.
authors.affiliation: Department of Science of Life, Institute of Biology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Ana
authors.initials: A
authors.lastname: Nikolic
authors.affiliation: Department of Science of Life, Institute of Biology, University of Modena and Reggio Emilia, Modena, Italy Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa, Pisa, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Ricci
authors.affiliation: MRC Centre of Epidemiology for Child Health, UCL Institute of Child Health, London, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sera
authors.affiliation: Department of Neurology, S Andrea Hospital, Mental Health and Sensory Organs (NESMOS), University of Rome 'Sapienza', Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bucci
authors.affiliation: Department of Science of Life, Institute of Biology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Govi
authors.affiliation: Department of Science of Life, Institute of Biology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Fabiano
authors.initials: F
authors.lastname: Mele
authors.affiliation: Department of Child Neurology and Psychiatry, IRCCS Institute 'C Mondino' Foundation, Pavia, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Department of Neurosciences and Reproductive and Odontostomatologic Sciences, University Federico II, Naples, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Ruggiero
authors.affiliation: Department of Neurosciences "Rita Levi Montalcini", University of Turin, Turin, Italy.
authors.forename: Liliana
authors.initials: L
authors.lastname: Vercelli
authors.affiliation: Department of Public Health and Neurosciences, University of Pavia, Pavia, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ravaglia
authors.affiliation: Department of Muscular and Neurodegenerative Disease, IRCCS Institute Giannina Gaslini, Genoa, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Brisca
authors.affiliation: Department of Molecular Medicine and Neuromuscular Disorders, IRCCS Institute Stella Maris, Pisa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fiorillo
authors.affiliation: IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Villa
authors.affiliation: IRCCS Foundation, C Besta Neurological Institute, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Maggi
authors.affiliation: Department of Neurosciences, University of Padua, Padua, Italy.
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Cao
authors.affiliation: Center for Neuromuscular Disease, University 'G d'Annunzio', Chieti, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: D'Amico
authors.affiliation: Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa, Pisa, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Siciliano
authors.affiliation: Department of Neurology, S Andrea Hospital, Mental Health and Sensory Organs (NESMOS), University of Rome 'Sapienza', Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Antonini
authors.affiliation: Department of Neurosciences and Reproductive and Odontostomatologic Sciences, University Federico II, Naples, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Santoro
authors.affiliation: Department of Neurosciences "Rita Levi Montalcini", University of Turin, Turin, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mongini
authors.affiliation: IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Moggio
authors.affiliation: IRCCS Foundation, C Besta Neurological Institute, Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Morandi
authors.affiliation: Department of Neurosciences, University of Padua, Padua, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Pegoraro
authors.affiliation: IRCCS S Camillo, Lido di Venezia, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Angelini
authors.affiliation: Center for Neuromuscular Disease, University 'G d'Annunzio', Chieti, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Muzio
authors.affiliation: Department of Neurosciences, University of Messina, Messina, Italy.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Rodolico
authors.affiliation: Department of Neurological and Movement Sciences, University of Verona, Verona, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Tomelleri
authors.affiliation: Department of Neurorehabilitation, IRCCS Institute Eugenio Medea Ca' Granada Ospedale Maggiore, Bosisio Parini, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Grazia D'Angelo
authors.affiliation: Department of Muscular and Neurodegenerative Disease, IRCCS Institute Giannina Gaslini, Genoa, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Bruno
authors.affiliation: Department of Child Neurology and Psychiatry, IRCCS Institute 'C Mondino' Foundation, Pavia, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Berardinelli
authors.affiliation: Department of Science of Life, Institute of Biology, University of Modena and Reggio Emilia, Modena, Italy Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Rossella
authors.initials: R
authors.lastname: Tupler
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007558:Italy; D053208:Kaplan-Meier Estimate; D008297:Male; D008840:Microfilament Proteins; D008875:Middle Aged; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D016601:RNA-Binding Proteins; D012042:Registries; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: C101270:FRG1 protein, human; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins