Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1-3 D4Z4 reduced alleles: Experience of the FSHD Italian National Registry

Ana Nikolic, Giulia Ricci, Francesco Sera, Elisabetta Bucci, Monica Govi, Fabiano Mele, Marta Rossi, Lucia Ruggiero, Liliana Vercelli, S. Ravaglia, Giacomo Brisca, Chiara Fiorillo, Luisa Villa, Lorenzo Maggi, Michelangelo Cao, Maria Chiara D'Amico, Gabriele Siciliano, Giovanni Antonini, Lucio Santoro, T. MonginiMaurizio Gualtiero Moggio, Lucia Morandi, E. Pegoraro, Corrado Angelini, A. Di Muzio, C. Rodolico, Giuliano Tomelleri, Maria Grazia D'Angelo, Claudio Bruno, Angela Lucia Berardinelli, Rossella Tupler

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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.

Original languageEnglish
Article numbere007798
JournalBMJ Open
Issue number1
Publication statusPublished - 2016

ASJC Scopus subject areas

  • Medicine(all)


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