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. Mongini & 11 others Maurizio 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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numbere007798
JournalBMJ Open
Volume6
Issue number1
DOIs
Publication statusPublished - 2016

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Facioscapulohumeral Muscular Dystrophy
Registries
Alleles
Age of Onset
Kaplan-Meier Estimate
Survival Analysis
Italy
Linear Models
Healthy Volunteers
Phenotype

ASJC Scopus subject areas

  • Medicine(all)

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Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1-3 D4Z4 reduced alleles : Experience of the FSHD Italian National Registry. / Nikolic, Ana; Ricci, Giulia; Sera, Francesco; Bucci, Elisabetta; Govi, Monica; Mele, Fabiano; Rossi, Marta; Ruggiero, Lucia; Vercelli, Liliana; Ravaglia, S.; Brisca, Giacomo; Fiorillo, Chiara; Villa, Luisa; Maggi, Lorenzo; Cao, Michelangelo; D'Amico, Maria Chiara; Siciliano, Gabriele; Antonini, Giovanni; Santoro, Lucio; Mongini, T.; Moggio, Maurizio Gualtiero; Morandi, Lucia; Pegoraro, E.; Angelini, Corrado; Di Muzio, A.; Rodolico, C.; Tomelleri, Giuliano; D'Angelo, Maria Grazia; Bruno, Claudio; Berardinelli, Angela Lucia; Tupler, Rossella.

In: BMJ Open, Vol. 6, No. 1, e007798, 2016.

Research output: Contribution to journalArticle

Nikolic, A, Ricci, G, Sera, F, Bucci, E, Govi, M, Mele, F, Rossi, M, Ruggiero, L, Vercelli, L, Ravaglia, S, Brisca, G, Fiorillo, C, Villa, L, Maggi, L, Cao, M, D'Amico, MC, Siciliano, G, Antonini, G, Santoro, L, Mongini, T, Moggio, MG, Morandi, L, Pegoraro, E, Angelini, C, Di Muzio, A, Rodolico, C, Tomelleri, G, D'Angelo, MG, Bruno, C, Berardinelli, AL & Tupler, R 2016, 'Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1-3 D4Z4 reduced alleles: Experience of the FSHD Italian National Registry', BMJ Open, vol. 6, no. 1, e007798. https://doi.org/10.1136/bmjopen-2015-007798
Nikolic, Ana ; Ricci, Giulia ; Sera, Francesco ; Bucci, Elisabetta ; Govi, Monica ; Mele, Fabiano ; Rossi, Marta ; Ruggiero, Lucia ; Vercelli, Liliana ; Ravaglia, S. ; Brisca, Giacomo ; Fiorillo, Chiara ; Villa, Luisa ; Maggi, Lorenzo ; Cao, Michelangelo ; D'Amico, Maria Chiara ; Siciliano, Gabriele ; Antonini, Giovanni ; Santoro, Lucio ; Mongini, T. ; Moggio, Maurizio Gualtiero ; Morandi, Lucia ; Pegoraro, E. ; Angelini, Corrado ; Di Muzio, A. ; Rodolico, C. ; Tomelleri, Giuliano ; D'Angelo, Maria Grazia ; Bruno, Claudio ; Berardinelli, Angela Lucia ; Tupler, Rossella. / Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1-3 D4Z4 reduced alleles : Experience of the FSHD Italian National Registry. In: BMJ Open. 2016 ; Vol. 6, No. 1.
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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.",
author = "Ana Nikolic and Giulia Ricci and Francesco Sera and Elisabetta Bucci and Monica Govi and Fabiano Mele and Marta Rossi and Lucia Ruggiero and Liliana Vercelli and S. Ravaglia and Giacomo Brisca and Chiara Fiorillo and Luisa Villa and Lorenzo Maggi and Michelangelo Cao and D'Amico, {Maria Chiara} and Gabriele Siciliano and Giovanni Antonini and Lucio Santoro and T. Mongini and Moggio, {Maurizio Gualtiero} and Lucia Morandi and E. Pegoraro and Corrado Angelini and {Di Muzio}, A. and C. Rodolico and Giuliano Tomelleri and D'Angelo, {Maria Grazia} and Claudio Bruno and Berardinelli, {Angela Lucia} and Rossella Tupler",
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T1 - Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1-3 D4Z4 reduced alleles

T2 - Experience of the FSHD Italian National Registry

AU - Nikolic, Ana

AU - Ricci, Giulia

AU - Sera, Francesco

AU - Bucci, Elisabetta

AU - Govi, Monica

AU - Mele, Fabiano

AU - Rossi, Marta

AU - Ruggiero, Lucia

AU - Vercelli, Liliana

AU - Ravaglia, S.

AU - Brisca, Giacomo

AU - Fiorillo, Chiara

AU - Villa, Luisa

AU - Maggi, Lorenzo

AU - Cao, Michelangelo

AU - D'Amico, Maria Chiara

AU - Siciliano, Gabriele

AU - Antonini, Giovanni

AU - Santoro, Lucio

AU - Mongini, T.

AU - Moggio, Maurizio Gualtiero

AU - Morandi, Lucia

AU - Pegoraro, E.

AU - Angelini, Corrado

AU - Di Muzio, A.

AU - Rodolico, C.

AU - Tomelleri, Giuliano

AU - D'Angelo, Maria Grazia

AU - Bruno, Claudio

AU - Berardinelli, Angela Lucia

AU - Tupler, Rossella

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

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