Centronuclear myopathies: genotype–phenotype correlation and frequency of defined genetic forms in an Italian cohort

• DOI: 10.1007/s00415-015-7757-9
• Publication Date: 2015-05-09T07:02:55Z
• Authors: Fabiana Fattori; Lorenzo Maggi; Claudio Bruno; Denise Cassandrini; Valentina Codemo; Michela Catteruccia; Giorgio Tasca; Angela Berardinelli; Francesca Magri; Marika Pane; Anna Rubegni; Lucio Santoro; Lucia Ruggiero; Patrizio Fiorini; Antonella Pini; Tiziana Mongini; Sonia Messina; Giacomo Brisca; Irene Colombo; Guja Astrea; Chiara Fiorillo; Cinzia Bragato; Isabella Moroni; Elena Pegoraro; Maria Rosaria D’A...; Enrico Alfei; Marina Mora; Lucia Morandi; Alice Donati; Anni Evilä; Anna Vihola; Bjarne Udd; Pia Bernansconi; Eugenio Mercuri; Filippo Maria San...; Enrico Bertini; Adele D’Amico
• Keywords: Adult; Male; Adolescent; Algorithm; Centronuclear; Congenital myopathy; DNM2; RYR1;; Algorithm; Centronuclear; Congenital myopathy; DNM2; RYR1; Adolescent; Adult; Age of Onset; Aged; Child; Child, Preschool; Cohort Studies; Connectin; Dynamin II; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Infant; Infant, Newborn; Italy; Male; Middle Aged; Muscle, Skeletal; Mutation; Myopathies, Structural, Congenital; Phenotype; Protein Tyrosine Phosphatases, Non-Receptor; Ryanodine Receptor Calcium Release Channel; Young Adult; Cohort Studies; Dynamin II; 03 medical and health sciences; 0302 clinical medicine; RYR1; Humans; Centronuclear; Connectin; Genetic Predisposition to Disease; Age of Onset; Child; Muscle, Skeletal; Genetic Association Studies; Aged; Congenital myopathy; Infant, Newborn; Infant; DNM2; Middle Aged; 3. Good health; Algorithm; Italy; Child, Preschool; Mutation; Algorithm; Centronuclear; Congenital myopathy; DNM2; RYR1; Neurology (clinical); Neurology; Centronuclear; Congenital myopathy; RYR1; DNM2; Algorithm; Adolescent; Adult; Age of Onset; Aged; Child; Child, Preschool; Cohort Studies; Connectin; Dynamin II; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Infant; Infant, Newborn; Italy; Male; Middle Aged; Muscle, Skeletal; Mutation; Myopathies, Structural, Congenital; Phenotype; Protein Tyrosine Phosphatases, Non-Receptor; Ryanodine Receptor Calcium Release Channel; Young Adult; Female; Algorithm; Centronuclear; Congenital myopathy; DNM2; RYR1; Adolescent; Adult; Age of Onset; Aged; Child; Child, Preschool; Cohort Studies; Connectin; Dynamin II; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Infant; Infant, Newborn; Italy; Male; Middle Aged; Muscle, Skeletal; Mutation; Myopathies, Structural, Congenital; Phenotype; Protein Tyrosine Phosphatases, Non-Receptor; Ryanodine Receptor Calcium Release Channel; Young Adult; Neurology; Neurology (clinical)

Centronuclear myopathies (CNMs) are a group of clinically and genetically heterogeneous muscle disorders. To date, mutation in 7 different genes has been reported to cause CNMs but 30 % of cases still remain genetically undefined. Genetic investigations are often expensive and time consuming. Clinical and morphological clues are needed to facilitate genetic tests and to choose the best approach for genetic screening. We aimed to describe genotype-phenotype correlation in an Italian cohort of patients affected by CNMs, to define the relative frequencies of its defined genetic forms and to draw a diagnostic algorithm to address genetic investigations. We recruited patients with CNMs from all the Italian tertiary neuromuscular centers following clinical and histological criteria. All selected patients were screened for the four 'canonical' genes related to CNMs: MTM1, DNM2, RYR1 and BIN1. Pathogenetic mutations were found in 38 of the 54 screened patients (70 %), mostly in patients with congenital onset (25 of 30 patients, 83 %): 15 in MTM1, 6 in DNM2, 3 in RYR1 and one in TTN. Among the 13 patients with a childhood-adolescence onset, mutations were found in 6 patients (46 %), all in DNM2. In the group of the 11 patients with adult onset, mutations were identified in 7 patients (63 %), again in DNM2, confirming that variants in this gene are relatively more common in late-onset phenotypes. The present study provides the relative molecular frequency of centronuclear myopathy and of its genetically defined forms in Italy and also proposes a diagnostic algorithm to be used in clinical practice to address genetic investigations.