Orphanet Journal of Rare Diseases (Sep 2018)
Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study
- Guja Astrea,
- Alessandro Romano,
- Corrado Angelini,
- Carlo Giuseppe Antozzi,
- Rita Barresi,
- Roberta Battini,
- Carla Battisti,
- Enrico Bertini,
- Claudio Bruno,
- Denise Cassandrini,
- Marina Fanin,
- Fabiana Fattori,
- Chiara Fiorillo,
- Renzo Guerrini,
- Lorenzo Maggi,
- Eugenio Mercuri,
- Federica Morani,
- Marina Mora,
- Francesca Moro,
- Ilaria Pezzini,
- Esther Picillo,
- Michele Pinelli,
- Luisa Politano,
- Anna Rubegni,
- Walter Sanseverino,
- Marco Savarese,
- Pasquale Striano,
- Annalaura Torella,
- Carlo Pietro Trevisan,
- Rosanna Trovato,
- Irina Zaraieva,
- Francesco Muntoni,
- Vincenzo Nigro,
- Adele D’Amico,
- Filippo M. Santorelli,
- the Italian CMD Network
Affiliations
- Guja Astrea
- Department of Developmental Neuroscience and Molecular Medicine Neuromuscular Unit and Child Neurology, IRCCS Fondazione Stella Maris
- Alessandro Romano
- Neuropathology Unit, Institute of Experimental Neurology and Division of Neuroscience, IRCCS San Raffaele Scientific Institute
- Corrado Angelini
- Fondazione San Camillo Hospital IRCCS
- Carlo Giuseppe Antozzi
- Department of Neuroimmunology and Neuromuscular Disorders, Neurological Institute “C. Besta” IRCCS Foundation
- Rita Barresi
- Rare Diseases Advisory Group Service for Neuromuscular Diseases, Muscle Immunoanalysis Unit, Dental Hospital, and The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases Institute of Genetic Medicine, University of Newcastle
- Roberta Battini
- Department of Developmental Neuroscience and Molecular Medicine Neuromuscular Unit and Child Neurology, IRCCS Fondazione Stella Maris
- Carla Battisti
- Department of Medical, Surgical and Neurosciences, University of Siena
- Enrico Bertini
- Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children’s Hospital
- Claudio Bruno
- Center of Myology and Neurodegenerative Disorders, G. Gaslini Institute
- Denise Cassandrini
- Department of Developmental Neuroscience and Molecular Medicine Neuromuscular Unit and Child Neurology, IRCCS Fondazione Stella Maris
- Marina Fanin
- Neurological Science Department and Venetian Institute of Molecular Medicine, University of Padua
- Fabiana Fattori
- Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children’s Hospital
- Chiara Fiorillo
- Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, “G. Gaslini” Institute
- Renzo Guerrini
- Pediatric Neurology Unit and Laboratories, Children’s Hospital A. Meyer-University of Florence
- Lorenzo Maggi
- Department of Neuroimmunology and Neuromuscular Disorders, Neurological Institute “C. Besta” IRCCS Foundation
- Eugenio Mercuri
- Pediatric Neurology Unit, Department of Women’s and Children’s Health, Università Cattolica del Sacro Cuore
- Federica Morani
- Department of Developmental Neuroscience and Molecular Medicine Neuromuscular Unit and Child Neurology, IRCCS Fondazione Stella Maris
- Marina Mora
- Department of Neuroimmunology and Neuromuscular Disorders, Neurological Institute “C. Besta” IRCCS Foundation
- Francesca Moro
- Department of Developmental Neuroscience and Molecular Medicine Neuromuscular Unit and Child Neurology, IRCCS Fondazione Stella Maris
- Ilaria Pezzini
- Department of Developmental Neuroscience and Molecular Medicine Neuromuscular Unit and Child Neurology, IRCCS Fondazione Stella Maris
- Esther Picillo
- Cardiomyology and Genetic Section, Department of Internal and Experimental Medicine, University of Campania “Luigi Vanvitelli”
- Michele Pinelli
- Department of Translational Medicine, Federico II University
- Luisa Politano
- Cardiomyology and Genetic Section, Department of Internal and Experimental Medicine, University of Campania “Luigi Vanvitelli”
- Anna Rubegni
- Department of Developmental Neuroscience and Molecular Medicine Neuromuscular Unit and Child Neurology, IRCCS Fondazione Stella Maris
- Walter Sanseverino
- Sequentia Biotech SL
- Marco Savarese
- Telethon Institute of Genetics and Medicine
- Pasquale Striano
- Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, “G. Gaslini” Institute
- Annalaura Torella
- Telethon Institute of Genetics and Medicine
- Carlo Pietro Trevisan
- Department of Neurological and Psychiatric Sciences, University of Padua
- Rosanna Trovato
- Department of Developmental Neuroscience and Molecular Medicine Neuromuscular Unit and Child Neurology, IRCCS Fondazione Stella Maris
- Irina Zaraieva
- Dubowitz Neuromuscular Centre (F. Muntoni), UCL Great Ormond Street Institute of Child Health
- Francesco Muntoni
- Dubowitz Neuromuscular Centre (F. Muntoni), UCL Great Ormond Street Institute of Child Health
- Vincenzo Nigro
- Telethon Institute of Genetics and Medicine
- Adele D’Amico
- Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children’s Hospital
- Filippo M. Santorelli
- Department of Developmental Neuroscience and Molecular Medicine Neuromuscular Unit and Child Neurology, IRCCS Fondazione Stella Maris
- the Italian CMD Network
- DOI
- https://doi.org/10.1186/s13023-018-0863-x
- Journal volume & issue
-
Vol. 13,
no. 1
pp. 1 – 9
Abstract
Abstract Background Dystroglycanopathy (α-DG) is a relatively common, clinically and genetically heterogeneous category of congenital forms of muscular dystrophy (CMD) and limb-girdle muscular dystrophy (LGMD) associated with hypoglycosylated α-dystroglycan. To date, mutations in at least 19 genes have been associated with α-DG. One of them, GMPPB, encoding the guanosine-diphosphate-mannose (GDP-mannose) pyrophosphorylase B protein, has recently been associated with a wide clinical spectrum ranging from severe Walker-Warburg syndrome to pseudo-metabolic myopathy and even congenital myasthenic syndromes. We re-sequenced the full set of known disease genes in 73 Italian patients with evidence of either reduced or nearly absent α-dystroglycan to assess genotype-phenotype correlations in this cohort. We used innovative bioinformatic tools to calculate the effects of all described GMPPB mutations on protein function and attempted to correlate them with phenotypic expressions. Results We identified 13 additional cases from 12 families and defined seven novel mutations. Patients displayed variable phenotypes including less typical pictures, ranging from asymptomatic hyperCKemia, to arthrogryposis and congenital clubfoot at birth, and also showed neurodevelopmental comorbidities, such as seizures and ataxic gait, as well as autism-spectrum disorder, which is seldom described in clinical reports of dystroglycanopathies. We also demonstrated that few mutations recur in the Italian GMPPB-mutated population and that alterations of protein stability are the main effects of GMPPB missense variants. Conclusion This work adds to the data on genotype-phenotype correlations in α-DG and offers new bionformatic tools to provide the conceptual framework needed to understand the complexity of these disorders.
Keywords
- Congenital muscular dystrophy
- Limb-girdle muscular dystrophy
- GMPPB
- Dystroglycanopathies
- Genotype-phenotype correlations
