title: GNE myopathy in Roma patients homozygous for the p.I618T founder mutation.
abstract: GNE myopathy is an autosomal-recessive disorder caused by mutations in the GNE gene, encoding the key enzyme in the sialic acid biosynthetic pathway, UDP-N-acetylglucosamine 2-epimerase/N-acetyl mannosamine kinase. We studied 50 Bulgarian Roma patients homozygous for p.I618T, an ancient founder mutation in the kinase domain of the GNE gene, dating before the Gypsy exodus from North West India. The clinical features in the Bulgarian GNE group can be described with disease onset mostly in the third decade, but in individual cases, onset was as early as 10 years of age. The majority of patients had foot drop as the first symptom, but three patients developed hand weakness first. Muscle weakness was early and severe for the tibialis anterior, and minimal or late for quadriceps femoris, and respiratory muscles were only subclinically affected even in the advanced stages of the disease. During a 15-year follow-up period, 32 patients became non-ambulant. The average period between disease onset and loss of ambulation was 10.34 ± 4.31 years, ranging from 3 to 20 years. Our analysis of affected sib pairs suggested a possible role of genetic modifying factors, accounting for significant variation in disease severity.
authors.affiliation: Department of Neurology, University Hospital Alexandrovska, Sofia Medical University, Sofia, Bulgaria. Electronic address: teodoratch@abv.bg.
authors.forename: Teodora
authors.initials: T
authors.lastname: Chamova
authors.affiliation: Department of Neurology, University Hospital Alexandrovska, Sofia Medical University, Sofia, Bulgaria.
authors.forename: Velina
authors.initials: V
authors.lastname: Guergueltcheva
authors.affiliation: Department of Cardiology, Medical Institute of Ministry of Interior Affairs, Sofia, Bulgaria.
authors.forename: Mariana
authors.initials: M
authors.lastname: Gospodinova
authors.affiliation: Laboratory of Molecular Myology, Friedrich-Baur-Institute, Department of Neurology, Ludwig Maximilians University, Munich, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Krause
authors.affiliation: Uniklinik Köln Institut für Humangenetik, Cologne, Germany.
authors.forename: Sebahattin
authors.initials: S
authors.lastname: Cirak
authors.affiliation: Department of Neurology, Medical University, Varna, Bulgaria.
authors.forename: Ara
authors.initials: A
authors.lastname: Kaprelyan
authors.affiliation: Department of Pediatrics and Medical Genetics, Medical University, Varna, Bulgaria.
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Angelova
authors.affiliation: Department of Neurology, University Hospital Alexandrovska, Sofia Medical University, Sofia, Bulgaria.
authors.forename: Violeta
authors.initials: V
authors.lastname: Mihaylova
authors.affiliation: National Genetics Laboratory, Molecular Medicine Center, Medical University, Sofia, Bulgaria.
authors.forename: Stoyan
authors.initials: S
authors.lastname: Bichev
authors.affiliation: Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Perth, Australia; Australian Genome Research Facility, Perth, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Chandler
authors.affiliation: Department of Neurosurgery, Ivan Rilski Hospital, Sofia, Bulgaria.
authors.forename: Emanuil
authors.initials: E
authors.lastname: Naydenov
authors.affiliation: Department of Neurology, Medical University, Varna, Bulgaria.
authors.forename: Margarita
authors.initials: M
authors.lastname: Grudkova
authors.affiliation: Medical Centre Plus, Varna, Bulgaria.
authors.forename: Presian
authors.initials: P
authors.lastname: Djukmedzhiev
authors.affiliation: Institute of Myology and Myology Research Centre, University Pierre et Marie Curie, UPMC-INSERM UMR 974, CNRS FRE 3617, GH Pitié-Salpêtrière, Paris, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
authors.affiliation: John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Oksana
authors.initials: O
authors.lastname: Pogoryelova
authors.affiliation: John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.affiliation: Department of Neuropathology, Charité - Universitätsmedizin Berlin, Germany.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Goebel
authors.affiliation: Population Health and Immunity Division, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia; Department of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.affiliation: Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Perth, Australia.
authors.forename: Luba
authors.initials: L
authors.lastname: Kalaydjieva
authors.affiliation: Department of Neurology, University Hospital Alexandrovska, Sofia Medical University, Sofia, Bulgaria; Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria.
authors.forename: Ivailo
authors.initials: I
authors.lastname: Tournev
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D018450:Disease Progression; D049310:Distal Myopathies / Q000150:complications / Q000208:ethnology* / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005500:Follow-Up Studies; D018703:Founder Effect; D006720:Homozygote; D006801:Humans; D008297:Male; D009097:Multienzyme Complexes / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D006178:Romani People; D055815:Young Adult
chemical_list: D009097:Multienzyme Complexes; C482901:UDP-N-acetylglucosamine 2-epimerase - N-acetylmannosamine kinase
keywords: Founder mutation; GNE myopathy; Phenotype