title: Heterozygous UDP-GlcNAc 2-epimerase and N-acetylmannosamine kinase domain mutations in the GNE gene result in a less severe GNE myopathy phenotype compared to homozygous N-acetylmannosamine kinase domain mutations.
abstract: BACKGROUND
  Glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE) myopathy, also called distal myopathy with rimmed vacuoles (DMRV) or hereditary inclusion body myopathy (HIBM), is a rare, progressive autosomal recessive disorder caused by mutations in the GNE gene. Here, we examined the relationship between genotype and clinical phenotype in participants with GNE myopathy.
  
  
  METHODS
  Participants with GNE myopathy were asked to complete a questionnaire regarding medical history and current symptoms.
  
  
  RESULTS
  A total of 71 participants with genetically confirmed GNE myopathy (27 males and 44 females; mean age, 43.1±13.0 (mean±SD) years) completed the questionnaire. Initial symptoms (e.g., foot drop and lower limb weakness) appeared at a mean age of 24.8±8.3 years. Among the 71 participants, 11 (15.5%) had the ability to walk, with a median time to loss of ambulation of 17.0±2.1 years after disease onset. Participants with a homozygous mutation (p.V572L) in the N-acetylmannosamine kinase domain (KD/KD participants) had an earlier disease onset compared to compound heterozygous participants with mutations in the uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase and N-acetylmannosamine kinase domains (ED/KD participants; 26.3±7.3 vs. 21.2±11.1 years, respectively). KD/KD participants were more frequently non-ambulatory compared to ED/KD participants at the time of survey (80% vs. 50%). Data were verified using medical records available from 17 outpatient participants.
  
  
  CONCLUSIONS
  Homozygous KD/KD participants exhibited a more severe phenotype compared to heterozygous ED/KD participants.
authors.affiliation: Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8551, Japan. yoshimur@ncnp.go.jp
authors.forename: Madoka
authors.initials: M
authors.lastname: Mori-Yoshimura
authors.forename: Kazunari
authors.initials: K
authors.lastname: Monma
authors.forename: Naoki
authors.initials: N
authors.lastname: Suzuki
authors.forename: Masashi
authors.initials: M
authors.lastname: Aoki
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kumamoto
authors.forename: Keiko
authors.initials: K
authors.lastname: Tanaka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tomimitsu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nakano
authors.forename: Masahiro
authors.initials: M
authors.lastname: Sonoo
authors.forename: Jun
authors.initials: J
authors.lastname: Shimizu
authors.forename: Kazuma
authors.initials: K
authors.lastname: Sugie
authors.forename: Harumasa
authors.initials: H
authors.lastname: Nakamura
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Oya
authors.forename: Yukiko K
authors.initials: YK
authors.lastname: Hayashi
authors.forename: May Christine V
authors.initials: MC
authors.lastname: Malicdan
authors.forename: Satoru
authors.initials: S
authors.lastname: Noguchi
authors.forename: Miho
authors.initials: M
authors.lastname: Murata
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002238:Carbohydrate Epimerases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D009097:Multienzyme Complexes; C482901:UDP-N-acetylglucosamine 2-epimerase - N-acetylmannosamine kinase; D017853:Phosphotransferases (Alcohol Group Acceptor); C018765:N-acylmannosamine kinase; D002238:Carbohydrate Epimerases; C100033:UDP acetylglucosamine-2-epimerase