title: Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation.
abstract: BACKGROUND
  Alpha-mannosidosis is caused by mutations in MAN2B1, leading to loss of lysosomal alpha-mannosidase activity. Symptoms include intellectual disabilities, hearing impairment, motor function disturbances, facial coarsening and musculoskeletal abnormalities.
  
  
  METHODS
  To study the genotype-phenotype relationship for alpha-mannosidosis 66 patients were included. Based on the predicted effect of the mutations and the subcellular localisation of mutant MAN2B1 in cultured cells, the patients were divided into three subgroups. Clinical and biochemical data were collected. Correlation analyses between each of the three subgroups of genotype/subcellular localisation and the clinical and biochemical data were done to investigate the potential relationship between genotype and phenotype in alpha-mannosidosis. Statistical analyses were performed using the SPSS software. Analyses of covariance were performed to describe the genotype-phenotype correlations. The phenotype parameters were modelled by the mutation group and age as a covariate. P values of <0.05 were considered as statistically significant.
  
  
  RESULTS
  Complete MAN2B1 genotypes were established for all patients. We found significantly higher scores in the Leiter-R test, lower concentrations of CSF-oligosaccharides, higher point scores in the Bruininks-Oseretsky Test of Motor Proficiency subtests (BOT-2); Upper limb coordination and Balance, and a higher FVC% in patients in subgroup 3, harbouring at least one variant that allows localisation of the mutant MAN2B1 protein to the lysosomes compared to subgrou 2 and/or subgroup 1 with no lysosomal localization of the mutant MAN2B1 protein.
  
  
  CONCLUSIONS
  Our results indicate a correlation between the MAN2B1 genotypes and the cognitive function, upper limb coordination, balance, FVC% and the storage of oligosaccharides in CSF. This correlation depends on the subcellular localisation of the mutant MAN2B1 protein.
authors.affiliation: Department of Clinical Genetics, Centre for Inherited Metabolic Diseases, Copenhagen University Hospital Rigshospitalet, 9 Blegdamsvej, 2100, Copenhagen, Denmark. line.gutte.borgwardt@regionh.dk.
authors.forename: Line
authors.initials: L
authors.lastname: Borgwardt
authors.affiliation: Department of Medical Genetics, Division of Child and Adolescent Health, University Hospital of North Norway, Tromsø, Norway. hilde.monica.stensland@unn.no.
authors.forename: Hilde Monica Frostad Riise
authors.initials: HM
authors.lastname: Stensland
authors.affiliation: Larix, CRO, Ballerup, Denmark. kjo@larix.dk.
authors.forename: Klaus Juul
authors.initials: KJ
authors.lastname: Olsen
authors.affiliation: Department of Clinical Genetics, Centre for Inherited Metabolic Diseases, Copenhagen University Hospital Rigshospitalet, 9 Blegdamsvej, 2100, Copenhagen, Denmark. Flemming.Wibrand@regionh.dk.
authors.forename: Flemming
authors.initials: F
authors.lastname: Wibrand
authors.affiliation: Department of Medical Genetics, Division of Child and Adolescent Health, University Hospital of North Norway, Tromsø, Norway. helle.klenow@unn.no.
authors.forename: Helle Bagterp
authors.initials: HB
authors.lastname: Klenow
authors.affiliation: Zentrum für Kinder - und Jugendmedizin, Villa Metabolica, Mainz, Germany. Dr.M.Beck@t-online.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Beck
authors.affiliation: Zentrum für Kinder - und Jugendmedizin, Villa Metabolica, Mainz, Germany. Yasmin.Amraoui@unimedizin-mainz.de.
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Amraoui
authors.affiliation: Zentrum für Kinder - und Jugendmedizin, Villa Metabolica, Mainz, Germany. Laila.Arash-Kaps@unimedizin-mainz.de.
authors.forename: Laila
authors.initials: L
authors.lastname: Arash
authors.affiliation: Zymenex A/S (Chiesi Group), Hilleroed, Denmark. jf@zymenex.com.
authors.forename: Jens
authors.initials: J
authors.lastname: Fogh
authors.affiliation: Department of Medical Genetics, Division of Child and Adolescent Health, University Hospital of North Norway, Tromsø, Norway. oivind.nilssen@uit.no.|Department of Clinical Medicine, Medical Genetics, University of North Norway, Tromsø, Norway. oivind.nilssen@uit.no.
authors.forename: Øivind
authors.initials: Ø
authors.lastname: Nilssen
authors.affiliation: Department of Clinical Genetics, Centre for Inherited Metabolic Diseases, Copenhagen University Hospital Rigshospitalet, 9 Blegdamsvej, 2100, Copenhagen, Denmark. christine.I.dali@regionh.dk.
authors.forename: Christine I
authors.initials: CI
authors.lastname: Dali
authors.affiliation: Department of Clinical Genetics, Centre for Inherited Metabolic Diseases, Copenhagen University Hospital Rigshospitalet, 9 Blegdamsvej, 2100, Copenhagen, Denmark. allan.meldgaard.lund@regionh.dk.
authors.forename: Allan Meldgaard
authors.initials: AM
authors.lastname: Lund
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008361:Mannosidases / Q000235:genetics / Q000378:metabolism*; D009844:Oligosaccharides / Q000134:cerebrospinal fluid; D010641:Phenotype; D055815:Young Adult; D008363:alpha-Mannosidosis / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D009844:Oligosaccharides; D008361:Mannosidases