title: Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands.
abstract: BACKGROUND
  Mucolipidoses II and III alpha/beta (ML II and ML III) are lysosomal disorders in which the essential mannose 6-phosphate recognition marker is not synthesised on to lysosomal hydrolases and other glycoproteins. The disorders are caused by mutations in GNPTAB, which encodes two of three subunits of the heterohexameric enzyme, N-acetylglucosamine-1-phosphotransferase.
  
  
  OBJECTIVE
  Clinical, biochemical and molecular findings in 61 probands (63 patients) are presented to provide a broad perspective of these mucolipidoses.
  
  
  METHODS
  GNPTAB was sequenced in all probands and/or parents. The activity of several lysosomal enzymes was measured in plasma, and GlcNAc-1-phosphotransferase was assayed in leucocytes. Thirty-six patients were studied in detail, allowing extensive clinical data to be abstracted.
  
  
  RESULTS
  ML II correlates with near-total absence of phosphotransferase activity resulting from homozygosity or compound heterozygosity for frameshift or nonsense mutations. Craniofacial and orthopaedic manifestations are evident at birth, skeletal findings become more obvious within the first year, and growth is severely impaired. Speech, ambulation and cognitive function are impaired. ML III retains a low level of phosphotransferase activity because of at least one missense or splice site mutation. The phenotype is milder, with minimal delays in milestones, the appearance of facial coarsening by early school age, and slowing of growth after the age of 4 years.
  
  
  CONCLUSIONS
  Fifty-one pathogenic changes in GNPTAB are presented, including 42 novel mutations. Ample clinical information improves criteria for delineation of ML II and ML III. Phenotype-genotype correlations suggested in more general terms in earlier reports on smaller groups of patients are specified and extended.
authors.affiliation: Greenwood Genetic Center, Charleston Office, Montague Oaks Office Park, N Charleston, SC 29418, USA. scathey@ggc.org
authors.forename: S S
authors.initials: SS
authors.lastname: Cathey
authors.forename: J G
authors.initials: JG
authors.lastname: Leroy
authors.forename: T
authors.initials: T
authors.lastname: Wood
authors.forename: K
authors.initials: K
authors.lastname: Eaves
authors.forename: R J
authors.initials: RJ
authors.lastname: Simensen
authors.forename: M
authors.initials: M
authors.lastname: Kudo
authors.forename: R E
authors.initials: RE
authors.lastname: Stevenson
authors.forename: M J
authors.initials: MJ
authors.lastname: Friez
mesh_terms: D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D009081:Mucolipidoses / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics*
chemical_list: D017855:Transferases (Other Substituted Phosphate Groups); C511050:GNPTAB protein, human