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Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands
  1. Sara S Cathey (scathey{at}
  1. Greenwood Genetic Center, United States
    1. Jules G Leroy (juliaan.leroy{at}
    1. Greenwood Genetic Center, United States
      1. Tim Wood (tim{at}
      1. Greenwood Genetic Center, United States
        1. Karisa Eaves
        1. Greenwood Genetic Center, United States
          1. Richard J Simensen (rsimensen{at}
          1. Greenwood Genetic Center, United States
            1. Mariko Kudo (mariko.kudo{at}
            1. Genzyme Corporation, United States
              1. Roger E Stevenson (res{at}
              1. Greenwood Genetic Center, United States
                1. Michael J Friez (friez{at}
                1. Greenwood Genetic Center, United States


                  Objectives: 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 synthesized onto 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. Clinical, biochemical, and molecular findings in 61 probands (63 patients) are presented in order to provide a broad perspective of these mucolipidoses.

                  Methods: GNPTAB was sequenced in all probands and/or parents. Activity of several lysosomal enzymes was measured in plasma, and GlcNac-1-phosphotransferase was assayed in leukocytes. 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 orthopedic 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 due to 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 age four 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.

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