Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation

Orphanet Journal of Rare Diseases

Allan Meldgaard Lund⁵  Christine I Dali⁵  Øivind Nilssen¹  Jens Fogh²  Laila Arash⁶  Yasmina Amraoui⁶  Michael Beck⁶  Helle Bagterp Klenow⁴  Flemming Wibrand⁵  Klaus Juul Olsen³  Hilde Monica Frostad Riise Stensland⁴  Line Borgwardt⁵ 

[1] Department of Clinical Medicine, Medical Genetics, University of North Norway, Tromsø, Norway;Zymenex A/S (Chiesi Group), Hilleroed, Denmark;Larix, CRO, Ballerup, Denmark;Department of Medical Genetics, Division of Child and Adolescent Health, University Hospital of North Norway, Tromsø, Norway;Department of Clinical Genetics, Centre for Inherited Metabolic Diseases, Copenhagen University Hospital Rigshospitalet, 9 Blegdamsvej, Copenhagen, 2100, Denmark;Zentrum für Kinder - und Jugendmedizin, Villa Metabolica, Mainz, Germany

关键词: CNS involvement;    Genotype-phenotype correlation;    MAN2B1;    Alpha-mannosidosis;   

Others  :  1219131
DOI  :  10.1186/s13023-015-0286-x

 received in 2015-02-09, accepted in 2015-05-19,  发布年份 2015

【 摘 要 】

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.

Conclusion

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.

【 授权许可】

   
2015 Borgwardt et al.

【 图 表 】

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