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

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.

A MANBA mutation resulting in residual beta-mannosidase activity associated with severe leukoencephalopathy: a possible pseudodeficiency variant.

BACKGROUND: beta-Mannosidosis (OMIM 248510) is a rare inborn lysosomal storage disorder caused by the deficient activity of beta-mannosidase, an enzyme encoded by a single gene (MANBA) located on chromosome 4q22-25. To date, only 20 cases of this autosomal recessive disorder have been described and 14 different MANBA mutations were incriminated in the disease. These are all null mutations or missense mutations that abolish beta-mannosidase activity. In this study, we characterized the molecular defect of a new case of beta-mannosidosis, presenting with a severe neurological disorder. METHODS: Genomic DNA was isolated from peripheral blood leukocytes of the patient to allow MANBA sequencing. The identified mutation was engineered by site-directed mutagenesis and the mutant protein was expressed through transient transfection in HEK293T cells. The beta-mannosidase expression and activity were respectively assessed by Western blot and fluorometric assay in both leukocytes and HEK293T cells. RESULTS: A missense disease-associated mutation, c.1922G>A (p.Arg641His), was identified for which the patient was homozygous. In contrast to previously described missense mutations, this substitution does not totally abrogate the enzyme activity but led to a residual activity of about 7% in the patient's leukocytes, 11% in lymphoblasts and 14% in plasma. Expression studies in transfected cells also resulted in 7% residual activity. CONCLUSION: Correlations between MANBA mutations, residual activity of beta-mannosidase and the severity of the ensuing neurological disorder are discussed. Whether the c.1922G>A mutation is responsible for a yet undescribed pseudodeficiency of beta-mannosidase is also discussed.

Early onset alpha-mannosidosis with slow progression in three Hispanic males.

Alpha-mannosidosis (AMS) is an autosomal recessive lysosomal storage disorder which results from a deficiency of lysosomal alpha-mannosidase [corrected] activity and displays a wide range of clinical phenotypes. Patients have traditionally been divided into type I, a more severe form that presents in infancy, and type II, a milder form that typically presents in later childhood. We describe three Hispanic males who presented in infancy with relatively mild forms of AMS. They were aged between 6 and 24 years at their last assessment. Homozygous mutations in the MAN2B1 gene were found in all three patients, one of which is a newly reported mutation. Two of the patients were brothers who were homozygous for the same MAN2B1 mutation. Despite being homozygous for the same mutation, the older brother had more severe developmental delay, hearing loss, and growth retardation. This report illustrates the difficulty in determining a strict genotype-phenotype correlation in AMS, and supports screening for oligosaccharides in children with neurodevelopmental delay with mild phenotypic signs and symptoms.