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

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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.

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.

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Most cited references 30

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Long-term follow-up of endurance and safety outcomes during enzyme replacement therapy for mucopolysaccharidosis VI: Final results of three clinical studies of recombinant human N-acetylgalactosamine 4-sulfatase.

David C Whitley, Laila Arash, Robert W. Steiner … (2008)

The objective of this study was to evaluate the long-term clinical benefits and safety of recombinant human arylsulfatase B (rhASB) treatment of mucopolysaccharidosis type VI (MPS VI: Maroteaux-Lamy syndrome), a lysosomal storage disease. Fifty-six patients derived from 3 clinical studies were followed in open-label extension studies for a total period of 97-260 Weeks. All patients received weekly infusions of rhASB at 1 mg/kg. Efficacy was evaluated by (1) distance walked in a 12-minute walk test (12MWT) or 6-minute walk test (6MWT), (2) stairs climbed in the 3-minute stair climb (3MSC), and (3) reduction in urinary glycosaminoglycans (GAG). Safety was evaluated by compliance, adverse event (AE) reporting and adherence to treatment. A significant reduction in urinary GAG (71-79%) was sustained. For the 12MWT, subjects in Phase 2 showed improvement of 255+/-191 m (mean+/-SD) at Week 144; those in Phase 3 Extension demonstrated improvement from study baseline of 183+/-26 m (mean+/- SE) in the rhASB/rhASB group at Week 96 and from treatment baseline (Week 24) of 117+/-25 m in the placebo/rhASB group. The Phase 1/2 6MWT and the 3MSC from Phase 2 and 3 also showed sustained improvements through the final study measurements. Compliance was 98% overall. Only 560 of 4121 reported AEs (14%) were related to treatment with only 10 of 560 (2%) described as severe. rhASB treatment up to 5 years results in sustained improvements in endurance and has an acceptable safety profile.

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Alpha-mannosidosis

Dag Malm, Øivind Nilssen (2008)

Alpha-mannosidosis is an inherited lysosomal storage disorder characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual disability. It occurs in approximately 1 of 500,000 live births. The children are often born apparently normal, and their condition worsens progressively. Some children are born with ankle equinus or develop hydrocephalus in the first year of life. Main features are immune deficiency (manifested by recurrent infections, especially in the first decade of life), skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum), hearing impairment (moderate-to-severe sensorineural hearing loss), gradual impairment of mental functions and speech, and often, periods of psychosis. Associated motor function disturbances include muscular weakness, joint abnormalities and ataxia. The facial trait include large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Slight strabismus is common. The clinical variability is significant, representing a continuum in severity. The disorder is caused by lysosomal alpha-mannosidase deficiency. Alpha-mannosidosis is inherited in an autosomal recessive fashion and is caused by mutations in the MAN2B1 gene located on chromosome 19 (19 p13.2-q12). Diagnosis is made by measuring acid alpha-mannosidase activity in leukocytes or other nucleated cells and can be confirmed by genetic testing. Elevated urinary secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic. Differential diagnoses are mainly the other lysosomal storage diseases like the mucopolysaccharidoses. Genetic counseling should be given to explain the nature of the disease and to detect carriers. Antenatal diagnosis is possible, based on both biochemical and genetic methods. The management should be pro-active, preventing complications and treating manifestations. Infections must be treated frequently. Otolaryngological treatment of fluid in the middle ear is often required and use of hearing aids is invariably required. Early educational intervention for development of social skills is needed and physiotherapy is important to improve bodily function. Orthopedic surgery may be necessary. The long-term prognosis is poor. There is an insidiously slow progression of neuromuscular and skeletal deterioration over several decades, making most patients wheel-chair dependent. No patients manage to be completely socially independent. Many patients are over 50 years of age.

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Exercise testing, 6-min walk, and stair climb in the evaluation of patients at high risk for pulmonary resection.

Grant Rice, K Stelmach, Dustin D. Holden … (1992)

To evaluate three types of exercise testing in prediction of death or prolonged mechanical ventilation after lung resection in high-risk patients, 16 patients underwent evaluation prior to resection. Eleven patients (group 1) had minor or no complications (arrhythmia, atelectasis, pneumonia) and five patients (group 2) died within 90 days of surgery. Exercise testing showed that group 1 had a longer 6-min walk distance and a higher stair climb than group 2. The maximum oxygen uptake on a cycle ergometer was not significantly different between groups, although only ten patients completed this test. Group 1 had a significantly greater calculated oxygen uptake with stair climbing than group 2. A 6-min walk distance of greater than 1,000 feet and a stair climb of greater than 44 steps were predictive of successful surgical outcome. Preoperative exercise testing is a useful adjunct to traditional spirometric testing in evaluation of the high-risk surgical patients.

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Author and article information

Contributors

Line Borgwardt: +4535454062 , line.gutte.borgwardt@regionh.dk

Hilde Monica Frostad Riise Stensland: hilde.monica.stensland@unn.no

Klaus Juul Olsen: kjo@larix.dk

Flemming Wibrand: Flemming.Wibrand@regionh.dk

Helle Bagterp Klenow: helle.klenow@unn.no

Michael Beck: Dr.M.Beck@t-online.de

Yasmina Amraoui: Yasmin.Amraoui@unimedizin-mainz.de

Laila Arash: Laila.Arash-Kaps@unimedizin-mainz.de

Jens Fogh: jf@zymenex.com

Øivind Nilssen: oivind.nilssen@uit.no

Christine I Dali: christine.I.dali@regionh.dk

Allan Meldgaard Lund: allan.meldgaard.lund@regionh.dk

Journal

Journal ID (nlm-ta): Orphanet J Rare Dis

Journal ID (iso-abbrev): Orphanet J Rare Dis

Title: Orphanet Journal of Rare Diseases

Publisher: BioMed Central (London )

ISSN (Electronic): 1750-1172

Publication date (Electronic): 6 June 2015

Publication date PMC-release: 6 June 2015

Publication date Collection: 2015

Volume: 10

Electronic Location Identifier: 70

Affiliations

[ ]Department of Clinical Genetics, Centre for Inherited Metabolic Diseases, Copenhagen University Hospital Rigshospitalet, 9 Blegdamsvej, 2100 Copenhagen, Denmark

[ ]Department of Medical Genetics, Division of Child and Adolescent Health, University Hospital of North Norway, Tromsø, Norway

[ ]Larix, CRO, Ballerup, Denmark

[ ]Zentrum für Kinder - und Jugendmedizin, Villa Metabolica, Mainz, Germany

[ ]Zymenex A/S (Chiesi Group), Hilleroed, Denmark

[ ]Department of Clinical Medicine, Medical Genetics, University of North Norway, Tromsø, Norway

Article

Publisher ID: 286

DOI: 10.1186/s13023-015-0286-x

PMC ID: 4465300

PubMed ID: 26048034

SO-VID: 684362d8-b2e4-4ef8-846a-ba26e29895bc

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 9 February 2015

Date accepted : 19 May 2015

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ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: alpha-mannosidosis,man2b1,genotype-phenotype correlation,cns involvement

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ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: alpha-mannosidosis, man2b1, genotype-phenotype correlation, cns involvement

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

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Coronaviruses, COVID-19 and SARS-CoV-2

Most cited references 30

Long-term follow-up of endurance and safety outcomes during enzyme replacement therapy for mucopolysaccharidosis VI: Final results of three clinical studies of recombinant human N-acetylgalactosamine 4-sulfatase.

Alpha-mannosidosis

Exercise testing, 6-min walk, and stair climb in the evaluation of patients at high risk for pulmonary resection.

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