Natural history of alpha mannosidosis a longitudinal study

Michael Beck,Klaus J Olsen,Paul Saftig,Dag Malm,Jean-Claude Michalski,Jiri Zeman,Jens Fogh,James E Wraith

doi:10.1186/1750-1172-8-88

Abstract

BackgroundAlpha-Mannosidosis is a rare lysosomal storage disorder, caused by the deficiency of the enzyme alpha-Mannosidase. Clinically it is characterized by hearing impairment, skeletal and neurological abnormalities and mental retardation. In order to characterize the clinical features and disease progression of patients affected by alpha-Mannosidosis, a survey study was conducted. 43 patients from 4 European countries participated in this longitudinal study. Age range of the participants was 3 to 42 years. For each patient a medical history, complete physical and neurological examination, joint range of motion and assessment of physical endurance and of lung function were completed. In addition, serum and urinary oligosaccharide levels were analysed.MethodsIn this multicenter longitudinal study clinical data of 43 alpha-Mannosidosis patients were collected. In addition to objective clinical measurements biochemical assays were performed.ResultsData analysis revealed a wide spectrum of clinical presentation regarding the severity and disease progression. Most clinical abnormalities were observed in the musculoskeletal and neurological system. All patients showed mental retardation and hearing loss from early childhood. An impairment in physical endurance was revealed by the 6-minute walk and 3-minute stair stair climb tests. There was only slight progression of a few clinical findings: Psychiatric troubles in both groups essentially, and respiratory dysfunction under 18 years. The serum and urinary oligosaccharide levels were increased in all affected individuals and correlated well with the 6-minute walk and 3-minute stair climb test results.ConclusionsThis study confirms that alpha-Mannosidosis is a very heterogeneous disorder regarding both, disease severity and progression. As it has been shown that Mannosidosis patients are able to perform lung function tests and the 6MWT and stair-climb test, these clinical parameters apparently can be used as clinical endpoints for clinical trials. Oligosaccharide levels appeared correlated with functional testing and may serve as biomarkers of disease severity, progression and response to treatment.Trial registrationClinicalTrials.gov Identifier = NCT00498420 and EuropeanCommission FP VI contract LHSM-CT-2006-018692.

Highlights

Alpha-Mannosidosis is a rare lysosomal storage disorder, caused by the deficiency of the enzyme alpha-Mannosidase
In patients affected by the mild form first symptoms such as hearing loss and skeletal abnormalities are often seen before the age of 10 years; later ataxia and mental retardation become more and more evident
The prevalence of alpha-Mannosidosis is not exactly known, Meikle et al have calculated a prevalence of 1 case in 1 million live births [5], a similar prevalence was observed in the Netherlands [6]

Summary

Introduction

Alpha-Mannosidosis is a rare lysosomal storage disorder, caused by the deficiency of the enzyme alpha-Mannosidase. It is characterized by hearing impairment, skeletal and neurological abnormalities and mental retardation. Alpha-mannosidosis (OMIM 248500) is a rare lysosomal storage disorder caused by the deficiency of alphaMannosidase (MAN2B1, EC 3.2.1.24), a lysosomal enzyme responsible for the degradation of N-linked oligosaccharides. Alpha-mannosidosis is a progressive disorder, and characteristic features include mental retardation, coarse facial appearance, hearing loss, skeletal deformities, central nervous system involvement and immune defects. In patients affected by the mild form first symptoms such as hearing loss and skeletal abnormalities are often seen before the age of 10 years; later ataxia and mental retardation become more and more evident. The prevalence of alpha-Mannosidosis is not exactly known, Meikle et al have calculated a prevalence of 1 case in 1 million live births [5], a similar prevalence was observed in the Netherlands [6]

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