Natural history of alpha mannosidosis a longitudinal study

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.

Ultra‐orphan lysosomal storage diseases: A cross‐sectional quantitative analysis of the natural history of alpha‐mannosidosis

“…However, it is possible, that screening patient populations with urine oligosaccharide excretion may be more cost effective in countries without funding for exome sequencing approaches. In our study, reported clinical features in alpha‐mannosidosis were developmental delay or cognitive impairment, bone anomalies, coarse facies, hearing loss, recurrent airway infections, dysmorphism, organomegaly, hernias, ataxia, short stature, and spasticity in descending order of frequency, which corroborates and expands the data presented by Beck et al Cluster analysis enabled the mathematical distinction of five statistically similar subgroups, which clinically exhibited overlapping neurological as well as generalized disease features suggesting that pattern of clinical features and manifestations are heterogeneous and a continuous spectrum rather than well‐delineated clinical subtypes. This observation is in accordance with other lysosomal storage disorders such as free sialic acid storage disease, Farber disease or Gaucher disease …”

“…Our literature search was conducted within Pubmed and did not include other databases such as Embase, therefore we cannot exclude the possibility that published cases might be missed. Beck et al assessed 43 patients over 2 years and focused on biomarker and softer clinical endpoints . The advantage of the latter study is that it was conducted prospectively and captured quantitative outcomes and their variability over time under a single protocol in a multicenter setting.…”

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

“…Thus, the values given at spirometry may be inaccurate for some of the patients [17, 18] and the relationship between the FVC% and the different subgroups may be uncertain.…”

Neuroimaging Findings in Pediatric Genetic Skeletal Disorders: A Review

“…General information: Rare, progressive lysosomal storage disorder due to deficiency of alpha‐mannosidase ( MAN2B1 ). Two distinct phenotypes: a severe form (type 1) with hepatomegaly and early death, and a mild form (type 2) with hearing loss, developmental delay, and slow progression with survival into adulthood . Incidence of .2 in 100,000 live births.…”