Natural history of alpha mannosidosis a longitudinal study

Michael Beck 0 Klaus J Olsen James E Wraith Jiri Zeman Jean-Claude Michalski Paul Saftig Jens Fogh Dag Malm 0 Center for Pediatric and Adolescent Medicine, University Medical Center , Langenbeckstrae 1, 55131 Mainz , Germany Background: Alpha-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. Methods: In this multicenter longitudinal study clinical data of 43 alpha-Mannosidosis patients were collected. In addition to objective clinical measurements biochemical assays were performed. Results: Data 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. Conclusions: This 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. - Background 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. Based on severity two distinct phenotypes of alphaMannosidosis have been described: A severe form (type I) with hepatomegaly and early death caused by severe infections [1], and an attenuated (mild) form (type II) with hearing loss, mental retardation and slow progression with survival into adulthood [2]. A further classification into a mild, moderate and severe type of alpha-Mannosidosis seems to be questionable as the clinical presentation varies considerably [3]. In this paper the term severe form (type I) and mild form (type II) are used. Type I alpha-Mannosidosis leads to early death, primarily caused by the involvement of the central nervous system and recurrent infections. 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. In alpha-Mannosidosis broad heterogeneity is seen not only in the clinical manifestations, but also in the spectrum of mutations of the alphaMannosidase gene (MAN2B1) that is located on chromosome 19p13.2. Currently, 125 different disease-causing mutations have been identified [4]. 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]. There are many reviews extensively describing the clinical manifestation of the lysosomal storage disorder alpha-Mannosidosis; a longitudinal study, however, evaluating the progression of the disease in a greater number of patients is lacking. Furthermore, the clinical reports that have been published so far have been based on a small number of patients and have not included quantitative measurements of clinical features. Therefore, the EU consortium HUE-MAN (Towards the Development of an Effective Enzyme Replacement Therapy for Human Alpha-Mannosidosis) was established in order to conduct a survey of the natural history study of the human disease alpha-Mannosidosis [7]. The purpose of this study was also to define possible clinical endpoints for future clinical trials. In addition, clinical phenotypes of selected European patients have been determined and important medical data such as the results of clinical and neurological investigations, ophthalmological and hearing examinations, lung and heart function and measurement of general endurance using the 6-minute walk test (6MWT) and 3-minute stair climb test (3MSCT) were collected. Methods Clinical evaluation The aim of this multicenter, multinational prospective study was to evaluate clinical and surrogate parameters known to be affected in alpha-Mannosidosis patients. The design of this observational study was open, non randomized with several objective clinical measurements, laboratory measurements and some investigator evaluated parameters. In addition, some patient assessed measurements (Quality of Life and Health Questionnaires) were collected. Informed consent was obtained prior to any study related activity and the subject, or the subjects legal guardian, provided consent using the Ethics Committee (EC)-approved consent form and with compliance to local and European Union regulations, International Conference on Harmonization (ICH) and Good Clinical Practice (GCP) standards. Only patients with the mild form (type II) were entered into this study if they had a documented deficiency of serum or leukocyte acid alpha-Mannosidase enzyme activity level. Patients had to be excluded from the study if they had received a bone marrow transplantation or had used an investigational drug within 30 days prior to study enrollment. Known medical conditions or serious intercurrent illness that could significantly interfere with study compliance were further exclusion criteria. In all subjects, clinical symptoms (with special emphasis on hearing difficulties and visual impairment) and history of infections, surgical procedures, hospitalizations and use of medication were recorded. The physical examination included vital signs, height and weight, eva (...truncated)