The Natural History of Alpha-Mannosidosis (HUE-MAN)
The natural history study of the rare lysosomal disease alpha-mannosidosis will answer the question; why the rare disease develops as it does?
|Study Design:||Time Perspective: Prospective|
|Official Title:||A Multicenter, Multinational Study That Will Evaluate Clinical and Surrogate Parameters Known to be Affected in Alpha-Mannosidosis Patients|
|Study Start Date:||May 2007|
|Study Completion Date:||November 2009|
|Primary Completion Date:||September 2009 (Final data collection date for primary outcome measure)|
Human alpha-mannosidosis is a rare genetic disorder, caused by the lack of lysosomal alpha-mannosidase, resulting in mental retardation, skeletal changes, hearing loss and recurrent infections. The lack of alpha-mannosidase causes a disorder of glycoprotein catabolism associated with abnormal levels and excretion of small mannose-rich oligosaccharides.
Alpha-mannosidosis belongs to a group of lysosomal storage disorders that includes more than 50 different diseases, with a cumulative frequency of about 1:10.000 world wide. The incidence of alpha-mannosidase disease has been estimated to be 1 in 500.000 (Australian and Norwegian study). The disease is not specific to any ethnic group.
Etiology and Pathogenesis:
Lysosomal alpha-mannosidase (LAMAN), in the following called mannosidase, is an enzyme that cleaves alpha-mannosidic linkages during the ordered degradation of oligosaccharides. Only after degradation, can the sugars leave the lysosomes, the cell and later the body. The deficiency in mannosidase activity causes a block in the degradation of glycoproteins resulting in lysosomal accumulation of mannose-rich oligosaccharide chains. Consequently, these sugars accumulate in the lysosomes as they are too large to leave. Finally, the lysosomes increase in size, producing vacuoles and impaired cellular function is induced by an unknown mechanism.
Affected children are usually born apparently normal and their condition worsens progressively without any possible treatment available to prevent this evolution. The clinical findings in alpha-mannosidosis include a broad range of symptoms, from an early lethal form to less symptomatic, chronic forms often initially diagnosed in childhood. Alpha-mannosidosis is frequently associated with corneal opacities, aseptic destructive arthritis, metabolic myopathy and immune deficiency. In the past alpha-mannosidosis was classified into two forms. A more severe infantile (type 1) phenotype that include rapid, progressive mental retardation; hepatosplenomegaly; severe dysostosis multiplex; and often death between 3 and 12 years of age. The juvenile-adult phenotype (type 2) is characterized by a milder and more slowly progressive course with survival into adulthood. The distinctions are not absolute, and symptoms and lethality may vary. In affected children that are born healthy, there is a window of opportunity for a therapy initiated at an early age to contribute to normal development and the prevention of other disease related complications.
To assess the short-term, natural history of subjects diagnosed with Alpha-Mannosidosis To establish the range and diversity of clinical symptomatology To evaluate short term (24 months) changes in disease parameters
|Department of Pediatrics, Charles University|
|Prague, Czech Republic, 12000 Prague|
|University of Mainz|
|Mainz, Germany, 55101|
|Department of Medicine, University of Tromsoe|
|Tromsoe, Norway, N-9038|
|Willink Biochemical Genetics Unit,. Royal Manchester Children's Hospital|
|Manchester, United Kingdom, M27 4HA|
|Principal Investigator:||Michael Beck, MD||Children's Hospital, University of Mainz|
|Principal Investigator:||Ed Wraith, MD||Willink Biochemical Genetics Unit, Royal Manchester Childern's Hospital|
|Principal Investigator:||Jiri Zeman, MD||Department of Pediatrics, Charles University|
|Principal Investigator:||Dag Malm, MD||Department of Medicine, University of Tromsoe|