Alpha- and beta-mannosidoses.

Area of Science:

• Biochemistry and Genetics
• Lysosomal Storage Diseases
• Metabolic Disorders

Background:

• Mannosidoses are a group of rare genetic disorders characterized by the accumulation of mannose-containing oligosaccharides.
• Accurate diagnosis and carrier detection are crucial for genetic counseling and understanding disease progression in mannosidoses.
• Existing animal models may not fully recapitulate the human pathology of beta-mannosidosis.

Purpose of the Study:

• To describe clinical, pathological, and biochemical findings in human mannosidoses.
• To evaluate diagnostic methods for beta-mannosidosis, focusing on carrier detection.
• To investigate the metabolic basis and cellular processing of accumulated substances in beta-mannosidosis.

Main Methods:

• Analysis of clinical, pathological, and biochemical data from patients with mannosidoses.
• Family studies utilizing granulocyte-rich white cell fractions for carrier detection.
• Metabolic labeling with [3H] mannose in cultured skin fibroblasts to identify accumulated compounds.

Main Results:

• Granulocyte-rich white cell fractions proved effective for carrier detection in beta-mannosidosis.
• Accumulation of Man beta 1-4GlcNAc was demonstrated in fibroblasts from a beta-mannosidosis patient.
• Evidence suggests alternative lysosomal egress pathways for the accumulated compound, including secretion.
• Beta-mannosidase deficient goats, while showing enzyme deficiency, present a more severe phenotype and different storage material, questioning their utility as a human model.

Conclusions:

• Granulocyte-rich white cell fractions are the preferred method for beta-mannosidosis carrier detection.
• Accumulated Man beta 1-4GlcNAc in fibroblasts highlights a specific metabolic defect and suggests novel cellular processing mechanisms.
• Beta-mannosidase deficient goats are not considered a faithful animal model for human beta-mannosidosis due to significant clinical and biochemical differences.