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A new variant of mannosidosis with increased residual enzymatic activity and mild clinical manifestation
Abstract:
A partial deficiency of alpha-mannosidase was found in cultured skin fibroblasts, serum, and extracts of leukoytes in two siblings with mild mental retardation, delayed speech, a suggestion of coarse or full facies, and limited mobility of the large joints. All other lysosomal enzymes tested were within the normal range. Their father demonstrated intermediate alpha-mannosidase activity. The addition of 2 mM Zn++ caused a 40% increase of the alpha-mannosidase activity in cell extracts of both patients and control subjects. pH profiles and Cellogel electrophoresis of the patients' cells indicated 20% residual activity of the acidic alpha-mannosidase isoenzyme (pH optimum at 4.0), whereas the activity of the isozyme with pH optimum of 6.0 was normal. Increasing substrate concentration (1--10 mM) demonstrated a 4 to 5-fold increase in the apparent Km of the acidic alpha-mannosidase in the patients' fibroblasts. This residual activity, however, was apparently not sufficient for the normal catabolism of mannose-containing molecules, since electron microscopic examination of the cultured fibroblasts demonstrated numerous lysosomal storage bodies.
Insights
Mild intellectual disability and developmental delays in siblings were linked to a partial deficiency in alpha-mannosidase enzyme activity. This enzyme defect impacts mannose metabolism, leading to cellular storage.
Area of Science:
- Biochemistry
- Genetics
- Cell Biology
Background:
- Lysosomal storage diseases are a group of inherited metabolic disorders caused by enzyme deficiencies.
- Alpha-mannosidosis is a rare lysosomal storage disease resulting from deficient alpha-mannosidase activity.
Observation:
- Two siblings presented with mild mental retardation, delayed speech, coarse facies, and joint mobility issues.
- Cultured fibroblasts, serum, and leukocytes showed partial alpha-mannosidase deficiency, with intermediate activity in the father.
- Electron microscopy revealed lysosomal storage bodies in patient fibroblasts.
Findings:
- Patients exhibited 20% residual activity of the acidic alpha-mannosidase isoenzyme, with altered kinetics (increased Km).
- Zinc supplementation partially increased enzyme activity in both patients and controls.
- Other lysosomal enzyme activities were normal, indicating specificity of the defect.
Implications:
- The identified partial alpha-mannosidase deficiency explains the observed clinical phenotype and cellular pathology.
- Understanding the specific isoenzyme defect and its kinetic properties is crucial for diagnosis and potential therapeutic strategies.
- This study highlights the role of alpha-mannosidase in the catabolism of mannose-containing glycoconjugates.