A new variant of mannosidosis with increased residual enzymatic activity and mild clinical manifestation

A partial deficiency of α-mannosidase was found in cultured skin fibroblasts, serum, and extracts of leukocytes 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 α-mannosidase activity. The addition of 2 mM Zn⁺⁺ caused a 40% increase of the α- 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 a-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 4to 5-fold increase in the apparent K_m of the acidic a-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. Speculation: This family supports the concept that mannosidosis is not a homogeneous syndrome but manifests clinical as well as biochemical heterogeneity. The partial activity of acidic α-mannosidase observed in the cultured fibroblasts (approximately 20%) was insufficient for normal catabolism and allows accumulation of α-mannoside-containing substrates leading to the abnormal phenotype. Nevertheless, this deduction is based on in vitro studies using a synthetic substrate. The observation that Zn⁺⁺ causes a 40% stimulation of acidic a-mannosidase activity in the patients' cells agrees with previous findings and may be of significance in the treatment of such cases.