SummaryA partial deficiency of a-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 a-mannosidase activity. The addition of 2 mM Zn++ caused a 40% increase of the amannosidase 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 a~~a r e n t K, of the acidic a-mannosidase in the patients' fibrobiasts. This residual activity, however, was apparently not sufficient for the normal catabolism of mannose-containing molecules, since electron microscopic examination of the culture; fibroblasts demonstrated numerous lysosomal storage bodies.
SpeculationThis family supports the concept that mannosidosis is not a homogeneous syndrome but manifests clinical as well as biochemical heterogeneity. The partial activity of acidic a-mannosidase observed in the cultured fibroblasts (approximately 20%) was insufficient for normal catabolism and allows accumulation of amannoside-containing substrates leading to the abnormal phenctype. Nevertheless, this deduction is based on in vitro studies using a synthetic substrate. The observation that Znf+ 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.Mannosidosis, a deficiency of the acidic form of a-mannosidase (EC 3.3.1.24) (14, 15), results in the accumulation of mannose-rich glycosylated compounds in the lysosomes of various tissues (1,12,15) and the excretion of similar compounds in the urine (13,17,18). Clinically, the disorder presents with mildly coarse facies, mild hepatosplenomegaly, skeletal changes, and psychomotor retardation. Human a-mannosidase is separable into two distinct isoenzymes in fibroblasts (16) and three distinct isoenzymes in liver (7). In the liver, two isoenzymes, supposedly lysosomal, have acidic optimal activity (pH 4.0-4.5), whereas the third, a nonlysosomal component, is optimally active at pH 6.0 (7). Patients with mannosidosis demonstrate either a complete deficiency or reduced activity of the acidic isoenzymes. Structural changes in the acidic isoenzyme demonstrate a 25-to 50-fold increase in apparent K, values and high susceptibility to heat inactivation 10 (4, 6, 8), whereas neutral a-mannosidase is normal (7, 11). The normal neutral a-mannosidase activity may explain the differing residual enzyme activities in various tissues of these patients. We wish to describe a family whose clinical and biochemical findings suggest a new variant of ...