A New Variant of Mannosidosis with Increased Residual Enzymatic Activity and Mild Clinical Manifestation

Abstract

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 ...

Mannosidosis in a Sudanese Child: Report of a Case with Review of the Literature

“…The Km app of the acidic mannosidase in the latter patients was elevated fourfold. The biochemical characteristics of the acidic mannosidase in our case were close to those reported by Bach et al 6 and reconfirm the presence of mannosidosis in the Middle East. The reasons for the altered lysosomal enzyme activities other than acidic mannosidase in lymphocyte and fibroblasts of our patient remain to be established (Table 1).…”

“…The present report as well as the article by Bach et al 6 indicate the presence of mannosidosis in the Middle East and Africa. It should be recommended that the list of differential diagnoses include mannosidosis in patients with Hurler-like features.…”

“…16 The lymphocyte acidic mannosidase was 0.6% in lymphocytes and 4% in fibroblasts in the patients reported by Vidgoff et al 4 ; the Km app value was not reported. In the variants of mannosidosis from Jerusalem reported by Bach et al, 6 the residual activity was 17% and 55% in fibroblasts and 3.4% and 5.7% in leukocytes at 2 mM substrate concentration. The Km app of the acidic mannosidase in the latter patients was elevated fourfold.…”

“…[3][4][5] Most of the cases have been reported from Europe and the United States. Apart from one family report, 6 we are not aware of case reports from Africa or the Middle East. This is a report of a Sudanese child whom we recently encountered.…”

Natural history of alpha mannosidosis a longitudinal study

“…Alpha-mannosidosis is a progressive disorder, and characteristic features include mental retardation, coarse facial appearance, hearing loss, skeletal deformities, central nervous system involvement and immune defects. Based on severity two distinct phenotypes of alpha-Mannosidosis have been described: A severe form (type I) with hepatomegaly and early death caused by severe infections [1], and an attenuated (mild) form (type II) with hearing loss, mental retardation and slow progression with survival into adulthood [2]. A further classification into a mild, moderate and severe type of alpha-Mannosidosis seems to be questionable as the clinical presentation varies considerably [3].…”