Rebecca S. Wappner

Effectiveness of Enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: A report from the Gaucher registry

PURPOSE Gaucher disease is the first lysosomal storage disorder to be treated with macrophage-targeted enzyme replacement therapy. Previous studies in relatively small numbers of patients demonstrated short-term efficacy of this treatment. This study describes the effects of 2 to 5 years of treatment on specific manifestations of type 1 Gaucher disease. SUBJECTS AND METHODS Physicians reported data from 1028 patients to the Gaucher Registry. Assessment of response included serial measurements of hemoglobin concentration, platelet count, liver and spleen volumes, and the occurrence of bone pain and bone crises. RESULTS Among anemic patients, hemoglobin concentration increased to normal or near normal within 6 to 12 months, with a sustained response through 5 years. In thrombocytopenic patients with intact spleens, the most rapid response occurred during the first 2 years, with slower improvement thereafter. The likelihood of achieving a normal platelet count decreased with increasing severity of baseline thrombocytopenia. In patients who had undergone splenectomy, platelet counts returned to normal within 6 to 12 months. Hepatomegaly decreased by 30% to 40% during follow-up; splenomegaly decreased 50% to 60%, but rarely to volumes below five times normal size. In patients with pretreatment bone pain or bone crises, 52% (67/128) were pain free after 2 years and 94% (48/51) reported no additional crises. CONCLUSION Enzyme replacement therapy prevents progressive manifestations of Gaucher disease, and ameliorates Gaucher disease-associated anemia, thrombocytopenia, organomegaly, bone pain, and bone crises.

Mevalonic Aciduria — An Inborn Error of Cholesterol and Nonsterol Isoprene Biosynthesis

A two-year-old boy presented with severe failure to thrive, developmental delay, anemia, hepatosplenomegaly, central cataracts, and dysmorphic features. Quantitative analyses of urinary organic acids revealed massive excretion of mevalonic acid, a metabolic precursor of cholesterol and nonsterol isoprenes: 46,000 to 56,200 mmol per mole of creatinine, as compared with 0.2 to 0.3 mmol per mole in normal children. The mevalonic acid concentration in plasma was also greatly increased at 440 mumol per liter (normal, less than 0.05). The activity of mevalonate kinase, the enzyme that catalyzes the first step in mevalonate metabolism, was severely deficient in the patients fibroblasts, lymphocytes, and lymphoblasts. In the subsequent pregnancy of the patients mother, gas chromatography-mass spectrometry demonstrated a marked elevation of mevalonic acid in the mothers urine and a 3000-fold elevation, as compared with control levels in the amniotic fluid, suggesting that the fetus was affected. The diagnosis was confirmed by demonstration of the deficiency of mevalonate kinase in amniocytes and ultimately in liver from the abortus. Intermediate activities of the enzyme in both parents indicated an autosomal recessive mode of inheritance. These observations identify an inherited disorder of cholesterol and nonsterol isoprene biosynthesis in humans.

Individualization of long-term enzyme replacement therapy for Gaucher disease

Gaucher disease, the most common lysosomal storage disorder, is a heterogeneous condition affecting multiple organ systems. Patients with nonneuronopathic (type 1) Gaucher disease may suffer from hepatomegaly, splenomegaly, thrombocytopenia, bleeding tendencies, anemia, hypermetabolism, skeletal pathology, growth retardation, pulmonary disease, and decreased quality of life. Enzyme replacement therapy (ERT) with mannose-terminated glucocerebrosidase (imiglucerase, Cerezyme, Genzyme Corporation, Cambridge, MA) reverses or ameliorates many of the manifestations of type 1 Gaucher disease. However, due to the variable pattern and severity of disease, and the uncertain manner of progression, implementation of treatment, choice of initial and maintenance imiglucerase dose, and evaluation of the therapeutic response must be tailored to the individual patient. For the past 14 years, the US Regional Coordinators of the International Collaborative Gaucher Group have individually and collectively developed extensive clinical experience in managing patients with Gaucher disease. In this review, we present recommendations for initial imiglucerase treatment and subsequent dose adjustments based on a schedule of regular assessment and monitoring, and achievement and maintenance of defined therapeutic goals.

Mevalonic aciduria: Family studies in mevalonate kinase deficiency, an inborn error of cholesterol biosynthesis

Mevalonic aciduria was found in a 19-month-old boy with severe failure to thrive and developmental delay (Sweetman et al., 1985; Hoffmann et al., 1986). Cardinal manifestations included recurrent anaemia, mild hepatosplenomegaly, bilateral central cataracts and dysmorphic features. Serum cholesterol was low (1.82.1mmol/L). Urinary organic ~acids were normal except for a large elevation of mevalonic acid, an intermediate in cholesterol biosynthesis. The activity of meval0nate kinase (ATP: mevalonate-5-phosphotransferase, EC 2.7.1.36), the enzyme catalysing the second committed step in cholesterol biosynthesis, was severely deficient in the patients fibroblasts, lymphocytes and lymphoblasts. We have developed an optimized assay for mevalonate kinase in extracts of cultured human fibroblasts utilizing [2-14C]mevalonate as substrate. The enzymatic products, [2-14C]mevalonate-5-phosphate and [2-14C]mevalonate-5-pyrophosphate, were separated and quantified by cellulose thin-layer chromatography. With heterozygote detection as a goal, we undertook a study of family members of the patient with mevalonic aciduria. This report presents the activities of mevalonate kinase in lysates of lymphocytes isolated from whole blood of these individuals and of controls.

Hurler syndrome: alpha-L-iduronidase activity in leukocytes as a method for heterozygote detection.

Extract: α-L-Iduronidase activity and β-galactosidase activity were determined in mixed leukocyte preparations in 10 families in which the Hurler syndrome had occurred. Affected patients, heterozygotes, and normal subjects were clearly distinguished by α-L-iduronidase activity alone. Patients had 0–3%, obligate heterozygotes 19–60%, and normal subjects 83–121% of the mean normal activity. There was no overlap between heterozygotes and normal subjects. Although the mean α-L-iduronidase to β-galactosidase ratio was significantly lowered in heterozygotes when compared with that of normal subjects, appreciable overlap was noted between the two groups.Speculation: Carriers and affected individuals for Hurler syndrome can be reliably detected using mixed leukocyte preparations for the determination of α-L-iduronidase activity. As technology improves enzyme assays will become reliable enough for determination of heterozygotes for an increasing number of disorders, thus enabling more thorough and accurate genetic counseling.

Letter to the Editor: White Cell Ornithine Transcarbamylase Activity Cannot Detect the Liver Enzyme Deficiency

Letter to the Editor: White Cell Ornithine Transcarbamylase Activity Cannot Detect the Liver Enzyme Deficiency

A NEW VARIANT OF GALACTOSEMIA

Galactosemia is an autosomal recessive defect in which the enzyme gal-l-P uridyl transferase (transferase) is decreased or absent in several tissues. Several variants of this enzyme have previously been described. We report here a family in which the proband CB has a new variant of transferase. CB developed anorexia and jaundice shortly after being placed on Similac. The diagnosis of galactosemia was considered when the Beutler fluorescence screening test revealed no detectable transferase activity. Studies of transferase properties; i.e. activity, heat stability at 50° C, and starch gel electrophoretic mobility of family members revealed the following.These data suggest that at least three alleles are present at the transferase loci in this family. The mother is a classic heterozygote; the father is a double heterozygote for the fast-moving and unstable transferase; and the patient is a double heterozygote for the fast-moving and classic galactosemia transferase.