Human salivary arginase and its deficiency in argininaemia.

Arginase from normal human mixed saliva was characterized. The enzyme was completely activated after a preincubation of 20 min at 55 degrees C and a Mn2+ final concentration of 5 mmol/l. The pH optimum was 9.6-9.8, and the Km for L-arginine was 4.2 +/- 0.7 mmol/l. In normal saliva only one form was found, which was chromatographically identical with the cationic form of arginase in liver and blood cells. Salivary arginase was completely precipitated by rabbit antiserum against human liver arginase. Arginase activity was not detectable in the saliva of patients suffering from argininaemia. Enzyme activities in the saliva of the heterozygous parents and the unaffected daughter were 0.08, 0.07 and 0.12 U/mg protein, respectively, whereas the activities in the saliva of 60 healthy adults and 8 children were 0.17 +/- 0.11 and 0.16 +/- 0.06 U/mg protein, respectively.

[CNS tumors with the clinical picture of meningitis]. / ZNS-Tumoren unter dem klinischen Bild einer Meningitis.

Incidentally CNS tumours may simulate acute bacterial or viral meningitis, cerebral abscess, and tuberculous or luetic basal meningitis. 64 cases from the literature are analysed together with 2 personal observations. This form of presentation is found most frequently in high-grade malignancy, i.e. in glioblastoma, medulloblastoma and ependymoma. In the group of benign CNS neoplasms dermoid and epidermoid cysts are most often associated with the meningeal syndrome. The only criterion facilitating a differentiation between acute bacterial meningitis and CNS malignancy is CSF culture. In individual cases an afebrile course, a normal sedimentation rate, and a normal WBC count may help to differentiate. In the presence of basal meningitic or diencephalic symptoms related to a prolonged course discrimination between brain tumour an tuberculous or luetic meningitis may become extremely difficult. In these cases the determination of creatine kinase BB isoenzyme and carcinoembryonic antigen in CSF may overcome the difficulty.

[Congenital hypophosphatasia]. / Die kongenitale Hypophosphatasie.

Hypophosphatasia represents an inborn enzymatic deficiency characterized by a reduced activity of alkaline phosphatase in serum and tissue and an increased urinary excretion of phosphoethanolamine. 278 cases have been described until the end of 1980. Based on the age of manifestation and the predominant clinical findings the following classification is possible: The prenatal form (49 cases) with caput membranaceum, skeletal deformities and respiratory distress has a mortality of 100%. The early infantile form (94 cases) shows rickets-like osseous anomalies, dystrophy, craniostenosis, nephrocalcinosis, mortality amounting to 40%. Diagnostic features of the infantile-juvenile form (112 cases) are premature loss of deciduous teeth, bone deformities, rickets-like findings, and short stature. Mortality is only 1%. The adult form (23 cases) often remains undiscovered and has a good prognosis. It presents with pseudofractures and pains in the bones as chief symptoms. Heredity is autosomal recessive in all four types of hypophosphatasia. Possibly in the adult form there is an additional autosomal dominant inheritance. Alkaline phosphatase deficiency affects all tissues excepting the intestinal isoenzyme. Urinary excretion of phosphoethanolamine is elevated. Values for calcium and inorganic phosphorus in serum are usually normal or only slightly increased. Marked hypercalcemia is observed in severely diseased patients affected by the early infantile form. In these cases hypercalcemia often leads to nephrocalcinosis and renal insufficiency. Since alkaline phosphatase is equally active as pyrophosphatase, reduced phosphatase activity induces an accumulation of pyrophosphate in serum and its increased excretion in urine. The precise pathogenetic mechanisms of hypophosphatasia are still unknown. Possibly, the accumulation of pyrophosphate implies a disorder of calcification. Postnatal diagnosis is based on clinical findings in association with decreased alkaline phosphatase activity and increased phosphoethanolamine excretion. For the detection of heterozygotes additional biochemical markers should be tested. These include the determination of alkaline phosphatase in leucocytes and cultured skin fibroblasts, the calculation of tubular phosphate reabsorption and the analysis of pyrophosphate and pyrophosphatases. The difficulty in ascertaining the carrier state is that the measurement of a single parameter may give normal results.(ABSTRACT TRUNCATED AT 400 WORDS)

Measurement of arginine transport in human erythrocytes using their intrinsic arginase activity: implications for the treatment of familial hyperargininemia.

A procedure making use of the intracellular arginase activity has been developed for measuring the transport of arginine across the human erythrocyte membrane. (1) The arginine translocation is carrier mediated with simple Michaelis-Menten kinetics, showing one high affinity, low capacity transport system characterized by a half saturation constant KT of 0.177 +/- 0.036 mmol/1, and a maximum velocity VT of 0.332 +/- 0.068 mumol X h-1 X ml-1 cells. (2) Competition experiments with lysine, ornithine and leucine indicated that the arginine transport system in specific for dibasic amino acids. (3) The value calculated for the intracellular arginine concentration agreed well with the values obtained by independent methods. (4) The low arginine transport rate of human erythrocytes can explain the failure to lower the hyperargininemia in familial hyperargininemia by blood transfusion with normal arginase-containing erythrocytes.

Isolation and identification of 2-oxo-5-guanidinovaleric acid in urine of patients with hyperargininaemia by chromatography and gas chromatography/mass spectrometry.

An unknown guanidino-positive peak has been identified in urines of three sisters affected with hyperargininaemia. Identification was made on the basis of its similarity with the liquid and thin-layer chromatographic characteristics of enzymatically synthesized 2-oxo-5-guanidinovaleric acid. Identification was also made by combined gas chromatography-mass spectrometry of the unknown compound peak. The synthesis of enzymatically formed 2-oxo-5-guanidinovaleric acid was controlled by nuclear magnetic resonance and combined gas chromatography-mass spectrometry.

Excretion of alpha-keto-delta-guanidinovaleric acid and its cyclic form in patients with hyperargininemia.

alpha-Keto-delta-guanidinovaleric acid, in equilibrium with its cyclic form, has been identified in the urines of three sisters affected with hyperargininemia. Identification was achieved on the basis of its similarity with the enzymatically synthesized compounds.

Arginase and free amino acids in hyperargininemia: leukocyte arginine as a diagnostic parameter for heterozygotes.

Arginase activity and free amino acids were measured in plasma, erythrocytes and leukocytes of patients with hyperargininemia and in controls. There is no arginase activity in the leukocytes and erythrocytes of homozygous patients; in heterozygotes it is normal to low. The activity is 50 to 100 times higher in leukocytes than in erythrocytes. In controls as well as in patients and heterozygotes, the amino acid concentrations are higher in leukocytes than in plasma and erythrocytes. In addition to the increased arginine in the three blood compartments (the result of an arginase deficiency), there is also an obvious decrease of aspartic acid in the erythrocytes of the patients. The arginine concentration in leukocytes of heterozygotes is as high as in homozygotes and can therefore be used as a diagnostic parameter for heterozygotes.

Acute bone marrow necrosis caused by streptococcal infection.

An 8 year old boy with a furuncle on the dorsum of the right foot, high fever, severe pain in the right knee joint, slight hepatosplenomegaly, leukopenia and thrombocytopenia was admitted with the working diagnosis of acute leukemia. However, an abundance of necrotic cells, together with clusters of streptococci, could be demonstrated in the bone marrow aspirate. After antibiotic therapy the boy recovered completely.

[Non-leukemic disease of the central nervous system in children with acute lymphoblastic leukemia. I. Somnolence syndrome (author's transl)]. / Cerebrale Komplikationen der Leukämiebehandlung. I. Das Apathiesyndrom.

Prophylactic irradiation of the skull and intrathecal application of methotrexate has proven to be highly effective in preventing central nervous system disease in acute lymphoblastic leukemia or non-Hodgkin-lymphoma. Prophylactic treatment may be complicated by a somnolence syndrome occuring 4--8 weaks after the end of irradiation. The main features of this clinical entity are somnolence, lethargy, dullness, anorexia, headache, and vomiting. EEG frequently displays a distinct slowing of activity. All symptoms are reversible after 3--49 days. The syndrome clearly is consequence of skull irradiation. Its metabolic basis probably is transient disturbance of myelinization.

[Non-leukemic disease of the central nervous system in children with acute lymphoblastic leukemia. III. Subacute sclerosing panencephalitis (author's transl)]. / Cerebrale Komplikationen der Leukämiebehandlung. III. Die subakute sklerosierende Panencephalitis.

Diseases of the central nervous system (CNS) occurring during treatment of acute lymphoblastic leukemia (ALL) may be of leukemic or nonleukemic origin. Well known examples for CNS disease of nonleukemic origin are somnolence following prophylactic CNS irradiation, methotrexate-induced encephalopathy and acute infections caused by bacteria, viruses and toxoplasma gondii. Less known is the fact that also subacute CNS infections may occur in patients undergoing cytostatic therapy. Progressive multifocal leukoencephalopathy and subacute sclerosing panencephalitis (SSPE) are examples of this category of disease. Up to now 11 well documented cases of SSPE were reported occurring during treatment of ALL. Main clinical features were disorders of behaviour, consciousness and speach, seizures, paresis and inappropriate secretion of ADH. Several authors were able to demonstrate a deficiency of cellular immunity in patients with SSPE. In some cases this deficiency was consistent with reduced reactivity of T-lymphocytes against measles antigen only. The presence of inhibiting factors may be responsible for this phenomenon. Other authors found a normal or increased function of cellular immunity in SSPE; In hamsters occurrence of SSPE is induced by the simultaneous injection of hamster-adapted SSPE virus and antihamster lymphocyte serum. We, therefore, conclude that also in humans SSPE appearing during treatment of ALL is due to immunosuppression.

Extracerebrospinal metastases in glioblastoma. Case report and review of the literature.

A malignant glioblastoma adherent to the dura mater was removed from the parieto-occipital lobe in a 12-year-old boy. The site of the tumor was subsequently irridiated by 4000 rads of Cobalt-60. Five months later the boy was readmitted complaining of pains in the pelvis an in both thighs. X-ray examination of the pelvis demonstrated multiple metastases. Investigation of bone marrow revealed replacement of normal haematopoiesis by a tumor cell population histologically identical to that of the brain tumor. Reviewing the literature 58 reports on glioblastomas with extracerebrospinal metastases could be found. Metastases were preferably localized in cervical or mediastinal lymph nodes, lungs, bones, liver, dura mater, and operative flap. It is suggested that extracerebrospinal metastases occur most frequently after the tumor has infiltrated the cranium and extracranial soft tissues. In the case reported here it is speculated that the tumor spread to extraneural tissues after invading the dural veins. The possible occurrence of extracerebrospinal metastases in glioblastoma emphasizes the necessity of additional chemotherapy.

Excretion of guanidino-derivates in urine of hyperargininemic patients.

Quantitative determinations were made for seven guanidino-derivates in urine of patients affected with hyperargininemia, lysine cystinuria, healthy children and adults, goats and monkey. The amount of all seven guanidino-derivates excreted in the urine with the exception of guanidino-succinic acid was large in the case of hyperargininemic patients. Guanidino-succinic acid is found in traces in the urine of these patients, even after arginine loading tests. There is apparently no similarity concerning the guanidino-derivates between the patients with hyperargininemia, a pathological status, and the arginase deficiency in goats and monkeys, a physiological phenomenon.

Use of enzyme-loaded erythrocytes in in-vitro correction of arginase-deficient erythrocytes in familial hyperargininemia.

The capacity of arginase-deficient erythrocytes of patients with familial hyperargininemia to produce urea and to catabolize arginine can be increased in vitro by introducing human liver arginase into their erythrocytes. The results of this study on a specific human model show that it is possible to change the metabolic function of a genetically defective erythrocyte by incorporating exogenous human enzyme. The in vivo application of enzyme-loaded erythrocytes for enzyme replacement therapy of inborn metabolic errors in humans must await in vivo studies on animal models.

[The "juvenile" type of chronic myelogenous leukemia (author's transl)]. / Der sogenannte infantile Typ der chronischen myeloischen Leukämie

The juvenile type of chronic myelogenous leukemia (CML) is characterized by hemorrhagic diathesis, hepatosplenomegaly, generalized enlargement of lymph nodes, reduced erythro- and thrombopoiesis, leukemic infiltration of bone marrow, and decreased activity of leukocyte alkaline phosphatase. The disorder differs from the adult type by the early manifestation of anemia and thrombocytopenia, the minor degree of leucocytosis, the failure to demonstrate the Philadelphia chromosome, and the presence of fetal markers in the patients' erythrocytes. The persistence of fetal markers in erythrocytes and the clinical manifestation in infancy and early childhood suggest that the disease is congenital in origin. The occurrence of CML of the juvenile type in an 8-year-old boy, which is reported in this paper, favors a postnatal acquisition of the disorder. The significance of hematological and cytogenetic findings and new aspects of nosological classification are discussed.

Unsuccessful trial of gene replacement in arginase deficiency.

The Shope virus following cutaneous inoculation produces skin papillomas in rabbits and induces a virus-coded arginase in the squameous epithelium of these papillomas. The only discernible effect of the virus inoculated intravenously in rabbits and other animals was a decrease of the serum arginine concentration. Intravenous injection in 3 hyperargininemic patients, however, did not influence the underlying metabolic disease.

Familial hyperargininaemia.

A third case of hyperargininaemia occurring in one family was studied from birth. In cord blood serum arginine concentration was only slightly raised, but arginase activity in red blood cell haemolysates was very low. In the urine on day 2 a typical cystinuria pattern was present. Arginine concentration in serum increased to 158 mumol/100 ml on the 41st day of life. Later determinations of the arginase activity in peripheral blood showed values below the sensitivity of the method. Blood ammonia was consistently high, and cystinuria was present. The enzymatic defect was further displayed by intravenous loading tests with arginine. Serum urea values were predominantly normal or near the lower limit of normal, suggesting the presence of other metabolic pathways of urea synthesis. In urine there was no excretion of guanidinosuccinic acid, while the excretion of other monosubstituted guanidine derivatives was increased, pointing to a connexion with hyperargininaemia. Owing to parental attitude, a low protein diet (1-5 g/kg) was introduced only late. The infant developed severe mental retardation, athetosis, and spasticity.