Seppo Autio

Salla disease: A new lysosomal storage disorder with disturbed sialic acid metabolism

Salla disease is a lysosomal storage disorder associated with increased urinary excretion of free sialic acid. The main clinical features in 34 patients were severe psychomotor retardation of early onset, ataxia, athetosis, rigidity, spasticity, and impaired speech. Growth retardation, thick calvarium, and exotropia were present in about half the patients. The amplitude of EEG decreased progressively with increasing age. Life span appears to be normal; the age range of the patients was 3 to 63 years. Genealogic studies suggest an autosomal mode of inheritance. A thin-layer method is described for the detection of increased urinary free sialic acid excretion. The basic defect is so far unknown.

Enzymatic Diagnosis and Carrier Detection of Aspartylglucosaminuria Using Blood Samples

Extract: The activity of the glycoprotein degrading lysosomal hydrolase, 4-L-aspartylglycosylamine amido hydrolase (AADGase, EC.3.5.1.26), was measured in plasma, buffy coat leukocytes, and separated lymphocytes (Ficoll separation) from 16 patients with aspartylglucosaminuria (AGU), 29 obligate heterozygotes, and 30 control subjects. In lymphocytes the AGU patients had unmeasurable or minimal AADGase activity with a mean of 3.9 U. The obligate heterozygotes showed AADGase activities ranging from 5 to 69 U with a mean of 34.1 U. Enzyme activities in the control group ranged from 91 to 243 U with a mean of 127.9 U, and were clearly separated from the values of the heterozygotes.In leukocytes the AGU patients had unmeasurable enzyme activity and obligate heterozygotes had enzyme levels closely similar to those in the lymphocytes from the same individuals. The AADGase activity in the leukocytes of the control group displayed a much wider variation than in the lymphocytes, ranging from 22 to 132 U with a mean of 70.7 U.In plasma the AGU patients had undetectable AADGase activity. The mean enzyme level of obligate heterozygotes was 72.2 U and that of control individuals 107.2 U, but the overlap between the groups was extensive. The results indicate that homozygous deficiency of AADGase, i.e., aspartylglucosaminuria, can be reliably diagnosed using plasma, leukocytes, or separated lymphocytes. For carrier detection only separated lymphocytes allow a satisfactory differentiation between heterozygous and normal individuals.A group of 31 siblings of verified AGU cases and 11 children of identified carriers, whose spouses had normal AADGase activity, were investigated using the lymphocyte assay. The observed and expected frequencies (on the basis of Mendelian probabilities) were closely similar, suggesting that the lymphocyte assay can be used reliably for carrier detection.Speculation: Demonstration of AADGase deficiency in plasma or in white blood cells offers an alternative method for the diagnosis of aspartylglucosaminuria. Large scale screening programs for AGU carrier detection with the lymphocyte enzyme assay are not considered practical and justified at present. Carrier screening among relatives of known AGU patients is, however, medically, economically, and psychologically advantageous, particularly since prenatal diagnosis and the possibility of preventive abortion can be offered to carrier-carrier matings.

Prenatal diagnosis and fetal pathology of I-cell disease (mucolipidosis type II)

Increased activity of several lysosomal hydrolases was demonstrated in amniotic fluid from a fifteenth week pregnancy in which the fetus had I-cell disease. Cultured cells from amniotic fluid had a decreased activity of the same enzymes. The diagnosis of I-cell disease was later confirmed by enzyme assays in cell cultures of fetal skin and by morphologic studies of several tissues from the aborted fetus. Electron microscopic studies of the fetal tissues and cultured fibroblasts had large numbers of typical inclusions of I-cell disease, thus substantiating the diagnosis and intrauterine manifestation of the disease. The results indicate that prenatal diagnosis of I-cell disease is possible with enzyme assays of amniotic fluid and in cultures of fetal cells from the fluid. Enzyme studies of amniotic fluid can provide a preliminary diagnosis within a few hours, but it is suggested that the definitive diagnosis should be based on assays in cultured cells from amniotic fluid.

Mannosidosis: Detection of the disease and of heterozygotes using serum and leucocytes

Abstract α-D-mannosidase activity in serum and leucocytes from normal individuals, patients with mannosidosis and their parents was measured at pH 4.4 and pH 6.0. When the results were expressed as total activity or specific activity at pH 4.4 in both tissues, or as a ratio of enzyme activity at the two pH conditions in serum, the disease could be diagnosed, but the heterozygotes could not be distinguished from the controls. However, all three groups could be recognised when acid α-mannosidase activity was related to total activity in serum and leucocytes. The distribution of α-mannosidases, as separated by ion-exchange chromatography was different in each tissue. The serum profile was unique, all components having substantial “neutral” activities which are unaltered in mannosidosis and carriers.

Detection of heterozygotes for aspartylglucosaminuria (AGU) in cultured fibroblasts

SummaryAspartylglucosaminuria (AGU) is an autosomally recessively inherited lysosomal storage disorder due to deficiency of a glycoprotein degradating enzyme 4-L-aspartylglycosylamine amido hydrolase (AADGase). Heterozygote detection in AGU is at the present only possible with enzyme assays on cultured fibroblasts. We have determined AADGase activity on cultured fibroblasts from 40 siblings of verified AGU patients in order to detect the heterozygotes among them. The results indicate that 24 cell lines had an AADGase activity compatible with hterozygous state of AGU and 16 cell lines had normal AADGase activity. The results are in good agreement with the theoretical expectations. AADGase activity was also determined in 9 cell cultures from amniotic fluid samples of midterm pregnancies. Amniotic cell cultures had AADGase activities similar to normal fibroblast cultures. AADGase assay on cultured cells from amniotic fluid is potentially applicable for prenatal diagnosis of AGU in high risk pregnancies.

Elevated levels of serum dolichol in aspartylglucosaminuria.

Slightly elevated serum dolichol levels have so far been demonstrated only in alcoholics. We now report two diseases with exceptionally high serum dolichol levels. They are autosomal, recessively inherited lysosomal storage diseases, aspartylglucosaminuria (AGU) and mannosidosis. In 16 patients with AGU the mean serum level of total dolichols (457 +/- 43 ng/ml) was more than two-fold when compared to healthy controls (170 +/- 4 ng/ml). In two patients with mannosidosis the levels were almost two-fold. The percentage distribution of the dolichol homologues with 18, 19 or 20 isoprene units did not differ between the patients and controls. The inclusion of an additional control group excluded the possible influence of mental retardation and imparied moving ability on the results. Elevated serum dolichols in patients with lysosomal storage diseases may reflect a disturbance in lysosomal function and serve as a diagnostic marker. The biochemical mechanisms leading to this phenomenon remain to be established.

Peroral lynestrenol and arterial disease in mentally retarded women. A case-control study based on autopsy findings.

Abstract. Autopsy findings from 170 non‐smoking and mentally retarded women aged 12–51 years were analysed for any epidemiological association between the use of peroral lynestrenol for inducing therapeutic amenorrhea (TA) and arterial disease Eighty‐six women had received lynestrenol continuously for an average of 81 months (range 2–220 months) and the other 84 had not After exclusion of 6 cases with known risk factors (diabetes, hypertension) predisposing to arterial disease, pathological arterial changes were found in 16 patients, 10 of them belonging to the TA group and 5 to the non‐lynestrenol group The incidence of arterial disease at autopsy at the age of 35 or more was 8/19 in TA patients and 1/15 in non‐lynestrenol patients (p = 0.078) The benefits of prolonged TA induced by lynestrenol in this group of patients must be weighed very carefully against the Dossible risks involved

Incidence of Neural‐tube Defects in Southern Finland from 1970 to 1983

of autoantibodies to a soluble cytoplasmic antigen in systemic lupus erythematosus and other connective tissue disease.’ Journal of Rheumatology. 6, 189-195. 3. Provost, T. T., Ahmed, R. R., Maddison, P., Reichlin, M. (1977) ‘Antibodies to cvtoplasmic antigens in lupus erythematosus: serological marker for systemic disease.’ Arthritis and Rheumatism, 20, 1457-1463. 4. Scott, J. S., Maddison, P. J., Taylor, P. V., Esscher, E., Scott, O., Skinner, R. P. (1983) ‘Connective-tissue disease antibodies to ribonucleoprotein, and congenital heart block.’ New England Journal of Medicine, 309, 209-2 12. 5. Litsey, S. E., Noonan, J. A,, O’Connor, W. N., Cottrill, C. M., Mitchell, B. (1985) ‘Maternal connective tissue disease and congenital heart block.’ New England Journal of Medicine,

Psychological Obstacles to Genetic Education

Medical knowledge and psychic reactions were studied in families affected by a progressive autosomal recessive disease, aspartylglucosaminuria. The information was given mainly in simple but written form. The subjects appeared to accept little correct information. Conversation did not appear to be of much value and intense emotional reactions were provoked. Attitudes towards the disease and patients could be divided into three groups: rational (30%), defensive (50%), and hostile (20%). The importance of early and repeated personal communication is emphasized.

CULTURED SKIN FIBROBLASTS IN DISORDERS OF GLYCOPROTEIN CATABOLISM AND I‐CELL DISEASE

during pregnancy might result in malformation. So far there is not good evidence that this is an important factor in humans, and it seems that neither fit frequency nor duration of epilepsy is related to the development of a malformed baby4. Obstetric factors are unlikely to be important. Hyperemesis, vaginal haemorrhage and toxaemia have been reported to be twice as common in the pregnancies of epilepticslO, but the relationship of these to anomalies is uncertain. Social factors are important, but do not fully explain the facts. Epileptic mothers include an excess of lower social groups (which themselves have an excess of congenital anomalies), but when each pregnancy has been matched for each confounding factor it still emerges that the epileptic group has an increased incidence of abnormal babies4, a. Genetic factors deserve further study, as there may be a genetic relationship between epilepsy and certain malformations. This would be particularly important for the many families in which both parents have epilepsy. Unfortunately there have been too many male chauvinists in this research field, and in considering only the mother they have neglected the man’s contribution to the abnormal child. At present it seems most probable that the teratogenicity of epilepsy may be explained by environmental factors, such as anti-convulsants, operating upon a pregnancy that is susceptible because of genetic predisposition. ROY MEADOW Department of Paediatrics and Child Health, University of Leeds, 27 Blundell Street, Leeds LS1 3ET.