Long-term follow-up of 12 patients with the late-onset variant of argininosuccinic acid lyase deficiency: no impairment of intellectual and psychomotor development during therapy.

To date, two variants of argininosuccinic acid lyase deficiency, the second most common enzymatic defect of the urea cycle, have been described. Most of the previous studies reported on outcomes involving neurological and intellectual impairment in affected children. This study is the first to demonstrate that the physical and mental development of such children can be normal and adequate for their age if they are treated with a low-protein diet and/or arginine supplements. Since 1973, 12 Austrian children suffering from argininosuccinic acid lyase deficiency have been detected in the Austrian Neonates Screening Program and could have been followed up. After confirmation of diagnosis, all the children were administered a daily arginine supplement (3 to 4 mmol/kg per day) in conjunction with either a normal diet or a special diet in which protein intake was restricted to 1.2 to 1.5 g/kg per day. Routine checks, including physical examination, determination of biochemical parameters, and IQ tests, were performed so the further development of these 12 patients with respect to treatment could be observed. It can be concluded that early treatment of partial argininosuccinic acid lyase deficiency results in normal intellectual and psychomotor development.

[21 years "Austrian Program for Early Detection of Congenital Metabolic Abnormalities." Did the screening programs also contribute scientific knowledge?]. / 21 Jahre "Osterreichisches Programm zur Früherfassung angeborener Stoffwechselanomalien". Brachten die Screening-Programme auch wissenschaftliche Erkenntnisse?

Before the introduction of the programme for the early detection of inborn errors of metabolism the discovery of the biochemical abnormality was merely the proof of a diagnoses based on characteristic features. Neonatal screening inverted the process and the biochemical anomaly became primary marker and symptoms were prevented by treatment. In reality, the subsequent development of symptoms was uncertain. In this way a great number of hitherto unknown metabolic anomalies was discovered. Screening methods for the first time allowed correct determination of the incidence of inherited disorders in different population. Important differences were uncovered intra- and internationally. Screening centres performing psychometry not only in homozygote patients, but also in heterozygote parents found that the heterozygotes for phenylketonuria (PKU) in spite of normal blood phenylalanine levels, are slightly subnormal intellectually. This is true also for early- and satisfactory-treated homozygotes. Increased intracellular phenylalanine concentrations in both could explain this slight intellectual subnormality which is, apparently, independent of the blood level. At least three treatment centres observed a decrease in IQ of 9 to 13 points between 1 and 8 years of age in early- and well-treated PKU patients being mostly still in the normal range. The IQ curves are parallel for these tree centres and independent of the age of diet discontinuation.

[Toxoplasmosis investigation of pregnant women and newborn infants (author's transl)]. / Die Toxoplasmose-Untersuchung von Schwangeren und Neugeborenen

In the serological screening of pregnant women for the prevention of congenital toxoplasmosis a positive test with low titre in the first trimester indicates almost with certainty a preconceptional infection. The probability that such a result derives from a very recent maternal infection leading to fetal infection is about 5 in 39,000. In view of the very high extra expenses involved and the unnecessary anxiety induced in many thousands of pregnant women and the sparse results the serological control of women showing positive tests with low or medium titre in the first trimester is not recommendable. There is no indication that preconceptional toxoplasma infection, especially the countless infections of longer standing with low titres, damage the fetus or lead to habitual abortion. Practically only H. Werner and his Berlin group, succeeded in isolating toxoplasma from abortion material of women not primarily infected during pregnancy but then in 20% of cases and in serologically-negative women also. The late importation of such opinions to Austria is deeply regrettable and should not be allowed to induce uncertainty in physicians and anxiety in our women. Accurate studies in very large numbers of preconceptionally-infected women did not reveal a single case of prenatal damage or congenital infection. Hence, the serological control of newborn infants of preconceptionally-infected women is not indicated. High titres (SF) detected during the first trimester indicate only a very low probability of damage to the fetus. Desmonts and Couvreur found not one infected infant amongst the offspring of 191 women with high titres at the beginning of pregnancy.

[The IQ of heterozygotes for phenylketonuria (PKU). indication of a blood phenylalanine-independent action of the PKU mutant (author's transl)]. / Uber das Intelligenzniveau (IQ) von Heterozygoten für Phenylketonurie (PKU). Hinweis auf eine Phenylalaninblutspiegel-unabhängige Wirkung der PKU-Mtante.

The IQ of parents of phenylketonuria-(PKU-)affected children is lower than that of parents with histidinemia-affected children (control group). The difference arises almost entirely from the verbal part of the Hamburg-Wechsler test. The IQ of the parents with histidinemia-affected children shows the same distribution as that of the normal population; heterozygosity for this condition does not appear to confer any intellectual advantage. In PKU patients treated at an early age and apparently adequately, a slight, but significant decrease in IQ becomes apparent between the ages of 6 and 8 years. This slight decrease also refers mainly to the verbal IQ. At 4 years of age all PKU patients are tested with Bühler-Hetzer, as well as the Kramer test. There is a significant difference between the results in favour of the Bühler-Hetzer test, which is much less verbal. Since heterozygotes for PKU never show elevated blood phenylalanine levels and, moreover, prenatal tyrosine deficiency, as argued by others, seems highly improbable, it is supposed that the PKU gene has a more direct influence on certain ganglion cells at least, with a consequent slight, but significant lowering of the verbal IQ in heterozygotes and satisfactorily-treated homozygotes for PKU. A slightly increased intracellular phenylalanine concentration in heterozygotes and apparently adequately-treated homozygotes need not to be reflected in raised blood levels and this could be an explanation for the observed IQ lowering. But it should not be overlooked that by far the greatest part of damage in PKU patients is caused by chronic phenylalanine poisoning which is well preventable by correct dietary treatment.

[Screening for congenital hypothyroidism in Austria (author's transl)]. / Screening auf angeborene Hypothyreose in Osterreich.

Screening for Hypothyroidism is part of the Austrian Newborn Screening for Inborn Errors and centralized (ca. 85.000 births/year). It began 1976 in 2 provinces and covers the whole country since 7.6.1978. Primary T4 and selective TSH on 3 mm discs is used. Control frequency is 0.14%, the frequency of permanent primary hypothyroidism is 1:4724. Hypothyroidism seems more frequent in Western- then in Eastern- Austria (1:4227 v. 1:5422). Hypothyroid babies are almost double as frequently born in September until November then in other quarters of the year. In 47 cases 28 male compare with 19 female. In 4 cases with low T4 and high TSH in the initial Tests T4 became normal within 13--27 days while TSH remained high.

[Toxoplasmosis screening of pregnant patients in Austria]. / Toxoplasmose-Screening bei Schwangeren in Osterreich.

The frequency of congenital Toxoplasma infection is strictly correlated with the frequency of Toxoplasma primary infection in child bearing age. The latter corresponds directly to the increase of contamination rate in the normal population between 20 and 40 years of age, if determined with a sensitive method detecting also low antibody concentrations with certainty (Sabin-Feldman-dye test). In four representative studies the relation was 0.52 conversions id est 0.26 congenital infection per 1 000 per 1% contamination increase. Most congenitally infected children seem normal in newborn age. Follow up studies for long enough periods--many years!--have shown that practically all these children develop sequelea, chorioretinitis and/or cerebral defects. Postnatal treatment does not influence this evolution but preventive treatment in pregnant women selected by serological screening uncovering primary infections does prevent fetal infections with their consequences.

[Screening of newborns for argininosuccinase deficiency. First experiences in Austria (author's transl)]. / Erste Erfahrungen mit einem Neugeborenen-Blutscreening auf Argininosuccinasemangel in Osterreich.

In 1973, the screening for argininosuccinase deficiency was taken up by the Austrian Metabolic Disorder Screening Program using Murphey's enzyme auxotroph test. Amongst 293802 tested newborn infants, two cases of this disorder could be identified, which under protein restricted diet had a normal development until now. Inhibition zones due to antibiotic or desinfectant contamination do not disturb test evaluation in contrast to the bacterial inhibition assay (Guthrie test). The frequency of "false positive" results is small (0.05%) as well as additional work for this test procedure. So screening for argininosuccinase deficiency seems to be a useful completion of a neonatal blood screening program.

[Routine screening for inborn errors using urine filterpaper specimens at age 4-5 weeks (author's transl)]. / Routinemässiges Harm-Zweitscreening aus harngetränktem Filterpapier

Since 1972 we have been using a urine screening for the detection of inborn errors of amino acid metabolism, which cannot be revealed in newborn-blood-screening with Guthrie's bacterial inhibition assay. It is performed at an age of 4-6 weeks by means of thin layer chromatography of urine specimens collected on filter paper using a method adapted by us for mass-screening. We tested 70,400 newborns and found 59 cases of incomplete Cystinuria, 9 of Prolinuria, 3 of Histidinaemia and one each of Hartnup disease, Alkaptonuria, Glycinuria and Hydroxyprolinuria. The problems of the disorders found are discussed. Comparison with newborn-blood-screening that 3 cases of Histidinaemia, proven by enzyme assay were missed by newborn-blood-screening because of their (still low) low blood levels. On the other hand we did not find additional cases of phenylalanine-metabolic disorders. These cases were probably all already detected by newborn-blood-screening. Homocystinuria, Maple syrup urine disease and Arginino-succinicaciduria which are rare diseases were neither found in the urine or blood tests. As disorders, detectable by means of urine screening exclusively and curable, are rare urine screening has to be reevaluated for its usefulness.

[Effects of social and medical changes on the results of pregnancy between 1963 and 1972. I. General: maternal age, number of pregnancies, birth-weight, prematurity, still-birth, mothers foreign workers (author's transl)]. / Einfluss soziologischer und medizinischer Veränderungen 1963-1972 auf das Schwangerschaftsergebnis. I. Allgemeiner Teil: Mütterliches Alter, Geburtennummer, Geburtsgewicht, Frühgeburtlichkeit, Totgeburtlichkeit, Gastarbeiter-Mütter

An analysis of 16,486 births in a city university obstetric department over 10 years showed: 1) The number of births in Austrians (A) declined by 30%, the number of guest worker's births (G) rose sharply from 1969 onwards and reached almost 20% of births in 1972. 2) The percentage of very young (under 21) A. mothers has not increased during the period, among G. mothers a younger age predominates but that will have to be related to the greater willingness of younger foreign women to emigrate. 3) In the last 10 years there have been more primiparous A. women and less with more than 4 children. Families became smaller. 77% A. mothers are between 16 and 30 years of age. G. mothers more often have their first or second child--related to selective emigration. 4) The accumulation of premature births in a University department apart, very young and relatively old A. mothers had much increased numbers of premature--defined by birth weight--children. G. mothers have not more children weighing less than 2501 g, but definitely more with low birthweight (2501-2750 g). 5) More than one third of A. children weighing less than 2501 g. are not premature according to time and among the children between 2501 and 3000 g. there also must be many prenatal dystrophics. 6) Still-births decrease in the lowest weights (less than 2501) the longer the pregnancy and rise steeply only after delay of birth by more than 2 weeks. It is lowest in slightly delayed births. With rising birthweights minimal stillbirths shift towards moderately early births. 7) Still-births are least common in heavy children of young mothers. 8) Premature births have not declined in A. mothers during the decade, premature stillbirth in A. mothers declined sharply since 1969. For G. mothers both prematurity and premature still-births have remained the same from 1969 to 1972.

[The influence on the outcome of pregnancies of sociologic and medical changes during 1963--1972. II. Special section: prenatal dystrophy, diabetogenic fetal disease, the impact of previous miscarriages and twins (author's transl)]. / Einfluss soziologischer und medizinischer Veränderungen 1963--1972 auf das Schwangerschaftsergebnis. II. Spezieller Teil: Pränatale Dystrophie, diabetogene Fetalkrankheit, Bedeutung vorangegangerner missglückter Graviditäten, Zwillinge

Analysis of 16 486 obstetric and neonatal case histories of the years 1963--1972. 30.7% of all neonates of Austrian (A) mothers showed one or more signs of placentar insufficiency. Pronounced prenatal dystrophy (p.d.) occurs in similar numbers in women with or without EPH gestosis, but has other important causes as well. In p.d. excentric umbilical cord insertion is more common than in neonates without dystrophy (56.4 : 52.4). Very young mothers often have neonates with p.d. During the ten year period p.d. increased considerably until 1967. After that it decreased slightly but not to the numbers at the start. These changes in frequency apply to all maternal age groups equally. Pronounced and highgrade p.d. in foreign workers' (f.w.) children is significantly more common than with A mothers (p 0.0001). Cushing's syndrome as a symptom of fetal disease due to diabetes has become rarer by over 50% owing to more intensive preventive measures; at the same time still-births of those weighing 4000 g or more have disappeared. The frequency of Cushing's syndrome rises according to the age of the mother from 0.8% to 3.5%. In Austrian mothers the number of previous abortions has decreased during these 10 years, just as has the number of births. The chances of actual pregnancies are the worse the higher the number of previous abortions. In f.w. mothers previous artificial abortions are far more numerous, but the outcome of pregnancy does not deteriorate with an increase in previous abortions. In A mothers the effects of previous premature or still births are the same as after abortions but much more pronounced. The percentage of normal births following premature births has fallen somewhat in A mothers during the ten year period, also after one miscarriage from 86% to 71%, probably owing to effective prevention of late abortions. Of 173 pairs of twins the first-born was heavier than the second in 71 instances. It is confirmed that the second twin is still-born almost twice as often as the first-born and this in twins of whom the second is heavier than the first. 11% of individual twins weith more than 3000 g and 28% between 2501 and 3000 g. The heavier the twins the lower the average age of the mother (from 30.8 to 26.6). The mothers whose first twin weighs more than 2500 g, the second less, appear to be younger than those with an inverse ratio (27.6 : 30.7).