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The need for regular blood-drawing in the management of chronic metabolic disorders may negatively influence the compliance of patients and their parents; noninvasive analytical procedures could well alleviate this burden. Using data obtained in six adult probands with phenylketonuria, we evaluate the feasibility of noninvasive prediction of phenylalanine blood concentrations from analysis of phenylalanine and creatinine in urine. Cross-validated regression equations correct for the significant inter-individual variation of phenylalanine fractional excretion rates. With sensitive and specific enzymatic assays for phenylalanine and creatinine, the accuracy of this noninvasive procedure may also become clinically satisfactory for the purpose of self-monitoring.

We present blood and urine levels of unconjugated o-hydroxyphenylacetic, phenyllactic and phenylpyruvic acids in 61 children (2 years of age and above) and juveniles with phenylketonuria on or partially off diet. The samples were obtained during 185 scheduled outpatient visits and have been analysed with gas chromatographic methods. The compiled data define reference ranges of phenylalanine transamination capacity and of renal transport of metabolites which may be of value in further studies on the pathogenesis of phenylketonuria.

A previous observation of decreased serum carnitine concentrations in phenylketonuria (PKU) was investigated in 169 patients either on a strict diet (n = 107; median: 8.1 years) or off diet (n = 62; median: 15.0 years). Fifty-seven metabolically healthy children (median: 8.5 years) served as controls. PKU patients on a strict diet and older than 2 years had significantly lower serum carnitine concentrations (19.4 +/- 5.4 mumol/l) than those off diet (29.6 +/- 6.7 mumol/l). PKU patients on diet also had significantly lower concentrations of haemoglobin and serum ferritin than those off diet. A linear correlation existed between total serum carnitine and ferritin concentrations up to 40 micrograms/l (r = 0.52; P less than 0.01). As iron is an essential cofactor of carnitine synthesis we conclude that reduced endogenous carnitine synthesis due to an inadequate availability of iron may be a major cause of low serum carnitine concentrations. The low carnitine content of the strict and highly protein-reduced diet additionally contributes to a decrease in the serum carnitine concentration. Our results show that a further optimization of the PKU diet increasing either iron availability or carnitine intake should be considered.

A male infant had severe muscular hypotonia from birth. Recurrent vomiting with dehydration and severe metabolic acidosis complicated the course. Elevated lactate (up to 12.3 mmol/l; n less than 2), pyruvate (0.4 mmol/l; n less than 0.05) and alanine levels were found in serum with an abnormal lactate/pyruvate ratio (greater than 30; n less than 15). In urine the concentrations of lactate, pyruvate, alanine and of several intermediates of the citric acid cycle were increased. In muscle, numerous disseminated "ragged red fibres" were found by light microscopy; muscle fibres were found to contain subsarcolemmal aggregates of mitochondria, lipid droplets and glycogen by electromicroscopical methods. Moreover, mitochondria with a typical circular arrangement of cristae were noticed. In liver homogenates normal activities of pyruvate carboxylase and pyruvate dehydrogenase complex were found; in liver mitochondria also succinate-cytochrome-c-oxidoreductase activity was normal. However, in muscle no succinate-cytochrome-c-oxidoreductase activity was detectable. The patient became increasingly lethargic and died because of sepsis at 5 months of age.

Clinical course and special diagnostic procedures in a 7 1/2 weeks old dystrophic infant with propionic acidemia are described. The disorder manifested with vomiting and diarrhea within the first week of life when the child was on a cow milk formula. Parenteral nutrition with glucose and electrolytes led to improvement. When oral nutrition with a cow milk formula was implemented again, an acute deterioration with diarrhoea and vomiting occurred. Thus, a diagnosis of cow milk allergy was suggested. There was also a severe muscular hypotony. Oral nutrition with a soybean formula did not prevent further clinical deterioration. At 7 1/2 weeks of age the patient died with symptoms of cardiogenic shock. The correct diagnosis was considered too late and confirmed post mortem. Clinical symptoms in the neonatal period like vomiting, muscular hypotony and failure to thrive should alert the physician to a possible diagnosis of a hereditary organic aciduria. Gas chromatography-mass spectrometry of urinary organics acids, in the present case, established the diagnosis. On autopsy, spongy degenerations were found in CNS.

While the positive effect of early dietary treatment on the intellectual development of patients with phenylketonuria (PKU) (McKusick 26160) has been clearly established, controversy exists regarding the termination of the phenylalanine-restricted diet in PKU-children. A strict dietetic scheme poses serious problems especially during school age and it may elicit psychosocial abnormalities in the children as well as in their families. This scheme should therefore be abandoned when development of recognizable CNS dysfunction is no longer to be expected.

In order to determine the chemical changes which might occur during post-tetanic potentiation, amino acids from the motor regions of the ventral horn of the spinal cord (potentiated and unpotentiated sides) of 10 different cats were analyzed. The intermittent tetanic stimulation of the Nn. gastroc. (only on the potentiated side) was carried out until a maximum of potentiation was reached (3--4 min). The monosynaptic reflexes were obtained from the ventral roots (L7 or S1) of both sides. The amino acids of the potentiated side were compared to those of the unpotentiated side (control) using a 14-C-dansyl chloride procedure. The two main amino acids considered to be excitatory neurotransmitters, glutamic acid and aspartic acid, showed a more than 20 per cent increase on the potentiated side as compared to the control side. Glycine, which plays an inhibitory role, especially in the spinal cord, reacted with 6 per cent decrease, whereas GABA which is also considered as an inhibitory neurotransmitter showed a change of + 11 per cent on the potentiated side as compared to the unpotentiated side. The importance of the potentiation time for those changes is pointed out.

For several years and under various aspects we have studied diet termination in twenty-two early and late treated patients with phenylketonuria. Time of diet termination was the completed eighth year. For evaluation of possible functional CNS deficits, we applied psychometric tests, methods for testing psychomotor behavior and, in addition, neurophysiological parameters and registrations of sleep EEG. EEG morphology was studied visually and the rhythms of the different phases of sleep were quantified by computerized spectral analysis. EEG was studied during diet therapy when phenylalanine levels in blood were low and after a relatively short period of four months with elevated phenylalanine blood levels. At least two years after diet termination with correspondingly elevated phenylalanine blood levels the EEG was studied once more. Compared to the respective findings before diet termination in these patients there were no significant changes of the sleep EEG seen, neither on visual nor on spectral analysis. We have seen in this study minor EEG changes in early treated children and overtly pathological EEG changes in late treated PKU patients with cerebral damage, both before and after diet termination. Ultrastructural CNS defects may be the cause of these anomalies which do not respond to the actual biochemical situation at the age of eight to ten years. The morphology of such defects may include altered synaptic maturation and may occur already in an early phase before the diet therapy is implemented.

Pseudomembranous colitis (PMC) is a potentially fatal complication in Hirschsprung's disease. The pathogenesis of PMC which usually takes a fulminant course, is obscure. The disease generally is associated with antibiotic therapy. We describe the clinical course and the pathological findings in a 7 1/2 months old infant with Hirschsprung's disease after surgical treatment. The pseudomembranous colitis of the patient with letal consequence is considered to be connected with antibiotic therapy.

Following 30-min intermittent post-tetanic potentiation of monosynaptic reflexes in the ventral horn of the spinal cord of 10 cats, the amino acid composition was analyzed after reacting with 14C-dansylchloride and by two-dimensional chromatography. The amino acids in comparable segments of the spinal cord from eight animals after ether anesthesia and from five animals who were operated on but not stimulated were also analyzed. In the latter the operation itself influenced the amino acid composition as compared to those animals who were anesthetized. Comparison between the different control groups showed that the operated animals can be used as a control for calculation of the changes caused by potentiation. The amino acids glycine, glutamic acid and aspartic acid, which act as either inhibitory or excitatory neurotransmitters, increased significantly after potentiation, as did the amino acids lysine, histidine, leucine, isoleucine, and proline.

We report the first case of lysinuric protein intolerance observed in Germany. A girl of Turkish ancestry suffered from severe dehydration at the age of 6 months after changing from breast milk to cow milk. Because of a microcytic hypochromic anaemia and erythrophagocytosis in the bone marrow a hematologic disease (Farquar's disease) was suspected. The definite diagnosis of lysinuric protein intolerance was eventually clarified by the following laboratory and clinical data: increased urinary excretion and low plasma concentration of lysine, arginine and ornithine, apathy, vomiting, diarrhea and hyperammonemia after an oral protein load, high serum LDH-activity, ferritinemia, and increased urinary excretion of orotic acid. Under therapy with citrullin and a low-protein diet the metabolic situation remained stable, even during infections. The bone marrow findings have been reported only in one further case of lysinuric protein intolerance.

Clinical course and special diagnostic procedures in a 7 1/2 weeks old dystrophic infant with propionic acidemia are described. The disorder manifested with vomiting and diarrhea within the first week of life when the child was on a cow milk formula. Parenteral nutrition with glucose and electrolytes led to improvement. When oral nutrition with a cow milk formula was implemented again, an acute deterioration with diarrhoea and vomiting occurred. Thus, a diagnosis of cow milk allergy was suggested. There was also a severe muscular hypotony. Oral nutrition with a soybean formula did not prevent further clinical deterioration. At 7 1/2 weeks of age the patient died with symptoms of cardiogenic shock. The correct diagnosis was considered too late and confirmed post mortem. Clinical symptoms in the neonatal period like vomiting, muscular hypotony and failure to thrive should alert the physician to a possible diagnosis of a hereditary organic aciduria. Gas chromatography-mass spectrometry of urinary organics acids, in the present case, established the diagnosis. On autopsy, spongy degenerations were found in CNS.

A total of 146 samples of amniotic fluid from the 15th to 43rd weeks of pregnancy were taken by either transabdominal amniocentesis or amniotomy during birth. In addition to the palmitic/stearic ratio (P/S) the following coagulation tests were determined: clotting time, modified prothrombin time, partial thromboplastin time (PTT), recalcification time and, in selected samples, thrombelastograms. In the course of pregnancy there is a significant shortening of all coagulation tests measured in amniotic fluid. Comparing the values obtained in the 15th to 18th and the 37th to 43rd weeks of gestation and literature results the following values may indicate fetal maturity: clotting time less than 100 sec., modified prothrombin time less than 80 sec., PTT less than 30 sec. and recalcification time less than 80 sec. The lower limit for P/S ratio in normal pregnancy is 5,0. In 58 cases, amniotic fluid was obtained in the 37th to 43rd week at most 24 hours before delivery; there was no case of RDS in this group. Eliminating intermediate P/S values of 4,5 to 5,0 a false negative rate of 1,7% for the prediction of fetal lung maturity was seen. The corresponding rate for the modified prothrombin time was 3,4% and for the clotting time 6,4%. In 7 RDS cases all cases could be properly predicted from the recalcification time and the PTT. The fetal lung maturity may be estimated by means of simple and rapid coagulation tests and this may facilitate the indication for RDS-prophylaxis. The determination of the L/S or P/S ratios, however, cannot yet be dispensed with.

An infant with an acute hepatitis B infection developed the chronic aggressive form of the disease. The immunoserologic findings in the child and his mother suggest a vertical hepatitis B virus transmission. The mother was found to be an asymptomatic HBs-Ag carrier but HBe-Ag negative. The importance of a screening program for HBs-Ag in pregnant women is discussed. It is suggested that newborns at risk should get passive-active immunisation post partum as early as possible.

The concentration of phenylalanine in plasma, whole venous and capillary blood, and paper-dried blood of 75 probands (25 healthy adults, 27 healthy children, and 23 patients with hyperphenylalaninaemia) were measured by use of a sensitive short column chromatography method. The comparison of the values in each group of probands by several statistic methods showed an excellent correlation of the phenylalanine concentration in paper-dried whole blood to those measured in venous plasma. Evaluation of the analytical method revealed a high sensitivity and accuracy by use of a sample volume of 50 microliter. We would therefore suggest that the estimation of phenylalanine for the diagnosis and therapy control in hyperphenylalanine is as accurate in paper-dried blood as in venous plasma and would simplify sampling for the patients as well as enhance the diagnosis and therapy control in hyperphenylalaninaemia.

A first case of congenital rubella with evidence of oligoclonal IgG in serum and cerebrospinal fluid during early manifestation is reported. The mother contracted the rubella infection during the first month of gestation. In addition to the more frequent symptoms of rubella embryopathy there were signs of active meningoencephalitis in the newborn. As a rare eye defect, bilateral congenital glaucoma was observed. Cranial computed tomography gave evidence predominantly for white matter involvement. Elevated IgG levels and oligoclonal IgG were found in both cerebrospinal fluid and serum. By means of quantitative estimation, a local synthesis of IgG in the central nervous system could be demonstrated.