Urinary excretion of dicarboxylic acids from patients with the Zellweger syndrome. Importance of peroxisomes in beta-oxidation of dicarboxylic acids.

The urinary excretion of adipic acid, suberic acid and sebacic acid from two patients with the cerebrohepato-renal syndrome of Zellweger was studied. The patients had a complete lack of peroxisomes in the liver as judged by electron microscopy. In the non-ketotic state, the total excretion of free and conjugated adipic acid, suberic acid and sebacic acid was increased by about 100%, 200% and 350%, respectively, as compared to the corresponding excretion from six healthy infants of the same age. The excretion of free dicarboxylic acid was increased to a considerably lesser extent than the free + conjugated dicarboxylic acid. In view of the presence of adipic acid in urine of the Zellweger patients, it is concluded that peroxisomes are not obligatory for beta-oxidation of medium-chain dicarboxylic acids in vivo. The relative accumulation of suberic acid and sebacic acid as compared to adipic acid is, however, consistent with a relative block in the conversion of suberic acid and sebacic acid into adipic acid in patients with the Zellweger syndrome.

Cerebral arterio-venous difference for hypoxanthine and lactate during graded asphyxia in the fetal lamb.

Hypoxanthine (HX) and lactate are degradation products from energy-rich intracellular substrates (ATP and glycogen), and their concentration will increase during anaerobic conditions, such as fetal asphyxia. In this study the accumulation of the two metabolites in blood during asphyxia was studied in 7 acutely exteriorized fetal lambs. The arterio-venous difference of HX and lactate over the brain was related to the function of the fetal brain as reflected by the somato-sensory evoked electroencephalogram potentials (SEP). Increased concentrations of HX in plasma and lactate in blood occurred simultaneously with deterioration of the SEP and the 3 variables correlate highly significantly. During normoxia, a net cerebral influx was found for HX, which in combination with severe asphyxia gradually changed to a net efflux. A linear correlation was found between the cerebral arterio-venous differences of HX and the impairment of the SEP. No such correlation existed for lactate. The results suggest, that the fetal brain has a high threshold for degrading its energy-rich intracellular purines.

Measurement of cerebral blood flow in the fetal lamb with a note on the flow-distribution.

The cerebral blood flow was measured in the acutely exteriorized fetal lamb by 133Xenon washout and microsphere distribution techniques. The measurements were performed at different blood gas levels. Regional cerebral blood flow was calculated from the microsphere distribution for five different parts of the brain. This gave estimates for blood flow in both the grey and white matter of the hemispheres, which were in close agreement with the cerebral blood flow estimated by the 133Xe washout technique. The microsphere distribution shows that the fetal cerebral hemisphere has a low blood flow compared to the basel parts of the brain and that this difference is increased during hypoxia and hypercarbia.

A case of lethal congenital dwarfism with accelerated skeletal maturation.

Details of a female infant, who was born after 29 weeks gestation and who died within minutes of birth, are presented. The infant was hydropic, showed macroglossia and had very short limbs with normal sized hands and feet. Apart from a preductal aortic coarctation the pathological findings were confined to the skeleton. The radiographical and histological findings are described in detail; they differ from those of previous studies of similar conditions.

Unsuccessful attempts to induce peroxisomes in two cases of Zellweger disease by treatment with clofibrate.

The cerebro-hepato-renal syndrome of Zellweger is a fatal hereditary disease and most of the affected infants die before the age of 6 months. Most probably the fatal outcome of the disease is due to an apparent complete lack of peroxisomes in the liver, kidneys, and brain. Treatment with clofibrate is known to increase drastically the number of peroxisomes in mammalian liver. We therefore treated two infants with the Zellweger syndrome with clofibrate (30 and 45 mg/kg body weight, respectively) for 3-4 wk. No clinical effect of the treatment was observed in any of the two cases, and the pattern of abnormal bile acids in serum did not change. No peroxisomes could be detected by electron microscopy of liver biopsies taken immediately after the treatment. Our failure to induce peroxisomes in the two Zellweger patients is in accord with the hypothesis that the protein missing in this autosomal recessive disease is absolutely essential for the formation of peroxisomes.

Does glucose administration affect the cerebral response to fetal asphyxia?

This study was designed to test whether the fetal brain has an increased resistance towards asphyxia at high levels of blood-glucose, compared with low levels. 35 fetal sheep were exteriorized and investigated under general anesthesia. Cerebral blood flow (CBF) was estimated with the 133Xenon-washout method. Cerebral uptake of oxygen, glucose, and lactate was measured. Somatosensory evoked potentials (SEP) were recorded. The fetuses were subjected to controlled asphyxia by ventilating the ewes with gas mixtures low in oxygen. The blood sugar levels of the fetuses were varied over a four-fold range. During normal oxygenation of the fetus variations in the blood glucose concentration induced considerable changes in the cerebral glucose uptake, whereas CBF and oxygen uptake were unaffected. During asphyxia, hyperglycemia was associated with rapid development of acidosis and reduction in cerebral oxygen consumption together with deterioration of the neurophysiological characteristics of the brain. Far from being beneficial during asphyxia, fetal hyperglycemia appeared to reduce the tolerance of the fetal brain towards asphyxia. This report together with other evidence provides support for the view that extra glucose might be disadvantageous for the asphyxiated fetus.

Central nervous system malformations and white matter changes in pseudo-neonatal adrenoleukodystrophy.

Clinical, biochemical and morphological findings in a 16-month-old infant girl with pseudo-neonatal adrenoleukodystrophy are reported. The parents were first cousins and the baby was born at term, small for gestational age. The neonatal period was characterized by convulsions resistant to treatment, generalized, severe muscle hypotonus, feeding difficulties and poor weight gain. Developmentally she remained at a neonatal level. A CT-scan showed low density of cerebral white matter and MR examination white matter changes, a thin corpus callosum, cerebellar malformation and dorsal displacement of the brainstem. There was an accumulation of very long chain fatty acids (VLCFA) in serum lipids and cultured skin fibroblasts but plasmalogen and phytanic acid levels were normal. A liver biopsy revealed enlarged peroxisomes staining for catalase. Three similar cases have been reported previously; in two of these there was a deficiency of acyl-CoA oxidase. MR evidence of leukodystrophy combined with gross cerebral and cerebellar morphologic changes have not been reported earlier.