Long-term follow-up of patients with phenylketonuria receiving tetrahydrobiopterin treatment.

Treatment with tetrahydrobiopterin (BH4), the natural cofactor of phenylalanine hydroxylase (PAH), can reduce blood phenylalanine (Phe) levels in patients with BH4-responsive phenylketonuria (PKU). A number of studies has reported on the short-term BH4 treatment of patients with PKU, but long-term data are lacking. Here, we describe the effects of long-term treatment with BH4 on 16 patients, who showed a >28% reduction in blood Phe following testing for BH4 overload. The mean dose of BH4 was 16 mg/kg body weight (range 5-36 mg/kg body weight). The mean treatment duration was 56 months (range 24-110 months). Of 16 patients, 14 achieved long-term Phe control with BH4 treatment, with a mean blood Phe concentration of 321 ± 236 µmol/l. The mean decrease from baseline in blood Phe levels in these 14 patients was 54.6%. Of the seven patients who required continued dietary restriction, Phe intake increased from 200-300 mg/day to 800-1000 mg/day. Factors that may cause fluctuation of Phe levels in BH4-treated patients include patients' PAH genotype, Phe intake, changes in protein catabolism or anabolism, and periods of illness or infection.

Significance of genotype in tetrahydrobiopterin-responsive phenylketonuria.

BACKGROUND: The value of genotyping to identify tetrahydrobiopterin-responsive (BH(4)-responsive) patients with phenylalanine hydroxylase (PAH) deficiency is a matter of debate. METHODS: We reviewed 250 cases of patients with PAH deficiency, using published data from 198 cases and unpublished data from 52 cases of patients attending our own clinic. Patients underwent analyses for BH(4) load and genetic mutations. Partial and full BH(4) responses were defined as a 10-29% decrease and a >or=30% decrease from baseline in blood phenylalanine levels, respectively. BH(4)-responsive alleles were identified from BH(4)-responsive patients as either homozygous for a specific allele or compound heterozygous for that allele with a null mutation. RESULTS: Most inconsistencies between observed genotype and BH(4) response were associated with mutations in the regulatory domain of PAH (p.R68S, p.I65T, p.L48S and p.F39C), where 20/62 alleles (32.2%) were non-responsive. In the catalytic domain (mutations p.Y414C, p.R261Q, p.E390G, p.A300S, p.R241C, p.A403V and p.V388M), only 8/125 alleles (6.4%) were non-responsive. Seven patients had a genotype with two BH(4)-responsive alleles resulting in no response or only a partial response to BH(4). Ten patients had identical genotypes but inconsistent responses in BH(4) load. CONCLUSIONS: These results show that BH(4) non-responsiveness is associated with genotype. However, patients with mutations in the regulatory domain show inconsistent results. In patients with two responsive alleles, non-responsiveness may be related to negative inter-allelic complementation. In patients with the same genotype and inconsistent results for BH(4) load, external factors such as intestinal absorption of BH(4), catabolic conditions or other genetic factors may be responsible. Further in vitro studies are necessary to clarify the genotype-phenotype correlation in patients with BH(4)-responsive PKU.

[Antepartum prevention and postnatal therapy of respiratory distress syndrome]. / Präpartale Prophylaxe und postnatale Therapie des Atemnotsyndroms.

The introduction of surfactant in the therapy of respiratory distress syndrome (RDS) reduced mortality and long term complications in very premature infants. Nevertheless, the obstetric management influences critically the outcome. In a prospective study of 116 premature infants with RDS treated with natural surfactant preparations after birth, mortality was significantly reduced by antepartum corticosteroid therapy suggesting a synergistic effect of corticosteroids and surfactant on the immature lung. It is assumed that a preventive administration of surfactant immediately after birth would benefit neonates at risk for RDS more than a delayed surfactant replacement after the development of RDS. But without a reliable assessment of fetal lung maturity before birth more than 50% of our premature infants with birth weights less than 1500 g would be exposed to surfactant unnecessarily. It is important that fetal asphyxia is avoided. Acquired respiratory distress syndrome occur even in premature infants after shock or meconium aspiration and may respond poorly to surfactant replacement. This is also the case in lung hypoplasia or perinatal infection, where the combined efforts of obstetricians and neonatologists are needed to attain better results.

[Effect of body position and positioning changes on lung function of ventilated premature and newborn infants]. / Einfluss von Körperposition und Lageveränderungen auf die Lungenfunktion beatmeter Früh- und Neugeborener.

We studied 21 intubated premature infants (wts 800-2800 g) with respiratory distress syndrome between day 2 and 10 to evaluate the effect of body position on lung mechanics and gas exchange. The dynamic compliance of the total respiratory system was similar in the prone and supine position. When the infant was turned from the supine or the prone position to the other one, a significant improvement of oxygenation was seen temporarily. Positioning did not significantly affect the dynamic compliance, the minute volume or pCO2. In circulatory stable premature infants a change of the body position probably alters the regional ventilation to perfusion ratio and leads to a reduction of intrapulmonary venous admixture.

Complement fragment C3a in plasma of asphyxiated neonates.

Recent clinical studies with adult polytrauma patients indicate that elevated plasma levels of anaphylatoxin C3a correlate with the subsequent development of the adult respiratory distress syndrome (ARDS). However, there are no parameters which allow a reliable diagnosis of ARDS in neonates. As the most predisposing condition for ARDS seems to be shock, plasma C3a was determined in 30 ventilated premature infants and neonates with respiratory distress syndrome (birth weights 660-3350 g) within the first 24 h post partum or 6-24 h after acute asphyxia or shock during the neonatal period. The range of C3a, measured by ELISA, was between 57 and 1000 ng/ml. In the asphyxia group (n = 15) peak levels of C3a in plasma (mean 388 ng/ml) were significantly higher (P less than 0.001) than in the control group (mean 153 ng/ml). In some neonates with suspected ARDS, additional samples were taken. A rise in C3a between days 2 and 8 was associated with a fatal outcome of the disease. As in adults, C3a might be a useful indicator for ARDS in neonates.

[Dexamethasone in the treatment of bronchopulmonary dysplasia]. / Dexamethason in der Behandlung der bronchopulmonalen Dysplasie.

Dexamethasone has been reported to benefit premature infants with bronchopulmonary dysplasia. 13 ventilator-dependent premature infants (birth weight 780-1270 g) with chronic lung disease received dexamethasone 0.5 mg/kg/day with tapering doses over 3 weeks. Dexamethasone therapy was associated with a temporary increase in urine output and blood pressure. All infants showed a significant fall in oxygen requirement and an increase of total pulmonary compliance during the first week. The endotracheal tube was successfully removed in all infants with Northway stage I/II BPD within the first week of treatment and no infant relapsed. But in Northway stage III/IV, only 2/9 infants could be weaned from the ventilator during the first course of treatment and in the majority treatment led only to a temporary improvement of pulmonary status. In parallel to the improvement of lung function we found in 7 infants a decrease of the total cell counts, the ratio PMN/macrophages and albumin in relation to urea in the bronchial lavages with a secondary rise in cases of a clinical relapse. Free elastase and fibronectin/albumin ratio in the bronchial lavage did not correlate to the clinical course. Dexamethasone seems to have not only an effect on fluid balance but also on the alveolar capillary leakage and the PMN influx into the lung. This might explain the superior effect of dexamethasone in patients with Northway stage I/II BPD in comparison to infants with Northway stage III/IV.

Evidence for a structural mutation (347Ala to Thr) in a German family with 3-ketothiolase deficiency.

The molecular basis of 3-ketothiolase deficiency (3KTD) was examined in a 3KTD family. Immunochemical analyses showed that mitochondrial acetoacetyl-CoA thiolase (T2) biosynthesized in the patient's fibroblasts (GK06) was unstable and that the parents and brother were obligatory carriers of 3KTD. When sequencing the PCR-amplified patient's T2 cDNA, we noted a G to A replacement which caused 347Ala to Thr substitution of the mature T2 subunit. Transfection analysis revealed that this substitution resulted in an instability of the T2 protein. Analyses of the T2 cDNA and gene of the family indicated that the patient was a compound heterozygote; the allele that derived from the mother had a point mutation (347Ala to Thr) and the other allele from the father has a mutation which would abolish the T2 gene expression. This report is apparently the first definition of a mutant allele for 3KTD, at the gene level.

[Adenovirus infection with hemorrhagic cystitis and pneumonia. Pathogen confirmation in urine by genome hybridization]. / Adenovirusinfektion mit hämorrhagischer Zystitis und Pneumonie. Erregernachweis im Urin durch Genomhybridisierung.

A-16-year old boy was admitted with fever, headache, dysuria, and brown-colored urine. The patient presented with hemorrhagic cystitis and bronchopneumonia. Infection with adenovirus was confirmed by detection of viral DNA in the patient's urine by the hybridisation technique.