Ágnes Schuler

Lower prevalence of IL-4 receptor α-chain gene 1902G variant in very-low-birth-weight infants with necrotizing enterocolitis

Abstract Background/purpose: Altered production of immunoregulatory cytokines is associated with the development of necrotizing enterocolitis (NEC) in preterm very low-birth-weight (VLBW) infants. According to data obtained in adults, functional genetic polymorphisms influence cytokine production capacity. The aim of this study was to evaluate whether functional polymorphisms of interleukin (IL)-1β, IL-4 receptor α-chain (IL-4ra), IL-6, and IL-10 genes might be associated with the risk of NEC in VLBW infants. Methods: Dried blood spot samples of 46 VLBW infants with NEC were analyzed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. Samples from 90 VLBW infants without NEC were used as controls. Results: Infants with NEC carried the mutant variant of IL-4ra less frequently than controls (0.125 v 0.224; P Conclusions: Carrier state of IL-4ra mutant allele might be associated with lower risk of NEC in VLBW infants. This genetic variant is associated with enhanced IL-4 effect. IL-4 is a major regulator of Th1-Th2 shift. The authors hypothesize that infants carrying the IL-4ra mutant allele might have Th2 skewness that might defend against the development of NEC.

Genetic Variants of TNF-α, IL-1β, IL-4 Receptor α-Chain, IL-6 and IL-10 Genes Are Not Risk Factors for Sepsis in Low-Birth-Weight Infants

The amount of inflammatory cytokines is a major determinant for the development of sepsis in very-low-birth-weight (VLBW) neonates. We investigated whether variants of tumor necrosis factor-α, interleukin (IL)-1β, IL-4 receptor α-chain, IL-6 and IL-10 genes, associated with altered cytokine production, might influence the risk and complications of sepsis in VLBW infants. We determined the presence of these genetic variants in dried blood samples of 33 septic, 35 infected and 35 healthy VLBW neonates by PCR and RFLP methods and analyzed their association with the risk and complications of sepsis. The frequencies of genetic variants did not differ in uninfected and in infected infants with or without sepsis. Moreover, none of the studied complications was associated with carrier state of any of genetic variants. Four of the 5 septic neonates with disseminated intravascular coagulation, however, carried simultaneously the variants of IL-1β and IL-10 genes. We concluded that these genetic polymorphisms do not influence the risk and course of sepsis in VLBW neonates.

Variance of ACE and AT1 receptor gene does not influence the risk of neonatal acute renal failure

Abstract. High neonatal activity of the renin-angiotensin system (RAS) is crucial for the maintenance of glomerular filtration of the newborn. The aim of the present study was to investigate whether genetic polymorphisms leading to lower angiotensin converting enzyme activity (ACE) or impaired functionality of angiotensin II (AII) type 1 receptor (AT1R) might predispose very low birth weight newborns (VLBWs) to the development of acute renal failure (ARF). The medical records of 110 VLBW infants were analyzed. ARF developed in 42 of them during the first postnatal week, while 68 neonates exhibited normal renal function. The ACE I/D polymorphism and the A1166C variants of AT1R were determined from dried blood samples. The frequency of the ACE I allele did not differ in ARF and non-ARF groups (0.307 and 0.284); the frequency of the AT1R C1166 variant was also the same in ARF and non-ARF groups (0.250 and 0.227). Although low activity of RAS has been implicated in the development of neonatal ARF and data indicated that the functionality of RAS is influenced by the I/D variants of the ACE gene and the A1166C variant of the AT1R gene, we could not demonstrate any effect of these polymorphisms on the development of ARF in VLBW infants.

Monamine oxidase inhibitors in tetrahydrobiopterin deficiency

Sir: Most patients suffering from inherited tetrahydrobiopterin (BH4) deficiency need, besides a phenylalanine restricted diet or BH4 administration, substitutive neurotransmitter therapy, with repeated daily doses of the precursors, L-dopa and 5-hydroxytryptophan (5-OH-Trp), in combination with carbidopa, an inhibitor of peripheral decarboxylases. Despite this treatment, patients may show random fluctuations in motor and cognitive performances, similar to the on-off phenomena occurring in Parkinsons disease following L-dopa treatment. Therapeutic inadequacy appears to be more frequent when larger doses of L-dopa are required, and could be related either to the interference between neurotransmitter metabolism and increased plasma phenylalanine levels [1] or to plasma dopamine fluctuations due to the short half-life of L-dopa [2]. Two patients suffering from 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency, both with unsatisfactory response to classical treatment, were treated with concurrent administration of deprenyl (seleginine, phenylisopropylmethylpropynilamine), a selective, irreversible inhibitor of monoamine oxidase B, which is being attempted in Parkinsons disease [3]. Case 1, the first child of non-consanguineous, Hungarian parents, was positive in the neonatal mass screening for phenylketonuria and had a definite diagnosis of PTPS in the 1st month of life. As traditional treatment failed in the control of symptoms and the infant developed myoclonic convulsions and EEG abnormalities, deprenyl therapy was introduced at 5 months of age. After several adjustments, a satisfactory clinical response was obtained with the schedule reported in Table 1. The child has now been on this therapy for more than 3 years. His somatic development is normal, motor development was delayed but is now appropriate for age; myoclonus has disappeared and EEG has normalized; the mental age is about 2.9 Table 1 Reduction of neurotransmitter precursors requirement following deprenyl administration in two patients with PTPS deficiency

Deprenyl in the treatment of patients with tetrahydrobiopterin deficiencies

Most patients suffering from tetrahydrobiopterin (BH 4 ) deficiency show an inadequate clinical outcome. Besides the administration of synthetic BH 4 or phenylalanine-restricted diet, neurotransmitter substitution with L-Dopa plus carbidopa (10:1) and 5-hydroxytryptophan is required. Motor and cognitive performances fluctuate apparently at random, especially when higher doses are required. To improve the clinical outcome and to avoid the late side-effects of the traditional L-Dopa treatment, an additional selective monoamine oxidase (MAO) B inhibitor, Deprenyl (selegiline), was introduced (Schuler et al 1995). Here we report on the clinical outcome of 8 patients with BH 4 deficiency, including our 7 years of experiences with additional deprenyl therapy.

Molecular and clinical analysis of patients with classic and Duarte galactosemia in western Hungary

ZusammenfassungHINTERGRUND: Die klassische Galaktosämie ist eine autosomal rezessiv vererbte Erkrankung, die durch eine gestörte Aktivität der Galactose-1-phosphat-Uridyltransferase verursacht wird und die im Rahmen eines Neugeborenen-Screenings erkannt werden kann. In Ungarn wurde das Neugeborenen-Screening 1976 eingeführt, es wird in 2 Zentren durchgeführt. Ziel der vorliegenden Studie war die molekulare Charakteriserung des Genotyps und die Analyse der Genotyp-Phänotyp-Korrelation bei Patienten mit der klassischen bzw. mit der Variante der Galaktosämie. PATIENTEN UND METHODEN: DNS Proben von 40 Patienten wurden mittels Polymerase-Kettenreaktion, gefolgt von direkter Sequenzierung untersucht. Die klinischen Daten wurden im Hinblick auf die gefundenen Genotypen analysiert. ERGEBNISSE: 16 verschiedene Sequenzvariationen wurden identifiziert, wobei auch 2 neue Missense-Mutationen (p.S297P, p.E146D) erfasst wurden. Die zwei am häufigsten gefundenen Mutationen waren p.Q188R und p.K285N mit einer Allel-Häufigkeit von 45% bzw. 31,2%. SCHLUSSFOLGERUNGEN: Die klinisch am schwersten verlaufenden Phänotypen waren in unserer Bevölkerung mit p.Q188R, p.K285N, p.X380R, p.S297P, p.M142K, p.R.204X, p.Q169K, und p.R407P Mutationen assoziiert. Die Manifestationen hängen aber von anderen genetischen und auch Umweltfaktoren ab.SummaryBACKGROUND: Classic galactosemia is an autosomal recessively inherited disorder caused by deficient activity of the enzyme galactose-1-phosphate uridyltransferase. The disorder can be detected by newborn screening and in Hungary the national screening program was launched in 1976 with two screening centers. The aim of this study was the molecular characterization of the genotypes and analysis of genotype-phenotype correlation among patients with classic or variant galactosemia. PATIENTS AND METHODS: DNA samples from 40 patients were analyzed by polymerase chain reaction followed by direct sequencing. RESULTS: 16 different sequence variations were identified, including two novel missense mutations (p.S297P, p.E146D). The two most common mutations were p. Q188R and p.K285N with allele frequencies of 45% and 31.2%, respectively. Clinical data were evaluated with respect to the genotypes found. CONCLUSIONS: The most serious clinical phenotypes in our population were associated with mutations p. Q188R, p.K285N, p.X380R, p.S297P, p.M142K, p.R.204X, p.Q169K and p.R407P, but manifestations depend on other genetic and environmental factors.

High frequencies of biotinidase (BTD) gene mutations in the Hungarian population

Biotinidase deficiency, an autosomal recessively inherited disorder, is characterized by neurologic and cutaneous symptoms and can be detected by newborn screening. In Hungary the national screening programme was launched in 1989 with two screening centres. Over 1,070,000 neonates from western Hungary were screened for biotinidase deficiency in the Budapest Screening Centre between 1989 and December 2008. In this period, 57 patients with profound or partial biotinidase deficiency from 50 families were identified through routine newborn screening. The incidence of the disorder in western Hungary is 1 in 18,700, which is about three times the worldwide incidence. Twenty-four different mutations were identified in patients including the c.406delC novel mutation in exon 3, which is a frameshift mutation. To better understand the background of the unusually high disease incidence, 100 healthy subjects from the Hungarian population were screened by PCR and RFLP for the frequencies of p.D444H, p.Q456H and p.A171T;p.D444H, the three most common BTD mutations. The frequencies were found to be 5.5, 0.5 and 0%, respectively. The results demonstrate that the frequencies of two of the most common biotinidase variant alleles are higher in the Hungarian population than in other Caucasian populations. This and the presence of a unique Hungarian mutation may explain the high incidence of biotinidase deficiency in Hungary.

[Frequencies of the Los Angeles and Duarte galactose-1-phosphate uridyltransferase variant alleles in the Hungarian population].

UNLABELLED Classical galactosaemia is an autosomal recessively inherited disorder caused by deficient activity of the enzyme galactose-1-phosphate uridyltransferase (GALT), which can be detected by newborn screening. The p.N314D mutation defines two variant forms of the GALT enzyme, the Los Angeles and Duarte, depending on the presence of additional base changes. AIM The aim of our study was to analyze a healthy Hungarian population for the frequencies of the Los Angeles and Duarte galactose-1-phosphate uridyltransferase variant alleles. METHODS DNA samples from 100 subjects were analyzed by polymerase chain reaction, followed by digestion with restriction endonucleases. RESULTS The frequencies of the p.N314D, the Los Angeles and the Duarte variants were 11.5%, 2.5% and 9%, respectively. CONCLUSIONS The allele frequencies of the Los Angeles and Duarte variant alleles in the Hungarian population correlate well with the allele frequencies in other healthy Caucasian populations.

A Los Angeles és Duarte galaktóz-1-foszfát-uridil- transzferáz-variánsok allélgyakorisága a magyar populációban

UNLABELLED Classical galactosaemia is an autosomal recessively inherited disorder caused by deficient activity of the enzyme galactose-1-phosphate uridyltransferase (GALT), which can be detected by newborn screening. The p.N314D mutation defines two variant forms of the GALT enzyme, the Los Angeles and Duarte, depending on the presence of additional base changes. AIM The aim of our study was to analyze a healthy Hungarian population for the frequencies of the Los Angeles and Duarte galactose-1-phosphate uridyltransferase variant alleles. METHODS DNA samples from 100 subjects were analyzed by polymerase chain reaction, followed by digestion with restriction endonucleases. RESULTS The frequencies of the p.N314D, the Los Angeles and the Duarte variants were 11.5%, 2.5% and 9%, respectively. CONCLUSIONS The allele frequencies of the Los Angeles and Duarte variant alleles in the Hungarian population correlate well with the allele frequencies in other healthy Caucasian populations.

A Los Angeles és Duarte galaktóz-1-foszfát-uridil-transzferáz-variánsok allélgyakorisága a magyar populációban@@@Frequencies of the Los Angeles and Duarte galactose-1-phosphate uridyltransferase variant alleles in the Hungarian population

UNLABELLED Classical galactosaemia is an autosomal recessively inherited disorder caused by deficient activity of the enzyme galactose-1-phosphate uridyltransferase (GALT), which can be detected by newborn screening. The p.N314D mutation defines two variant forms of the GALT enzyme, the Los Angeles and Duarte, depending on the presence of additional base changes. AIM The aim of our study was to analyze a healthy Hungarian population for the frequencies of the Los Angeles and Duarte galactose-1-phosphate uridyltransferase variant alleles. METHODS DNA samples from 100 subjects were analyzed by polymerase chain reaction, followed by digestion with restriction endonucleases. RESULTS The frequencies of the p.N314D, the Los Angeles and the Duarte variants were 11.5%, 2.5% and 9%, respectively. CONCLUSIONS The allele frequencies of the Los Angeles and Duarte variant alleles in the Hungarian population correlate well with the allele frequencies in other healthy Caucasian populations.