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Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases, affecting approximately one in 10,000 live births and with a carrier frequency of approximately one in 35. The disease is caused by a deficiency of the ubiquitous protein survival of motor neuron (SMN), which is encoded by the SMN1 and SMN2 genes. Due to a single nucleotide polymorphism in exon 7, SMN2 produces less full-length transcript than SMN1 and cannot prevent neuronal cell death at physiologic gene dosages. On the other hand, the copy number of SMN2 affects the amount of SMN protein produced and the severity of the SMA phenotype. SMN gene dosage analysis can determine the copy number of SMN1 to detect carriers and patients heterozygous for the absence of SMN1 exon 7. This study provides copy number estimation of SMN1 gene by real-time PCR technique in 56 SMA type I., II., III. patients, 159 parents and healthy relatives and in 152 undefined SMA patients. Among the family members, 91 carriers have been detected and in 56 patients homozygous deletion of SMN1 exon 7 has been confirmed. Moreover, in 12 patients compound heterozygosity of SMN1 exon 7 mutation has been detected, thus providing the possible diagnosis of SMA. In 94 patients, copy number of SMN2 has also been evaluated and a good correlation has been found with the phenotype of the disease. Due to the genetic complexity and the high carrier frequency, accurate risk assessment and genetic counselling are particularly important for the families. These new results provide improvement of the diagnostic service in SMA in Hungary with focus on proper genetic counselling and possible enrolment of the patients in future therapeutic interventions.

Muscular dystrophies are a genetically heterogeneous group of degenerative muscle disorders. This article focuses on two severe forms of muscular dystrophies and provides genetic data for a large cohort of Hungarian patients diagnosed within the last few years by the authors. The Duchenne/Becker muscular dystrophy (DMD/BMD) is caused by mutations in the dystrophin gene, which is located on chromosome Xp21. The genetic analysis of dystrophin is usually performed by multiplex polymerase chain reaction (PCR), which detects approximately 95% of all deletions but does not distinguish between one and two copies of the exons investigated. The present work, therefore, concentrates on the improvement of the diagnostic panel for the analysis of DMD/BMD in Hungary. Radioactively labelled cDNA probes, encompassing the whole dystrophin gene detect all the deletions and the analysis is quantitative. In addition, the new multiple ligation-dependent probe amplification (MLPA) technique was recently introduced that enabled more reliable and faster quantitative detection of the entire dystrophin gene. The genomic basis of facioscapulohumeral muscular dystrophy (FSHD) is associated with contraction of the D4Z4 repeat region in the subtelomere of chromosome 4q. In case of FSHD, molecular genetic criteria still have to be improved because of the complexity of the disorder.

Cartilage-hair hypoplasia is a rare, autosomal recessive primary immunodeficiency disorder characterized by predominantly T-cell deficiency and metaphyseal chondrodysplasia. The authors summarize current knowledge on molecular genetics, diagnostic characteristics and therapeutic options of this inherited immunodeficiency.

Human astroviruses (HAstV) are the causative agents of viral gastroenteritis mainly in children worldwide. This study investigated the epidemiology and genotype diversity of HAstVs detected in children admitted to hospital with gastroenteritis in Hungary. Stool samples were collected from children with diarrhea at the Municipal "Szent László" Hospital, Budapest, Hungary, between January 2002 and December 2002. Of 2,758 samples, 607 were negative for both rotaviruses and bacterial pathogens and were tested for astroviruses using a reverse transcriptase-polymerase chain reaction (RT-PCR) targeting the open reading frame (ORF2), capsid region. Astrovirus was detected in 10 samples (1.6%) by RT-PCR. Astrovirus infection was more frequent among children 49 to 60 months of age. Genotyping of positive samples was performed by type-specific RT-PCR and confirmed by sequence analysis. Phylogenetic analysis was performed using a 203 nucleotide consensus length of the 3'-end of the capsid gene. Type-specific RT-PCR and sequence analysis detected genotypes 1 (50%), 4 (30%), 3 (10%), and 8 (10%) among the children admitted to hospital. Genotype 1 was the predominant genotype, but genotypes 3, 4, and 8 were also present indicating the importance of emerging genotype 8 infections. Two distinct genotype 4 variants were observed during this study. Sequence analysis confirmed type-specific RT-PCR results in the capsid region. This is the first comprehensive report on the occurrence of HAstV infections in Central/Eastern Europe.

We studied a female patient initially diagnosed with Costello syndrome who carries an apparently balanced translocation, t(1;22) (q24.3;q13.1). Molecular characterization of the translocation revealed a mosaic of two derivative chromosomes 1 in her peripheral blood lymphocytes, in one of which the coding region of the platelet-derived growth factor (PDGFB; chromosome 22q13.1) gene was disrupted. Both the initial translocation and the secondary intrachromosomal rearrangement appear to have occurred by nonhomologous (illegitimate) recombination. In 18 patients with Costello syndrome, mutation analysis of the genes belonging to the PDGF/R family, PDGFA, PDGFB, PDGFC, PDGFD, PDGFRA, and PDGFRB, revealed no pathogenic mutations. Reevaluation of the clinical symptoms of the translocation patient challenges the diagnosis of Costello syndrome in this patient. In total RNA isolated from lymphocytes of the translocation patient, we identified four different fusion transcripts consisting of PDGFB exons and parts of chromosome 1q24.3. In two of the mRNAs, exon 6 of PDGFB, encoding the 41 C-terminal amino acid residues, was absent. Immunofluorescence analysis showed that the wild-type protein was dispersed and formed a network-like structure in the extracellular matrix, whereas the two aberrant PDGFB proteins were localized in aggregates. We speculate that the biological consequences of the mutant PDGFB allele contributed to the unique disease phenotype of the translocation patient.

An occupational epidemiological study was organised among workers in an acrylonitrile using factory in Hungary. Of the 888 workers, 783 were included in the study and three groups were differentiated: Group A (N = 452) with direct and continuous exposure, Group B (N = 171) with direct but occasional exposure and Group C (N = 160) without direct exposure, as referent. There were two main objectives: to determine the occurrence of cancer in workers and congenital abnormalities in their liveborn infants. The study did not indicate a higher occurrence of cancer among workers: only one lung cancer patient was found, prostate cancer did not occur. Among congenital abnormalities, the group of specified multiple congenital abnormalities showed a higher rate than expected but characteristic defect-pattern was not found among seven multimalformed babies, though five had cardiovascular malformations. In conclusion, our study did not indicate the carcinogenic, mutagenic and teratogenic effect of acrylonitrile among workers using this chemical in the factory.

MTHFR encodes a critical enzyme in folate and homocysteine metabolism and the C677T allele of the MTHFR gene has some association with an increased risk for neural-tube defects and for adult cardiovascular diseases. As part of an international collaborative study the prevalence of C677T homozygous genotype was 11.1% while the frequency of C677T heterozygous condition was 45.2% in the Hungarian neonate sample. These findings underscore the clinical importance of the C677T variant in the Hungarian population and urge population-based prevention of conditions related to such gene.

Objective: In 1982, Tolarova(4) found a reduction in the recurrence rate of isolated cleft lip (CL) with or without cleft palate (CP; CL +/- CP) after periconceptional supplementation with a multivitamin including a very high dose (10 mg) of folic acid. The Hungarian randomized, double-blind, controlled trial of periconceptional supplementation with a multivitamin including a physiologic dose (.8 mg) of folic acid did not show any preventive effect on the first occurrence of isolated CL +/- CP and CP. However, the general evaluation of congenital abnormalities in the Hungarian Case-Control Surveillance of Congenital Abnormalities indicated, among others, a reduction of isolated CL +/- CP and CP after the use of high doses of folic acid in the critical period for the development of these congenital abnormalities in the 12-year dataset between 1980 and 1991. We hypothesized that the prevention of orofacial clefts by folic acid has a dose-dependent effect, and this hypothesis was tested in 2 recent Hungarian datasets., Design: In a prospective cohort study, the occurrence of isolated CL +/- CP and CP was studied in the newborn infants born to mothers with or without periconceptional folic acid-containing (.8 mg) multivitamin supplementation. Supplemented women with confirmed pregnancy were recruited from the participants of the periconceptional service. Unsupplemented women were invited to take part in the study after the first visit between the 8th and 12th week of gestation in the antenatal care. Supplemented and unsupplemented women were matched based on age, socioeconomic status, and residence. In contrast, the occurrence of high-dose (in general daily 6 mg) folic acid supplementation was evaluated in the case-control pairs of CL +/- CP and CP, particularly during the critical period of these 2 types of orofacial clefts in the 17 years dataset of the Case-Control Surveillance of Congenital Abnormalities, between 1980 and 1996. Cases were selected from the population-based Hungarian Congenital Abnormality Registry, whereas population controls without congenital abnormality were ascertained from the national birth registry. Two population controls were matched to every case according to sex, week of birth, and district of parental residence. The drug uses, including pregnancy supplements as folic acid, were evaluated based on retrospective self-reported maternal questionnaire and prospective medically documented data of antenatal care logbook., Results: In the prospective cohort study, of 3019 informative offspring (termination of pregnancies in the second and third trimesters because of fetal defect, stillborn fetuses, and liveborn infants) in the supplemented group, 3 had CL +/- CP and 1 was affected with CP, whereas of 3432 informative offspring in the unsupplemented group, 2 had CL +/- CP and 1 had CP. The lack of preventive effect was in agreement with the result of the previous Hungarian randomized double-blind controlled trial; thus, these 2 datasets were combined. The preventive effect of a folic acid containing multivitamin used in the periconceptional period for the first occurrence of isolated CL +/- CP and CP was estimated by the Mantel-Haenszel test. Of 5488 supplemented women, 6 had CL +/- CP, and of 5821 unsupplemented women, 4 had CL +/- CP. Of 5489 supplemented women, 1 had CP, and of 5823 unsupplemented pregnant women, 3 had CP. The Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996, included 38 151 population controls (1.8% of the Hungarian births) and 22 865 cases with congenital abnormalities. Within the latter group, 1368 had isolated CL +/- CP, and 596 had CP. A significantly more frequent use of high-dose folic acid (in general daily 6 mg) supplementation was found in controls than in cases of 1246 case-control pairs of CL +/- CP group and of 537 case-control pairs of CP group, respectively. (ABSTRACT TRUNCATED)

The results of an environmental mutation and teratologic epidemiological study are presented which was performed in inhabitants living in the surrounding region of an acrylonitrile factory in Nyergesújfalu. The endpoint of the study was congenital abnormalities in 46,326 infants born to mothers living in the 30 settlements of the study region within a 25 km radius of the acrylonitrile factory between 1980 and 1996. The ascertainment of cases with congenital abnormalities was based on the dataset of the Hungarian Congenital Abnormality Registry complemented with the review of pediatric, pathology and cytogenetic records. A particular attention was paid to the indicators of germinal mutations as sentinel anomalies, Down syndrome and unidentified multiple congenital abnormalities and the indicators of teratogens as the specific pattern of multiple congenital abnormalities. Three congenital abnormalities: pectus excavatum in Tata, 1990-1992 (OR with 95%CI: 78.5, 8.4-729.6), undescended testis in Nyergesújfalu between 1980 and 1983 (8.6, 1.4-54.3) and in Esztergom, 1981-1982 (4. 2, 1.3-13.5) and clubfoot in Tata, 1980-1981 (5.5, 1.5-20.3) showed significant time-space clusters in the study region. There was a decrease in risk of undescended testis with increasing distance from the acrylonitrile factory. An unusual increase was found in the combination of oral cleft and cardiac septal defects in multimalformed babies in Tatabánya, 1990. The detailed analysis of congenital abnormalities in all settlements of a given territory may help to detect clusters of congenital abnormalities and their possible relation to the environmental hazards., (Copyright 1999 Elsevier Science B.V.)

Objective: The purpose of this study was to examine the timing and consequences of suicide attempts by self-poisoning during pregnancy., Methods: A population-based prospective study was organised in the toxicological in-patient hospital in Budapest which is responsible for health services for adult inhabitants poisoned by ingesting chemicals in Budapest and the surrounding area involving 3 million people between 1985 and 1993. All women aged between 16 and 50 years (22969) who were admitted to the study hospital due to suicide attempts by drug ingestion were examined by a sensitive serum pregnancy test., Results: Of 559 self-poisoned pregnant women, two died. The peak period of suicide attempts was found to be in the first postconceptual month and its majority resulted in a very early fetal loss. The second highest figure was recorded in the second postconceptual month. Thus, 61% of suicide attempts occurred before the third postconceptual month. Later pregnancies had a significantly lower proportion of attempting suicide parallel with advanced fetal development., Conclusions: Most suicide attempts by self-poisoning occurred after the early recognition of unwanted pregnancies and most resulted in a very early fetal loss. Pregnancies with advanced gestation months had a significantly lower proportion of attempting suicide.

A series of 22 women who suffered from mushroom poisoning while pregnant have been identified among adults receiving treatment between 1960 and 1993 in a specialist clinic in Budapest, Hungary. In most cases, the poisonings were attributed to Amanita phalloides, verna, and related species. Of these, 20 went to term, and data were collected on gestational age, birth weight, and both major and minor congenital anomalies. Mean birth weight (but not gestational age) was lower than in the control series, suggesting that maternal poisoning may have led to intrauterine growth retardation. Two children were identified with major abnormalities (one of whom had fetal alcohol syndrome related to alcohol abuse by the mother). The prevalences of both major and minor anomalies were similar to the prevalence in the matched control group and to the rate in a more recent control series examined according to the same protocols. However, the statistical power to detect teratogenic effects is limited, especially as only five of the mothers suffered the poisoning episode during the first trimester.

Suicide attempts by drug ingestion during pregnancy provides an opportunity to study the teratogenicity of large doses of drugs in human beings. Data of a population-based prospective study of all pregnant women admitted to the toxicological inpatient hospital in Budapest which is responsible for the health provision of chemical poisoned persons from a 3 million study population. Of 22,969 self-poisoned women, 645 were pregnant and 559 attempted suicide by drug ingestion during pregnancy during the study period (1985-1993). Two died. The peak of suicide attempts was found in the first month of fetal development, and its great majority resulted in a very early fetal death, the so-called chemical pregnancy. Thus 61% of suicide attempts occurred before the third month. Later pregnancies had a protective effect against suicide parallel with advanced months of fetal development.

Objective: To identify the teratogenic risk of large doses of various drugs taken by women in attempting suicide., Methods: This population-based, prospective, epidemiologic study involved 559 women with pregnancy verified by a serum pregnancy test who were admitted to the toxicologic inpatient clinic in Budapest responsible for providing health services to chemically poisoned individuals from a population of 3 million. Each self-poisoned woman was matched for age and gestational age with a control selected from among participants in periconceptional care., Results: Two of 559 self-poisoned pregnant women died. One hundred seventy-eight infants born to mothers who poisoned themselves during pregnancy either were examined personally or had appropriate medical data available. After excluding eight infants with fetal alcohol syndrome born to heavy-drinking mothers, the rate of congenital abnormalities in study infants (9.0%) did not significantly exceed the rate of control infants (6.1%). Thus, no teratogenic effect of drugs used for self-poisoning could be identified, even though large doses of drugs were used in 27 cases between the 3rd and 8th weeks of fetal development. This sample was not large enough to evaluate single drugs separately., Conclusion: Drugs taken by women in attempting suicide do not seem to pose a risk for structural birth defects in the offspring.

The female consultant had two mentally retarded boys from her two marriages. The clinical symptoms and Fra-X chromosomes indicated their Martin-Bell disease. The daughter of the consultant is healthy and Fra-X negative. She is pregnant and insisted on her molecular genetic diagnosis due to an international collaboration. Both affected brothers had FRAXA genes with a full mutation including more than 200 CGG methylated repeats. The consultant female was in the phase of premutation, however, her healthy daughter had two normal 50% methylated genes with 19 and 26 CGG repeats. Thus there is no recurrence risk for Martin-Bell disease in her fetus.

The article summarises the statistical data of bone marrow transplantation (BMT) carried out in Hungary between 1990-1995 in yearly distribution. Since the first BMT up to the end of 1995, 168 BMT were performed. The number of transplantations since 1990 to our days was gradually increasing. As a result of this activity in the three transplantation centers (National Institute of Haematology and Immunology, St. László Hospital and County Hospital in Miskolc) 36 allogeneic and 12 autologous BMT were performed in 1995. Out of the allogeneic BMT cases, 14% of them were completed with unrelated, donors in the last three years. The most frequent indications for allogenic BMT are: chronic myeloid leukaemia (CML), acute lymphoid leukaemia (ALL), acute myeloid leukaemia (AML), myelodysplasia, severe aplastic anaemia. Child allogenic BMTs are carried out on pediatric patients in St. László Hospital in leukaemia, severe aplastic anaemia cases and children born with immunodeficiency. Autologous BMTs started in an organised way in 1995 for adult patients in cases of non-Hodgkin lymphoma, Hodgkin lymphoma and for children with solid tumour indication in the Miskolc Centre. BMT activity in Hungary compared with international data, especially within Europe, shows a significant drop behind. To calculate for ten million inhabitants, the optimal BMT activity should be between 100-200 transplantations (allogeneic and autologous BMT together) in 1994. Among the Central European countries Hungary and Poland fall most behind. Autologous BMTs in most countries of Europe are above of allogeneic BMTs in numbers as indication in cases of lymphoma and solid tumours (first of all mamma carcinoma) comes into focus. This summary emphasises the most important difficulties in connection with the development of the National BMT program.

The authors analyse the experiences of their Genetic Counseling Clinic between 1979-1992. They show the formation of the motives of presenting and consulting. They range the consultants in three etiological categories (genetical, teratological and clinical entities). The proportion of new consultants increased fourfold and this tendency documents unambiguously the claim of family planners for this very important medical service. The proportion of Mendelian disorders, mutagen risk and consanguinity are relatively continuous. Because of teratogen risk the rate of presenting decreased moderately. The proportion of consultants shows a definite increase of multifactorial frequent disorders, which they value as a favorable tendency. For decreasing of unjustified cases they suggest the necessity of pre-screening.

Of 15 live births in one Hungarian village in 1989-90, 11 (73%) were affected by congenital abnormalities and 6 were twins. Of the 11, 4 had Down syndrome. Likely causes of such clusters (known teratogenic factors, familial inheritance, consanguinity) were excluded. A case-control study and environmental investigations pointed the finger of suspicion at the excessive use of trichlorfon at local fish farms. The content of this chemical was very high in fish (100 mg/kg) and several pregnant women, including all mothers of babies with Down syndrome, had consumed contaminated fish in the critical period for the congenital abnormalities observed.