[Quantitative analysis of the genes determining spinal muscular atrophy]. / A spinalis izomatrophiát meghatározó survival motoneuron gének kvantitatív analízise.

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.

Genetic and demographic features of X-linked agammaglobulinemia in Eastern and Central Europe: a cohort study.

Primary immunodeficiency disorders are a recognized public health problem worldwide. The prototype of these conditions is X-linked agammaglobulinemia (XLA) or Bruton's disease. XLA is caused by mutations in Bruton's tyrosine kinase gene (BTK), preventing B cell development and resulting in the almost total absence of serum immunoglobulins. The genetic profile and prevalence of XLA have not previously been studied in Eastern and Central European (ECE) countries. We studied the genetic and demographic features of XLA in Belarus, Croatia Hungary, Poland, Republic of Macedonia, Romania, Russia, Serbia, Slovenia, and Ukraine. We collected clinical, immunological, and genetic information for 122 patients from 109 families. The BTK gene was sequenced from the genomic DNA of patients with a high susceptibility to infection, almost no CD19(+) peripheral blood B cells, and low or undetectable levels of serum immunoglobulins M, G, and A, compatible with a clinical and immunological diagnosis of XLA. BTK sequence analysis revealed 98 different mutations, 46 of which are reported for the first time here. The mutations included single nucleotide changes in the coding exons (35 missense and 17 nonsense), 23 splicing defects, 13 small deletions, 7 large deletions, and 3 insertions. The mutations were scattered throughout the BTK gene and most frequently concerned the SH1 domain; no missense mutation was detected in the SH3 domain. The prevalence of XLA in ECE countries (total population 145,530,870) was found to be 1 per 1,399,000 individuals. This report provides the first comprehensive overview of the molecular genetic and demographic features of XLA in Eastern and Central Europe.

[Cartilage-hair hypoplasia]. / Porc-haj hypoplasia.

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.

[Calpain-3 gene defect causing limb gird muscular dystrophy in a Hungarian family]. / Végtagövi izomdisztrófiát okozó kalpaindefektus egy magyar családban.

Limb gird muscular dystrophies (LGMD2) are a clinically and genetically heterogeneous group of hereditary diseases with autosomal recessive trait, characterized by progressive atrophy and weakness predominantly in the proximal limb muscles. The authors present clinical, histological, immunohistochemical and immunoblot results of two sisters suffering from so far unclassified autosomal recessive limb girdle muscular dystrophy. Haplotype analysis for genes possibly involved in autosomal recessive limb girdle muscular dystrophies was performed in the genetically informative family. All of the results pointed to a molecular genetic defect of the calpain-3 (CAPN3) gene. Direct sequencing of the CAPN3 gene revealed compound heterozygous state for two mutations previously described in association with limb girdle muscular dystrophy, proving pathogenicity. The authors would like to emphasize the importance of the above described combined strategy in diagnosing limb girdle muscular dystrophies.

One-year survey of astrovirus infection in children with gastroenteritis in a large hospital in Hungary: occurrence and genetic analysis of astroviruses.

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.

Disruption of the PDGFB gene in a 1;22 translocation patient does not cause Costello syndrome.

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.

Occupational epidemiological study of workers in an acrylonitrile using factory with particular attention to cancers and birth defects.

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.