Genetic-epidemiologic study of haemophilia A and B in Hungary

All known surviving haemophiliacs A and B and their relatives were reexamined by laboratory and clinical methods and evaluated by a genetic-epidemiologic approach in 4 north-western countries of Hungary. The prevalence of haemophilia A and B patients born in the fifties was 2.73 and 0.25 per 10,000 persons, respectively. The reproductive fitness was found to be 0.3 in haemophilia A, and 0.8 in haemophilia B patients. The mutation rates calculated by the indirect method were 6.3 x 10(-5) for haemophilia A and 0.2 x 10(-5) for haemophilia B.     

Regional co-ordinator for haemophilia in domiciliary practice.

The North-east Thames Region has appointed a nursing sister to co-ordinate the organisation of care for haemophiliacs in the region. As a result of the appointment, facilities for home treatment have expanded rapidly. Several associate centres providing care to haemophiliacs have been set up around the region in addition to the four main haemophilia centres, which are all in the south-west corner of the region. As well as providing support and supervision of patients on home treatment, the co-ordinator helps to place haemophiliac children in suitable schools, maintains the regional register of haemophiliacs, and has a more general role in ensuring that services are available where they are needed throughout the region.     

Treatment results of childhood Hodgkin's lymphoma in Hungary

Lymphomas are the third most frequent malignancies in childhood. The Hungarian Pediatric Oncology Group was founded in 1971, and since then the same chemotherapeutic protocols have been used in the whole country. In this study we analyzed the data of childhood Hodgkin's lymphoma in Hungary in the last 11 years (1988-1998). We also compared our results with the international (German) data. The incidence of Hodgkin's lymphoma (0-15 years) was 7.1/1,000,000 child/year (the same for non-Hodgkin's lymphoma was 7.5/1,000,000/year); 5.5% of all pediatric malignancies in Hungary). The patients were treated according to the German DAL-HD-82 and 90 protocols. The therapy consisted of 2-6 cytostatic blocks, depending on the stage, followed by involved field irradiation. The overall survival was 94.7+/-2.0% at 5 years and 91.9+/-2.7% at 10 years. These results are very similar to the German data: 94% at 5 years and 93% at 10 years. The good results are due to the well organised network and the uniformed treatment. The results may be ameliorated by using autologous bone marrow transplantation.     

Psychological disturbance in children with haemophilia.

OBJECTIVE--To assess the need for formal psychotherapeutic intervention in children attending a children''s haemophilia clinic after some of them had been diagnosed as positive for HIV. DESIGN--Comparison of haemophiliac children with matched control groups of diabetic and healthy children. SETTING--The West of Scotland Children''s Haemophilia Centre, Glasgow. PATIENTS--43 Children aged 3 to 16 years with mild, moderate, and severe clotting disorders were matched with control groups of 46 diabetic children and 42 physically healthy children. INTERVENTIONS--Parents of children aged 3-5 years were interviewed with the behaviour screening questionnaire. Children aged 6 to 16 were assessed by parental and teacher report using standardised questionnaires and self report using a computerised depression inventory. All were scored numerically according to the presence of symptoms of emotional and behavioural problems. MAIN OUTCOME MEASURES--The groups were compared for mean scores on each rating device and for number of children achieving scores within the pathological range. RESULTS--In the 6-16 age group five haemophiliac children, five diabetic children, and three healthy children scored in the pathological range on the parent questionnaire, as did two, three, and five respectively on the teacher questionnaire and four, four, and eight on the depression inventory. There was no significant difference across the three groups. Analysis of mean scores similarly showed no significant difference across groups. In contrast, the single measure used for younger children showed an increase in behavioural difficulties among the diabetic children. CONCLUSION--Haemophiliac children attending the West of Scotland Centre were no more disturbed than their diabetic or healthy peers despite the identification of HIV infection within the clinic and the widespread adverse publicity associated with AIDS and HIV infection.     

Incidence of non-cholera vibrios in Hungary.

In the period 1971 to 1976, 200 non-cholera vibrio (NCV) strains were isolated in Hungary; 18 of the cultures were derived from 34 729 faecal and 182 from 237 surface water samples. Ninety-two strains belonged to the Heiberg-Smith group I and 108 to group II. Two strains failed to give the string test and 3 were pteridine resistant. The strains were classified into 48 serotypes according to Smith's system. Faecal NCV strains belonged to serotypes 46 and 328; these serotypes did not occur in water. Of the 18 faecal strains 13 were isolated from 18 048 persons who had travelled in cholera-infected areas, and 5 strains from persons who had never left Hungary (2 from 4559 patients with diarrhoea and 3 from 6061 healthy individuals). These data indicate that although NCV are present in the environment, they play an insignificant role in enteric infections in Hungary.     

Aetiological studies of hypospadias in Hungary.

A complex aetiological (epidemiological, teratological and genetic) study was made in 294 index patients with simple isolated hypospadias. The epidemiological study conducted by the help of personal interviews of the mothers revealed a higher frequency of index patients among children born between August and December, among twins, mainly monozygotic, and finally in the lower birth weight groups and among first-borns. The teratological study showed a higher frequency in mothers of index patients who had had sex hormone treatment, mainly progestogen, before the 16th gestational week. This seems to indicate the aetiological role of fetal androgen deficit caused by the regulation disturbances of human choriogonadotropin. The genetic family study completed by personal examination of first-degree male relatives showed a familial clustering (4.0% versus a point prevalence of 0.44% in live-births). Both the pattern of affected relatives (h2 values 0.62 +/- 0.21 and 0.72 +/- 0.33 in fathers and brothers, respectively, not differing significantly from each other) and further characteristics (other malformations were not frequent in relatives) correspond to the multifactorial-threshold model.     

Molecular pathology of haemophilia B.

Direct sequencing of amplified genomic DNA has been used to investigate the molecular basis of haemophilia B and thus identify specific amino acids that are essential for maintenance of structure or function of factor IX. Substitution of Cys 336, Asn 120 results in loss of circulating factor IX antigen and deletion of Arg 37 in gross reduction of circulating protein and loss of activity, while substitution of Arg -4, Arg 333, Asp 64 and Pro 55 cause loss of function without marked reduction in protein serum levels. Frameshift or point mutations resulting in marked loss of coding information are found in patients who develop antibodies to administered factor IX. An enhanced rate of mutation is evident at two CpG dinucleotides in the factor IX gene, which accounts for approximately 25% of all point mutations causing haemophilia B known to date. Direct sequencing of mutations also permits, for the first time, rapid and unequivocal prenatal and carrier diagnoses, in all cases, by eliminating the need for informative segregation of markers.     

Incidence of congenital heart disease in Hungary.

A survey was planned for establishing the point prevalence at birth of congenital heart disease and for assessing at the same time the efficacy of a screening for such anomalies. This model included: (1) exact determination of the population under survey; (2) approximately complete ascertainment of all persons in the population studied; (3) identical principles of cardiologic screening; (4) application of modern cardiologic diagnostic methods, and (5) a sample of over 2,000 persons. 23 cases of congenital heart diseases were found among 2,259 children born 1963 in a defined Hungarian territory. This means a point prevalence of 10.2+/-2.1% live births. (An additional 6 doubtful cases were not taken into account.) From the 12 cases diagnosed in vivo, 10 were detected by the screening.     

Haemagglutination-inhibiting antibodies to B.K. virus in Hungary.

Antibody inhibiting the haemagglutination by B.K. virus was found in 64% of the serum samples collected from 949 subjects in Hungary. The frequency of seropositivity was the lowest (17%) among infants 1 and 2 years of age and the highest (93%) in the age group 16 to 20 years. The subsequent age groups showed a slow continuous decline. The age-distribution curve drawn on the basis of the geometric means of titres has two peaks, one between 3 and 5 years of age and another between 21 and 30 years of age, reaching 6.74 and 7.05, respectively, as expressed in terms of log2 units. The prevalence of haemagglutination-inhibiting antibody to B.K. virus in Hungary and its distribution by age are similar to those reported from other European countries.     

RNA repair for haemophilia A

The mainstay of gene transfer studies is the use of wild-type cDNAs to effect phenotypic correction of diseases. However, this strategy is not feasible for genetic diseases caused either by mutations of large genes or by dominant-negative mutations, or where the regulation of the gene is critical. In this review, we will discuss a novel RNA reprogramming strategy - spliceosome-mediated RNA trans-splicing - where the pre-messenger RNA is modified by the splicing of two independent RNA species. The use of trans-splicing to effect phenotypic change in the hereditary bleeding disorder haemophilia A will be discussed.