Influence of different spectra of NOTCH3 variants on the clinical phenotype of CADASIL - experience from Slovakia.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary vascular disorder causing ischaemic attacks and strokes in middle-aged adults. Though the clinical spectrum includes some typical symptoms, recognition of the disease, especially at an earlier stage, is very difficult because of the highly variable manifestation and incomplete clinical picture. Characteristic brain MRI findings and the presence of pathogenic variants in the NOTCH3 gene are fundamental for CADASIL diagnosis. In this paper, we provide the first comprehensive report on CADASIL patients from Slovakia. Altogether, we identified 23 different pathogenic variants in 35 unrelated families. In our cohort of patients with clinical suspicion of CADASIL, we found a causal genetic defect and confirmed the diagnosis in 10.2% of cases. We present the case reports with up-to-date unpublished NOTCH3 variants and describe their phenotype-genotype correlation: p.(Cys65Phe), p.(Pro86Leu/Ser502Phe), p.(Arg156*), p.(Cys408Arg), p.(Tyr423Cys), p.(Asp1720His), and p.(Asp1893Thrfs*13). The most frequently described location for pathogenic variants was in exon 4, whereas the most common single variant was p.Arg1076Cys in exon 20. Based on the results of our study, we propose a re-evaluation of the criteria for the selection of patients suitable for NOTCH3 gene analysis. We hereby state that the currently used protocol of a high score requirement is not ideal for assessing molecular analysis, and it will be desirable to be less strict in criteria for genetic testing.

[Nijmegen breakage syndrome in Slovakia]. / Nijmegen breakage syndrom na slovensku.

BACKGROUND: The autosomal recessive Nijmegen breakage syndrome (NBS) is a DNA repair disorder due to a mutation in the NBS1 gene on 8q21. Hyperradiosensitivity and high risk for lymphoreticular malignancy are important reasons for early diagnosis and prevention by avoidance of ionisation. The frequency of NBS heterozygotes of the mutation 657de15, which is predominant in the Slavic population was estimated to be in the range of 1:90-1:314 in different parts of Poland, and 1:128-154 among Czech newborns, born 20 years ago. METHODS AND RESULTS: Lower prevalence of affected homozygotes born in Czechoslovakia in the period 1969- 1992 (24 among 5.2 million newborns corresponds to 1:271000) than expected on the basis of carrier frequency is explained to be due to underdiagnosing because the rate of prenatal lethality in the NBS families is not increased or it is even lower than in the general population. The underdiagnosing of NBS is emphasized also by the mean age at diagnosis (7.5 years) although severe microcephaly is present at birth. The possibility to offer effective prevention of primary and secondary malignancies becomes the motivation for interdisciplinary collaboration with paediatricians, neurologists, immunologists and clinical geneticists. A decrease of the mean age down to 6 months at diagnosis among the 11 newly recognized patients has been achieved in the previous 4 years. The occurrence of homozygotes was relatively higher in Slovakia with 5 million inhabitants (14 patients in 11 families) than in the Czech Republic with a population of 10 million (21 patients in 14 families), and therefore the frequency of NBS heterozygotes was studied among 2996 newborns born in 2002-2003 in 12 maternity hospitals of west, middle and east Slovakia. Surprisingly, only 3 heterozygotes were found. CONCLUSIONS: This discrepancy of heterozygote frequency and the number of homozygotes shows that due to traditional subisolates the population is not in the genetic equilibrium. It explains the high prevalence of alcaptonuria in Slovakia in the middle of last century, which is a rare disorder in other countries.

[Incidence of spinal muscular atrophy and Duchenne's muscular dystrophy in the juvenile population of central Slovakia]. / Incidencia spinálnej svalovej atrofie a Duchenneovej svalovej dystrofie v detskej populácii stredného Slovenska.

Spinal muscular atrophy, type I-III and Duchenne muscular dystrophy belong to the most frequent neuromuscular diseases in children. The purpose of this work was to determine the incidence of these two diseases in liveborn children in the years 1975 to 1989 in the south part of middle Slovakia. The common incidence of all three types of spinal muscular atrophy was 1 in 5631 liveborn children (most frequent was the Werdnig-Hoffmann disease, type I--1 in 12,286). This fact confirms, that this disease belongs to the most frequent autosomal recessive diseases in children of our region too. The incidence of Duchenne muscular dystrophy was 1 in 4827 liveborn boys. The figure is in the range of the published data of the incidence of this disease. The deletion in the dystrofin gene was proved in 70% of affected boys. (Tab. 3, Fig. 1, Ref. 24).

[Genetic mental retardation in the district of Banská Bystrica]. / Geneticky podmienená mentálna retardácia v okrese Banská Bystrica.

The authors investigated the prevalence of mental retardation (MR) in 6-14-year-old children in the district of Banská Bystrica. The aim was to assess the prevalence of MR and the ratio and character of genetic factors participation in its genesis. The group was based on the Uniform records of defective children and health records of children from special schools and social care institutes in 1987. From a total of 23,510 children 510 (2.16%) suffered from MR. In the population of gipsy children the authors found 21.5% with MR, while in the population of non-gipsy children the percentage was 0.9%. Genetic examinations were made in 106 children with MR. In 33 of these (31.1%) there was evidence of a genetic aetiology (monogenic disease in 21, chromosomal aberration in 11 and in one instance polyfactorial disease); a non-genetic aetiology was found in 21 children (19.8%). The aetiology was not elucidated in 52 children (49.0%). The authors emphasize the importance of genetic prevention for reducing the number of children with MR but draw attention also to non-medical factors which may play a part in the aetiology of mental retardation in a part of the child population.

Terminal deletion with stable acentric fragment of 1q in a child with congenital malformations.

The terminal deletion with stable acentric fragment of 1q was found in a girl with multiple congenital malformations and severe mental retardation. The karyotype of both parents was normal, and the aberration appears de novo. The medium did not influence the expression of the aberration.