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 We present the case reports with up-to-date unpublished NOTCH3 variants and describe their phenotype-genotype correlation: p.(Cys65Phe), p.(Pro86Leu/Ser502Phe), p.(Arg156*), p.(Cys408Arg), p.(Tyr423Cys),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.

[Two siblings with bilateral congenital knee dislocations: case report]. / Dvaja súrodenci s bilaterálnymi vrodenými luxáciami v kolenných klboch - kazuistika.

Congenital dislocation of the knee and congenital permanent dislocation of the patella are rare disorders usually associated with complex syndromes. Two cases of siblings, girl and boy, who had the same clinical phenotype of this disorder are presented. The diagnosis of Desbuquois dysplasia was made and its autosomal recessive heredity was confirmed by genetic analysis. DNA samples were sent for a molecular genetic analysis of the skeletal dysplasia. The girl was surgically treated for a complete (grade 3) anterior dislocation of the tibia on the femur in the first year of life. Redressing casts had not previously been applied to avoid the risk of damaging the epiphysis. The left knee was operated on by the method, as described by Curtis and Fisher, at the age of six months. The Kirschner wire was removed after one month and a plaster cast was applied to maintain the flexion required. At seven post-operative weeks physiotherapy was started with temporary use of a knee brace. The right knee was managed by a similar procedure at four months after the first surgery. Normal walking was achieved at the age of 21 months. Knee motion was symmetrically restricted, with 5 to 90 degrees of flexion. The boy was first seen at our out-patient department after his sister had achieved full walking ability. He was 10 years old at that time and presented with walking problems due to nearly 30 degrees of bilateral knee contractures. Permanent dislocation of both patellae was treated by the surgical technique described by Stanisavljevic. Revision surgery of the right knee due to patellar lateralization was required two years after the primary surgery; it was performed using the Campbell's technique. A corrective osteotomy of the left proximal tibia because of progressive genu valgum was carried out at four years following the first operation. At the last follow-up, the boy was 16 years old and the knee range of motion bilaterally was 0 to 120 degrees with good alignment of both knees. As a result of surgical treatment the two patients gained ability to walk without problems. Key words: bilateral congenital knee dislocation, patella, Desbuquois dysplasia, siblings, skeletal dysplasia, case report.

Peroxisomal D-bifunctional protein deficiency: First case reports from Slovakia.

D-bifunctional protein deficiency (#OMIM 261515) is a rare autosomal recessive hereditary metabolic disorder causing severe clinical and biochemical abnormalities that are usually fatal in the course of the first years of life. This disease is classified as single enzyme peroxisomal disorder affecting the ß-oxidation pathway in this compartment. In this paper we present a full overview of the clinical presentation, magnetic resonance imaging, biochemical and molecular data of two Slovak D-bifunctional protein deficient patients. In the clinical presentation of both patients severe generalized hypotonia, depression of neonatal reflexes, craniofacial dysmorphism and seizures dominated starting from the second day of life. In both patients, who died up to two years of life, we found elevated plasma levels of very long chain fatty acids and we identified the presence of causative mutations in the HSD17B4 gene. In the first case, we found the homozygous mutation c.46G>A, which is responsible for a defect in the dehydrogenase domain. In the second patient, the heterozygous mutations c.1369A>G and c.1516C>T were present and functionally they are related to the hydratase domain of the protein. This combination of mutations in the second patient is very rare and has not been reported until now. The presence of mutations was examined in all family members, and the resulting data were successfully utilized for prenatal diagnosis.