StatusThe thesis was presented on the 18 October, 2019
Approved by NCAA on the 6 December, 2019
Abstract– 1.56 Mb / in romanian
ThesisCZU 77.2:611.73 (478)
4.02 Mb /
Thesis structure: introduction, 5 chapters, obtained results synthesis, general conclusions, practical recommendations, bibliography of 306 titles, 188 pages basic text, 40 images, 24 tables, 4 algorithms, 16 annexes. Study results were published in 76 scientific papers.
The field of study: human genetics, molecular biology and medical genetics. Goal: Genetic features appreciation of neuromuscular diseases in the Republic of Moldova and an efficient molecular-genetic diagnostic strategy elaboration for personalized patients monitoring.
1. Spectrum and relative frequencies appreciation of the most frequent hereditary neuromuscular diseases forms in a group of patients in Republic of Moldova.
2. Genetic features evaluation of neuromuscular pathologies "nucleus" (Duchenne/Becker's myodistrophy, spinal amyotrophy, type 1A hereditary motosensory neuropathy) and molecular diagnostic algorithms elaboration.
3. To study the population-genetic features of polymorphic allele distribution of MTHFR (C677T, A1298C), MTR (A2756G), MTRR (A66G) and eNOS (4a/4b) genes in the research (D/BMD patients) and control groups.
4. Investigated genes polymorphic variants contribution study for the genetic risk determination of myopathic process rapid evolution.
5. Studied genes polymorphisms interactions type and power determination in D/BMD patients at the different stage of disease.
6. Develop a molecular diagnosis strategy that would include pacients individual characteristics for predictive and personalized medicine.
Methodology: Two types of study - retrospective cohort and case-control studies.
Thesis scientific novelty and originality consists of relative frequency of neuromuscular pathologies assessment in the Republic of Moldova population (23,5: 100000). For the first time polymorfic allele frequencies of MTHFR, MTRR, MTR and eNOS genes in the D/BMD and control group were determined. For the first time modifying genes influence on the pathogenesis of D/BMD was determined. The disease prognosis system in children with D/BMD was argued based on DMD deletion gene type impact analysis and genotyping data for MTHFR, MTR, MTRR and eNOS gene polymorphisms.
The main new results for science and practice. The types and the interaction power of the MTHFR, MTR, MTRR, and eNOS gene patterns in D/BMD were studied and their role in pathogenesis was determined along with mutations in the DMD gene in case of pathologic progression at different ages (9 and 12 years) as a criterion for the gravity of the myopathic process.
Thesis theoretical value consists of a new proposed scheme for myopathic process development, allowing individualized treatment. Major mutations in the corresponding genes and their frequencies in a group of patients were determined for 3 nozological forms.
Research applicative value: Clinical-diagnostic and molecular-genetic algorithms for the diagnosis of frequently encountered hereditary neuromuscular diseases in Republic of Moldova have been implemented. A molecular-diagnostic strategy for personalized D/BMD patients monitoring has been developed.
Results implementation. Research results were applied in the practice of the Laboratory of Human Molecular Genetics and neurology departments of IMSP IMC.