Genetic background of neurological diseases

Szekeres Márta
Genetic background of neurological diseases.
[Thesis] (Unpublished)

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Abstract in foreign language

4.1 The MTHFR A1298C variant in leukoaraiosis Previous studies demonstrated that an elevated serum homocysteine level may be associated with LA. Also, an elevated serum homocysteine level is presumed to be associated with an endothelial dysfunction or microangiopathy. The genetic studies relating to the MTHFR C677T variant suggest that, although the 677T variant is unfavourable because it raises the serum homocysteine level, it does not increase the risk of contracting LA if it is present on its own. We also demonstrated earlier that the 677T variant in combination with other genetic variants increases the risk of contracting LA. The present study reveals that a person carrying either a heterozygous A1298C or a homozygous 1298CC variant is at a higher risk of contracting LA than one carrying neither of them. This genetic variant has not been examined so far in any LA case–control study. Our findings therefore suggest for the first time that the A1298C variant may be more important than the C677T variant in the evolution of LA. We also found that the heterozygous C677T and A1298C variants do 8 not pose a risk of contracting LA if they are present by themselves. However, their combination in the same person leads to a marked risk of contracting LA. Here, although the number of patients displaying the combination of the two heterozygous MTHFR variants was low, the significance level relating to the approximately tenfold increase in the unfavourable combination in the LA group compared with that in the control group suggests that there is a definite link. At present the exact cause of this synergistic effect is not known. However, two possible explanations readily emerge. They are: (1) the two variants can potentially increase the serum homocysteine level in an additive manner and (2) the co-occurrence of the two unfavourable MTHFR genetic variants may influence the regulation of the enzyme. A properly balanced regulation of the MTHFR may be a key factor that can define the daily shifts in the serum homocysteine level. The clustering of the A1298C and C677T variants might give rise to an unfavourable regulatory nature in the dynamically changing activity of the MTHFR. Then the presence of the two heterozygous variants might result in a significantly unfavourable phenotype of the conformation of the enzyme protein. 4.2 The absolute number of mitochondria per cell in leukocyte cells in leukoaraiosis The basic contents for mDNA and dmDNA were found to be statistically the same in the LA group and control group, and the K value was significantly lower for the LA group than that for the control group. This suggested that there was a larger proportion of dmDNA present. Having dmDNA may possibly lead to a mitochondrial malfunction in the following way: a, lower energy production; b, a lower free radical scavenging capacity; c, a lower rate of adaptation to the prevailing demand for energy production; d, a narrower range in the adjustment to the prevailing energy demand; e, a lower metabolic function capacity in general; f, a greater extent of free radical production; and g, a general malfunction of the mitochondrial genetic regulation. No genetic or biochemical data is available to suggest which of these postulated mechanisms actually exist, but a lower and narrower energy capacity appears probable as the main pathomechanism behind LA. It was demonstrated earlier at the molecular level that LA can arise from a very slight, but chronic level of hypoxia, which may be caused by various environmental and genetic susceptibility factors. Our present findings agree with the earlier ones that uncoupling protein genetic variants play a role in the development of LA. The uncoupling proteins govern the electro-chemical gradient between the inner and outer spaces of the mitochondria, this gradient being essential for the energy production of the mitochondria. If dmDNA is associated with any kind of biochemical malfunction, an uncompensated and larger proportion of dmDNA in the cells may be unfavourable from an energetic viewpoint. Our results appear to indicate that the lower the difference between the contents of mDNA (which compensates for malfunctions of the dmDNA) and dmDNA, the larger the risk of contracting LA in a given individual...

Item Type: Thesis (PhD)
Creators: Szekeres Márta
Hungarian title label: Neurológiai kórképek genetikai háttere
Divisions: Doctoral School of Interdisciplinary Sciences
Discipline label: Medicine > Theoretical Medicine
Defence date label: 2016. November 03.
Item ID: 3113
MTMT id: 3195419
doi: https://doi.org/10.14232/phd.3113
Date Deposited: 2016. Sep. 26. 08:14
Last Modified: 2020. Jul. 16. 14:29
Depository no.: B 6091
URI: http://doktori.bibl.u-szeged.hu/id/eprint/3113
Defence/Citable status: Defended.

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