Vanishing Twins & MTHFR Gene Polimorphisms; Coincidence or Biological Fact Prof. M. Sinan Beksaç, Head of Perinatal Medicine, Department of Obstetrics and Gynecology Hacettepe University, Ankara
Vanishing Twins & MTHFR Gene Polimorphisms; Coincidence or
Biological Fact
Prof. M. Sinan Beksaç, Head of Perinatal Medicine,
Department of Obstetrics and Gynecology Hacettepe University, Ankara
Vanished fetus in multiple pregnancy
• Vanishing Twin: One fetus with positive FHR plus gestational sac/fetus without FHR at 8th gestational week
• One growing fetus plus one small gestational sac/fetus without FHR at 12-14 gestational week.
• Single fetus at 20th gestational week
35 vanishing twins between «January 2010-December 2012» & Methylene Tetra Hydrate
Folate Reductase Gene Polimorphisms
• MTHFR 1317 polimorphism is not included
• Other mutations !
MTHFR Enzyme Mutations Number %
Normal 4 10,5
Heterozygot A1298C 9 23,7
Heterozygot C677T 2 5,3
Heterozygot 677+1298 (compound Heterozygot ) 9 23,7
Homozygot A1298C 5 13,2
Homozygot C677T 6 15,8
Total 35 100
The rate of MTHFR polimorphisms in «vanishing twin» cases is more than 90 %. If this is true what is the
biological fact behind «vanishing twins»
• «Methylene Tetra Hydro Folate Reductase» which is mainly responsible from the METHYLATION processes of other substances (enzymes, aminoacids, nucleotids, DNA, etc) & ENZYME ACTIVITY IS REDUCED…
MTHFR Mutations Enzyme Activity
Homozygote C677T mutation 66%
Heterozygote C677T mutation 33%
Homozygote A1298C mutation 40%
Heterozygote A1298C mutation 40%
Compound Heterozygotes C677T & A1298C ??
1317 mutations ??
Is «vanishing twin» the result of ….
• Impaired methylation processes?
• Or can we talk about «complex enzyme pathway disorders»
We do not know the answer ? • Multifactorial !
• Genetical!
• Impaired gametogenesis
• Hereditary factors
• Embryogenesis problem
• Environmental/ teratological factor (ICSI/IVF; about 10 %)
• Metabolic
• Male factor
Methionine Homocysteine
Methionine Synthase
B12
Methyltetrahydrofolate (active folic acid) Tetrahydrofolate
Methylenetetrahydrofolate (dietary folic acid)
MTHFR
dUMP dTMP DNA-Thymine
Cysteine and Propionyl-CoA
B6 Cystathionine b-Synthase
SAM (S-Adenosyl-L-methionine)
SAH (S-Adenosyl-L-homocysteine)
ATP
Methionine Homocysteine Homocysteine Homocysteine Homocysteine
Dihydrofolate B2, B3, B6!
monohydrofolate
dihydrofolate
B2, B3, B6!
Impaired Methylation
Cytosine 5-Methylcytosine
Methyl Group
DNA Methyltransferase
Gene Switched “on” TRANSCRIPTION Gene Switched “off” NO TRANSCRIPTION
Methionine Homocysteine
Methionine Synthase
B12
Methyltetrahydrofolate (active folic acid) Tetrahydrofolate
Methylenetetrahydrofolate (dietary folic acid)
MTHFR
dUMP dTMP DNA-Thymine
Cysteine and Propionyl-CoA
B6 Cystathionine b-Synthase
SAM (S-Adenosyl-L-methionine)
SAH (S-Adenosyl-L-homocysteine)
ATP
Methionine Homocysteine Homocysteine Homocysteine Homocysteine
Dihydrofolate B2, B3, B6!
monohydrofolate
dihydrofolate
B2, B3, B6!
Cytosine 5-Methylcytosine
Methyl Group
DNA Methyltransferase
Gene Switched “on” TRANSCRIPTION Gene Switched “off” NO TRANSCRIPTION
HACETTEPE MODEL
B12
Folates
THF 5-MeTHF
MTHFR
Methionine Homocysteine
Homocysteine Methyltransferase
SAM SAH
Adenosyl Homocysteinase
Methionine Adenosyl Transferase
Cytosine 5-Methylcytosine
Methyl Group
DNA Methyltransferase
Gene Switched “on” TRANSCRIPTION
Gene Switched “off” NO TRANSCRIPTION
B12
5,10-methylene tetrahydrofolate
THF 5-MeTHF
Methionine Homocysteine
Methionine Synthase
SAM SAH
Adenosyl Homocysteinase
Methionine Adenosyl Transferase
Cytosine 5-Methylcytosine
Methyl Group
DNA Methyltransferase
Gene Switched “on” TRANSCRIPTION
Gene Switched “off” NO TRANSCRIPTION
Cystathionine
Cystathionine Synthase
B6
B2 MTHFR
Nucleic Acid Synthesis
C T G C T 3’ 5’
C G G C T 3’ 5’
RNA Polimeraz
C T G C T 3’ 5’
Mutasyon Genetik Etki
RNA Polimeraz Mutasyon Yok DNA Dizisi Normal Epigenetik Etki
RNA Polimeraz
Methionine Homocysteine
Methionine Synthase
B12
Methyltetrahydrofolate (active folic acid) Tetrahydrofolate
Methylenetetrahydrofolate (dietary folic acid)
MTHFR
dUMP dTMP DNA-Thymine
Cysteine and Propionyl-CoA
B6 Cystathionine b-Synthase
SAM (S-Adenosyl-L-methionine)
SAH (S-Adenosyl-L-homocysteine)
ATP
Methionine Homocysteine Homocysteine Homocysteine Homocysteine
Dihydrofolate B2, B3, B6!
monohydrofolate
dihydrofolate
B2, B3, B6!
Cytosine 5-Methylcytosine
Methyl Group
DNA Methyltransferase
Gene Switched “on” TRANSCRIPTION Gene Switched “off” NO TRANSCRIPTION
HACETTEPE MODEL