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

We do not know the biological fact behind vanishing twins!

But we are free to think about it !!!

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