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congenital malformations are the leading cause of infant mortality in developing countries and a major cause of health problems in surviving children
. neural tube defects ( ntds ) are common group of central nervous system anomalies affecting 0.52 per 1000 pregnancies worldwide . despite the high prevalence and traumatic consequences for affected individuals and their families , causes of ntd
identification of the causative factors is confounded by the fact that the majority of these malformations appear to result from a combination of genetic and environmental factors .
a strong genetic component is indicated by the high recurrence risk for siblings of affected individuals .
methylenetetrahydrofolate reductase ( mthfr ) mutations are commonly associated with hyperhomocysteinemia . through defects in homocysteine metabolism , they have been implicated as risk factors for ntds and unexplained recurrent embryo losses in early pregnancy .
folate sufficiency is thought to play an integral role in phenotypic expression of mthfr mutations .
the best - characterized mthfr genetic polymorphism is a common missense mutation consisting of 677ct transition , resulting in thermolabile enzyme variant that has reduced catalytic activity .
another common genetic polymorphism of mthfr is a missense mutation consisting of nucleotide 1298ac transition , resulting in decreased mthfr activity , which is more pronounced in homozygous than heterozygous state .
a 19-year - old lady , gravida - 3 , abortion - 2 with history of 2 months amenorrhoea presented to our obstetric outpatient department .
her past obstetric history revealed that both of her previous pregnancies were terminated during early second trimester in the view of anencephaly .
it was interesting to note from patient 's family history that her mother also had consanguineous marriage , married to her maternal uncle .
she had nine pregnancy losses due to anencephaly / ntds as shown in the family pedigree chart [ figure 1 ] .
pedigree family chart patient and her husband were referred to a geneticist and were subjected to gene mutation studies , karyotyping , and biochemical analysis .
genotype of patient was identified to have cc and cc genotypes , suggesting a wild status at 677 and homozygous mutant status at 1298 , respectively , of the mthfr gene .
genotype of husband was identified to have ct and aa , suggesting a heterozygous status at 677 and wild status at 1298 , respectively , of the mthfr gene .
patient 's biochemical analysis revealed : 
 serum vitamin b12 = 245.5 pg / ml ( normal = 211.00940.00 pg / ml),serum folic acid = 14.0 ng / ml ( normal = 3.120.0 ng / ml),plasma homocysteine = 3.20 mol / l ( normal = 4.7015.00 mol / l ) 
  serum vitamin b12 = 245.5 pg / ml ( normal = 211.00940.00 pg / ml ) , serum folic acid = 14.0 ng / ml ( normal = 3.120.0 ng / ml ) , plasma homocysteine = 3.20 mol / l ( normal = 4.7015.00 mol / l )
mutations in mthfr and other genes associated with homocysteine metabolism have been reported as causes of hyperhomocysteinemia .
mthfr gene mutation are by far the most common etiology of mild to moderate form of hyperhomocysteinemia .
homozygocity for the common 677ct mutation , which produces an alanine to valine amino acid substitution within the predicted catalytic domain of mthfr enzyme causing thermolability of the enzyme , is a risk factor for ntds .
homozygosity for thermolabile mthfr variant predisposes individuals to development of hyperhomocysteinemia , especially during times of folate insufficiency .
another mutation in the same gene , the 1298ac mutation which changes a glutamate into alanine residue .
this mutation destroys an mboii recognition site , results in decreased mthfr activity , which is more pronounced in the homozygous than heterozygous state . neither the homozygous nor the heterozygous state is associated with higher plasma homocysteine or a lower plasma folate concentration , phenomena that are evident with homozygosity for 677ct mutation .
when compared with heterozygosity for either the 677ct or 1298ac mutations , the combined heterozygosity for the 1298ac and 677ct mutations was associated with reduced mthfr specific activity , higher homocysteine levels and decreases plasma folate levels . combined heterozygosity for both mthfr mutations results in similar features as observed in homozygotes for 677ct mutation .
several studies have shown that folate levels in mothers of children with ntds are not deficient but are in the lower range of control levels .
1298ac mutation is also a risk factor for ntds , but with a smaller relative risk than the 677ct mutation .
indeed , the frequency of the 1298ac mutation in ntd - affected children tended to be increased , which also suggests that this mutation is a genetic risk factor for this developmental anomaly . especially under conditions of low intake of folates or during high requirements of folate , like pregnancy , this mutation could become of clinical importance . by analyzing the frequency distribution of the 677tt and 677ct/1298ac genotypes among ntd patients and their mothers , the protective role of folate in the etiology of ntd is 36%50% . in order to obtain high enough methylenetetrahydrofolate levels for an adequate homocysteine metabolism ,
several studies have pointed out that folate intake high enough to prevent ntds can not be achieved by a diet of folate nutrition
. only intake of folate supplements or fortified foods such as flour and cereals can achieve these daily recommended values .
since periconceptional folate administration reduces the risk for ntd for > 72% , there may still be other defective genes present in the folate , vitamin- b12 , or homocysteine metabolism associated with an increased risk of ntd offspring .
methylenetetrahydrofolate reductase ( mthfr ) gene mutations have been implicated as risk factors for neural tube defects ( ntds ) . 
 the best - characterized mthfr genetic mutation 677ct is associated with a 24 fold increased risk of ntd if patient is homozygous for this mutation . 
 this risk factor is modulated by folate levels in the body . 
 a second mutation in the mthfr gene is an ac transition at position 1298 . 
 the 1298ac mutation is also a risk factor for ntd , but with a smaller relative risk than 677ct mutation . under conditions of low folate intake or high folate requirements , such as pregnancy , 
 this mutation could become of clinical importance . 
 we present a case report with mthfr genetic mutation , who presented with recurrent familial pregnancy losses due to anencephaly / ntds .