Can a low-cost dietary intervention cut down the risk of Down syndrome? If a team of researchers from the Banaras Hindu University (BHU), Varanasi, is to be believed, it can.
Professor of human molecular genetics Rajiva Raman and his colleagues at BHU have shown that an adequate intake of two B vitamins - folate (B9) and B12 - by women when they plan a pregnancy can substantially reduce the risk of Down syndrome, one of the most common genetic birth defects in babies.
Those with Down syndrome have some degree of intellectual disability, characteristic facial features, and often suffer from heart defects and other health problems. The severity of these problems varies greatly among affected individuals.
Down syndrome, which is seen to affect one in 700 newborn babies globally, results from a chromosomal abnormality. The cells of affected individuals contain a third copy of chromosome 21 whereas a normal human being has 23 pairs of chromosomes, inherited equally from the father and mother.
Down syndrome occurs generally because something goes wrong during fertilisation. A developing egg or sperm cell may divide incorrectly, causing it to have an extra chromosome number 21.
The BHU study, published last week in the journal Human Reproduction, clearly indicates that deficiency of the two B vitamins exacerbates a mother's risk of delivering a baby with Down syndrome. The study, carried out between 2008 and 2012, enrolled 151 Down syndrome babies and their parents and a matching number of healthy controls. All volunteers were tested for folate, B12 and homocysteine - a key amino acid known to play an important role in regulating gene expression - in their blood. The scientists also screened them for seven defective gene mutations that are known to predispose mothers to deliver babies with Down syndrome.
Significantly, these mutations are found to be in genes associated with the folate-homocysteine metabolism. The sufficient levels of folate and B12 are seen to be necessary for proper uptake of homocysteine, which is a precursor for two important amino acids called methionine and cysteine. While methionine plays a key role in regulation and expression of genes, cysteine is involved in protein synthesis, among other things.
Higher levels of homocysteine in the blood is indicative of abnormal production of these important biomolecules and this condition - called hyperhomocysteinemia - is known to increase the risk of nearly 50 diseases including heart attacks, strokes and Alzheimer's. Abnormal homocysteine levels are also linked to fatal neural tube defect and birth of babies with low weight, which heightens the risk of developing diabetes and cardiovascular problems later in life.
While 56 per cent of mothers of Down syndrome babies had at least four or more defective genetic mutations, only 10 per cent of mothers of healthy babies carried similar extent of mutation load.
"The study has yielded some surprising results," says Raman, who has been studying birth defects associated with folate-B12 deficiency for decades. "It has clearly indicated that when a mother had poor nutritional levels, particularly inadequate levels of folate and B12, she has a higher risk of delivering babies with Down syndrome," says the CSIR Emeritus Professor of BHU's department of zoology. We have shown that this risk is either mitigated or substantially curtailed when mothers have adequate levels of the nutrients," he explains.
The team also found maternal micronutrient status can modulate genetic susceptibility. "A deficiency of folic acid and vitamin B12 could increase the disease risk whereas optimal levels of these nutrients could decrease the disease risk," says Krishna Kishore Sukla, a postdoctorate fellow at Raman's lab and first author of the paper.
"Our study is the first comprehensive one that elucidates the increased risk of Down syndrome due to synergistic effect of severe micronutrient deficiency (folates and B12) and certain risky gene variants," he says.
People with Down syndrome are known to suffer from many other ailments, including coronary heart disease. Sukla stresses that the idea that nutritional intervention during an early stage of life can ameliorate the severity of various associated disorders in Down syndrome children is an "interesting prospect" to work on.
"This study is significant," holds Krishnadas Nandagopal, head of the genetics department of Calcutta University who specialises in Down syndrome. "For the first time somebody has shown that a dietary intervention can possibly of reducing the risk of a chromosomal abnormality which has no cure," Nandagopal says. More studies in other populations are needed to corroborate the findings, he adds.
In addition to genetic predisposition, advanced maternal age at pregnancy is a known risk of Down syndrome. While the risk of having a baby with Down syndrome is one in 1,250 at the age of 25, the risk is one in 400 at 35 and one in 100 at the age of 40, studies in advanced countries in the past have shown.
The fact that 80 per cent of mothers of Down syndrome children who participated in the current study were below 35 actually indicates their poor nutritional levels.
An earlier study by the BHU team has shown that 40 per cent of the population in four Indian states, Chhattisgarh, Jharkhand, Bihar and Uttar Pradesh, are B12 deficient. Hyperhomocysteimia is found in 30 per cent of the population. "This actually indicates a higher susceptibility of giving birth to babies with Down syndrome," Raman says.
