UAMS Leads Search for Answers on Cleft Palate, Other Biotin-related Birth Defects
| LITTLE ROCK — Does an elusive vitamin deficiency cause cleft palates and shortened limbs in some babies?
A biochemist at the University of Arkansas for Medical Sciences (UAMS) College of Medicine is leading the study of how biotin, a micronutrient found in liver, egg yolk, milk, and yeast, may affect fetal development. There appears to be a link between the pregnant woman’s biotin intake and cleft palates, in which the roof of the baby’s mouth is split. There also may be a link to severely shortened arms and legs.
Dr. Donald M. Mock’s work is important enough that the National Institutes of Health have given him a rare Merit Award – a commitment to at least another decade of research funding at about $225,000 per year. Mock has already received NIH funding for his research for 18 consecutive years; the NIH Merit Award is a signal that the federal agency expects him to continue making important discoveries about the relationship of biotin, a member of the B complex group of vitamins to birth defects. Mock’s Merit Award is the first at UAMS.
The American Journal of Clinical Nutrition praised Mock and his colleagues in 2002 for their persistent research. The group at UAMS (along with Dr. J. Gerald Quirk, an obstetrician formerly at UAMS and now at State University of New York) has established a reliable urine test for mild, or marginal, biotin deficiency – a critical step in the painstaking process of confirming and explaining why biotin deficiency causes birth defects.
Mock has been studying biotin since 1979, when he stumbled upon the diagnosis for an eight-month-old girl’s heartbreaking ailments, including an abnormally short intestine, hair loss, skin rash, and extreme lethargy. At the time, Mock was a fellow in pediatric gastroenterology at the University of California-San Francisco.
“I walked into the pediatric treatment room at Moffitt Hospital and saw these surgeons doing a dressing change on an eight-month-old girl. She had an abnormally short intestine, rash, hair loss, and was very inactive despite the IV nutrition. I asked, ‘When are you going to properly diagnose that zinc-deficient kid?’ The surgery team treated her for zinc deficiency but she didn’t get better, so they came back, asking ‘What else could this be?’ I knew of 1940s studies of biotin deficiency and I’d seen inborn errors of metabolism that related to biotin, but no one had diagnosed biotin deficiency in an IV-fed patient.” Nonetheless, Mock speculated that the baby suffered from biotin deficiency. He gave her biotin supplements and she improved dramatically.
The New England Journal of Medicine published a report of the case. Now biotin is a standard part of intravenous feedings and such cases no longer occur. This clinical observation launched Mock’s studies of biotin; he is recognized as one of the world’s leading researchers in the field.
Now a professor of biochemistry, molecular biology and pediatrics in the UAMS College of Medicine, Mock has confirmed and extended research findings in Japan that mild biotin deficiency causes defects in the roof of the mouth and shortened limbs in animals. The defects seem to occur early in pregnancy in animals with biotin deficiency.
Mock also has determined that mild biotin deficiency occurs in at least one third of normal human pregnancies. He and his research team have perfected a laboratory test for biotin deficiency that eventually may help obstetricians identify women who need extra biotin during pregnancy. Thanks to volunteers in related studies, Mock and his research group have developed the technique for detecting biotin at the tiny level of two parts per trillion. Volunteers live in the UAMS General Clinical Research Center for four weeks, eating a low-biotin diet and providing regular blood and urine samples.
Mock stresses that the researchers at UAMS only induce mild biotin deficiency in volunteers in order to devise a reliable laboratory test for the deficiency. The deficiency they induce in the volunteers is too mild to cause symptoms. The researchers also exclude pregnant women from the project in order to protect their fetuses.
Many unanswered questions about biotin remain, however. The link between biotin deficiency and birth defects in animal subjects does not prove a link in humans, so Mock is collecting blood samples from newborn babies with defects at UAMS to determine their biotin status at birth.
If the link can be proven in humans, scientists will also need to determine exactly how severe the deficiency must be to cause defects, and why it occurs in some women and not in others. Is there a genetic basis for severe biotin deficiency in pregnancy? If so, can women with the genetic predisposition be identified through a simple genetic test – and can they receive safe levels of supplemental biotin during pregnancy?
Meanwhile, Mock does not recommend that pregnant women take biotin supplements on their own, because neither the link between biotin deficiency and certain birth defects, nor a safe level of biotin supplement, are clear yet.
In some ways, Mock’s research descends from studies of folate therapy in pregnancy, which prevents neural tube defects. After scientists established the link between folate supplementation and prevention of neural tube defects in the 1990s, the federal government ordered manufacturers of bread and other foods with enriched flour to add folic acid to their products. Scientists, including a group at UAMS and the National Center for Toxicological Research at Jefferson, Ark., continue to analyze the role of folic acid in fetal development. One avenue of research involves pregnant women who have babies with neural tube defects despite appearing to consume enough folate. One possible explanation is that those women belong to a genetic subgroup that needs more than the normal amount of folic acid to have healthy babies.