After almost a decade of work and an almost detective search for cases around the world, an international consortium of doctors and scientists has identified a genetic cause of the most common nervous system malformation in newborns, myelomeningocele. This condition is the most serious form of spina bifida, a set of congenital defects in the nervous system that require surgery and cause lifelong disability.
In 1980, pediatrician Richard Smithers and obstetrician Elizabeth Hibbard, who worked for years in low-income maternity hospitals where congenital malformations were common, discovered that a vitamin could dramatically reduce cases of neural tube defects, the fetal structure of which arises the brain and the central nervous system. It was folic acid, a compound since then recommended for all pregnant women. Despite the historic discovery of these two Britons, the lack of vitamin supplements or the poor adherence of mothers means that thousands of babies continue to be born with spina bifida around the world, especially in developing countries, but also in rich countries, including Spain. This is partly because not all cases respond to folic acid supplements.
“When a family is told that they are going to have a baby with spina bifida, the exact cause is not known,” explains Carmen Gil, president of the Spanish federation of patients with spina bifida. In Spain there are 31,700 people with spina bifida and hydrocephalus. Among these patients, more than 50% are of working age and only 40% reach the age of 66. Unlike other countries, in Spain there is no official record, so it is not unknown how many children continue to be born each year with these malformations. Those affected suffer lifelong recurrent infections, kidney failure, lack of vision due to hydrocephalus, and irreversible cognitive sequelae. “The families comment with great sadness that they have taken care of the diet and the entire pregnancy, and that despite everything the baby has this problem. And we are talking about the most serious malformation known that is compatible with life. This study can help people know more about this ailment and even that over time, perhaps progress can be made in prevention,” he adds. The main demands of this group are that they be recognized as having the right to early retirement and free medication they need.
It is thought that in 70% of cases it is due to genetic causes and that there are probably also environmental factors that play a role. In 2015, a international consortium to sequence the genome of 715 “trios” affected by myelomeningocele, the two parents and the affected child. The study has collected and analyzed genetic samples from patients in the United States, Canada, Mexico, Brazil, Egypt, Nigeria, Italy, Pakistan and Georgia. In many cases it was known whether the mothers had taken folic acid during pregnancy. The work has identified a genetic mutation in six patients that multiplies the risk of malformations by 23. Some of them inherited the mutation from their parents and others developed it spontaneously during pregnancy.
In a second phase of study, scientists have analyzed another genetic database with data from more than 1,522 people who have the identified mutation, called 22q11.2 deletion. This genetic variant causes problems with the heart and other organs. The analysis of this database identified nine patients with this mutation, one of them in Madrid. The study, published this Thursday in Science, reference of the best world science, estimates that carriers have up to 15 times more risk of suffering from malformations of the nervous system. This genetic syndrome occurs in one in every 992 pregnancies and one in every 2,148 births, highlights the work, signed by 63 authors from 10 countries, including Sixto García-Miñaurspecialist in clinical genetics at the La Paz Hospital in Madrid, recently retired.
The detected deletion, also known as DiGeorge syndrome, affects dozens of genes. The researchers carried out a new round of experiments in mice to investigate the effect on the nervous system of deactivating different genes involved. Their results suggest that the probable cause of the terrible malformations is in the gene CRKL, involved in many communication processes between cells and fundamental in the correct development of the embryo. Researchers have shown in mice that folic acid decreases the severity of congenital lesions, but does not eliminate them completely. There are cases that are resistant to this contribution, which is similar to what happens in humans.
Donna M. McDonald-McGinn, medical geneticist at the Children’s Hospital of Philadelphia (United States) and co-author of the study, explains its relevance and therapeutic potential. “This study opens an unparalleled window into understanding many common birth defects, developmental differences, and psychiatric illnesses, as it is the most common microdeletion syndrome,” she explains. “In addition, deletion of chromosome 22q11.2 is the most common cause of syndromic palatal anomalies and schizophrenia, and the second most common cause of congenital heart disease and developmental delay after Down syndrome. Providing insight into the etiology of less common associated features such as myelomeningocele is equally important, as once we can identify essential developmental genes such as CRKL we can begin to consider targeted therapies as well as potential environmental modifiers such as folic acid and neural tube defects,” he adds.
Encarna Guillén, president of the Spanish Association of Human Genetics and pediatrician at the Virgen de la Arrixaca Clinical Hospital, highlights the importance of this study. “Until now we knew that the causes of this disease were both genetic and environmental. Being able to unravel the weight of each of these factors is a path that must be explored. In fact, the deletion detected, which is the lack of part of chromosome 22, is one of the most frequent known. It is very interesting that they show that folic acid can counteract the effects of the deletion, which makes it even more important that future mothers follow the recommendations of taking the appropriate dose of folic acid, even opening the possibility of reviewing the criteria to include to mothers who have this deletion to put even more emphasis on taking this supplement,” he highlights.
Lluis Montoliu, molecular biologist at the National Center for Biotechnology (CNB-CSIC), evaluates the new study. “Without a doubt, the results are interesting in basic research and suggest that the deletion of this region of chromosome 22 is somehow involved in the appearance of myelomeningocele.” But the expert in rare diseases and genetic editing also remembers that this new mutation does not determine whether someone will suffer from this disease. There are many people who have it and do not develop the condition and others who do not have it and still suffer from spina bifida, which once again highlights that this is a disease with many genetic and environmental factors that have yet to be identified.
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