New Directions For Down Syndrome Research
By Paddy Jim Baggot, M.D.
The history of therapeutic research in the field of Down syndrome is a fascinating one.
In the 1930s, Canadian physician Henry Turkel attempted to treat children with the disorder using a very strong series of vitamins which he called his “u-series.” The vitamins used in the Turkel treatment included very high dosages of B vitamins - as much as a hundred times the recommended daily allowances. In recent years interest in his work has dwindled.
Fifty years later, Ruth Harrell, M.D., published an exploratory study on the use of megadoses of vitamins and other nutritional supplements to treat children with Downs and other forms of mental deficiency. Harrell claimed that over a period of many months of treatment, there was an IQ increase in treated children, most noticeably in children with Down syndrome. Harrell’s work ignited a firestorm of controversy. Nine papers were published in which the authors claimed that they replicated Harrell’s methods, but not her results. Harrell claimed that her opponents did not use the same dosages. It should be pointed out that neither Harrell nor her critics checked the study population for evidence of vitamin deficiencies before treatment was administered.
By 1990, it appeared that treatments for Down syndrome using vitamins and other nutritional supplements had largely fallen into disrepute.
Unfortunately, the therapeutic gap was quickly filled by the widespread use of prenatal diagnosis for chromosomal disorders and the abortion of suspected affected fetuses. Today, as many as 90% of children in the womb suspected of having Down syndrome are aborted.
It appears that less and less attention has been given to the possibility that a fetus with Down syndrome could be “helped” in a way other than killing him or her.
Most Michael Fund readers are aware that in the late 1950s, Dr. Jerome Lejeune of the University of Paris discovered the cause of Down syndrome. He was the first person who attributed the mental retardation syndrome to a chromosomal cause.
As a prolife geneticist with a deep love for children with Down syndrome, Dr. Lejeune was disheartened by the fact that his important discovery of the extra chromosome in Down syndrome had lead to widespread killing of affected children in the womb. He decided to devote his life’s work to finding a cure and/or treatment for the disorder.
In 1978, Dr. Lejeune, who held the Chair of Fundamental Genetics at the University of Paris , became a co-founder and Director of Medical Research for the Michael Fund. His clinical testing program was conducted at Children’s Hospital in Paris .
Among Dr. Lejeune’s important research findings was that children with Down syndrome have difficulties with monocarbon metabolism (folate and B12) and hypothyroidism.
Dr. Lejeune also conducted an intense research program on the biochemistry of Down syndrome. Some of his published findings suggest that children with Downs who participated in his clinical studies underwent a degree of neurologic improvement.
After the death of Dr. Lejeune in 1984, his research laboratory at the University of Paris was closed and his staff was dispersed. Happily, Dr. Marie Peeters, a close worker with Dr. Lejeune continued to assist the Michael Fund with its new research program which had been transferred to the United States .
This is where my interest in the Michael Fund’s research program began.
In 1995, I submitted a grant proposal on fetal gene therapy to the IFGR/Michael Fund. In response to my initial proposal, the Director of the Michael Fund asked me to formulate a grant proposal for the treatment of Down syndrome.
At first, this seemed to be a dead end. I had been taught in medical school that neurologic, genetic or congenital conditions had no cure. Still I was aware that detrimental changes in the brain of a fetus with Downs appear to occur after the 20th week of gestation. This opens the door to therapeutic intervention before the disease affects the brain.
In college I worked in a biochemical laboratory at St. Louis University . This lab later came under the direction of Dr. James Shoemaker, who developed a method to analyze metabolism globally.
I decided to use Dr. Shoemaker’s method to analyze amniotic fluid in cases of Down syndrome. I submitted a grant proposal to the Michael Fund titled “Biochemical Analysis of Folate-Dependent Metabolites in Amniotic Fluid.” The Michael Fund agreed to finance the three-year $165,000 study. This grant became the start of my long-time love affair with the Michael Fund.
My approach was similar to that of Dr. Lejeune in that I was looking at Down syndrome as a biochemical problem rather than a chromosomal problem. On the other hand it was different from Dr. Lejeune in that I was investigating Down syndrome in its earlier stages of development - in the fetal period.
There are many rare but well understood disorders in biochemical genetics. These are called inborn errors of metabolism. Many of these disorders have treatments. The treatments are often vitamins or other nutrients. A genetic fellowship had already introduced me to the world of biochemical genetics.
I knew that the problem needed not only to be redefined, but, reimagined. Unlike the abortion of chromosomally-damaged children, the biochemical approach appeared to me to open new and truly therapeutic pathways for treatment of Down syndrome fetuses.
Biochemically, one usually looks at a single relevant pathway. There are more than a hundred of essential biochemical pathways. One can think of each pathway as a dot that can be light or dark. By itself one dot contains little meaning. A group of such dots in a digital photograph could take on meaning. Many of the biochemical pathways could be considered at once using Dr. Shoemaker’s approach. Using a global biochemical approach, one can characterize Down syndrome as a biochemical problem. Indeed many non-biochemical disorders (for example autism) have been characterized biochemically and these characterizations suggest treatment.
Initially, my research centered on pathways involving folate metabolism. This was because earlier research conducted by Drs. Lejeune and Peeters suggested a problem of folate deficiency in Down syndrome. And indeed we did find an abnormality in the pathway of folate metabolism.
When we compared our work with other similar research, we found that our results can be explained by a gene that was present in chromosome 21.
There are normally 2 copies of chromosome 21 in each cell. With Down syndrome, there is an extra copy of chromosome 21. That means that there are three copies of each gene on chromosome 21. Gene products of chromosome 21 will be increased by 50%. What we saw in our data was that the substrate of the gene product was reduced by similar amount. When a result is caused by a 50% increase of gene product, this is called the gene dosage effect. As far as we know, we were the first to show gene dosage effect on this gene, and the first to show gene dosage effect in amniotic fluid.
As part of our comprehensive global survey, we looked at carbohydrates and simple sugars. It revealed no major abnormalities. It was important to look at simple sugars because one syndrome of mental retardation known as galactosemia is characterized by an excess of a simple sugar, galactose. This work was published online at Internet Journal of Gynecology and Obstetrics.
In 2008, our research team was blessed with the publication of two additional articles in the prestigious medical journal Fetal Diagnosis and Therapy.*
One article involved the metabolites of vitamin B6 deficiency. This had already been carefully studied some time ago. In the original study of Down syndrome children, oxalate was abnormal and two other markers of vitamin B6 deficiency were not elevated. Oxalate is a marker of vitamin B6 deficiency. Our data was similar to the original study in children. Oxalate was elevated and the other markers of vitamin B6 were not elevated.
There had been earlier studies on the effects of vitamin B6 on neurologic function. Children with Down syndrome had shown improvement in auditory brainstem evoked response when given B6. This was thought to be cause by the action of vitamin B6 converting 5hydroxytryptamine (5HT) to serotonin. 5hydroxytryptamine is a nutritional supplement and serotonin is a neurotransmitter of the brain. Researchers have had a similar result using 5hydroxytryptamine. At that time, supplements of 5hydroxytryptamine became available from the Far East . Unfortunately these supplements were contaminated and caused seizures causing, once again, this whole area of research to fall into disrepute.
Our research papers on organic acids have also been recently published in Fetal Diagnosis and Therapy. The organic acid analysis is usually used to evaluate rare inborn errors of metabolism. In these diseases, there is a defect in an enzyme. The reactants and substrates of the enzymes are greatly elevated where as the products may be lower or absent. Some of these enzymes will work better if they are treated with large amounts of a vitamin co-factor. Our data showed numerous vitamin B2 metabolites were elevated. Since each inborn error metabolism is rare, it’s not credible that more than one would be present. The fact that numerous metabolites were elevated suggests that vitamin B2 or riboflavin were deficient. As far as we know, there are no published studies of organic acids in either fetuses or children. Thus, our global approach to metabolism opens up new avenues for future research.
Our studies demonstrate that the biochemical problems seen in the Down syndrome fetus are quite similar to the postnatal child or adult with Down syndrome. The growing equivalence of prenatal and postnatal results suggests that whatever is true for one is true for the other. This is a powerful generalization.
Over the past 50 years, there has been a tremendous improvement in the average quality of life and longevity of persons with Down syndrome. This improvement has not come from a single treatment, but from an accumulation of many therapies, each making their own contribution.
For example, the research findings of Berkeley researcher Marian Diamond demonstrate that either biochemical influences (hormones) or educational or stimulatory influences can alter the thickness of the cerebral cortex leading to improved learning skills.
There are new technologies which can aid this type of research. Advanced MRI and ultrasound machines can image the cerebral cortex.
Newer assessment tools for neurologic performance in very young children have also become available.
These advances will make it easier to demonstrate the clinical and anatomical effects of new therapeutic treatments.
There are new and exciting horizons opening up in the field of chromosomal research. Our two new publications suggest treatment that may help fetuses and children.
We have it on the Highest Author ity that, “Whatsoever you do unto the least of my brethren, that you do unto Me.” (Mat.25: 40) Will you please help us?
* Fetal Diagnosis and Therapy at http://content.karger.com/ProdukteDB/produkte.asp?Aktion=JournalHome&ProduktNr=224239
Early Research Program
Dr Lejeune Passed Away on April 3rd, 1994
Dr. Jerome Lejeune was a Professor of Fundamental Genetics in the Facultyof Medicine of Paris, and Director of Medical Research for The Michael Fund. Dr. Lejeune discovered the genetic basis of Down's Syndrome - that is the presence of an extra chromosome - thus becoming the first researcher to elucidate the genetic mechanism of an inherited disorder. He also received the first Kennedy award and the William Alien Memorial Medal, and was a member of the French, American, British, Swedish, Italian, Argentinian, and Pontifical Academies of Science. At present Dr. Lejeune's research is directed toward preventing and treating the harmful consequences of the extra chromosome in Down's Syndrome: he believed that a cure is within reach. Dr. Lejeune is also known internationally as one of the most prominent and outspoken advocates of the unborn, and has called prenatal detection of the disease for the purpose of abortion "a desperate mockery of medicine."
In the Fall of 1996, Peter Kummant, Chairman of the Board of the International Foundation for Genetic Research, popularly known as The Michael Fund, awarded its first major United States grant for curative Down syndrome research to Dr. Paddy Jim Baggot.
The three year research grant project of $165,000 titled Biochemical Analysis of Folate- Dependent Metabolites in Amniotic Fluid, which has been extended to 2001, is directed at the development of early prenatal treatment for preborn children affected by chromosomal disorders specifically Down syndrome, the most common chromosomal abnormality. In Down syndrome, each cell contains three copies of chromosome number 21, a condition known as Trisomy 21 – resulting in a 50% increase in gene dosage for each gene on chromosome 21 and a resultant degree of mental retardation for the individual. Previous chromosomal studies funded by the MF/IFGR and conducted by Dr. Jerome Lejeune and his staff including Dr. Marie Peeters-Ney, our current Director of Medical Research, at the Institut de Prognese in Paris beginning in 1978, have demonstrated that many metabolic abnormalities known to adversely affect brain development have been detected in the child born with Down syndrome.
The first year of the Baggot grant was taken up by a comprehensive world-wide literature search on the biochemical effects of Down syndrome. Citations were dictated along with a brief summary of each article in preparation for a comprehensive annotated bibliography written by Dr. Baggot. Dr. Baggot acknowledges the assistance of Josie Placides and Suzanne Baggot in the preparation of the annotated bibliography. During this same time period Dr. Baggot completed a biochemical analysis of eightynine amniotic fluid specimens with special attention to the folate-dependent metabolite known as FIGLO. These findings were initially presented at the American Association of Prolife Obstetricians and Gynecologists at which time Dr. Baggot received the Dr. Matthew Bulfin Research Award. Dr. Baggot’s initial investigation demonstrated the remarkable interconnection that exists in the realm of biochemistry – that is, the substrate (input) or product or co-factors of one reaction may influence other reactions and vice verse. As Dr. Lejeune has amply demonstrated biochemical reactions are very complex. One can only fully understand a particular biochemical reaction by viewing it within the context of other reactions affecting it. Because of the complex and interconnected nature of the problem Dr. Baggot decided to analyze all of the data at once rather than taking one pathway at a time. Dr. Baggot wishes to acknowledge the tireless efforts of his research assistant at the Pope Paul VI Institute in Omaha Nebraska, Jeremy Kalamarides .
According to Dr. Baggot, “We know that the most important events in brain development are the earliest ones, and later developments are less important… therefore any effective treatment for Down syndrome and related chromosomal disorders which result in mental retardation should begin prenatally – at the early stages of pregnancy. In this matter timing is of the essence.”
Dr. Baggot will use the remainder of his grant funds to continue to expand and refine his data on folate-dependent metabolites to determine specific biochemical deficiencies or excesses known to be relevant to Down syndrome including metabolites of organic acids, amino acids, neurotransmitters and carbohydrates.
Dr. Peter Kummant, Chairman of the Board of the Pittsburgh-based International Foundation for Genetic Research/The Michael Fund, has announced the awarding of the pro-life agency's first major U.S. grant to Dr. Paddy Jim Baggot, Director of Maternal Fetal Medicine and Human Genetics at the Pope Paul VI Institute, Omaha, Nebraska.
The three year $165,000 research grant project, Biochemical Analy¬sis of Palate-Dependent Metabolites in Amniotic Fluid, will assay and eval¬uate archival (previously stored) amniotic fluid specimens from Down Syn¬drome and non-Down Syndrome pregnancies using gas liquid chromatography-mass spectrometry to determine specific biochemical deficiencies known to be relevant to the chromosomal disorder, including metabolites of organic acids, amino acids, neurotransmitters and carbohydrates.
Recent findings suggest that mental retardation resulting from disordered brain development in the preborn patient with Down Syndrome (Trisomy 21) begins after 22 weeks gestation
(Volpe, 1995; Wisniewski et al, 1984). These findings open up the possibility of treatment of metabolic defects early in the pregnancy aimed at decreasing neurological damage to the affected preborn child.
Historically, many metabolic abnormalities known to adversely affect brain development have been detected in the child or adult with Down Syndrome. Earlier results from chromosomal research funded by The Michael Fund and directed by Dr. Jerome Lejeune (the discoverer of the extra chromosome in Down Syn¬drome and of the translocation in man) at the Institut de Prognese in Paris (1978-1994) have revealed sig¬nificant differences in plasma and uterine amino acid concentrations be¬tween normal patients and those with Down Syndrome.
The new Michael Fund research project will extend the work of the late Dr. Jerome Lejeune, who died on April 3, 1994 in Paris, to the fetal period of human development to determine if biochemical abnormalities found in the Down Syndrome patient postnatally are also found in the Down Syndrome patient prenatally. This approach may open new vistas for under¬standing the causes of mental retarda¬tion in Down Syndrome, and for thera¬pies for affected children in utero.
Unfortunately, the lag in thera¬peutic chromosomal research has lead to a popular attitude of despair, causing some scientists to promote the selective abortion or infanticide of affected children as a means of eliminating the disorders.
The Michael Fund is dedicated to reversing this destructive uni¬versal trend by opening up new doors of therapy in the field of mental retardation associated with chromomal disorders such as Down Syndrome and continuing the curative research program of Dr. Lejeune in the United States.