March Is Trisomy Awareness Month Down Syndrome: It’s Mitochondrial and It’s Treatable

miChael G. lamB mD

“Mitochondrial dysfunction plays a primary role in the neurodevelopmental anomalies and neurodegeneration of Down syndrome subjects.” That statement came from Drs. Mollo and Nitti’s group in the Department of Molecular Medicine at the University of Naples in the June 2019 issue of Frontiers in Genetics. Two years earlier, Valenti et al noted that “dysfunctional mitochondria and mitochondrial dependent activation of intracellular stress cascades are critical initiating events in many neurodevelopmental and neurodegenerative diseases including Down syndrome.” Helguera et al at the University of California in 2013 stressed that “mitochondrial dysfunction and oxidative stress are common features of Down syndrome”. More recently a 2021 study out of Spain (M. Pilar Bayone-Bafalvy et al) had the title “Down Syndrome is an Oxidative Phosphorylation Disorder”. In this paper they state that “Down syndrome is the most common genomic disorder of intellectual disability and is caused by trisomy of the 21st chromosome. Several genes in this chromosome repress mitochondrial biogenesis”. These are just a few of the many published articles linking Down syndrome to defects in oxidative phosphorylation secondary to mitochondrial dysfunction. Decades ago, famed geneticist and co-discoverer of trisomy 21, Jerome Lejeune postulated that Down syndrome would turn out to be a metabolic disease. Some mitochondrial metabolic disorders are treatable, and others are potentially treatable. Down syndrome has thus at the very least become a potentially treatable metabolic condition.

One would think that this type of discovery would be heralded and make medical headlines. It did not and it is not clear why not. In fact, it can safely be stated that most pediatricians, internists, obstetricians, and family medicine specialists are unfamiliar with this literature even though it is extensive. The lack of familiarity with this research even includes physicians working in “Down Syndrome Clinics”. It’s not because this data is relatively new, because this research goes back to more than 20 years ago with work done by S.H. Kim that demonstrated decreased levels of mitochondrial respiratory enzymes in Down syndrome fetuses and adults. Since then, the increase in studies involving mitochondrial dysfunction, mitochondrial dysmorphology, and even mitochondrial therapies related to Down syndrome has been exponential and yet physician awareness of these reports has been minimal. Most of these reports have been in genetics, pharmacology, molecular medicine, biochemistry, and neuroscience journals and that may be part of the problem. In the past 20 years, multiple review articles on these topics have been published but none of them are in the 4 major pediatric journals: The Journal of Pediatrics, JAMA Pediatrics, Lancet Child and Health, and Pediatrics. One wonders why a topic with this much biochemical and genetic research and involving a common disabling pediatric condition has apparently been ignored by the major pediatric journals.

A lot of the initial work regarding the relationship between Down syndrome and mitochondrial dysfunction was done in mice with trisomy 16 (a Down syndrome animal model). These studies uniformly showed mitochondrial enzyme deficiencies, a decreased amount of mitochondrial DNA, defects in oxidative phosphorylation, reduced energy production (i.e. high energy phosphate compounds), increased oxidative stress, abnormal mitochondrial cristae, a reduction in mitochondrial membrane potential, and abnormal cytoarchitectural ordering of mitochondria. Studies in human Down syndrome cells cultured in vitro have confirmed the results observed in the trisomy 16 mouse models. These abnormalities were exhibited at various ages (fetus, child, and adult) in several different Down syndrome cell types including amniocytes, neuronal stem cells, fibroblasts, brain cells, cardiac myocytes, blood monocytes, blood lymphocytes and skeletal muscle cells. The study of cultured neuronal stem cells by Mollo and Esposito et al showed mitochondrial dysfunction as early as seven days and a marked tendency to form glial cells rather than functional neuronal cells. The study involving skeletal muscle was an in vivo study using phosphorus magnetic resonance spectroscopy. The cardiac myocyte studies suggested that more severe mitochondrial dysfunction was associated with the presence of congenital heart disease. The fact that mitochondrial abnormalities were evident in fetal, childhood, and adult cells of various types points to the mitochondrial abnormalities being congenital and in all cell types.

The in vivo study demonstrates that this problem with mitochondrial function is a significant issue in live patients and not just found in cultured cells.

The study of mitochondrial disease in Down syndrome is not confined simply to cell morphology, biochemistry. and cell physiology. Detailed genetic studies have also been a part of this research. As far back as 1995, Abruzova published on the role of mitochondrial DNA in trisomy 21. Three years later she presented a paper at the 6th world Congress on Down syndrome in Madrid, dealing with “why is it necessary to study the role of the mitochondrial genome in Trisomy 21 pathogenesis”. Subsequent studies showed that multiple genes affecting mitochondria are located on chromosome 21. A decreased level of ATPase (a mitochondrial DNA product) has also been documented in Down syndrome patients. So, there have been both nuclear and mitochondrial genes identified as abnormal. This data suggests that oocyte mitochondrial dysfunction is involved in the pathogenesis of the chromosomal non-disjunction in the syndrome. Mitochondrial dysfunction has also been implicated in heterotaxy and defective migration of embryonic cells in Down syndrome. This is because normal ATPase generation is required for those processes. In this regard, it’s notable that trisomy 18, trisomy 13, and Klinefelter syndrome patients also have been reported as having abnormal mitochondrial function, cellular oxidative stress and or anomalies of the mitochondrial genome. This is all consistent with oocyte mitochondrial dysfunction being a causative factor in several conditions in which nondisjunction is present. Mitochondrial function generally worsens with advancing age. This helps to explain why non-disjunction is more common in older mothers. Mitochondrial dysfunction has also been implicated in autism spectrum disorder, fragile X syndrome and fetal alcohol spectrum disorders (alcohol is a mitochondrial toxin).

Mitochondrial medicine and the understanding of normal and pathologic mitochondrial anatomy and physiology is at the cutting edge of modern medicine. It will only become more important in the future. Of significance here is the fact that at least some mitochondrial disorders are treatable with agents such as ubiquinol, carnitine, and alpha lipoic acid. Down syndrome now presents the option of being treatable. In the January 2023 issue of “Mitochondrion”, Ganguly and Kadam wrote that “a number of pharmacologically active natural compounds such as polyphenols, antioxidants, and flavonoids show convincing outcomes for reversal of the dysfunctional mitochondrial network and oxidative metabolism and improvement of intellectual skills in mouse models of Down syndrome and humans with Down syndrome”. In another 2023 article, Tan et al commented that “it is prudent that improving Down syndrome pathophysiologic conditions or quality of life may be feasible by targeting something as simple as mitochondrial biogenesis and function”. Fatty acid supplements seem to be beneficial in the mouse model of Down syndrome. One case study showed that fish oil rich in omega 3 fatty acids reversed mitochondrial dysfunction and was well tolerated in a Down syndrome child. Another group has reported modest improvement in coordination and muscle function in Down syndrome children treated with ubiquinol (Co-enzyme Q). Agents that have caused a dramatic improvement and even reversal of mitochondrial network abnormalities and abnormal bioenergetics include metformin, pioglitazone, reservatrol and EGCG (epigallocatochin 3 gallate). Those studies were done with in vitro cultures of Down syndrome cells. Metformin is an especially exciting therapeutic option since it has a long history of use, multiple other indications, an acceptable safety profile, crosses the blood brain barrier, and has been used in children. The in vitro benefits of metformin are impressive. In their paper on metformin treatment, Izzo et al concluded that “metformin represents a promising strategy to counteract mitochondrial dysfunction in Down

Continued on Page 18 syndrome”. Currently, the University of California is conducting a metformin study to treat fragile X syndrome and its’ associated obesity. There are also multiple trials using metformin regarding longevity and aging. Presently, however, there are no therapeutic trials available in the U.S.A. involving either metformin or pioglitazone in Down syndrome. A recent internet search showed that there are also no American controlled trials using flavanoids, fatty acids, polyphenols, or ubiquinol. This is difficult to comprehend given the fact that for over a decade there has been a lot of convincing evidence that Down syndrome is a mitochondrial disease that in vitro responds well to these agents.

An internet survey of several Down syndrome clinics in the Eastern United States at major medical centers showed no mention of mitochondrial dysfunction or mitochondrial treatment on their web sites. Most of these clinics did offer the option of genetic counselling and prenatal diagnosis. Prenatal diagnosis affords the option of abortion as a “treatment”. Early stimulation programs and learning therapies were generally offered by all the clinics. In the absence of controlled trials, should Down syndrome patients be afforded the option of “off label” structured empiric treatment with metformin? This might be particularly advantageous because of the safety profile plus the added benefit of metformin in obese pre-diabetic patients (a common problem with Down syndrome). Given the potential benefits, it would seem justified that metformin be offered as an empiric option. The possibility of offering a structured trial of the other agents with in vitro effectiveness should also be considered especially in regard to supplements of ubiquinol and fatty acids which have minimal side effects. Additionally Down syndrome patients should prudently avoid known mitochondrial toxins including alcohol, valproic acid, chloramphemicol, gentamycin, and tobramycin. It is possible that other antibiotics could also be hazardous in Down syndrome given the fact the mitochondria likely evolved from primitive bacteria. The potential for Down syndrome to be a treatable medical condition should have been received with enthusiasm and excitement. This has not been the case. Perhaps this is due to the fact that major pediatric journals have neglected this topic. This may also be due in part to certain physician attitudes regarding Down syndrome and people with cognitive dysfunction. Studies have documented that a significant percentage (as much as 24%) of practicing physicians and resident physicians are “not comfortable” caring for people with Down syndrome. It is hoped that this article may help a bit in making morephysicians aware of this literature and the available treatment options.

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The American College of Surgeons – Southwestern Pennsylvania Chapter is excited to host its annual “Most Interesting Case Presentations” event. This event provides surgical residents the opportunity to present their most interesting cases for review and discussion. Presentations are judged by a panel of surgeons. Cash prizes are awarded to the three most interesting cases.

AGENDA

6:00 PM

EXECUTIVE BOARD MEETING (Invite Only)

6:30 PM – 7:00 PM

COCKTAILS

7:00 PM – 8:00 PM

PRESENTATIONS & DINNER

Awards

1ST PLACE - $500

2ND PLACE - $300

3RD PLACE - $200

OPEN TO ALL GENERAL SURGERY RESIDENTS AND SURGICAL SPECIALTY RESIDENTS.

SAVE THE DATE!

Registration coming soon.

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