Use of CoQ10 in Children with Prader-Willi Syndrome (1999)


about pws and coq10
Prader-Willi Association USA
International Prader-Willi Syndrome Organization
CO-ENZYME Q10 (CoQ10)


Co-enzyme Q10 is a co-enzyme produced in the human body and found in the powerhouse of each cell, the mitochondria, as well as every other cell organelle.  It is responsible for 95% of the energy, which is produced in the body and which is required to run all the body systems:  the cardiovascular system, the central nervous system, the musclo-skeletal system, the gastro-intestinal system, the genito-urinary system, the endocrine system, the immune system, the respiratory system, the thermo-regulatory system, the speech and auditory systems and all the senses, the skin’s integrity.  In other words, everything the body does requires energy.

  Co-enzyme Q10 is a relatively new molecule in science. Although present since creation, it was discovered in 1957 at the Enzyme Research Center at the University of Wisconsin.  It was isolated from beef heart mitochondria by Fredrick Crane.  Different forms of CoQ—CoQ6 through CoQ12—were soon found to be in all cell membranes and in all cell organelle membranes in all species in both the animal and plant kingdoms.  In man, CoQ10 is found.  In the human body, it’s production is highest in the first two decades of life and decreases gradually thereafter.  Most of the food we eat contains CoQ10, especially meat protein and dark green leafy vegetables.  It is found in beans, peas, and large nuts, but not in small grains.  Formula and milk have no CoQ10, but do have the nutritional substrates required for CoQ10 synthesis.  Processing and cooking foods reduces the CoQ10 content.

CoQ10 has five known functions in the body

1. CoQ10 is responsible for 95% of the energy produced in the body.
2. CoQ10 is a potent intracellular antioxidant.
3. CoQ10 prevents atherosclerosis.
4. CoQ10 prevents abnormal protein synthesis and thus age related degenerative diseases.
5. CoQ10 stabilizes all cell membranes.

   The role of CoQ10 in energy synthesis was part of a Nobel Prize awarded to Sir Peter Mitchell in 1978.


MITOCHONDRIA: ENERGY PRODUCING ORGANELLES (“POWERHOUSE”) OF ALL LIVING CELLS

   Production of energy is strictly a mitochondrial function. Mitochondria are found in all living cells.  They are small bean-shaped structures with outer and inner membranes.  Five percent of the total body energy is produced in the breakdown of food substances to NADH, which occurs in the outer membrane of the mitochondria.  The inner membrane is the location of the proteins (Complexes I, II, III, and IV) for the synthesis of energy.  The remaining ninety-five percent of energy is produced here in the presence of oxygen.  This occurs when NADH (from the outer membrane) is converted to energy (ATP) through electron transfer.  CoQ10 and Cytochrome C are the mediators for electron transfer through Complex II and III.  Of these three intermediates (NADH, CoQ10, and Cytochrome C), CoQ10 is the only one found to be deficient in patients with low energy syndromes, including Prader-Willi syndrome.  Low energy syndrome patients do not show a deficiency of NADH or Cytochrome C.

   Multiple genetic and non-genetic mitochondrial disorders have been described.  In many of these clinical conditions, low CoQ10 content has been found in the body.  Because production of energy requires CoQ10, deficiencies of it result in reduced energy synthesis.  Under conditions of reduced CoQ10, the mitochondria show morphological changes in size, shape and location.  They dry up to raisin-like organelles and are found clumped together rather that being distributed evenly throughout the cell.  This results in clinical conditions that affect infants, children, and adults.  Included in these are Prader-Willi syndrome, muscular dystrophy, multiple sclerosis, Huntington’s Chorea, chronic fatigue syndrome, Parkinson’s disease, hypothyroid disease, heart failure, some forms of cancer, and effects of excessive drug therapy with certain pharmaceuticals. 

   DNA is found in all mitochondria.  It is responsible for reproduction of mitochondria, which occurs under conditions of increased cell activity such as exercise and training. Trained individuals have higher numbers and greater distributions of mitochondria in skeletal muscle compared to non-trained individuals.  Under conditions of muscle dysfunction in adults, such as hypotonia and atrophy, the mitochondria have been shown to be abnormal and non-functional.  In the case of CoQ10 deficiencies, this is known to occur in adults when blood levels are reduced to 0.55ug/ml or less.  CoQ10 replacement in individuals with known deficiencies significantly increases mitochondrial energy synthesis and results in an improved clinical condition and quality of life.  In adults and the elderly this response is slow when compared to the response seen in infants and young children with Prader Willi syndrome.


LOW ENERGY SYNDROME


Low energy syndromes have been linked to poor nutrition, digestive disorders, endocrine disorders, Vitamin B deficiencies, mitochondrial dysfunction, age and CoQ10 deficiency.  In most people, CoQ10 deficiency occurs in old age.  This is probably due to two things, either a dietary deficiency in substrates required to make CoQ10 or an overall dysfunction of the biochemical mechanisms responsible for CoQ10 synthesis.  It is uncommon for children and young adults to be deficient in CoQ10.  In infants with Prader-Willi syndrome, there appears to be an inability of the body to adequately produce and/or utilize CoQ10.  Without adequate CoQ10, energy synthesis in the inner membrane of the mitochondria is limited.  Thus, in children with Prader-Willi syndrome who have CoQ10 deficiency and normal mitochondria, CoQ10 replacement should enhance energy synthesis and therefore metabolic activity in all body systems.  If the mitochondrial mechanism is undeveloped or non functional, then CoQ10 replacement may have limited effects unless the mitochondrial function can be revived.
THE MITOCHONDRIAL-LOW ENERGY-CoQ10 STORY

   Energy is required for all the body systems to function, including the synthesis of the steroids, hormones, enzymes, and coenzymes required for muscle energetics, physical and mental growth, and development of sex characteristics.  Without energy, the caloric content of food cannot be converted to useful energy and thus it is stored as fat and hunger persists.  Hence it may be possible that multiple symptoms of Prader-Willi syndrome are related to an endogenous CoQ10 deficiency or to abnormal mitochondrial complexes in the energy synthesis mechanism.  Some of the symptoms include: muscle hypotonia, difficulty sucking and swallowing, low metabolic rate, hypothermia, poor growth pattern, mental retardation and delayed speech development, hypogonadism, hypopigmentation, osteoporosis, hyperphagia, obesity, and diabetes (Type II).

   Today, we know much more about Prader-Willi syndrome than we did three decades ago.  Most of this is in the field of genetics.  No specific biochemical marker (hormone or enzyme) had been found until recently.  No widely accepted treatment for this condition has been formulated except for the use of growth hormone to stimulate growth and calorie restriction to prevent obesity.  We have found below normal plasma CoQ10 levels in a majority (80%) of children with Prader-Willi syndrome tested between the ages of a few days and eighteen years.  Whether this is a result of the genetic abnormality or is a separate entity causing the low energy characteristics in these children is unknown.  The symptoms of Prader-Willi syndrome certainly point to a CoQ10 deficiency and thus an abnormal mitochondrial energy synthesis mechanism.


USE IT OR LOSE IT

   When mitochondria are not stimulated by sufficient amounts of CoQ10, they shrivel, migrate and clump in one area of the cell.  This renders the mitochondria virtually useless.  This can happen even in the presence of adequate CoQ10 when it is not properly utilized.  Mitochondria can be rejuvenated by a combined therapy of exercise and increasing plasma CoQ10 levels above normal.  Without adequate numbers of functioning mitochondria or CoQ10, energy synthesis is significantly reduced.  Even slight deficiencies of plasma CoQ10 can result in mitochondrial dysfunction because six to eight times more molecules of CoQ10 are required than Cytochrome C and fifty times more than NADH dehydrogenase.  Thus a small shift in CoQ10 could render small skeletal muscle groups inactive.

        Until this past year, we had only one example of the benefits of CoQ10 replacement in a child with Prader-Willi syndrome who has both a chromosomal 15 abnormality and a Complex II and III involvement, where CoQ10 is an essential cofactor.  For the first six months of life, this child did not cry or move and was fed via an NG tube.  Within three days of starting CoQ10 , the child began to develop suckling reflexes and was able to “put her toes in her mouth”.  With continued CoQ10 replacement, crawling, standing and walking occurred between eight and twelve months. Today, nearly five years later, in the absence of any nutritional, hormonal, or drug intervention other than CoQ10 replacement, this child has normal physical and mental development.  Speech patterns, physical skills, and cognitive function are in the normal range for the age level.

   In this one child who has had CoQ10 replacement for an extended interval possible answers for others can be given to the mitochondria-low energy-CoQ10 story.

In the past year, through our research we have seen several more examples of the benefits of CoQ10  in children with Prader-Willi syndrome.

    So, is CoQ10 one of the keys required to unlock the unknown management possibilities of Prader-Willi syndrome?  Today, we have some answers, but more questions have arisen.

That’s the great thing about research, with answers come more  questions.

   Currently SIBR, Inc. is conducting the first study of CoQ10 deficiency and replacement in treatment of Prader-Willi syndrome.  Several encouraging observations have been made by parents, physicians, therapists, and caretakers.  These observations give us hope as we enter into this “Millennium of Hope” .

Newborns respond to CoQ10 replacement within 24 hours, indicating that the mitochondria are present and functional.

Five and six year old children respond to CoQ10 replacement within three to five days. 

Neonates who cannot swallow develop good swallowing and suckling reflexes within 12 to 16 hours after a dose of CoQ10.

Children with Prader-Willi syndrome taking CoQ10 show improved bone density within a few short months.  Absorption of minerals for making strong bones requires energy.

CoQ10 replacement improves strength in the muscles controlling eye movements.  Parents also report improved eye motion and less eye position distortion.

CoQ10 replacement increases and helps regulate body temperature.  Children have discovered the new found thrill of playing out in the cold without hypothermia and of sleeping through the   night with less covers.

Older children are losing weight when taking CoQ10.  With increased energy (Basal Metabolic Rate) there is increased caloric use and thus weight loss rather than weight gain.

Some parents report a reduction in the foraging for food since starting CoQ10 replacement.

Some parents of children with Prader-Willi syndrome who have “normal” levels of CoQ10 have reported that with CoQ10 supplementation these children display too much energy and physical activity.  These parents have reduced the CoQ10 intake by 50%.

Nearly all parents have reported improvement in speech patterns and in control of vocal sounds since starting CoQ10 replacement.

Some parents report that since taking CoQ10 their child has shown verbal improvement, with and without aggression.  Could this new found ability to speak endow the child with a new power?

Milestones, such as turning over, sitting, standing and walking, are met at near normal ages in children given CoQ10 replacement before six months of age.

Parents and teachers report that since starting CoQ10 replacement the children show improved organizational skills and cognitive function.

Low in utero activity during the third trimester of pregnancy suggests low endogenous CoQ10 synthesis in the fetus. 

CoQ10 does not pass the placental barrier (Dr. Littarru, Italy).

In normal healthy babies, plasma CoQ10 at birth is 0.15ug/ml and doubles every two weeks until a level of 0.78 to 0.8 is reached.

CoQ10 replacement, with and without the use of growth hormone, seems to reduce scoliosis.

After adding CoQ10 to the growth hormone therapy, scoliosis seems to have been stayed.


RAYS OF HOPE

   Eight months ago we had multiple questions and few answers about the effects of CoQ10  in children with Prader-Willi syndrome.  Now we have some exciting insights.  In the twenty children who are in this study, we have observed the most significant improvements in gross and fine musculo-skeletal function and energetics in those children with the greatest deficiency of endogenous CoQ10.  In those children with more normal levels of endogenous CoQ10, with supplementation we have also seen improved muscle energetics with improved physical endurance, better muscle tone, improved cognitive function and verbal skills.  The magnitude of change has not been the same in all children and none of the older children have (yet) achieved a “normal” degree of musculo-skeletal function.  Nor did we expect them to in such a short interval of treatment.  But time with continued replacement or supplementation and increasing activity may continue to improve mitochondrial function and push these children farther toward normal. 

   In the past few months we have had the opportunity to follow the response in newborns with Prader-Willi syndrome.  We have followed them through the first four months of life.  In these children, CoQ10 replacement allowed them to go home without a feeding tube.  These children, unable to move or nurse the first week of life, developed significant motor skills in just three days of receiving 30mg/kg of CoQ10 daily.  They went home nursing, wiggling and with a strong cry.  For the parents and physicians this was unexpected.  But, to all the parents who have fought the feeding problems and the NG tube and slow skeletal muscle progress, we thank you for sharing your experiences and your tremendous insight to this still poorly understood syndrome.

   Again, what we have learned in the eight months is most significant.  Skeletal muscle mitochondria appear to be functional in children who have Prader-Willi syndrome since we see very quick response, within days, compared to the slow response of severalmonths seen in older patients with mitochondrial dysfunction such as Congestive Heart Failure, muscular dystrophies, chronic fatigue syndrome, cerebral ataxia, Parkinson’s disease, etc.  Quick response in infants suggests that the hypotonia is due to a true skeletal muscle CoQ10 deficiency and not to nonfunctional mitochondria.  Granted the numbers of mitochondria in skeletal muscle may be less in infants and children with Prader Willi syndrome since they have hypotonia in utero and after birth.  Increasing muscle function and demand for oxidative energy synthesis is the stimulus for the production of more mitochondria.  This should occur in time as muscle energetics increase and muscles grow and become stronger.  Hence the quicker and more obvious effects seen in infants as opposed to older children.  Our study clearly has shown the beneficial effects of CoQ10 replacement or supplementation in all children with Prader-Willi syndrome.  However, much more knowledge relative to tissue CoQ10 levels and mitochondrial morphology and biochemistry must be gained.  Questions as to the causative factor for low CoQ10 as seen in the child with Prader-Willi syndrome, and not in other children, must be investigated.  How do CoQ10 levels relate to the genetic disorder?  Does chromosome 15 have a role in CoQ10 synthesis and use?  Why do we see such low levels in some affected children and not others?  Does the absence of adequate CoQ10 cause the mitochondria to be fewer in number and/or dysfunctional?  Can they be revived with higher levels of replacement CoQ10?  Should we wait to see what happens in this child or automatically start them on replacement upon diagnosis to prevent degeneration of the skeletal muscle mitochondria?  Is this genetic syndrome the same in all children?  Are there mitochondrial gene abnormalities as well as nuclear genes?  What is the etiology of diminished CoQ10 synthesis in some children and not others?  What is the anatomy of the mitochondria in skeletal muscle compared to cardiac or smooth muscle?  Can CoQ10 be given in utero to infants who during the third trimester display hypotonia?  Could this prevent the hypotonia and difficulty suckling and swallowing present at birth?  Will CoQ10 replacement increase endogenous CoQ10 synthesis in children with Prader-Willi syndrome?  Once improvement has been maximized, what is the proper maintenance dose? 

  

   We have some new answers as to the use of CoQ10 replacement in management of Prader-Willi syndrome.  But we must design and implement the experiments, which will allow us to definitively solve the low energetics, hypotonia, obesity, speech apraxia, low bone density, scoliosis, and other clinical manifestations of this and perhaps other similar syndromes.

A myriad of questions with hidden answers to be revealed by  research.


SIBR, Inc.

   SIBR, Inc. is a contract research organization established to develop and implement clinical trials.  SIBR is dedicated to providing quality clinical trials to the nutraceutical, pharmaceutical, and medical device industries.  SIBR was founded in 1995 by Dr. William V. Judy.

   Dr. Judy received his Ph.D. in Physiology and Biophysics from West Virginia University Medical Center in 1971.  His training and work have been in the central and peripheral nervous systems and control mechanisms in bioenergetics, temperature regulation, and cardiovascular function.  He served as an aerospace scientist with NASA-MSC and conducted in-flight cardiovascular and thermal regulatory experiments.  He has served as a professor at IU School of Medicine.  He has done clinical research at Methodist and St. Vincent Hospitals in Indianapolis and Sarasota Memorial Hospital in Sarasota, Florida.  He is an author and world renowned lecturer.

   Dr. Willis W. Stogsdill joined SIBR at its inception in 1995 serving as Medical Director.  Dr. Stogsdill received his M.D. from IU School of Medicine.  He was a Family Practitioner for 15 years after which he took a residency in Anesthesiology.  He practiced Cardiac Anesthesia for 22 years at St. Vincent Hospital.  While there he founded the Respiratory Therapy Department and did research in noninvasive cardiovascular monitoring.  He is active in medical politics and served as chairman of the Intensive Care and Anesthesia Departments.

   Dr. Judy’s introduction to CoQ10 occurred in 1960 as a graduate student.  In the early 1970’s, Dr. Karl Folkers, the “Father” of CoQ10, asked him to become involved in CoQ10 research in patients with low energy syndrome.  He has published many works on CoQ10, Congestive Heart Failure, Chronic Fatigue Syndrome, and bioenergetics.  His involvement in mitochondrial energy synthesis began in 1973.

  Currently Dr. Judy and Dr. Stogsdill are conducting an ongoing survey concerning the effects of CoQ10 replacement or supplementation in children with Prader-Willi syndrome.  This effort was stimulated by the results and information gained by Dr. Judy during five years of CoQ10 replacement in one child with Prader-Willi syndrome.  This current program is the second step in SIBR’s efforts to investigate the probable connection between mitochondria, low energy, and CoQ10.

   SIBR is very grateful to all of the children, parents and families, physicians, nurses, therapists, caretakers, and others who have participated in this survey. 





NOTE:Our only experience has been using the Cyto-Med

CoQ10  in  the treatment of Prader-Willi syndrome.

We do not have experience with other forms of CoQ10


All of these observations warrant further study.  They are rays of light shedding new insight into the syndrome itself and into the treatment.  These observations raise new questions and give life to new theories.  For instance, the immediate response in newborns would indicate that the mitochondria are functioning.  Their rapid response as opposed to the slower response in older children and adults might indicate that the earlier the treatment with CoQ10 replacement the more positive results we will obtain.  With early intervention, i.e. at birth or immediately upon diagnosis, we may prevent the mitochondria from shriveling up and thus requiring more time with higher levels of CoQ10 replacement and exercise to revive them.  Could the fact that the heart and other vital organs develop normally in the child with Prader-Willi syndrome, while musculo-skeletal development and thus gross and fine motor skills are delayed, be indicative that in the presence of a CoQ10 deficiency there may be a shunt of CoQ10 to the vital organs?  Could the fact that affected children, who have “normal” CoQ10 plasma levels, show improvement in various areas when given high doses indicate that there are different “normal” levels or that there may be a higher threshold in these children?

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