Guest guest Posted July 23, 2005 Report Share Posted July 23, 2005 Someone had queried about mitochondrial disease: This from a very savvy mom who knows a lot about this problem ( Plant.) I agree with Dr. Kelley from Kennedy-Krieger--about 20% of kids with PDD have mitochondrial disease. The outlook for kids with mito is not always bad. Some researchers believe that in some cases the percentage of " good " mitochondria can be increased over time. Both of my boys have responded very well to the mito cocktail, nighttime carb loading, and carnitor. For Evan, treating the underlying mitochondrial dysfunction and glutathione deficiency have helped immensely. He has shown so much progress since starting treatment in 2001. Here are some treatment recommendations from Dr. Cohen and Dr. Kelley-- vitamins and supplements--The mito cocktail can enhance enzyme function and improve energy generation. Some of the supplements are antioxidants and can protect against damage from oxidative stress (which may slow the progression of the disease) dietary--avoid fasting, small frequent meals, bedtime snack, manipulation of fats and carbohydrates avoidance of stressful factors--esp. physiologic stress cold and heat stress, " starvation " when not eating frequently enough, lack of sleep, other stressors e.g. long car rides, or prolonged exercise (I would not recommend the SCD unless the parents can find plenty of legal carbs) avoidance of toxins--alcohol, smoke, MSG, and aspirin Dr. Kelley from Kennedy-Krieger suspects Complex I for mito-PDD kids, so I am also including the diet recommendations for Complex I-- " In patients with complex I deficiency, the addition of extra fats to the diet should theoretically result in more energy production. This is because the metabolism of protein and carbohydrate produces electrons that must flow through complex I, which is obviously not working properly in complex I deficiency, but fats produce electrons that in addition to flowing through complex I, also produce electrons that can flow through complex II (bypassing complex I). Therefore, if complexes II, III, IV, and V are working properly, fats should be slightly more effective in energy production. A small clinical study yielded mixed results, with some patients improving and others not. " If a child with mito has chronic headaches riboflavin can help. Evan started having chronic headaches (which are common in mito). Anti-inflammatories did not reduce the pain much. We added more riboflavin because riboflavin was one of Dr. Cohen's recommendations for headache pain at the UMDF conf in 2002. " Riboflavin has been proposed to act therapeutically by one of several potential mechanisms including inhibition of the breakdown of complex I by providing more resistance to proteolysis or stabilizing the mitochondrial membrane. It has been used with some success in some patients with mitochondrial disease without any apparent side effects. " ************************************* I believe that there is one DAN doctor who is a classically trained geneticist. His name is Kahler and I think that he has treated mito kids. He was at s Hopkins, but The DAN list has his current phone listed as . Enns at Stanford is also clinical geneticist, and he recently received a grant for UMDF to study GSH levels, reactive oxygen species production, lipid peroxidation products and mitochondrial membrane potential in patients with mitochondrial disease. I know a mother who took her children to see him, and she was pleased with his testing. I do not have any first hand experience with either doctor. Dr. Kelley looked at Evan's records, and I would trust his medical expertise for any child with an ASD diagnosis. Kids with mito are more likely to have reactions to vaccines, so I am sure this is part of the vaccine injury story. I have read research that stated that mercury and other toxins can have a negative impact on the mitochondria. The article " A primary care physician's guide: The Spectrum of Mitochondrial Disease " by Naviaux MD, PhD includes lead, cyanide, and mercury toxicity in the listing of disorders sometimes associated with mitochondrial dysfunction--it is under the heading " environmental " on page 5. Also kids with mito have increased difficulty dealing with sickness in general. Kids with mito tend to get sick more often and experience setbacks when they are ill. Cytokines that are produced during illness or immune activation (from autoimmune disease, vaccines, or allergies) can have a negative effect on mitochondrial function because they increase oxidative stress. For kids with mito and PDD, it is critical to keep their glutathione levels as high as possible. Glutathione is very important because it is the main antioxidant that services the mitochondria. Iron-sulfur centers and glutaredoxin also play a strong role in Complex I dysfunction so it is disordered sulfur chemistry not just low glutathione levels. Kids with ASDs were also found to have sub-par carnitine levels, I suspect it is a combination of the two (mild mitochondrial dysfunction and disordered sulfur metabolism) that is causing problems. Check out this quotation-- GSH is an antioxidant which protects mitochondria from lipid peroxidation (51) and when depleted may render complex I susceptible to free radical attack. Previously, depletion of GSH has been shown to cause enlargement and degeneration of brain mitochondria (52) and a decrease in complex IV activity in purified brain mitochondrial preparations (53). GSH also plays a role in protection of sympathetic neurons in vivo from the effects of the neurotoxin, 1-methyl-4-phenylpyridinium (54) and when mesencephalic cultures are treated with L-BSO, toxicity is potentiated upon exposure to the succinate dehydrogenase inhibitor, malonate (55). These results suggest that, under conditions of GSH depletion, mitochondria are more vulnerable to metabolic insult, which results in a compromise in energy metabolism. J Inherit Metab Dis. 2005;28(1):81-8. Glutathione deficiency in patients with mitochondrial disease: implications for pathogenesis and treatment. Hargreaves IP, Sheena Y, Land JM, Heales SJ. Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, WC1N 3BG, London, UK. ihargrea@... Glutathione (GSH) is a key intracellular antioxidant. With regard to mitochondrial function, loss of GSH is associated with impairment of the electron transport chain (ETC). Since GSH biosynthesis is an energy-dependent process, we postulated that in patients with ETC defects GSH status becomes compromised, leading to further loss of ETC activity. We performed electrochemical HPLC analysis to determine the GSH concentration of 24 skeletal muscle biopsies from patients with defined ETC defects compared to 15 age-matched disease controls. Comparison of these groups revealed a significant (p < 0.001) decrease in GSH concentration in the ETC-deficient group: 7.7 +/- 0.9 vs 12.3 +/- 0.6 nmol/mg protein in the control group. Further analysis of the data revealed that patients with multiple defects of the ETC had the most marked GSH deficiency: 4.1 +/- 0.9 nmol/mg protein (n = 4, p < 0.05) when compared to the control group. These findings suggest that a deficiency in skeletal muscle GSH concentration is associated with an ETC defect, possibly as a consequence of diminished ATP availability or increased oxidative stress. The decreased ability to combat oxidative stress could therefore cause further loss of ETC activity and hence be a contributing factor in the progressive nature of this group of disorders. Furthermore, restoration of cellular GSH status could prove to be of therapeutic benefit in patients with a GSH deficiency associated with their ETC defects. Nutr Neurosci. 2001;4(3):213-22 Sulfur amino acid deficiency depresses brain glutathione concentration. Paterson PG, Lyon AW, Kamencic H, Andersen LB, Juurlink BH. College of Pharmacy and Nutrition, Cameco Multiple Sclerosis and Neuroscience Research Center, University of Saskatchewan, Saskatoon, Canada. phyllis.paterson@... Dietary sulfur amino acid content is a major determinant of glutathione concentration in some tissues. We examined whether brain glutathione (GSH), a key component of antioxidant defense important for minimizing ischemic injury, was also responsive to short-term sulfur amino acid deficiency. Female Long- adult rats were fed a sulfur-deficient L-amino acid defined diet for five days; the control diet was supplemented with L-cystine and L-methionine (n = 6). Sulfur amino acid deficiency was confirmed by a reduction in liver cysteine and GSH concentrations, marked decreases in food intake, and weight loss. GSH concentration analyzed by reverse-phase high performance liquid chromatography was significantly depressed in the neocortex and thalamus of deficient rats. Brain cysteine was not decreased in a parallel manner. Classical glutathione peroxidase activity was increased in the liver and brain of sulfur amino acid deficient rats. This suggests an upregulation of antioxidant defense but these findings may be complicated by alterations in tissue composition. The depletion of brain GSH by a reduced supply of dietary precursors may be important during brain ischemia when the rate of GSH utilization and the need for synthesis are increased. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1913-7. Glutathione deficiency leads to mitochondrial damage in brain. Jain A, Martensson J, Stole E, Auld PA, Meister A. Department of Pediatrics, Cornell University Medical College, New York, NY 10021. Glutathione deficiency induced in newborn rats by giving buthionine sulfoximine, a selective inhibitor of gamma-glutamylcysteine synthetase, led to markedly decreased cerebral cortex glutathione levels and striking enlargement and degeneration of the mitochondria. These effects were prevented by giving glutathione monoethyl ester, which relieved the glutathione deficiency, but such effects were not prevented by giving glutathione, indicating that glutathione is not appreciably taken up by the cerebral cortex. Some of the oxygen used by mitochondria is known to be converted to hydrogen peroxide. We suggest that in glutathione deficiency, hydrogen peroxide accumulates and damages mitochondria. Glutathione, thus, has an essential function in mitochondria under normal physiological conditions. Observations on turnover and utilization of brain glutathione in newborn, preweaning, and adult rats show that (i) some glutathione turns over rapidly (t 1/2, approximately 30 min in adults, approximately 8 min in newborns), (ii) several pools of glutathione probably exist, and (iii) brain utilizes plasma glutathione, probably by gamma-glutamyl transpeptidase-initiated pathways that account for some, but not all, of the turnover; thus, there is recovery or transport of cysteine moieties. These studies provide an animal model for the human diseases involving glutathione deficiency and are relevant to oxidative phenomena that occur in the newborn. There is a yahoo group that focuses on kids with mito/metabolic disorders and autism spectrum disorders. I would encourage to join the group. http://health.groups.yahoo.com/group/Meta-mito-autism/ Take care, Quote Link to comment Share on other sites More sharing options...
Guest guest Posted July 23, 2005 Report Share Posted July 23, 2005 What kind of testing do you do to diagnose mito? Our son is pretty low glutathione, needs to eat frequently and low carnitine so I wondered if we should check? We've only seen metabolics once who recommended more carnitine testing but was happy he had good muscle tone. But it is kinda hard to explain to a non-DAN that if my son doesn't follow a strict diet he can barely walk straight in just a couple of days and I don't want something to get overlooked. Thanks, Marie > Someone had queried about mitochondrial disease: This from a > very savvy mom who knows a lot about this problem ( Plant.) > > I agree with Dr. Kelley from Kennedy-Krieger--about 20% of kids with PDD have mitochondrial disease. The outlook for kids with mito is not always bad. Some researchers believe that in some cases the percentage of " good " mitochondria can be increased over time. Both of my boys have responded very well to the mito cocktail, nighttime carb loading, and carnitor. For Evan, treating the underlying mitochondrial dysfunction and glutathione deficiency have helped immensely. He has shown so much progress since starting treatment in 2001. > > Here are some treatment recommendations from Dr. Cohen and Dr. Kelley-- > > vitamins and supplements--The mito cocktail can enhance enzyme function and improve energy generation. Some of the supplements are antioxidants and can protect against damage from oxidative stress (which may slow the progression of the disease) > > dietary--avoid fasting, small frequent meals, bedtime snack, manipulation of fats and carbohydrates > > avoidance of stressful factors--esp. physiologic stress cold and heat stress, " starvation " when not eating frequently enough, lack of sleep, other stressors e.g. long car rides, or prolonged exercise (I would not recommend the SCD unless the parents can find plenty of legal carbs) > > avoidance of toxins--alcohol, smoke, MSG, and aspirin > > Dr. Kelley from Kennedy-Krieger suspects Complex I for mito-PDD kids, so I am also including the diet recommendations for Complex I-- " In patients with complex I deficiency, the addition of extra fats to the diet should theoretically result in more energy production. This is because the metabolism of protein and carbohydrate produces electrons that must flow through complex I, which is obviously not working properly in complex I deficiency, but fats produce electrons that in addition to flowing through complex I, also produce electrons that can flow through complex II (bypassing complex I). Therefore, if complexes II, III, IV, and V are working properly, fats should be slightly more effective in energy production. A small clinical study yielded mixed results, with some patients improving and others not. " > > If a child with mito has chronic headaches riboflavin can help. Evan started having chronic headaches (which are common in mito). Anti-inflammatories did not reduce the pain much. We added more riboflavin because riboflavin was one of Dr. Cohen's recommendations for headache pain at the UMDF conf in 2002. > > " Riboflavin has been proposed to act therapeutically by one of several potential mechanisms including inhibition of the breakdown of complex I by providing more resistance to proteolysis or stabilizing the mitochondrial membrane. It has been used with some success in some patients with mitochondrial disease without any apparent side effects. " > ************************************* > I believe that there is one DAN doctor who is a classically trained geneticist. His name is Kahler and I think that he has treated mito kids. He was at s Hopkins, but The DAN list has his current phone listed as . Enns at Stanford is also clinical geneticist, and he recently received a grant for UMDF to study GSH levels, reactive oxygen species production, lipid peroxidation products and mitochondrial membrane potential in patients with mitochondrial disease. I know a mother who took her children to see him, and she was pleased with his testing. I do not have any first hand experience with either doctor. Dr. Kelley looked at Evan's records, and I would trust his medical expertise for any child with an ASD diagnosis. > > Kids with mito are more likely to have reactions to vaccines, so I am sure this is part of the vaccine injury story. I have read research that stated that mercury and other toxins can have a negative impact on the mitochondria. The article " A primary care physician's guide: The Spectrum of Mitochondrial Disease " by Naviaux MD, PhD includes lead, cyanide, and mercury toxicity in the listing of disorders sometimes associated with mitochondrial dysfunction--it is under the heading " environmental " on page 5. Also kids with mito have increased difficulty dealing with sickness in general. Kids with mito tend to get sick more often and experience setbacks when they are ill. Cytokines that are produced during illness or immune activation (from autoimmune disease, vaccines, or allergies) can have a negative effect on mitochondrial function because they increase oxidative stress. For kids with mito and PDD, it is critical to keep their glutathione levels as high as possible. > > Glutathione is very important because it is the main antioxidant that services the mitochondria. Iron-sulfur centers and glutaredoxin also play a strong role in Complex I dysfunction so it is disordered sulfur chemistry not just low glutathione levels. Kids with ASDs were also found to have sub-par carnitine levels, I suspect it is a combination of the two (mild mitochondrial dysfunction and disordered sulfur metabolism) that is causing problems. > > Check out this quotation-- > > GSH is an antioxidant which protects mitochondria from lipid peroxidation (51) and when depleted may render complex I susceptible to free radical attack. Previously, depletion of GSH has been shown to cause enlargement and degeneration of brain mitochondria (52) and a decrease in complex IV activity in purified brain mitochondrial preparations (53). GSH also plays a role in protection of sympathetic neurons in vivo from the effects of the neurotoxin, 1- methyl-4-phenylpyridinium (54) and when mesencephalic cultures are treated with L-BSO, toxicity is potentiated upon exposure to the succinate dehydrogenase inhibitor, malonate (55). These results suggest that, under conditions of GSH depletion, mitochondria are more vulnerable to metabolic insult, which results in a compromise in energy metabolism. > > > J Inherit Metab Dis. 2005;28(1):81-8. > Glutathione deficiency in patients with mitochondrial disease: implications for pathogenesis and treatment. > > Hargreaves IP, Sheena Y, Land JM, Heales SJ. > > Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, Queen Square, WC1N 3BG, London, UK. ihargrea@i... > > Glutathione (GSH) is a key intracellular antioxidant. With regard to mitochondrial function, loss of GSH is associated with impairment of the electron transport chain (ETC). Since GSH biosynthesis is an energy-dependent process, we postulated that in patients with ETC defects GSH status becomes compromised, leading to further loss of ETC activity. We performed electrochemical HPLC analysis to determine the GSH concentration of 24 skeletal muscle biopsies from patients with defined ETC defects compared to 15 age-matched disease controls. Comparison of these groups revealed a significant (p < 0.001) decrease in GSH concentration in the ETC-deficient group: 7.7 +/- 0.9 vs 12.3 +/- 0.6 nmol/mg protein in the control group. Further analysis of the data revealed that patients with multiple defects of the ETC had the most marked GSH deficiency: 4.1 +/- 0.9 nmol/mg protein (n = 4, p < 0.05) when compared to the control group. These findings suggest that a deficiency in skeletal muscle GSH concentration is associated with an ETC defect, possibly as a consequence of diminished ATP availability or increased oxidative stress. The decreased ability to combat oxidative stress could therefore cause further loss of ETC activity and hence be a contributing factor in the progressive nature of this group of disorders. Furthermore, restoration of cellular GSH status could prove to be of therapeutic benefit in patients with a GSH deficiency associated with their ETC defects. > > > Nutr Neurosci. 2001;4(3):213-22 > Sulfur amino acid deficiency depresses brain glutathione concentration. > Paterson PG, Lyon AW, Kamencic H, Andersen LB, Juurlink BH. > > College of Pharmacy and Nutrition, Cameco Multiple Sclerosis and Neuroscience Research Center, University of Saskatchewan, Saskatoon, Canada. phyllis.paterson@u... > > Dietary sulfur amino acid content is a major determinant of glutathione concentration in some tissues. We examined whether brain glutathione (GSH), a key component of antioxidant defense important for minimizing ischemic injury, was also responsive to short-term sulfur amino acid deficiency. Female Long- adult rats were fed a sulfur-deficient L-amino acid defined diet for five days; the control diet was supplemented with L-cystine and L-methionine (n = 6). Sulfur amino acid deficiency was confirmed by a reduction in liver cysteine and GSH concentrations, marked decreases in food intake, and weight loss. GSH concentration analyzed by reverse-phase high performance liquid chromatography was significantly depressed in the neocortex and thalamus of deficient rats. Brain cysteine was not decreased in a parallel manner. Classical glutathione peroxidase activity was increased in the liver and brain of sulfur amino acid deficient rats. This suggests an upregulation of antioxidant defense but these findings may be complicated by alterations in tissue composition. The depletion of brain GSH by a reduced supply of dietary precursors may be important during brain ischemia when the rate of GSH utilization and the need for synthesis are increased. > > Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1913-7. > Glutathione deficiency leads to mitochondrial damage in brain. > Jain A, Martensson J, Stole E, Auld PA, Meister A. > Department of Pediatrics, Cornell University Medical College, New York, NY 10021. > > Glutathione deficiency induced in newborn rats by giving buthionine sulfoximine, a selective inhibitor of gamma- glutamylcysteine synthetase, led to markedly decreased cerebral cortex glutathione levels and striking enlargement and degeneration of the mitochondria. These effects were prevented by giving glutathione monoethyl ester, which relieved the glutathione deficiency, but such effects were not prevented by giving glutathione, indicating that glutathione is not appreciably taken up by the cerebral cortex. Some of the oxygen used by mitochondria is known to be converted to hydrogen peroxide. We suggest that in glutathione deficiency, hydrogen peroxide accumulates and damages mitochondria. Glutathione, thus, has an essential function in mitochondria under normal physiological conditions. Observations on turnover and utilization of brain glutathione in newborn, preweaning, and adult rats show that (i) some glutathione turns over rapidly (t 1/2, approximately 30 min in adults, approximately 8 min in newborns), (ii) several pools of glutathione probably exist, and (iii) brain utilizes plasma glutathione, probably by gamma-glutamyl transpeptidase-initiated pathways that account for some, but not all, of the turnover; thus, there is recovery or transport of cysteine moieties. These studies provide an animal model for the human diseases involving glutathione deficiency and are relevant to oxidative phenomena that occur in the newborn. > > > There is a yahoo group that focuses on kids with mito/metabolic disorders and autism spectrum disorders. I would encourage to join the group. > > > http://health.groups.yahoo.com/group/Meta-mito-autism/ > > Take care, > > > Quote Link to comment Share on other sites More sharing options...
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