CREATING SYNTHESIS
When Is a Rare Disease Not so Rare? Implications for Medical Nutrition Therapy Jeffrey Bland, PhD, Associate Editor
Jeffrey Bland, PhD, is the president and founder of the Personalized Lifestyle Medicine Institute in Seattle, Washington. He has been an internationally recognized leader in nutrition medicine for more than 25 years. Dr Bland is the cofounder of the Institute for Functional Medicine (IFM) and is chairman emeritus of IFM’s Board of Directors. He is the author of the 2014 book The Disease Delusion: Conquering the Causes of Chronic Illness for a Healthier, Longer, and Happier Life.
R
ecently, I had a conversation with a master clinician and teacher who is a living legend in the functional medicine world, Dr Sidney Baker. As we talked, he reminded me of another discussion we had had—one that took place more than 25 years ago. That discussion related to a patient of Dr Baker’s, an individual who had a chronic fat digestion problem that seemed intractable: All the traditional diagnostic tests had come back with no definitive diagnosis and the use of pancreatic enzyme supplements did not seem to alleviate the symptoms. Dr Baker reminded me that I suggested he read an article describing the role that taurine has in the synthesis of bile acids. This article described how defects in bile acid synthesis were found in some children to be a result of genetic alterations in the conjugation of taurine with bile salts, thereby resulting in a functional bile acid deficiency.1,2 Following our conversation all those many years ago, Dr Baker tried taurine supplementation in his patient, and this individual’s chronic digestive problem resolved permanently. In our recent discussion of this long-ago case, both Dr Baker and I observed that taurine supplementation has continued to be studied for the past 2-plus decades, and in some individuals with fat maldigestion and steatorrhea, clinical trials using 1500 to 2000 mg of taurine have demonstrated resolution of fat intolerance.3 It has recently been reported that a fat-modified enteral medical food that contains supplemental taurine and carnitine improves feeding tolerance in critically ill patients.4 Response to taurine supplementation is related to genetic uniqueness among differing individuals in bile acid synthesis. Not long after my conversation with Dr Baker, I ran into one of my former students—a woman who had taken 14
Integrative Medicine • Vol. 15, No. 1 • February 2016
the medical school biochemistry course I taught in the 1970s. She also mentioned a memory, and this one involved me discussing the relationship between zinc deficiency in infants and the skin disorder acrodermatitis enteropathica (AE). This former student, who had gone on to become a physician, saw an infant in her practice decades after my lecture who presented with an inflammation of the skin that resembled the slides I had shown—images of patients with AE treated by Dr Lucille Hurley at the University of California, Davis—so many years earlier. Dr Hurley had discovered that the cause of AE in these children resulted from feeding them cow’s milk, which contains a zinc binding protein that prevents proper zinc absorption.5 Some children have a genetic predisposition for this condition due to differences (compared with the population at large) in the way they absorb and metabolize zinc. These conversations caused me to reflect. I recognized that both conditions are rare. They also are undoubtedly related to unique genetic differences between “normal” and “dysfunctional.” But, I pondered: When does a condition go from being a more common functional disorder that varies from mild to moderate in its presentation to the more severe form of a “rare disease?” This question started swirling around my mind like bees in a hive. For the next few weeks, I seemed to come back again and again to it: When is a rare disease not so rare? I began to explore the vitamin dependent genetic metabolism diseases of infancy, such as megaloblastic anemia, which results from an inborn error of vitamin B12 metabolism; with this condition, the amount of supplementation needed varies from individual to individual, ranging from several-fold to several hundredfold the recommended intake of the vitamin to achieve adequate vitamin B12 status.6 At what point in this spectrum of differing vitamin B12 needs does a functional disorder become a rare disease? When does medical nutrition therapy become pharmacology? I came to recognize that this concern could be applied to virtually all the essential nutrients for which there are recognized clinical biomarkers for defining inadequacies.7 This question—where is the line?—can even be applied to conditions traditionally considered monogenetic metabolic disorders, such as phenylketonuria (PKU). PKU is well known to be a result of a mutation in the gene that Bland—Creating Synthesis
codes for the enzyme phenylalanine hydroxylase and regulates the conversion of the amino acid phenylalanine to tyrosine. A defect in this enzyme causes phenylalanine to accumulate in the tissues to the point of toxicity, while producing a tissue tyrosine deficiency. Because tyrosine is necessary as a precursor to the dopamine neurotransmitter family in the central nervous system, deficiency can result in serious effects on brain development, learning, and behavior.8 Individuals who carry the altered gene for phenylalanine hydroxylase are generally identified through a screening test given to all newborns, and the traditional course of treatment is to put the infant or child on a phenylalanine-restricted diet. What is important to understand, however, is that not all children who have PKU express the same phenotype. PKU can exist as mild, moderate, or severe phenotypes. Variations in severity are due to not only differences in homozygosity versus heterozygosity in the phenylalanine hydroxylase gene, but also other factors that control the amount and activity of the enzyme. One of these other considerations is tetrahydrobiopterin, or BH4, the cofactor for the phenylalanine hydroxylase enzyme. In children with mild to moderate PKU, studies have shown that BH4 supplementation can result in lowered plasma phenylalanine and increased tyrosine levels.9 There is now good evidence that responsiveness to BH4 supplementation is related to as many as 74 other distinct genetic alterations beyond the traditional defect in phenylalanine hydroxylase.10 Long-term follow-up studies demonstrating that children with PKU treated with tetrahydrobiopterin therapy have good clinical outcomes and that the dose required for reducing plasma phenylalanine varies considerably from one child to another have now been published.11 So when does a child have the rare disease PKU, and when does a child have a slower metabolism of phenylalanine that produces mild metabolic dysfunction? There are many more children in the category of mild to moderate forms of PKU than there are children with the classic severe form of PKU. In the case of metabolic conditions, we often study the most extreme cases of a dysfunction and call it a rare disease because its symptom profile is the most severe and most easily identified. As we learn more about how metabolism is controlled by families of genes that work as a network rather than single genes working independently, we better understand that metabolic disorders exist on a continuum, ranging from the most extreme inborn error to that of more complex genotypic states that are not seen as a “rare disease” but rather as “functional” in origin. In his landmark 1968 paper titled “Orthomolecular Psychiatry: Varying the Concentration of Substances Normally Present in the Human Body May Control Mental Disease,” I believe Dr Linus Pauling was the first to define this concept.12 Dr Pauling proposed that the functioning of the body is affected by the molecular concentrations of many substances that are normally Bland—Creating Synthesis
present, such as taurine, zinc, and tetrahydrobiopterin. He described natural metabolites and nutrient-derived substances in the body as orthomolecular substances (ortho, meaning “right” or “correct”). The optimum concentrations of these substances for specific individuals may vary greatly. Individuals who have unique genetic needs for specific orthomolecular substances may require levels of these substances greater than they can achieve in a “normal” or “average” diet and, therefore, are candidates for personalized medical nutrition therapy. Dr Bruce Ames further developed this concept in an important review paper titled “High-dose Vitamin Therapy Stimulates Variant Enzymes With Decreased Coenzyme Binding Affinity: Relevance to Genetic Disease and Polymorphisms.”13 Dr Ames points out that more than 50 human genetic diseases linked to defective enzyme function that result from known genetic mutations can be remediated or ameliorated by the administration of high doses of the vitamin component of the corresponding coenzyme that regulates the activity of the enzyme. Because all of these nutrient-related genetic diseases exist in mild to severe forms, it is possible for each of these conditions to relate to many different genetic polymorphisms with varying nutrient needs. How does this apply to understanding the difference between the need for drug treatment of a rare disease that derives from an inborn error of metabolism and a functional metabolic defect that requires medical nutrition therapy? When I opened the November 14, 2015, issue of The Lancet, a clinical example that defines the question jumped off of page 1924: “Treatments for Rare Diseases: Molybdenum Cofactor Deficiency.” This editorial describes a research study involving the treatment of a cohort of infants with molybdenum cofactor deficiency associated with the loss of activity of the enzyme sulfite oxidase, which is clinically characterized by severe and progressive neurological damage and intractable seizures.14 Until this cofactor therapy was developed, there had been no effective treatment for this condition. The early results of this pharmacological intervention in severe cases of inborn molybdenum cofactor deficiency with the precursor of the molybdenum cofactor are very encouraging and indicate the cofactor therapy (without giving the enzyme itself) is able to restore enough of the enzyme function to reduce the progression of the pathology. Clinically speaking, this protocol is similar to the treatment of PKU with the cofactor BH4 that activates the genetically modified enzyme phenylalanine hydroxylase to the extent that improved metabolism results. In a sense, these examples support the Pauling and Ames orthomolecular medicine concept. But what about cases of molybdenum cofactor uniqueness that represent a more mild form of genetic uniqueness related to molybdenum binding? It is this question that illustrates the differences between pharmacological treatment of a rare genetic metabolism Integrative Medicine • Vol. 15, No. 1 • February 2016
15
disease and a functional disorder that is responsive to medical nutrition therapy. It is known that both sulfite oxidase and xanthine oxidase require molybdenum for their activity.15,16,17 It has been shown that apparently healthy infants have different molybdenum binding activities to its cofactor18 and that there are several different genetic polymorphisms that control the synthesis of the molybdenum cofactor and its binding to molybdenum.19 It is also important to note that molybdenum can be displaced from the sulfite oxidase molybdenum cofactor by other substances, making it more dependent on the availability of molybdenum from the plasma.20 States of functional molybdenum insufficiency can therefore exist and represent an opportunity for medical nutrition therapies. In individuals with a functional molybdenum deficiency, chronic symptoms of sulfite sensitivity are often present. These symptoms may include allergic-like symptoms such as wheezing, hives, and flushing, as well as gastrointestinal issues such as upset stomach and diarrhea. Rather than a rare disease of molybdenum cofactor deficiency, this example represents a chronic sensitivity to sulfite due to slightly impaired sulfite oxidase activity. Sulfite sensitivity can be treated by either removing the exposure to sulfite containing foods or, in the case of molybdenum deficiency, repletion of molybdenum at the daily intake of 100 μg per day. The takeaway for me is that “rare” diseases often represent only the tip of an iceberg under which reside many other less-severe forms of the metabolic disturbance that are not diseases but rather varying forms of dysfunction. A continuum exists that is based on activating the enzyme that is derived from the genetic polymorphism. Likewise, there is a continuum of therapeutic choices: In less-severe forms of the condition, medical nutrition therapy is often the treatment of choice, whereas in the severe disease that results from a specific monogenetic mutation, a pharmacological approach to activating the enzyme may be the more appropriate treatment. In the not-so-distant past, a belief existed that little could be done—management of symptoms, at best—for the treatment of “genetic” disorders. Today, we have a greater opportunity to truly understand the origins of genetically related metabolic diseases and to tailor personalized therapies based on the severity of the condition and the needs of each individual patient.
16
Integrative Medicine • Vol. 15, No. 1 • February 2016
References
1. Walker S, Stiehl A, Raedsch R, Kloters P, Kommerell B. Absorption of ursoand chenodeoxycholic acid and their taurine and glycine conjugates in rat jejunum, ileum, and colon. Digestion. 1985;32(1):47-52. 2. Powell GK, Jones LA, Richardson J. A new syndrome of bile acid deficiency—a possible synthetic defect. J Pediatr. 1973;83(5):758-766. 3. Smith LJ, Lacaille F, Lepage G, Ronco N, Lamarre A, Roy CC. Taurine decreases fecal fatty acid and sterol excretion in cystic fibrosis. A randomized double-blind trial. Am J Dis Child. 1991;145(12):1401-1404. 4. Qiu C, Chen C, Zhang W, Kou Q, Wu S, et al. A fat-modified enteral formula improves feeding tolerance in critically ill patients: a multicenter, singleblind, randomized controlled trial. JPEN J Parenter Enteral Nutr. September 8, 2015. pii: 0148607115601858. 5. Eckhert CD, Sloan MV, Duncan JR, Hurley LS. Zinc binding: A difference between human and bovine milk. Science. 1977;195(4280):789-790. 6. Baumgartner MR. Vitamin-responsive disorders: Cobalamin, folate, biotin, vitamins B1 and E. Handb Clin Neurol. 2013;113:1799-1810. 7. McNulty H, Scott JM. Intake and status of folate and related B-vitamins: Considerations and challenges in achieving optimal status. Br J Nutr. 2008;99(Suppl 3):S48-S54. 8. Giovannini M, Verduci E, Salvatici E, Paci S, Riva E. Phenylketonuria: Nutritional advances and challenges. Nutr Metab (Lond). 2012;9(1):7. 9. Muntau AC, Roschinger W, Habich M, Demmelmair H, Hoffmann B, et al. Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med. 2002;347(26):2122-2132. 10. Tao J, Li N, Jia H, Liu Z, Li X, et al. Correlation between genotype and the tetrahydrobiopterin-responsive phenotype in Chinese patients with phenylketonuria. Pediatr Res. 2015;78(6):691-699. 11. Scala I, Concolino D, Della Casa R, Nastasi A, Ungaro C, et al. Long-term follow-up of patients with phenylketonuria treated with tetrahydrobiopterin: A seven-year experience. Orphanet J Rare Dis. February 2015;10:14. 12. Pauling L. Orthomolecular psychiatry. Varying the concentrations of substances normally present in the human body may control mental disease. Science. 1968;160(3825):265-271. 13. Ames BN, Elson-Schwab I, Silver EA. High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): Relevance to genetic disease and polymorphisms. Am J Clin Nutr. 2002;75(4):616-658. 14. Wilcken B. Treatments for rare diseases: Molybdenum cofactor deficiency. Lancet. September 3, 2015. pii: S0140-6736(15)00125-7. 15. Cohen HJ, Fridovich I, Rajagopalan KV. Hepatic sulfite oxidase. A functional role for molybdenum. J Biol Chem. 1971;246(2):374-382. 16. Johnson JL, Hainline BE, Rajagopalan KV. Characterization of the molybdenum cofactor of sulfite oxidase, xanthine, oxidase, and nitrate reductase. Identification of a pteridine as a structural component. J Biol Chem. 1980;255(5):1783-1786. 17. Moriwaki Y, Yamamoto T, Higashino K. Distribution and pathophysiologic role of molybdenum-containing enzymes. Histol Histopathol. 1997;12(2):513-524. 18. Sievers E, Dorner K, Garbe-Schonberg D, Schaub J. Molybdenum metabolism: Stable isotope studies in infancy. J Trace Elem Med Biol. 2001;15(2-3):185-191. 19. Reiss J, Johnson JL. Mutations in the molybdenum cofactor biosynthetic genes MOCS1, MOCS2, and GEPH. Hum Mutat. 2003;21(6):569-576. 20. Yoshida M, Nakagawa M, Hosomi R, Nishiyama T, Fukunaga K. Low molybdenum state induced by tungsten as a model of molybdenum deficiency in rats. Biol Trace Elem Res. 2015;165(1):75-80.
Bland—Creating Synthesis
When Is a Rare Disease Not so Rare? Implications for Medical Nutrition Therapy Jeffrey Bland, PhD, Associate Editor
Jeffrey Bland, PhD, is the president and founder of the Personalized Lifestyle Medicine Institute in Seattle, Washington. He has been an internationally recognized leader in nutrition medicine for more than 25 years. Dr Bland is the cofounder of the Institute for Functional Medicine (IFM) and is chairman emeritus of IFM’s Board of Directors. He is the author of the 2014 book The Disease Delusion: Conquering the Causes of Chronic Illness for a Healthier, Longer, and Happier Life.
R
ecently, I had a conversation with a master clinician and teacher who is a living legend in the functional medicine world, Dr Sidney Baker. As we talked, he reminded me of another discussion we had had—one that took place more than 25 years ago. That discussion related to a patient of Dr Baker’s, an individual who had a chronic fat digestion problem that seemed intractable: All the traditional diagnostic tests had come back with no definitive diagnosis and the use of pancreatic enzyme supplements did not seem to alleviate the symptoms. Dr Baker reminded me that I suggested he read an article describing the role that taurine has in the synthesis of bile acids. This article described how defects in bile acid synthesis were found in some children to be a result of genetic alterations in the conjugation of taurine with bile salts, thereby resulting in a functional bile acid deficiency.1,2 Following our conversation all those many years ago, Dr Baker tried taurine supplementation in his patient, and this individual’s chronic digestive problem resolved permanently. In our recent discussion of this long-ago case, both Dr Baker and I observed that taurine supplementation has continued to be studied for the past 2-plus decades, and in some individuals with fat maldigestion and steatorrhea, clinical trials using 1500 to 2000 mg of taurine have demonstrated resolution of fat intolerance.3 It has recently been reported that a fat-modified enteral medical food that contains supplemental taurine and carnitine improves feeding tolerance in critically ill patients.4 Response to taurine supplementation is related to genetic uniqueness among differing individuals in bile acid synthesis. Not long after my conversation with Dr Baker, I ran into one of my former students—a woman who had taken 14
Integrative Medicine • Vol. 15, No. 1 • February 2016
the medical school biochemistry course I taught in the 1970s. She also mentioned a memory, and this one involved me discussing the relationship between zinc deficiency in infants and the skin disorder acrodermatitis enteropathica (AE). This former student, who had gone on to become a physician, saw an infant in her practice decades after my lecture who presented with an inflammation of the skin that resembled the slides I had shown—images of patients with AE treated by Dr Lucille Hurley at the University of California, Davis—so many years earlier. Dr Hurley had discovered that the cause of AE in these children resulted from feeding them cow’s milk, which contains a zinc binding protein that prevents proper zinc absorption.5 Some children have a genetic predisposition for this condition due to differences (compared with the population at large) in the way they absorb and metabolize zinc. These conversations caused me to reflect. I recognized that both conditions are rare. They also are undoubtedly related to unique genetic differences between “normal” and “dysfunctional.” But, I pondered: When does a condition go from being a more common functional disorder that varies from mild to moderate in its presentation to the more severe form of a “rare disease?” This question started swirling around my mind like bees in a hive. For the next few weeks, I seemed to come back again and again to it: When is a rare disease not so rare? I began to explore the vitamin dependent genetic metabolism diseases of infancy, such as megaloblastic anemia, which results from an inborn error of vitamin B12 metabolism; with this condition, the amount of supplementation needed varies from individual to individual, ranging from several-fold to several hundredfold the recommended intake of the vitamin to achieve adequate vitamin B12 status.6 At what point in this spectrum of differing vitamin B12 needs does a functional disorder become a rare disease? When does medical nutrition therapy become pharmacology? I came to recognize that this concern could be applied to virtually all the essential nutrients for which there are recognized clinical biomarkers for defining inadequacies.7 This question—where is the line?—can even be applied to conditions traditionally considered monogenetic metabolic disorders, such as phenylketonuria (PKU). PKU is well known to be a result of a mutation in the gene that Bland—Creating Synthesis
codes for the enzyme phenylalanine hydroxylase and regulates the conversion of the amino acid phenylalanine to tyrosine. A defect in this enzyme causes phenylalanine to accumulate in the tissues to the point of toxicity, while producing a tissue tyrosine deficiency. Because tyrosine is necessary as a precursor to the dopamine neurotransmitter family in the central nervous system, deficiency can result in serious effects on brain development, learning, and behavior.8 Individuals who carry the altered gene for phenylalanine hydroxylase are generally identified through a screening test given to all newborns, and the traditional course of treatment is to put the infant or child on a phenylalanine-restricted diet. What is important to understand, however, is that not all children who have PKU express the same phenotype. PKU can exist as mild, moderate, or severe phenotypes. Variations in severity are due to not only differences in homozygosity versus heterozygosity in the phenylalanine hydroxylase gene, but also other factors that control the amount and activity of the enzyme. One of these other considerations is tetrahydrobiopterin, or BH4, the cofactor for the phenylalanine hydroxylase enzyme. In children with mild to moderate PKU, studies have shown that BH4 supplementation can result in lowered plasma phenylalanine and increased tyrosine levels.9 There is now good evidence that responsiveness to BH4 supplementation is related to as many as 74 other distinct genetic alterations beyond the traditional defect in phenylalanine hydroxylase.10 Long-term follow-up studies demonstrating that children with PKU treated with tetrahydrobiopterin therapy have good clinical outcomes and that the dose required for reducing plasma phenylalanine varies considerably from one child to another have now been published.11 So when does a child have the rare disease PKU, and when does a child have a slower metabolism of phenylalanine that produces mild metabolic dysfunction? There are many more children in the category of mild to moderate forms of PKU than there are children with the classic severe form of PKU. In the case of metabolic conditions, we often study the most extreme cases of a dysfunction and call it a rare disease because its symptom profile is the most severe and most easily identified. As we learn more about how metabolism is controlled by families of genes that work as a network rather than single genes working independently, we better understand that metabolic disorders exist on a continuum, ranging from the most extreme inborn error to that of more complex genotypic states that are not seen as a “rare disease” but rather as “functional” in origin. In his landmark 1968 paper titled “Orthomolecular Psychiatry: Varying the Concentration of Substances Normally Present in the Human Body May Control Mental Disease,” I believe Dr Linus Pauling was the first to define this concept.12 Dr Pauling proposed that the functioning of the body is affected by the molecular concentrations of many substances that are normally Bland—Creating Synthesis
present, such as taurine, zinc, and tetrahydrobiopterin. He described natural metabolites and nutrient-derived substances in the body as orthomolecular substances (ortho, meaning “right” or “correct”). The optimum concentrations of these substances for specific individuals may vary greatly. Individuals who have unique genetic needs for specific orthomolecular substances may require levels of these substances greater than they can achieve in a “normal” or “average” diet and, therefore, are candidates for personalized medical nutrition therapy. Dr Bruce Ames further developed this concept in an important review paper titled “High-dose Vitamin Therapy Stimulates Variant Enzymes With Decreased Coenzyme Binding Affinity: Relevance to Genetic Disease and Polymorphisms.”13 Dr Ames points out that more than 50 human genetic diseases linked to defective enzyme function that result from known genetic mutations can be remediated or ameliorated by the administration of high doses of the vitamin component of the corresponding coenzyme that regulates the activity of the enzyme. Because all of these nutrient-related genetic diseases exist in mild to severe forms, it is possible for each of these conditions to relate to many different genetic polymorphisms with varying nutrient needs. How does this apply to understanding the difference between the need for drug treatment of a rare disease that derives from an inborn error of metabolism and a functional metabolic defect that requires medical nutrition therapy? When I opened the November 14, 2015, issue of The Lancet, a clinical example that defines the question jumped off of page 1924: “Treatments for Rare Diseases: Molybdenum Cofactor Deficiency.” This editorial describes a research study involving the treatment of a cohort of infants with molybdenum cofactor deficiency associated with the loss of activity of the enzyme sulfite oxidase, which is clinically characterized by severe and progressive neurological damage and intractable seizures.14 Until this cofactor therapy was developed, there had been no effective treatment for this condition. The early results of this pharmacological intervention in severe cases of inborn molybdenum cofactor deficiency with the precursor of the molybdenum cofactor are very encouraging and indicate the cofactor therapy (without giving the enzyme itself) is able to restore enough of the enzyme function to reduce the progression of the pathology. Clinically speaking, this protocol is similar to the treatment of PKU with the cofactor BH4 that activates the genetically modified enzyme phenylalanine hydroxylase to the extent that improved metabolism results. In a sense, these examples support the Pauling and Ames orthomolecular medicine concept. But what about cases of molybdenum cofactor uniqueness that represent a more mild form of genetic uniqueness related to molybdenum binding? It is this question that illustrates the differences between pharmacological treatment of a rare genetic metabolism Integrative Medicine • Vol. 15, No. 1 • February 2016
15
disease and a functional disorder that is responsive to medical nutrition therapy. It is known that both sulfite oxidase and xanthine oxidase require molybdenum for their activity.15,16,17 It has been shown that apparently healthy infants have different molybdenum binding activities to its cofactor18 and that there are several different genetic polymorphisms that control the synthesis of the molybdenum cofactor and its binding to molybdenum.19 It is also important to note that molybdenum can be displaced from the sulfite oxidase molybdenum cofactor by other substances, making it more dependent on the availability of molybdenum from the plasma.20 States of functional molybdenum insufficiency can therefore exist and represent an opportunity for medical nutrition therapies. In individuals with a functional molybdenum deficiency, chronic symptoms of sulfite sensitivity are often present. These symptoms may include allergic-like symptoms such as wheezing, hives, and flushing, as well as gastrointestinal issues such as upset stomach and diarrhea. Rather than a rare disease of molybdenum cofactor deficiency, this example represents a chronic sensitivity to sulfite due to slightly impaired sulfite oxidase activity. Sulfite sensitivity can be treated by either removing the exposure to sulfite containing foods or, in the case of molybdenum deficiency, repletion of molybdenum at the daily intake of 100 μg per day. The takeaway for me is that “rare” diseases often represent only the tip of an iceberg under which reside many other less-severe forms of the metabolic disturbance that are not diseases but rather varying forms of dysfunction. A continuum exists that is based on activating the enzyme that is derived from the genetic polymorphism. Likewise, there is a continuum of therapeutic choices: In less-severe forms of the condition, medical nutrition therapy is often the treatment of choice, whereas in the severe disease that results from a specific monogenetic mutation, a pharmacological approach to activating the enzyme may be the more appropriate treatment. In the not-so-distant past, a belief existed that little could be done—management of symptoms, at best—for the treatment of “genetic” disorders. Today, we have a greater opportunity to truly understand the origins of genetically related metabolic diseases and to tailor personalized therapies based on the severity of the condition and the needs of each individual patient.
16
Integrative Medicine • Vol. 15, No. 1 • February 2016
References
1. Walker S, Stiehl A, Raedsch R, Kloters P, Kommerell B. Absorption of ursoand chenodeoxycholic acid and their taurine and glycine conjugates in rat jejunum, ileum, and colon. Digestion. 1985;32(1):47-52. 2. Powell GK, Jones LA, Richardson J. A new syndrome of bile acid deficiency—a possible synthetic defect. J Pediatr. 1973;83(5):758-766. 3. Smith LJ, Lacaille F, Lepage G, Ronco N, Lamarre A, Roy CC. Taurine decreases fecal fatty acid and sterol excretion in cystic fibrosis. A randomized double-blind trial. Am J Dis Child. 1991;145(12):1401-1404. 4. Qiu C, Chen C, Zhang W, Kou Q, Wu S, et al. A fat-modified enteral formula improves feeding tolerance in critically ill patients: a multicenter, singleblind, randomized controlled trial. JPEN J Parenter Enteral Nutr. September 8, 2015. pii: 0148607115601858. 5. Eckhert CD, Sloan MV, Duncan JR, Hurley LS. Zinc binding: A difference between human and bovine milk. Science. 1977;195(4280):789-790. 6. Baumgartner MR. Vitamin-responsive disorders: Cobalamin, folate, biotin, vitamins B1 and E. Handb Clin Neurol. 2013;113:1799-1810. 7. McNulty H, Scott JM. Intake and status of folate and related B-vitamins: Considerations and challenges in achieving optimal status. Br J Nutr. 2008;99(Suppl 3):S48-S54. 8. Giovannini M, Verduci E, Salvatici E, Paci S, Riva E. Phenylketonuria: Nutritional advances and challenges. Nutr Metab (Lond). 2012;9(1):7. 9. Muntau AC, Roschinger W, Habich M, Demmelmair H, Hoffmann B, et al. Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med. 2002;347(26):2122-2132. 10. Tao J, Li N, Jia H, Liu Z, Li X, et al. Correlation between genotype and the tetrahydrobiopterin-responsive phenotype in Chinese patients with phenylketonuria. Pediatr Res. 2015;78(6):691-699. 11. Scala I, Concolino D, Della Casa R, Nastasi A, Ungaro C, et al. Long-term follow-up of patients with phenylketonuria treated with tetrahydrobiopterin: A seven-year experience. Orphanet J Rare Dis. February 2015;10:14. 12. Pauling L. Orthomolecular psychiatry. Varying the concentrations of substances normally present in the human body may control mental disease. Science. 1968;160(3825):265-271. 13. Ames BN, Elson-Schwab I, Silver EA. High-dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased K(m)): Relevance to genetic disease and polymorphisms. Am J Clin Nutr. 2002;75(4):616-658. 14. Wilcken B. Treatments for rare diseases: Molybdenum cofactor deficiency. Lancet. September 3, 2015. pii: S0140-6736(15)00125-7. 15. Cohen HJ, Fridovich I, Rajagopalan KV. Hepatic sulfite oxidase. A functional role for molybdenum. J Biol Chem. 1971;246(2):374-382. 16. Johnson JL, Hainline BE, Rajagopalan KV. Characterization of the molybdenum cofactor of sulfite oxidase, xanthine, oxidase, and nitrate reductase. Identification of a pteridine as a structural component. J Biol Chem. 1980;255(5):1783-1786. 17. Moriwaki Y, Yamamoto T, Higashino K. Distribution and pathophysiologic role of molybdenum-containing enzymes. Histol Histopathol. 1997;12(2):513-524. 18. Sievers E, Dorner K, Garbe-Schonberg D, Schaub J. Molybdenum metabolism: Stable isotope studies in infancy. J Trace Elem Med Biol. 2001;15(2-3):185-191. 19. Reiss J, Johnson JL. Mutations in the molybdenum cofactor biosynthetic genes MOCS1, MOCS2, and GEPH. Hum Mutat. 2003;21(6):569-576. 20. Yoshida M, Nakagawa M, Hosomi R, Nishiyama T, Fukunaga K. Low molybdenum state induced by tungsten as a model of molybdenum deficiency in rats. Biol Trace Elem Res. 2015;165(1):75-80.
Bland—Creating Synthesis
