Availability of Medical Foods and Dietary †Free Samples to Students

Question: Discuss about the Availability of Medical Foods and Dietary. Answer: Introduction: During early 1900s, Sir Archibald Garrod realised that the genetic disease in human results from certain enzymatic deficiency. The enzymatic deficiency results from the recessive traits which are inherited in a Mendelian manner. Such inherited human diseases are known as Inborn Error of Metabolism, the term coined by Sir Archibald Garrod. One of the first diseases that were studied under the banner of Inborn Errors of Metabolism is Alkaptonuria or Phenylketonuria (PKU) (Voet and Voet, 2012). Phenylketonuria is one of most studies disease under the domain of Inborn Errors of Metabolism. It is disease which occurs as a result of deficiency of an enzyme known as homogenetisate dioxygenase. Homogentisate dioxygenase is an important enzyme involved in the pathway of phenylalanine catabolism. Deficiency of the enzyme Homogentisate dioxygenase prevents the breakdown of homogenetic acid, an intermediate of the phenyl alanine catabolism pathway, to dissociate into Maleylacetoacetate. This un dissociated homogenetic acid or homogentisate gets excreted through urine. Urine with high concentration of homogenetic acid exhibit black colouration and hence the disease is also known as alkaptonuria (black) or phenylketonuria (since resulting out of faulty phenyl alanine catabolism) (Voet and Voet, 2012). Classic PKU results from the deficiency of phenylalanine hydroxylase (PAH). PAH is the first enzyme involved in the phenylalanine break down and it converts Phenylalanine into Tyrosine. Victims suffering from classic PKU have lighter skin and hair colour in comparison to their siblings. This is due to the fact that tyrosine hydroxylation, the first reaction involved in the pathway of black pigment skin formation (melanine) is inhibited by the elevated levels of phenylalanine (Voet and Voet, 2012). Serial Number Name of the Enzymes 1 Phenylalanine hydroxylase 2 Aminotransferase 3 Para hydroxy phenylpyruvate dioxygenase 4 Homogentisate dioxygenase 5 Maleylacetoacetate isomerase 6 Fumaryl acetoacetate Table: List of Enzymes Involved in Phenylalanine Degradation Source: Created by author Clinical Findings on Phenylketonuria Source Key Findings Brief Explanation (Voet and Voet, 2012) Black coloration of urine along with arthiritis The persons who are suffering from Alkaptoniria are known as Alkaptonurics. They suffer no ill effects. However, they encounter severe arthritis during the later stages of their life. Moreover, their urine darkening increases at an alarming rate because of the rapid oxidation of homogenetic acid excreted in urine under the contact of atmospheric oxygen. (Voet and Voet, 2012) Mental Retardation and Excess of Phenylalanine in blood Severe mental retardation occurs during few months after birth if the disease is not detected and treated immediately. PKU is an inability to hydroxylate phenylalanine. The patients who are suffering from PKU have increased levelof blood phenylalanine or a condition known as hyperphenylalaninemia. The excess of phenylalanine is transaminated to phenylpyruvate. This high concentration of phenylalanine in blood leads to brain dysfunction Prick, Hop and Duvekot, 2012 Phenylketonuria in pregnant mothers Untreated hyperphenylalaninemia or phenylketonuria during pregnancy may result in the generation of nonphenylketonuric offspring. However, neonatal sequelae, suffers from microcephaly (protruding of the forehead), intellectual disability and congenital heart disease (CHD). Microcephaly or facial dysmorphism is evident during the first trimester of pregnancy of women with high blood concentration of phenylalanine. A proper dietary supplement to control phenylalanine concentrations can prevent this unwanted outcome among the new born. Starting treatment before conception is one of the most recommended way to fight back against this sequelae condition. Ghaziuddin and Al-Owain, 2013 Phenylketonuria results in mental dysfunction Phenylketonuria results in mental dysfunction like autism. Autism is a special spectrum of mental disorder that is characterized by high rate of social communicative deficits with restricted interests. It is rare disease occurring in about only 1% of the total population.Apart from phenylketonuria, glucose-6posphate deficiency has also been found responsible for this disease. Glucose 6-phosphate deficiency is another disease that falls under the category of inborn errors of metabolism. de Groot et al., 2013 Phenylketonuria causes cognitive brain impairment Elevated blood concentration of phenylalanine (Phe) in phenylketonuria (PKU), are thought to impair the entire transportation pathway of large neutral amino acids (LNAAs) from blood stream to the neurons of the brain. This impairment is thought to underlie the complex cognitive deficits which are common in PKU. PKU also causes reduced cerebral protein synthesis thus leading to further mental impairment. Therapy and Treatment of this Disorder Infant screening technique due to the detection of high levels phenyl alanine in blood have led to the elucidation of the deficiency of the enzyme 5,6,7,8tetrahydrobiopetrin (BH4) and PAH co-factor. In such cases, patient are externally supplied with L-3,4-dihydroxyphenyalanine (L-DOPA) and 5-hydroxytryptophan. These are the metabolic precursor of the neurotransmitters like norepinephrine and serotonin. Since tryptophan hydroxylase and tyrosine hydroxylase, the PAH homologs that produce these psychological amines require BH4 as an important cofactor. But adding BH4 alone is not enough as BH4 is largely unstable and fail to cross the blood vein barrier, restricting the chances of effective treatment (Voet and Voet, 2012; Leuretet al., 2012). In most of the cases, where the patients suffers from PKU due to the deficiency of PAH enzyme, all the tyrosine breakdown enzymes are found within the normal limits. In such cases, the treatment involves, low phenyl alanine diet along with period monitoring of phenyl alanine in blood while ensuring that it remains within the normal level during first 5 to 10 years of life. The adverse effect of hyper phenylalanineinemia tends to disappear after that age. Protein like meat, fish, eggs and dairy products are excluded from the diet plan of PKU patients. The standard diet of PKU patient is rich in low protein natural food like fruits, vegetables and cereals. This type of special dietary regime provides low polysaturated fatty acids and cholesterols. Vitamins like folates, A, C, D, E and B2, B6, B12 along with carnitine taurine, iron, zinc, selenium, calcium, are deficient in the paediatric population suffering from PKU due to the low protein content in their diet. Thus, patients with PKU require long-term dietary counselling and daily external supplement of micronutrients (Giovannini at al., 2012; Campet al., 2012). Mental retardation of facaial malformation of the offsprings arising out of the phenylketonuric mother can be effectively prevented via maintaining the blood concentration of phenylalanine. The estimate range of phenylalanine must stay in between 120 to 300 micro mole per litre. Such restricted phenyl alanine range can only be obtained via providing the mother with phenylalanine restricted diet (Teissier et al., 2012). Problems with Curing of the Disease Providing dietary supplements and giving external supply of enzyme is the only way out in the pathway of treating inborn errors of metabolism like PKU. Since the problem lies in the genetic level (recessive faulty gene) complete cure of the disease via a directed therapeutic approach is not possible. The genetic back of the metabolic pathway remains the same. The only way out is to reduce the high concentration of phenylalanine in blood in order to fight back against mental retardation and other associated problems producing debilitating outcomes during childhood. Moreover, at time PKU is not directly expressed in the offspring but they show certain kind of mental retardation which is common with the parents who have a recessive gene for PKU. In that case, if the proper treatment of the expecting mother with low phenylalanine diet is the only way out to restrict the possible chances of disease manifestation in an indirect way (Hennermann et al., 2012). Metabolic pathways can be defined as a series of enzymatic reactions occurs in a sequence based manner to produce specific end products. The intermediates or the reactants which are produced in the middle of the enzymatic reaction are known as metabolites. Since the body of any organism like humans is an interconnected array of several metabolites such that it is body of human or rather say mammals has been biochemically designed with several metabolic pathways. Metabolism can further be sub divided into two separate pathways namely Catabolism and anabolism (Voet and Voet, 2012). Catabolism: Catabolism is known as the degradation pathway. In this pathway, the nutrients are broken down into is smaller constituents via exergonic process (evolution of energy) in order to salvage the components and to generate free energy (mostly ATP or Adenosine Triphosphate) (Voet and Voet, 2012). Anabolism: Anabolism on the other hand is defined as bio synthesis pathway. In this pathway, the biomolecules unite to give rise to the final completed product (Voet and Voet, 2012). The free energy which is released via the process of catabolism is utilised in the anabolism. The energy is conserved via the synthesis of ATP from ADP (Adenosine Diphosphate) and Phoshate molecule. At times energy synthesis also occurs via the synthesis of the coenzyme NADP+ (Nucleoside Adenosine DiPhosphate) or NADPH. Thus ATP and NADPH are the two major energy source available to aid the anabolic pathways (Voet and Voet, 2012). Metabolic pathways are characterized to be exergonic in nature (reserviour of large negative free energy) and irreversible. The irreversibility of the process means, each pathway once started must proceed up to its completion since free negative energy is spontaneous. Moreover, it the two metabolites are interconvertible, the pathways from the first step tp the second step must differ from the pathway from the second step to the back (towards the first step). This is due to the fact that metabolite 1 when converted into metabolite 2, it undergoes via exergonic process. But the conversion into metabolite 2 back to metabolite 1 requires that very supply of the free energy in order to carry the reaction against the hill. Every metabolic pathway has a first committed step, if the pathway pass through that committed step then it is bound to reach up to its end product. This is due to the fact that, although most metabolic pathways are reversible, the majority of their component reactions functions close to equilibrium. All metabolic pathways are regulated and in eukaryotes, each metabolic pathway occurs in specific cellular location (Voet and Voet, 2012). Organelle Function Mitochondria Amino Acid breakdown, electron transport chain, fatty acid oxidation, citric acid cycle Cytosol Glycolysis, pentose phosphate pathway, fatty acid biosynthesis Nucleus DNA replication, transcription, RNA processing Table: Cellular Location of Specific Metabolic Pathway Source: Created by author Metabolic Breakdown of Amino Acids The degradation of amino acids converts them into citric acid cycle intermediates or any other precursor products. While inside the citric acid cycle they are metabolised into carbon dioxide (CO2) and water (H2O) or is used in the process of gluconeogeneisis. The oxidative break down of the amino acids via the catabolic pathway amounts to about 10 to 15 percentage of the total metabolic energy generated by the animals (Voet and Voet, 2012). Glucogeneic amino acids whose carbon skeletons are degraded into pyruvate, alpha ketoglutarate, succinyl coA or oxaloacetate are therefore salvaged into glucose precursors. Ketogenic amino acids on the other hand, whose carbon skeletons are broken down into acetyl CoA or acetoacetate are converted into ketone bodies or fatty acids. For example, alanine, the simplest form of amino acids is glucongenic in nature. It is transaminated into pyruvate and can be further be converted into glucose via the process of gluconeogenesis. Leucine is a ketogenic amino acid. The carbon skeleton of leucine is converted into acetyl coA and acetoacetate. Since animals do not have any specific metabolic pathway to convert acetyl coA or acetoacetate into gluconeogenic precursor, no synthesis of carbohydrate is feasible from the breakdown of these two amino acids (lysine and luceine) and hence the are known as true ketogenic amino acids. Isoleucine, phenylalanine, threonine, tryptofan and tyrosine are both glucogenic and ketogenic. For example, isoleucine is simultaneously broken down via the process of catabolism into succinyl coA and acetyl coA and hence can be regarded as a precursor of both carbohydrate and ketone bodies (Voet and Voet, 2012). References Camp, K.M., Lloyd-Puryear, M.A. and Huntington, K.L., 2012. Nutritional treatment for inborn errors of metabolism: indications, regulations, and availability of medical foods and dietary supplements using phenylketonuria as an example.Molecular genetics and metabolism,107(1), pp.3-9. Available at https://www.sciencedirect.com/science/article/pii/S1096719212002612. [Accessed 30 Sept. 2017] de Groot, M.J., Hoeksma, M., Reijngoud, D.J., de Valk, H.W., Paans, A.M., Sauer, P.J. and van Spronsen, F.J., 2013. Phenylketonuria: reduced tyrosine brain influx relates to reduced cerebral protein synthesis.Orphanet journal of rare diseases,8(1), p.133. https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-8-133[Accessed 30 Sept. 2017] Ghaziuddin, M. and Al-Owain, M., 2013. Autism spectrum disorders and inborn errors of metabolism: an update.Pediatric neurology,49(4), pp.232-236. https://www.sciencedirect.com/science/article/pii/S0887899413003433 [Accessed 30 Sept. 2017] Giovannini, M., Verduci, E., Salvatici, E., Paci, S. and Riva, E., 2012. Phenylketonuria: nutritional advances and challenges.Nutrition metabolism,9(1), p.7. Available at https://nutritionandmetabolism.biomedcentral.com/articles/10.1186/1743-7075-9-7. [Accessed 30 Sept. 2017] Hennermann, J.B., Roloff, S., Gebauer, C., Vetter, B., von Arnim-Baas, A. and Mnch, E., 2012. Long-term treatment with tetrahydrobiopterin in phenylketonuria: treatment strategies and prediction of long-term responders.Molecular Genetics and Metabolism,107(3), pp.294-301. https://www.sciencedirect.com/science/article/pii/S1096719212003629 [Accessed 30 Sept. 2017] Leuret, O., Barth, M., Kuster, A., Eyer, D., De Parscau, L., Odent, S., Gilbert-Dussardier, B., Feillet, F. and Labarthe, F., 2012. Efficacy and safety of BH4 before the age of 4 years in patients with mild phenylketonuria.Journal of inherited metabolic disease,35(6), pp.975-981. https://link.springer.com/article/10.1007/s10545-012-9464-3[Accessed 30 Sept. 2017] Nelson, D.L., 2013. i Cox, MM" Lehninger Principles of Biochemistry"(2013). Prick, B.W., Hop, W.C. and Duvekot, J.J., 2012. Maternal phenylketonuria and hyperphenylalaninemia in pregnancy: pregnancy complications and neonatal sequelae in untreated and treated pregnancies.The American journal of clinical nutrition,95(2), pp.374-382. 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