Assignment 2: Module/Week 8 You should read chapter 19 (Phenylketonuria) from your Clinical Studies in Medical Biochemistry textbook (by Rosenthal and Glew) then answer the following questions; 1. How would you justify the observation that two different patients possessing the same mutation in the PAH enzyme may exhibit very different phenotypes with respect to PA metabolism ? 2. How can you explain the observation that in some individuals with a mutation to the PAH enzyme outside the BH4-binding site show a decrease in serum PA levels when given dietary BH4 ? 3. What would you propose as the least expensive and most rapid method to identify the existence of a defect in BH4 metabolism as the cause of a patient's PKU or HPA? 4. Based on metabolic pathways, what phenotypic differences would you expect to observe between individuals suffering from either a defect in BH 4 metabolism or a defect in the PAH enzyme? 5. Based on biochemical and physiological mechanisms, how can you explain impaired brain development as a consequence of uncontrolled PKU?

Phenylketonuria

Q1. The justification of the observation of the two distinctive patients having the same mutation in PAH enzyme and exhibiting different phenotypes concerning PA metabolism.

The PAH enzyme function in the absorption of the phenylalanine combined in diet to a different amino acid used by the body to generate the brain's neurotransmitters. The body PAH gene is found on the chromosome and has 13 exons. Mutation can be natural phenotypically or pathogenic due to interference to enzyme function and structure. Several diseases that cause mutation are known in individuals with HPA and noted on the metamorphosis records for PAH. Some of the PAH mutations are said to be more severe as compared to others depending on the impact on enzyme function and structure. A vast difference in phenotype is explained in patients who are not treated, and the treated patients show an extensive difference in the biochemical and phenylalanine tolerance. The PAH action on a patient can be foreseen after the identification of the genotype, as long as mutations are expressed. The mutation analysis indicates a more comprehensive evaluation and analysis of the untreated patients' intellectual phenotypes and genotypes are possible.

Q2. The explained observation in people with mutation to the PAH enzyme away from the B4H binding site indicating a reduction in serum PA when provided with BH4

The BH4 receptive PAH shortage is a type of classical phenylketonuria. There is a mutation leading to a reduced amount of PAH enzyme. The shortage of PAH due to the mutation of PAH leads to the natural fault of PKU. The signs of the illness is a higher focus on L-Phe found in the blood serum. To decrease or avoid psychological retardation caused by the development of L-Phe's neurotoxic metabolites, patients with serious PKU should receive medication that has minimal L-Phe diet from their childhood. The effort to relate the responsiveness to BH4 with PKU genotype aims at specific mechanism significance for the subset of PAH mutations. The mutations come up in stated mutant enzymes variant with a slight required similarity for BH4 of the normal PAH phenotypes. The excess consumption of BH4, therefore, makes it potential for the changed enzymes to overpower the little binding similarity for the BH4, allowing the subsection of PAH to undertake hydroxylation reaction. The lack of an efficient PAH leads to an alternative transaminase path – the only present way for PA disposal.

Q3. The proposed method of identifying the presence of a damage in BH4 metabolism using the most rapid and less expensive way as the origin of patient’s HPA or PKU

The BH4 therapy in HPA and PKU has caused the recommendations that all the cases can be assessed by adopting the BH4 loading test. In a BH4 loading test, the infants believed to suffer from tetrahydrobiopterin deficiency are given BH4. The test is essential in differentiating other diseases from the common phenylketonuria. The level of Raised phenylalanine drops following the BH4 loading test. Sapropterin therapy can be an essential procedure for the patients only if the harmless PA levels is not accomplished by diet therapy and in a rebellious patient. Moreover, the utilization of BH4 when pregnant in the BH4 responsive expectant women is an excellent option to achieve the strict blood PA goals levels. With the greatest challenge of staying with PKU being the adherence to strict die, the treatment can permit a subset of typically mild HPA and PKU cases and a few cases of medium PKUs to minimize the demand for PA free protein diet and still obtain the goals of treatment.

Q4.  The phenotypic difference expected to be seen in people suffering from defect BH4 and PAH enzyme, focusing on metabolic pathways

The oral supplementation of PAH cofactor BH4 is the primary pharmacological therapy used by patients suffering from PKU. There is less information concerning the molecular basis of the BH4 responsiveness. There are some patients who are known to react positively to BH4 administration by significantly reducing the phenylalanine blood level. For example, treatment can be done using BH4 instead of minimal Phe in combination with the diet. Hyperphenylalanineemia can lead to the impaired combination of BH4, the core factor in tyrosine, phenylalanine, and tryptophan hydroxylation reactions. All the HPAs raised by BH4 are inherited. They account for people with high Phe levels in most populations. For people with high Phe from an environment where PAH is not common, the risk of affected people of having an illness is much higher.

Q5. The explanation of impaired brain development as a result of unrestricted PKU, focusing on psychological and biochemical mechanisms

The mutation in the PAH gene causes PKU, a disease that changes the brain cells. The broken protein enables a hazardously high amount of phenylalanine to collect in the brain, therefore poisoning the brain cells. If an individual with PKU takes in plenty of phenylalanine, the results can lead to mental retardation. Phenylalanine can be obtained in a diet that has protein. In the absence of the enzyme, phenylalanine levels develop in the body, hence infecting the central nervous system. If neurotransmitter is not made at the required level, the brain will not work properly. High blood Phe levels cause neurotransmitters disruptions like dopamine and serotonin, which are essential for memory, mood, motivation, and learning.

OUTLINE

Phenylketonuria

Thesis Statement: Phenylketonuria (PKU) is an inherent error of metabolism that outcomes in reduced breakdown of the amino acid phenylalanine. If untreated, PKU can cause behavior problems, intellectual disability, mental disorder and seizures. This paper focuses on answering the following five questions.

1. The justification of the observation of the two distinctive patients having the same mutation in PAH enzyme and exhibiting different phenotypes concerning PA metabolism.
2. The explained observation in people with mutation to the PAH enzyme away from the B4H binding site indicating a reduction in serum PA when provided with BH4
3. The proposed method of identifying the presence of a damage in BH4 metabolism using the most rapid and less expensive way as the origin of patient’s HPA or PKU
4. The phenotypic difference expected to be seen in people suffering from defect BH4 and PAH enzyme, focusing on metabolic pathways
5. The explanation of impaired brain development as a result of unrestricted PKU, focusing on psychological and biochemical mechanisms