A Comprehensive Exploration of Metabolism, Pathophysiology, Genetics

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About this sample


Words: 2241 |

Pages: 5|

12 min read

Published: Feb 13, 2024

Words: 2241|Pages: 5|12 min read

Published: Feb 13, 2024

Table of contents

  1. Metabolism of Phenylalanine
  2. What is phenylalanine
    Metabolism of phenylalanine
    Further metabolism of tyrosine
  3. Pathophysiology of Phenylketonuria
  4. What is Phenylketonuria
  5. Pathophysiology of PKU
  6. Genetics and Inheritance of PKU
  7. Symptoms, Diagnosis and Treatment of PKU
  8. Symptoms
  9. Explanation of the blood test results
  10. Pregnancy and PKU
  11. Breastfeeding
    Neonatal testing for metabolic disorders
  12. Conclusion

The scenario presents a 4-month pregnant female with Phenylketonuria (PKU). Due the teratogenic effects that phenylalanine has on a foetus, her GP has advised her to go on a low-protein diet. The distress that this caused to Nuria made her drastically change her eating habits to the extent that after her monthly blood test her GP got concerned. The GP then decided to refer Nuria to a PKU treatment centre for nutritional evaluation and genetic counselling.

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In the following paragraphs I will explain the following learning objectives.

  1. Unknown terms
  2. Metabolism of phenylalanine
  3. Pathophysiology of PKU
  4. Genetics and inheritance of PKU
  5. Diagnosis, Symptoms and Treatment of PKU
  6. Explanation of the Nuria’s blood test results
  7. PKU and pregnancy
  8. Neonatal test for metabolic diseases
  9. Unknown terms

Teratogenic= a term that describes a substance that may cause the disruption or abnormal development of a foetus resulting to congenital defects. The word is derived from the Greek word for monster ‘τέρας’. [Chanapa, T. (2014).]

Microcephaly= a condition where the head of the foetus is smaller than normal caused by substances that may cause brain damage in vivo including alcohol, cigarette smoking and in this case phenylalanine. [ MedicineNet. (2019).]

Mental retardation= when an individual has intellectual ability equal or less than IQ 70 together with decreased ability for independent daily function. [Webster, M. (2019) ]

Metabolism of Phenylalanine

What is phenylalanine

Phenylalanine is an essential aromatic amino acid and it is a precursor of tyrosine which in turn is a precursor of catecholamines like tyramine, dopamine, epinephrine and norepinephrine. Phenylalanine can be found in high concentrations in the brain and plasma. An average adult should digest 5-8 g of phenylalanine a day. [National Center for Biotechnology Information]

Metabolism of phenylalanine

Phenylalanine can be metabolised into tyrosine by phenylalanine hydroxylase in the presence of molecular oxygen and the coenzyme tetrahydrobiopterin (BH4) with one molecular oxygen becoming the hydroxyl group on tyrosine and the other being reduced to water. Whilst BH4 is oxidised into dihydrobiopterin (BH2) which is the regenerated via NAHD- requiring dihydropteridine reductase. [A. Harvey, R. and Ferrier, D. (2019).]

Further metabolism of tyrosine

As tyrosine is made from an essential amino acid then it constitutes a non-essential amino acid of the body. Tyrosine is the precursor of catecholamines; dopamine, norepinephrine and epinephrine. Firstly, tyrosine if hydroxylated by tyrosine hydroxylase to form 3,4-dihydroxulphenylalalnine (DOPA). Then DOPA is further decarboxylated to form dopamine via pyridoxal phosphate which is then hydroxylated to by dopamine beta-hydroxylase to produce norepinephrine. Norepinephrine is then n-methylated via S-adenosylmethionine to produce epinephrine. DOPA could be converted by tyrosinase to dopaquinone to then form melanin in the epidermis of skin, specifically in melanocytes. A further important metabolite of tyrosine is thyroid hormones. Final metabolites of phenylalanine metabolism are fumarate and acetoacetate which are used to produce energy. In the case of PKU, phenylalanine side reactions may occur producing phenylpyruvate and phenylethylamine. These by-products result in aminoaciduria meaning excess amino acid in urine. [A. Harvey, R. and Ferrier, D. (2019).]

Figure 1: A diagram showing the different metabolites arising from phenylalanine and the catalyst and by-products of each reaction. [Fernanda Schuck, et al. (2015).]

Pathophysiology of Phenylketonuria

What is Phenylketonuria

Phenylketonuria is an inherited protein metabolic disorder associated with the inability of an individual to metabolise phenylalanine resulting to the accumulation of the substance in the body due to the lack of either enzyme phenylalanine hydroxylase or dihydrobiopterin reductase. [Al Hadif, N. and Christodoulou, J. (2015).], [Pietz, J., et al . (1999).]

Pathophysiology of PKU

Since phenylalanine cannot be metabolised in the body would suggest that with a normal diet an affected individual would have increased concentration of phenylalanine in their blood plasma, which in turn is toxic for the brain. The pathophysiology of PKU is not fully understood however there are 2 models which are hypothesised [A. Dyer, C. (1999).]. One being that the increased phenylalanine concentration in the brain causes neuroxicity. The other being the lack of neurotransmitters which are produced by the metabolism of phenylalanine to tyrosine, like dopamine, could also cause the adverse effects of PKU. [Schuck, et al. (2015).]

Genetics and Inheritance of PKU

As briefly explained before PKU is an autosomal recessive disease caused by the mutation of the phenylalanine hydroxylase (PAH) which is found on chromosome 12q23.2 or from many amino mutations at the PAH locus that affect coenzyme tetrahydrobiopterin (BH4) giving rise to non- PKU HPA [Robin A Williams, J., et al. (2008).]. Inactive or less effective PAH would deter the metabolism of phenylalanine to tyrosine and its constituents. [Reference, G. (2019).]

Autosomal would suggest that it only affects the 22 non-sex chromosomes and recessive would mean that for an individual to have the phenotype for this disease he must inherit one allele from each parent [Reference, G. (2019).]. In this instance, the mother is affected as the father is not affected and is also not a carrier so the probability of the child having the disease is 0%, however there is 50% of him being a carrier. If the father was to be a carrier then the probability of the child having the disease would be 50% and being a carrier 50% as well.

Figure 2: An illustration showing the inheritance pattern of an autosomal recessive disorder when both of the parents are carriers of the faulty gene. [Plus, M. (2019).]

Symptoms, Diagnosis and Treatment of PKU


Symptoms would occur when the condition is not treated at early stages of life. The effects of phenylalanine may include brain and nervous system damage resulting in learning disabilities. Other symptoms may include: [ NHS (2019).], [NIH. (2019).]

  • Behavioural difficulties
  • Fairer skin, hair and eyes due to the decreased production of melanin
  • Eczema
  • Recurrent vomiting
  • Jerking movement in arms and legs
  • Tremors
  • Epilepsy
  • Musky smell of breath, skin and urine
  • Growth retardation
  • Microcephaly or small head size


  • New-born blood spot screening would be conducted to show increased levels of phenylalanine in the blood using tandem mass spectroscopy.
  • Genetic screening to show the presence of a mutation of PAH gene. This could be also use to explain the genetic heritance of her disease and the probability of the child having the disease. [Cindie, S. (2017).]


There is no cure for PKU, however the symptoms can be controlled with a strict dietary. This includes a low-protein diet avoiding high-protein foods. This would include: [NIH. (2019).]

  • Meat
  • Eggs
  • Nuts
  • Soybeans
  • Dairy products
  • Control of intake of other foods like potatoes and cereal

Special avoidance of aspartame as it can be metabolised in the body to phenylalanine.

Protein must not be excluded completely from the diet as phenylalanine is an essential amino acid thus cannot be metabolised by the body. As tyrosine cannot be made in the body, supplementation would be necessary.

Medication could also be prescribed like Sapropterin dihydrochloride, brand name Kuvan, is an approved treatment for PKU. Kuvan is a form of BH4 that aids the body in breaking down phenylalanine. However, a reason for a person not breaking down phenylalanine is having too little BH4. Hence, the use of Kuvan only helps certain people to reduce the amount of phenylalanine in their blood. Kuvan alone will not decrease the amount of phenylalanine to the level required and hence should be used alongside the PKU diet. [Rohr, F., et al (2004).]

Genetic counselling should be conducted in case of genetic conditions, like Nuria’s. This usually entrails: [NHS. (2016).]

How the parents should cope in case their child is affected

  • Provides information concerning the chance of other family members being carriers
  • Building a support group around the parents and the affected

The GP recommended this action due to Nuria’s fear that her child may also be affected by PKU. In this way she will be able to learn how genetic traits are passed down and the probability of her child having the disease would also dependent on her husband’s genotype.

Explanation of the blood test results

The low levels of haemoglobin (Hb), haematocrit (Hct), mean corpuscular volume (MCV) and ferritin could be linked with the drastic diet changes that Nuria implemented on herself to ensure that her child is not exposed to high levels of phenylalanine. From her test result it can be deducted that she has iron deficit which may be causing her microcytic anaemia. Due to her further protein restricted diet, she may not be able to get enough iron from her food as iron is high -protein containing foods like meat, fish and nuts. [ (2019).]

However, as folate is substituted for pregnant women, there is no decrease in folate in her blood sample.

Pregnancy and PKU

Prior to and during conception women with PKU must follow a strict PKU diet in order to protect the foetus from the teratogenic effects of high maternal blood phenylalanine which can be transferred to the foetus via the placenta. Dietary management alongside new-born screening have greatly decreased the morbidity of untreated PKU in infancy. Thus, Phenylalanine levels should be measured 2 to 3 times a week together with amino acid, vitamins, mineral and trace element. Tyrosine should be also supplemented together with various vitamins and minerals. Ultrasound scans could be used to check for microcephaly however the definition of microcephaly is controversial as there is no clear definition of the term. [R. Carol, M., et al. (2018)].


Levels of Phenylalanine in breastmilk for affected women is higher than normal. However, their breastfed infants should have a normal phenylalanine level so no adverse effects can be caused from breast feeding if the child is not affected by the disease. [ (2015).]

Neonatal testing for metabolic disorders

A complete examination needs to be carried out within 72 hours of births. This would include checking the baby’s eyes with a torch to assess movement, heart for any abnormal heart sound like murmur and their hips to check for their joints, which if left untreated could cause permanent joint problems in the future.

A hearing test would also be conducted by health care professional before the baby is discharged or 4-5 weeks after birth. Hearing defects may affect baby’s development, so early diagnosis is needed for the increase probability of developing language, speech and communication skills.

As previously mentioned, a blood sample wold be required to test PKU. This involves a health care professional bricking the heel of the baby to get 4 drops of blood on to a special card. Then the blood can be tested for 9 rare serious conditions including:

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  • Sickle cell disease
  • Cystic fibrosis
  • Congenital hypothyroidism
  • Phenylketonuria (PKU)
  • Medium-chain Acyl-CoA Dehydrogenase Deficiency (MCADD)
  • Maple Syrup Urine Disease (MSUD)
  • Isovaleric Acidaemia (IVA)
  • Glutaric Acidria Type 1 (GA1)
  • Homocystinuria (HCU) [NHS. (2018).]


In conclusion, this scenario emphasises the need for people affected by PKU to seriously monitor their diet in order to combat the adverse effects that increase phenylalanine would have in their body. Especially for expecting mothers, like Nuria, as due to her fear that her condition may affect her child, she exposed herself to anaemia. In cases like this special treatment centres would be necessary for nutritional evaluation and guidance. Genetic counselling helping the families understand the measures needed to be taken if their child is to be affected, or even to explain to them the probability of them having an affected child.


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  2. A. Harvey, R. and Ferrier, D. (2019). Biochemistry. 5th ed. Lippincott, Williams & Wilkins, pp.278-282.
  3. (2015). Management of Women With Phenylketonuria - ACOG. [online] Available at: [Accessed 18 Feb. 2019].
  4. Al Hadif, n. and Christodoulou, J. (2015). Phenylketonuria: a review of current and future treatments. [online] PubMed Central (PMC). Available at: [Accessed 18 Feb. 2019].
  5. Chanapa, T. (2014). Teratogens | The Embryo Project Encyclopedia. [online] Available at: [Accessed 18 Feb. 2019].
  6. Cindie, S. (2017). Phenylketonuria: Causes, Symptoms, and Diagnosis. [online] Healthline. Available at: [Accessed 18 Feb. 2019].
  7. (2019). Foods to Fight Iron Deficiency. [online] Available at: [Accessed 18 Feb. 2019].
  8. Fernanda Schuck, et al. (2015). Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations. Aging and Disease, 6(5), p.390.
  9. MedicineNet. (2019). Microcephaly Prognosis, Causes, Symptoms, and Diagnosis. [online] Available at: [Accessed 18 Feb. 2019].
  10. National Center for Biotechnology Information. PubChem Compound Database; CID=6140, (accessed Feb. 18, 2019)
  11. NHS. (2016). Genetic testing and counselling. [online] Available at: [Accessed 18 Feb. 2019].
  12. NHS. (2019). Phenylketonuria. [online] Available at: [Accessed 18 Feb. 2019].
  13. (2018). Newborn blood spot test. [online] Available at: [Accessed 18 Feb. 2019].
  14. NIH. (2019). How do health care providers diagnose phenylketonuria (PKU)?. [online] Available at: [Accessed 18 Feb. 2019].
  15. NIH. (2019). What are common symptoms of phenylketonuria (PKU)?. [online] Available at: [Accessed 18 Feb. 2019].
  16. NIH. (2019). What are common treatments for phenylketonuria (PKU)?. [online] Available at: [Accessed 18 Feb. 2019].
  17. (2019). Phenylketonuria Etiology - Epocrates Online. [online] Available at: [Accessed 17 Feb. 2019].
  18. Pietz, J., et al . (1999). Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. Journal of Clinical Investigation, 103(8), pp.1169-1178.
  19. Plus, M. (2019). Autosomal recessive: MedlinePlus Medical Encyclopedia. [online] Available at: [Accessed 18 Feb. 2019].
  20. R. Carol, M., et al. (2018). Phenylketonuria in pregnancy. [online] Obstetrics & Gynaecology. Available at: [Accessed 18 Feb. 2019].
  21. Reference, G. (2019). Phenylketonuria. [online] Genetics Home Reference. Available at: [Accessed 18 Feb. 2019].
  22. Reference, G. (2019). What are the different ways in which a genetic condition can be inherited?. [online] Genetics Home Reference. Available at: [Accessed 18 Feb. 2019].
  23. Robin A Williams, J., et al. (2008). Phenylketonuria: An Inborn Error of Phenylalanine Metabolism. [online] PubMed Central (PMC). Available at: [Accessed 18 Feb. 2019].
  24. Rohr, F., et al (2004). The Resource Mothers Study of Maternal Phenylketonuria: Preliminary findings. Journal of Inherited Metabolic Disease, [online] 27(2), pp.145-155. Available at: [Accessed 17 Feb. 2019].
  25. Schuck, et al. (2015). Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations. Aging and disease. 6. 390-9. 10.14336/AD.2015.0827.
  26. Webster, M. (2019). Definition of MENTAL RETARDATION. [online] Available at: [Accessed 18 Feb. 2019].   
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A Comprehensive Exploration of Metabolism, Pathophysiology, Genetics. (2024, February 13). GradesFixer. Retrieved May 29, 2024, from
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