Course:MEDG550/Student Activities/Phenylketonuria
"Phenylketonuria" (fenyl-key-tone-ureea), also known as PKU, is a condition passed on from parents to child. PKU is caused when substance called phenylalanine (Phe) is not digested properly by the body. As a result, the Phe builds up and can cause damage to the brain.[1][2] Since Phe is a component of the proteins found in our food, treatment of PKU requires decreasing the amount of protein in the diet. Early and continued diet modification is essential to prevent signs and symptoms of PKU.
Other names for PKU
- Phenylalanine hydroxylase deficiency
- PAH deficiency
Signs and Symptoms
At birth, babies with PKU will not show signs or symptoms. [2] However, if not treated, phenylalanine will build up over time in their system and may lead to the symptoms listed below. Symptoms can range in severity and can start to be seen within a few months after birth. [3]
Signs and symptoms commonly seen in untreated PKU patients: [3]
Possible Psychiatric Symptoms
- Delayed development
- Behavioral, emotional and social difficulties
- Overactive, tantrums, unable to focus
- Intellectual disability
- Psychiatric disorders
- Seizures
Possible Physical Symptoms
- Light colored skin and hair
- Musty odor to the sweat, breath and urine
- Smaller than average head size (microcephaly)
- Low bone strength
- Skin rash (eczema)
Screening and Diagnosis
In developed countries, nearly all babies with PKU will be diagnosed shortly after birth because of newborn screening. [4] [5] Newborn screening is done during the first 24-48 hours of life by pricking a baby's heel to test a small amount of blood for increased levels of phenylalanine. A positive newborn screen for high phenylalanine levels is not enough information to diagnosis a child with PKU. If your baby has a positive PKU newborn screen, additional blood or urine tests will need to be done to confirm a diagnosis of PKU. [3] [2] Genetic testing can also be done to confirm a diagnosis of PKU. [4]
Treatment and Diet
To significantly reduce the sings and symptoms of PKU, diagnosed individuals are usually put on a very low phenylalanine (low protein) diet. The ideal time to start this diet modification is in infancy, where the baby is put on phe-free formula. Throughout life, nutrient-rich formulas are included in an individual's diet so that they can receive necessary proteins without phe.
High protein foods, which generally contain high levels of phe, should be avoided. These include, but are not limited to:
- Milk
- Cheese
- Eggs
- Nuts
- Soybeans, beans, peas
- Meats (chicken, beef, pork, fish)
- Aspartame sweetener
- Beer
"Medical foods" and special nutrient products are available as alternatives made with reduced phenylalanine levels. [3] For approximately 30-50% of PKU patients, an FDA-approved supplement called sapropterin dihydrochloride, with brand name Kuvan, can improve phenylalanine break down, reducing the need for a strict diet. [6]
Canadians have access to the National Food Distribution Centre, which distributes subsidized food for PKU patients that is low in phenylalanine. Recipes are also available on their website: https://nfdc.info/home.php
Frequency by Ethnicity (live births)
Incidence of PKU varies by population.
- Canada: 1:22,000 [1]
- United States 1:10,000 [1]
- Turks: 1:2600 [7]
- Irish: 1:4500 [8]
- Northern Europe: 1:10,000 [1]
- Eastern Asia: 1:10,000 [1]
- Japanese: 1:143,000 [9]
- Finnish: 1:200,000 [1]
- Ashkenazi Jewish: 1:200,000 [1]
Genetics
Humans are made up of billions of cells and inside of these cells are molecules of DNA. Genes are small segments of DNA that contain instructions for how to make proteins, which carry out important tasks in the body. Changes in the DNA sequence of a gene are like spelling mistakes that alter the set of instructions. Depending on the type of change, this may have an impact on the protein that is produced.
PKU is caused by spelling mistakes in the PAH gene. Normally, the gene says “break down Phe” in which case the person will have proper breakdown of Phe because a protein called phenyalaline hydroxylase (PAH) is working as it should. In the case of PKU, there is a spelling mistake and this sentence now reads “break down She”. The meaning is lost and the protein doesn't work properly, leading to a buildup of Phe.
Inheritance Pattern
PKU passes through a family in an autosomal recessive pattern. Every individual has two copies of every gene in their bodies: one copy inherited from their mother and one copy inherited from their father. As an autosomal recessive disorder, both copies of the PAH gene must not be working properly in order for a person to be affected by PKU. People who have one non-working copy of PAH are referred to as "carriers". Carriers will not develop PKU because they have one copy which is still working and can make up for the gene which is not working, but there is a 50% chance that they will pass on the non-working copy to any child that they have. When two carriers have a child together, there are three possibilities for their baby:
- 25% chance that their child will inherit two working copies, one from both mother and one from father, and will be unaffected by PKU
- 50% chance that their child will inherit one working copy and one non-working copy, meaning that they will be not be affected by PKU, but will be a carrier themselves
- 25% that their child will inherit two non-working copies and will be affected by PKU
PKU affects both boys and girls equally.
Genetic Counselling
Genetic counsellors are health care professionals who are specially trained to help patients understand and adapt to genetic diagnoses. If a family member has PKU, it may be helpful to have genetic counselling in order to better understand what the implications are for you and your loved ones.
Recurrence Risk
If both parents are carriers (they both have one non-working PAH gene) the chance of having a child with PKU is 25% for each pregnancy. If a couple already has a child with PKU, this means that they are both carriers and there is a 25% chance of PKU in every future pregnancy.
If a patient with PKU has a child with a partner who is not a carrier, there is a very low chance that their baby will have PKU, but the child will be a carrier. If the partner of a PKU patient is a carrier, their child will have a 50% chance of having PKU and a 50% chance of being a carrier.
Testing Options
Carrier Testing
If the specific gene changes causing PKU in a family are known, family members can be tested to see if they are carriers. If a person with PKU wants to have a baby, their partner can have carrier testing to determine the chance of having a baby with PKU. [10]
Prenatal Testing
If the changes causing PKU in the family are known, a pregnancy can be tested to determine if the fetus has PKU. This prenatal testing can be performed through one of the following procedures:[10]
- Chorionic Villus Sampling (CVS): A sample of the placenta is taken through the belly or cervix at 11-13 weeks of pregnancy.
- Amniocentesis: A sample of the fluid surrounding the baby is taken by inserting a needle through the belly after 15 weeks of pregnancy.
These procedures have a risk of miscarriage.
Preimplantation Genetic Diagnosis
If the changes causing PKU in the family are known, the parents' embryos produced by IVF could be evaluated and only the embryo's without PKU could be used for a potential pregnancy. This would prevent having a pregnancy or child with PKU, but is a costly procedure. [10]
Women with PKU during Pregnancy
It is especially important that women with PKU stick to their strict low-phenylalanine diet during pregnancy to reduce the risk of a child with maternal PKU syndrome (MPKUS). Raised or highly variable phenylalanine levels during pregnancy can cause MPKUS in the developing baby. A baby with MPKUS can be very small, have a lower IQ, a small head (microcephaly), heart problems and other complications. [11] Moms with PKU are encouraged to still breast feed babies who do not have PKU. [3]
Psychological & Economic Considerations in the Management of PKU
- Some individuals with PKU can tolerate certain levels of Phe. This can sometimes pose difficulties when individual's are adhering to a very regulated meal plan or when they feel like they would like more food choices. It may be beneficial for individuals with PKU to see a health care professional (e.g. dietitian) regularly to discuss meal planning options in order to increase feasibility and reduce guilt after eating specific foods.
- Although a portion of the PKU diet is subsidized, individuals may face hardships when it comes to affording all of the necessary foods and management options. It may be beneficial for individuals with PKU to consider consulting a specialized social worker who can evaluate and assess their needs, living conditions, and financial circumstances in order to best support them in finding appropriate PKU resources.
Patient Resources
Vancouver Adult Metabolic Clinic
http://adultmetabolicdiseasesclinic.ca/
Canadian PKU and Allied Disorders
www.canpku.org
The US National PKU Alliance
https://npkua.org/
Children's PKU Network
http://www.pkunetwork.org/Childrens_PKU_Network/Home.html
UK National Society for PKU (NSPKU)
www.nspku.org
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Scriver CR, Kaufman S. Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly SW, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. New York, NY: McGraw-Hill; 2001:1667-724 Cite error: Invalid
<ref>tag; name "hi" defined multiple times with different content - ↑ 2.0 2.1 2.2 Jerry Vockley, Hans C. Andersson, Kevin M. Antshel, et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genetics in Medicine (2014) 16, 188–200 doi:10.1038/gim.2013.157
- ↑ 3.0 3.1 3.2 3.3 3.4 Camp KM, Parisi MA, Acosta PB, et al. Phenylketonuria Scientific Review Conference: state of the science and future research needs. Mol Genet Metab. 2014 Jun;112(2):87-122. doi: 10.1016/j.ymgme.2014.02.013. Epub 2014 Mar 6.
- ↑ 4.0 4.1 Nenad Blau. Genetics of Phenylketonuria: Then and Now. Human Mutation. Volume 37, Issue 6 June 2016 Pages 508–515
- ↑ Joseph A. Raho. 2009. The Changing Moral Focus of Newborn Screening: An Ethical Analysis by the President’s Council on Bioethics Appendix Newborn Screening: An International Survey
- ↑ Burnett JR. Sapropterin dihydrochloride (Kuvan/phenoptin), an orally active synthetic form of BH4 for the treatment of phenylketonuria. IDrugs. 2007 Nov;10(11):805-13.
- ↑ Ozalp I, Coskun T, Tokatli A, Kalkanoglu HS, Dursun A, Tokol S, Koksal G, Ozguc M, Kose R. Newborn PKU screening in Turkey: at present and organization for future. Turk J Pediatr. 2001;43:97–101
- ↑ DiLella AG, Kwok SC, Ledley FD, Marvit J, Woo SL. Molecular structure and polymorphic map of the human phenylalanine hydroxylase gene. Biochemistry. 1986;25:743–9.
- ↑ Aoki K, Wada Y. Outcome of the patients detected by newborn screening in Japan. Acta Paediatr Jpn. 1988;30:429–34
- ↑ 10.0 10.1 10.2 Debra S Regier and Carol L Greene. Phenylalanine Hydroxylase Deficiency. GeneReviews® Accessed Jan. 11, 2016
- ↑ R.R. Lenke, H.L. Levy Maternal phenylketonuria and hyperphenylalaninemia. An international survey of the outcome of untreated and treated pregnancies N. Engl. J. Med., 303 (1980), pp. 1202–1208