What Is Phenylketonuria?

  • Deepika RanaBachelor of Dental Surgery(BDS), Dentistry , H.P.Government Dental College, IGMC Shimla.Himachal Pradesh
  • Jialu Li Master of Science in Language Sciences (Neuroscience) UCL

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A newborn brings much joy to its parents. Any parent who has a newborn and is tested soon after birth may find it distressing. Phenylketonuria, also known as PKU, is one such ailment. Phenylalanine, the tiny substance that causes PKU, is found in many foods. It's like a hidden troublemaker that can affect the brain.

Phenylalanine accumulates in the body in high amounts due to a genetic disorder known as PKU. The body needs phenylalanine for regular metabolic processes, but when levels stay consistently higher, complications might occur.

You'll learn more about PKU, including its aetiology, symptoms, diagnosis, available treatments, and the most recent developments in the field. Continue reading for a detailed description of this rare but critical illness.

Overview

PKU is an inborn error of metabolism (IEM) that is brought about by missense mutations in the phenylalanine hydroxylase (PAH) gene. PAH is responsible for catalysing the hydroxylation of phenylalanine (Phe) to tyrosine (Tyr). PKU is a member of a group of amino acids known as "toxic accumulation-IEMs," in which an amino acid or one of its metabolites is the circulating toxin.

As long as there is one functional enzyme carrying the wild-type allele, mutations in an enzyme like PAH are recessive. Tetrahydrobiopterin (BH4) acts as a cofactor in this reaction by attaching itself to the catalytic region of PAH. Liver enzymes are the primary source of PAH. PKU occurs by elevated blood Phe levels and decreased blood Tyr levels. PKU in neonates can appear normal at birth, with early signs occurring several months later.1 

PKU frequency differs throughout populations. The incidence is 350 cases per million live births, and the rate is about 4 cases per 100,000 people in the U.S. general population. PKU affects between 0.04% and 1% of the patients in intellectual disability clinics. There is a low reported incidence (1:50,000) among Black Americans.

  • The Yemenite Jewish population (1:5300)
  • Scotland (1:5300)
  • Estonia (1:8090)
  • Hungary (1:11,000)
  • Denmark (1:12,000)
  • France (1:13,500)
  • the United Kingdom (1:14,300)
  • Norway (1:14,500)
  • China (1:17,000)
  • Italy (1:17,000)
  • Canada (1:20,000)
  • Minas Gerais State in Brazil (1:20,000)
  • and the former Yugoslavia (1:25,042) are among the countries with a high incidence
  • Finland (<1:100,000) and Japan (1:125,00) have low incidences2

Pathophysiology and cause

More than a thousand mutations cause PKU, the most frequent of which is the substitution of tryptophan (Trp) for arginine (Arg) at position 408 (Arg408Trp). Mutations in PAH that cause PKU result in elevated blood levels of Phe and decreased levels of Tyr because of reduced PAH activity. Blood Phe levels greater than 1200 micromolar suggest "classic" PKU caused by the Arg408Trp mutation.

Mild PKU, with blood Phe levels between 600 and 1200 micromolar, and mild hyperphenylalaninemia, with blood Phe levels below 600 micromolar, occur by less severe mutations. Most PKU patients are compound heterozygotes, meaning they have two distinct PKU alleles. For instance, individuals with PKU may carry two severe alleles (severe/severe) or one severe allele and one mild allele (severe/moderate).

PKU's pathophysiology relates to high Phe and its metabolites, including phenylpyruvate, a keto acid. Due to Tyr's significance as a precursor to the catecholamine neurotransmitters adrenaline, norepinephrine, and dopamine, decreased Tyr levels may also have severe effects. Tyr is also a precursor of melanin, the skin pigment. Less melanin production and pale skin and hair can result from less Tyr.

Uncertainty exists regarding the specific molecular pathophysiological pathways behind the cognitive impairment in PKU. One potential underlying cause for the neurodegeneration seen in PKU patients is increased oxidative stress. Affected neurotransmitter metabolism, reduced brain protein synthesis, and energetics are additional pathways enabling PKU pathogenesis.1

Signs and symptoms

At birth, children with untreated PKU appear normal. But around three or six months of age, infants start to get bored in their environment. Developmentally delayed and with decreased pigmentation on their skin by the time they turn one year old, the children suffer from the disorder.

The following representation illustrates how signs and symptoms fall into categories.

Created by: Deepika Rana (Canva)

Cognitive issues

  • Intellectual disabilities
  • Learning difficulties

Neurological symptoms

Physical signs

  • Skin rashes similar to eczema
  • A musty odour that results from the body's excess phenylalanine in the urine, breath, or skin
  • Because the body is unable to convert phenylalanine into melanin, the pigment responsible for an individual's colour, the result is fair skin and blue eyes
  • Hair loss
  • Increased incidence of keratosis pilaris
  • Decreased number of pigmented nevi
  • Scleroderma like plaques
  • Increased incidence of pyogenic infections

Behavioural problems

  • Attention deficits
  • Irritability

Developmental delays

Hyperactivity

Diagnosis

PKU diagnosis entails the following steps:

Prenatal diagnosis

Early in pregnancy, foetuses with classical PKU can be successfully detected using Polymerase chain reaction (PCR) in conjunction with amniocentesis.6

Newborn screening

In the United States, PKU is detected through the state newborn screening programme, which uses tandem mass spectrometry (MS/MS) to analyse the Phe/Tyr molar ratio on a filter paper blood spot (from a heel prick). Typically, this test follows a day or two after birth. Babies with high blood Phe may also have a BH4 deficit, which can cause elevated Phe levels.1

Laboratory studies

Evaluating blood samples during the first week of life. Repeat screening is necessary for children with PKU due to the wide range of phenylalanine concentrations over 24 hours. The quickest and easiest way to diagnose phenylketonuria is still to measure the amount of phenylpyruvic acid in the urine. Although 2-4 dinitrophenylhydrazine, which parallels the ferric chloride response, can be used to confirm this, ferric chloride is the most accessible reagent in the typical laboratory.

Urine tests, such as the ferric chloride test, are rarely performed in modern medicine and may yield negative results in the first month of life. Urine neopterin and biopterin levels, as well as erythrocyte dihydropteridine reductase, should be measured.2,7

Magnetic resonance imaging (MRI)

According to preliminary data, brain phenylalanine levels can be measured using cranial magnetic resonance spectroscopy (MRS), and these levels may be more predictive of outcome than blood phenylalanine levels. Nevertheless, this research runs in a few centres, and there is debate over the practicality of such cutting-edge technology.2

Treatment and management

Maintaining optimum health for those with PKU requires routine monitoring with a lifetime commitment to dietary and medical restrictions. Treating and managing PKU is done by

Dietary management

A strict low-phenylalanine diet followed for life is the cornerstone of PKU treatment. For most PKU patients, the natural protein or dietary phenylalanine must be limited to 25% or less of regular consumption to keep blood phenylalanine concentrations within the target ranges recommended by the European PKU Guidelines. It necessitates avoiding or limiting all foods strong in protein, as seen in the graphic below.

Created by: Deepika Rana (Canva)

A balanced diet for an individual with PKU includes a protein substitute enhanced with all the necessary vitamins, minerals, and ± long-chain fatty acids to fulfil nutritional needs; it also promotes the consumption of fruits and vegetables that have phenylalanine levels of less than 75 mg/100 g; extra water combined with low-protein foods like pasta and bread at most meals to offer calories, fullness, and variation.

The European PKU guidelines recommend encouraging breastfeeding as a phenylalanine source rather than utilising standard infant formula. Growth and weight gain are achieved with acceptable blood phenylalanine control when combined with a baby formula free of phenylalanine.10

Medications

Large neutral amino acid consumption is beneficial for patients who resist nutritional therapy. These could inhibit phenylalanine entry into the brain by competing with it at the blood-brain barrier. They might also cause a little drop in plasma phenylalanine levels. Sapropterin, a commercially accessible and FDA-approved version of the tetrahydrobiopterin (BH4) cofactor, has been shown to significantly lower plasma phenylalanine levels in some PKU patients.

The FDA authorised pegvaliase (Palynziq), the first enzyme replacement, in May 2018 to lower phenylalanine levels in PKU-affected adults whose uncontrolled phenylalanine levels exceed 600 µmol/L. Phenylalanine ammonium lyase, an enzyme that can replace phenylalanine hydroxylase (PAH), is injected into the patient as a pegylated SC injection.2

Therapy for pregnant patients

The ideal range for maternal blood phenylalanine levels should be 2–6 mg/dL (120–360 µmol/L) by dietary management. Any time throughout pregnancy, treatment can lessen the severity of developmental delay. Before getting pregnant, assigned females at birth (AFAB) with PKU should begin a phenylalanine-restricted diet. Those who are already pregnant or thinking about getting pregnant should receive treatment in metabolic or PKU clinics.

Long-term Monitoring

Keeping track of phenylalanine levels occurs twice a week in neonates, once a week in infants, once every three weeks or biweekly in toddlers, and then once a month in adults. It is critical to keep blood phenylalanine levels within the recommended range and monitor fluctuations in these levels. Phenylalanine sampling once a week is advisable during pregnancy.2

Risk factors

The main risk factors for phenylketonuria (PKU) are associated with the condition's hereditary inheritance and are depicted in the table below:

Risk factorsReason
Inherited genetic mutationsOne mutant gene from each parent is the primary risk factor for PKU. If the PKU-causing gene mutates in both parents, the child's chances of developing the disorder are enhanced.11
EthnicityPeople with relatives from a specific region are more likely to have certain genetic illnesses, such as PKU. Gene variants inherited from common ancestors have similarities with individuals who originated in the same geographic area.

PKU is more common in Americans who are of European or Native American descent. Individuals with African, Hispanic, or Asian ancestry are far less likely to have it.3

Complications

Treatment-related subtle attention and performance deficits in planning and organising continue in treated patients. These deficiencies may impede academic achievement and are associated with phenylalanine levels. Increased risk of depression, anxiety, and inattention are just a few of the neuropsychiatric diseases that PKU patients appear to experience more frequently than people in general. Research indicates that elevated phenylalanine levels worsen these symptoms, whereas lower levels improve them.2

FAQs

Which sweetener is best avoided by those having PKU?

A sweetener called aspartame, added to food and beverages, should be avoided by those with PKU, which contains phenylalanine.4

Can you develop PKU later in life?

Despite being a childhood condition, PKU can occasionally manifest as a prevalent neurological disease with early onset symptoms at late ages.5

Are there new PKU treatments or therapies under development?

Novel approaches to treating PKU have been made possible by developments in gene therapy. The reduction of dietary protein sources, tailoring of Phe intake, and blood testing to track Phe levels are some of these. Other new strategies involve enzyme enhancement therapy (EET) using tetrahydropterin, enzyme and cell-directed therapy.8,9

Summary

Although PKU is a rare genetic disorder, people can live happy, productive lives if they receive an early diagnosis and follow dietary guidelines. Genetic counselling is advised to help families that have a history of PKU make educated decisions. PKU is difficult to manage, but it is possible to lead regular lives with the correct assistance.

References

  1. Stone WL, Basit H, Los E. Phenylketonuria. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Oct 31]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK535378/
  2. Phenylketonuria (Pku): practice essentials, background, pathophysiology. 2022 Oct 10 [cited 2023 Oct 31]; Available from: https://emedicine.medscape.com/article/947781-overview#showall
  3. What are the common symptoms of phenylketonuria (Pku)? | nichd - eunice kennedy shriver National Institute of Child Health and Human Development [Internet]. 2016 [cited 2023 Oct 31]. Available from: https://www.nichd.nih.gov/health/topics/pku/conditioninfo/symptoms
  4. Newbould E, Pinto A, Evans S, Ford S, O’Driscoll M, Ashmore C, et al. Accidental consumption of aspartame in phenylketonuria: patient experiences. Nutrients [Internet]. 2021 Feb 23 [cited 2023 Nov 1];13(2):707. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926728/
  5. Tufekcioglu Z, Cakar A, Bilgic B, Hanagasi H, Gurvit H, Emre M. Adult-onset phenylketonuria with rapidly progressive dementia and parkinsonism. Neurocase [Internet]. 2016 May 3 [cited 2023 Nov 1];22(3):273–5. Available from: https://www.tandfonline.com/doi/full/10.1080/13554794.2016.1142567
  6. Hu WM, Hsaio KJ, Cheng CY, Su TS, Wang PH, Yang ML. Prenatal diagnosis of classical phenylketonuria with polymerase chain reaction, automatic sequencing, and linkage analysis with short tandem repeats. Taiwanese Journal of Obstetrics and Gynecology [Internet]. 2005 Mar 1 [cited 2023 Nov 1];44(1):52–6. Available from: https://www.sciencedirect.com/science/article/pii/S1028455909601078
  7. Allen RJ. The detection and diagnosis of phenylketonuria. Am J Public Health Nations Health [Internet]. 1960 Nov [cited 2023 Nov 1];50(11):1662–6. Available from: https://ajph.aphapublications.org/doi/pdf/10.2105/AJPH.50.11.1662
  8. Zuñiga Vinueza AM. Recent advances in phenylketonuria: a review. Cureus [Internet]. [cited 2023 Nov 1];15(6):e40459. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10349532/
  9. Strisciuglio P, Concolino D. New strategies for the treatment of phenylketonuria(Pku). Metabolites [Internet]. 2014 Nov 4 [cited 2023 Nov 1];4(4):1007–17. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279156/
  10. MacDonald A, van Wegberg AMJ, Ahring K, Beblo S, Bélanger-Quintana A, Burlina A, et al. PKU dietary handbook to accompany PKU guidelines. Orphanet Journal of Rare Diseases [Internet]. 2020 Aug 4 [cited 2023 Nov 2];15(1):171. Available from: https://doi.org/10.1186/s13023-020-01391-y
  11. Elsevier – patient education │phenylketonuria, pediatric [Internet]. [cited 2023 Nov 3]. Available from: https://elsevier.health/en-US/preview/phenylketonuria-pediatric

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This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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Deepika Rana

Bachelor of Dental Surgery(BDS), Dentistry , H.P.Government Dental College, IGMC Shimla.Himachal Pradesh

Hi, I am Deepika Rana Dentist by profession finished my Clinical Research Certification Programme from Duke NUS Medical school, Singapore in 2022. I joined Klarity’s internship because of my ongoing desire to learn and educate others about medicine through Writing. I enjoy producing articles that give readers detailed information about a variety of ailments that can be accessed through the Health Library created by Klarity.

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