Overview
Proteins are essential for the body´s function. They are made up of amino acids, which vary in sequence to create different proteins. There is a great variety of amino acids, but only 20 are used by humans. Among these, nine are essential amino acids that the body cannot produce on its own, including phenylalanine.1
Phenylalanine is essential for protein formation. However, only 10 to 20% of what is consumed through the diet is necessary, with the remainder being converted into tyrosine, a non-essential amino acid. The conversion occurs through an enzyme called phenylalanine dehydrogenase (PAH). The deficiency or absence of the PAH gene2 is called phenylketonuria.3
Phenylketonuria
Phenylketonuria is a rare hereditary disease in various neonatal screening programs.3 This disease is inherited recessively, which means that two mutations are needed in each PAH gene (one from the father and one from the mother) for the disease to occur. On the other hand, only a mutation in this gene makes the newborn a carrier.4, 5 It is recommended that diagnosis be early, within 48 to 72 hours, and treatment be started within the first ten days of life.2 PKU is a disease with a high degree of comorbidity where once symptoms appear, their reversal is less likely. Therefore, early treatment is essential.
PKU symptoms
The clinical presentation of the disease is diverse. It will depend on multiple factors, such as the type of mutation, the degree of deficiency of the enzyme that converts phenylalanine, and the control of phenylalanine levels in the blood (most important during the child's development stage). The age at which treatment begins and adherence determine the time and levels of PHE to which the child has been exposed during their developmental stage.7
The symptoms will vary according to the time of treatment start. There are three possible scenarios: children who have not received treatment, children with late treatment, and children with timely treatment. Although the symptoms and the degree are different, neuropsychiatric impairment is seen in all three groups.
In those children who did not receive treatment during infancy and childhood, classic symptoms are described as the presence of severe intellectual disability with a characteristic "mousy" odour, skin, and iris pigmentation, reduced hair, and eczema. Other associated symptoms are developmental delay, psychiatric symptoms, growth issues, and skin conditions.7
In those who have received a diagnosis and timely treatment, evidence has been found that they present neuropsychological symptoms such as less attention, lack of impulse control, and less cognitive flexibility.8 In addition, an association has been found between children treated promptly and ADHD.
Among the psychiatric symptoms are Autism Spectrum Disorder (ASD) and Attention Deficit Disorder with Hyperactivity (ADHD). ASD is a group of conditions that affect brain development during childhood and are characterised by impaired social interaction and repetitive patterns of interests, activities, and behaviour.9 PKU has been associated with the presence of autism in those patients with late diagnosis and treatment.10 ADHD is a condition that affects the way a person can concentrate and control their behaviour. People with ADHD may struggle to pay attention and be hyperactive (moving constantly) or impulsive (acting without thinking). Unlike ASD, it has been found that about 40% of children with PKU who have received prompt treatment develop ADHD. It indicates that both patients with early treatment and those with delayed treatment develop symptoms.11
In summary, there is a variety in the presentation of symptoms according to age and phenylalanine levels.
PKU symptoms in infants
Infants, defined as those younger than one year of age, can present with a variety of symptoms associated with phenylketonuria (PKU). These symptoms are detailed below in different categories:
Neurological symptoms
Neurological symptoms are the most common in phenylketonuria. Because the first months of life are where the most extraordinary neuronal growth occurs, a lack of treatment adherence can cause neuronal damage.12 Among the neurological symptoms are.2, 13
- Convulsion: Sudden, uncontrolled electrical disturbance in the brain that can cause changes in behaviour, movements, and consciousness
- Poor academic achievement or intellectual disability
- Muscular weakness
- Lack of growth in head size according to age
- Stiffness
- Cerebellar ataxia: A condition where coordination, balance, and speech are affected due to cerebellar problems
- Tremor or involuntary movement
- Encephalopathy: A condition characterised by confusion, memory problems, changes in behaviour, or difficulty with coordination and movement
Developmental delays
Children with untreated PKU experience global developmental delays, including language, motor, behavioural, and social outcomes. This is reflected in their IQ, which declines to 40 or lower at one year of age.14
Skin conditions
Among the conditions that affect the skin in phenylketonuria are musty sweat odour on the skin and urine, eczema or rash on the skin, and hypopigmentation including hair and eyes.6
Growth issues
Infant growth depends on environmental factors, nutrition, and health conditions. Part of the assessment of infant development involves measuring height, weight, and head circumference. In infants with PKU, there is no consensus on how the disease affects these parameters, so more studies must be carried out. However, there is a decrease in head size in those over two years of age.11, 12
Summary
Phenylketonuria (PKU) is a rare inherited disorder that affects the body's ability to process phenylalanine, an essential amino acid. Without proper treatment, PKU can lead to severe neurological and developmental problems, especially in infants. The presentation of PKU symptoms in infants varies depending on factors such as the timing and adequacy of treatment.
Due to rapid neuronal growth during the early months of life, neurological symptoms are common in infants. These symptoms may include seizures, intellectual disability, muscle weakness, growth delays, stiffness, tremors, and encephalopathy. Developmental delays also affect language, motor skills, behaviour, and social outcomes. Skin conditions such as musty sweat odour, eczema, and hypopigmentation are prevalent in PKU infants. Additionally, growth issues, including decreased head circumference, may be present.
Early diagnosis and prompt treatment within the first days of life are crucial to prevent or minimise the severity of PKU symptoms. However, some neurological and developmental impairments may persist even with timely intervention. Further research is needed to fully understand the impact of PKU on infant growth and development and to optimise treatment strategies for better outcomes.
FAQs
What is phenylketonuria?
Phenylketonuria is a rare condition in which the body cannot properly break down the phenylalanine amino acid.
How did my child get PKU?
PKU is inherited, so the individual inherits two faulty copies related to this condition, one from each parent.
What is the treatment for PKU?
Treatment involves following a diet restricted in phenylalanine while the child is growing.
What happens if phenylketonuria is left untreated?
Without treatment, individuals will experience varying degrees of irreversible neurological damage.
Can untreated phenylketonuria lead to brain damage?
Yes, untreated individuals will experience brain damage.
If I have another child, will that child have PKU?
For a child to have PKU, both parents must carry the gene. Therefore, there is a 25% chance that the next child will be born with the disease.
References
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- Elhawary NA, AlJahdali IA, Abumansour IS, Elhawary EN, Gaboon N, Dandini M, et al. Genetic etiology and clinical challenges of phenylketonuria. Hum Genomics. 2022 Jul 19;16:22.
- Fabie NAV, Pappas KB, Feldman GL. The Current State of Newborn Screening in the United States. Pediatr Clin North Am. 2019 Apr;66(2):369–86.
- van Spronsen FJ, Blau N, Harding C, Burlina A, Longo N, Bosch AM. Phenylketonuria. Nat Rev Dis Primers. 2021 May 20;7(1):1–19.
- Al Hafid N, Christodoulou J. Phenylketonuria: a review of current and future treatments. Transl Pediatr. 2015 Oct;4(4):304–17.
- Stone WL, Basit H, Los E. Phenylketonuria. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 Apr 7]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK535378/
- Ashe K, Kelso W, Farrand S, Panetta J, Fazio T, De Jong G, et al. Psychiatric and Cognitive Aspects of Phenylketonuria: The Limitations of Diet and Promise of New Treatments. Front Psychiatry. 2019 Sep 10;10:561.
- Bilder DA, Noel JK, Baker ER, Irish W, Chen Y, Merilainen MJ, et al. Systematic Review and Meta-Analysis of Neuropsychiatric Symptoms and Executive Functioning in Adults With Phenylketonuria. Dev Neuropsychol. 2016 May 18;41(4):245–60.
- Mughal S, Faizy RM, Saadabadi A. Autism Spectrum Disorder. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 Apr 12]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK525976/
- Khemir S, Halayem S, Azzouz H, Siala H, Ferchichi M, Guedria A, et al. Autism in Phenylketonuria Patients. Journal of Child Neurology [Internet]. 2016 Jan 12 [cited 2024 Apr 12]; Available from: https://journals.sagepub.com/doi/10.1177/0883073815623636
- Beckhauser MT, Beghini Mendes Vieira M, Moehlecke Iser B, Rozone De Luca G, Rodrigues Masruha M, Lin J, et al. Attention deficit disorder with hyperactivity symptoms in early-treated phenylketonuria patients. Iran J Child Neurol. 2020;14(1):93–103.
- Yildiz Celik S, Bebek N, Gurses C, Baykan B, Gokyigit A. Clinical and electrophysiological findings in patients with phenylketonuria and epilepsy: Reflex features. Epilepsy & Behavior. 2018 May 1;82:46–51.
- Sadek AA, Hassan MH, Mohammed NA. Clinical and neuropsychological outcomes for children with phenylketonuria in Upper Egypt; a single-centre study over 5 years. Neuropsychiatr Dis Treat. 2018 Oct 5;14:2551–61.
- van Vliet D, van Wegberg AMJ, Ahring K, Bik-Multanowski M, Blau N, Bulut FD, et al. Can untreated PKU patients escape from intellectual disability? A systematic review. Orphanet Journal of Rare Diseases. 2018 Aug 29;13(1):149.
- Zaffanello M, Zamboni G, Tatò L. Growth parameters in newborns with hyperphenylalaninaemia. Paediatric and Perinatal Epidemiology. 2002 Jul 1;16(3):274–7.
- Shakiba M, Alaei M, Saneifard H, Mosallanejad ASHAKIBA M, Alaei M, SANEIFARD H, MOSALLANEJAD A. Assessment of Anthropometric Indices in Patients with Phenylketonuria. Iran J Child Neurol. 2020;14(2):27–39.