Phenylketonuria Complications

Overview

Phenylketonuria (PKU), sometimes referred to as phenylalanine hydroxylase (PAH) deficiency, is an innate metabolic error. The people affected by this condition must start treatment as a newborn and maintain it throughout their whole life. The phenylalanine hydroxylase (PAH) gene, which is responsible for catalysing the hydroxylation of phenylalanine (Phe) to tyrosine (Tyr), is the most common source of missense mutations that cause phenylketonuria (PKU), an inborn error of metabolism (IEM).¹

Epidemiology

Phenylketonuria's prevalence varies greatly around the globe. Approximately one instance per 10,000 live births occurs in Europe, yet in some regions of the continent, the rate is higher.² Due to high levels of consanguinity in the community, persistent hyperphenylalaninemia is found in roughly one out of every four thousand newborns in Northern Ireland and Turkey.^3,4 

With one instance per 100,000 people, Finland has the lowest frequency in all of Europe.⁵One case per 15,000 people is the prevalence in the USA.⁶ The frequency in Latin America ranges from roughly one case per 50,000 to one per 25,000 births; it is often higher in the southern part of the continent than in the other parts.⁷

Prevalence rates in Asia are estimated to range from approximately one per 15,000 to one per 100,000 births in some areas of China, less than one per 200,000 in Thailand, and approximately one per 70,000 births in Japan.^8,9,10 Phenylketonuria seems to be extremely rare in Africa, but moderate hyperphenylalaninemia is particularly common in Spain.^6,11

Pathophysiology

PKU is caused by more than 1000 mutations, the most frequent of which is the substitution of tryptophan (Trp) for arginine (Arg) at position 408 (Arg408Trp). PKU-causing mutations in PAH are typically caused by decreased PAH expression or activity, which raises Phe and lowers Tyr levels in the blood. The majority of PAH mutations that cause PKU are caused by PAH instability or misfolding.¹² PKU classified as "classic" when blood Phe levels are more than 1200 micromolar is caused by the Arg408Trp mutation. Less severe mutations cause moderate hyperphenylalaninemia, where blood Phe levels are less than 600 micromolar, and mild PKU when blood Phe levels range from 600 to 1200 micromolar. Phe is an essential amino acid, and its conversion to Tyr is normally well-regulated to provide sufficient levels for protein synthesis while maintaining levels sufficiently low to be non-toxic.¹²

Most PKU patients have 2 different PKU variants: They are compound heterozygotes.¹³ PKU patients can, for example, have 2 severe alleles (severe/severe) or 1 severe allele and 1 mild allele (severe/mild). It is possible that some mild PAH gene variants code for an enzyme with reduced affinity for BH4 (a Km variant) and/or an enzyme variant with increased stability and half-life as a result of BH4 binding. Some 49% of PKU patients respond to oral BH4 supplementation with a 30% decrease in blood Phe levels despite having normal levels of BH4.¹³

Importance of understanding complications for effective management

To stop permanent harm, PKU should be managed throughout life and should begin as soon as possible following diagnosis by newborn screening (NBS) such as intellectual disability and neurological damage.¹⁴ For the best results, especially in the early years of life, stringent blood Phe control is crucial in addition to initiating medication as soon as possible.¹⁵ PKU is managed by reducing dietary intake of Phe through low-protein diets and amino acid substitutions, acid supplements, as well as diets and supplements low in protein.

Many individuals with PKU find that dietary treatment strategies are ineffectual because of persistent adherence problems] or insufficient Phe-lowering effects.^16,17 Additionally, a long-term Phe restriction in diet is linked to a deficiency in vitamins and/or minerals.¹⁸ 

It is only possible to comprehend the disease's effects on specific patients and the healthcare system overall by taking into account all coexisting conditions that have an impact on individuals. PKU is frequently linked to behavioural, cognitive, and neuropsychiatric problems. However, little is known about the whole spectrum of systemic comorbidities that result from both PKU and prolonged exposure to increased blood Phe.

Complications

Neurological complications

Neurological complications in early treated AwPKU are often associated with the motor system, including ataxia, tremor, and spastic paraparesis. However, reports of visual impairment, seizures, deficits in cognitive functioning, and psychiatric manifestations have also been made, while findings are based on the literature review and patient cases the exact mechanism underlying PKU's neurological manifestations is still unknown, but most studies link it to the neuropathophysiology of the disease, which is marked by abnormal cerebral myelination, which manifests as white matter lesions, and reduced brain levels of monoaminergic neurotransmitters (serotonin, dopamine, and noradrenaline).¹⁹

Individuals who are diagnosed with PKU later in life or who have poor metabolic control during infancy typically exhibit early-onset developmental delay, impaired intellect, and/or seizures. These symptoms may or may not be accompanied by additional neurological symptoms or indications.²⁰ Neurological abnormalities, including tremors, ataxia, seizures, paraparesis, stereotypies, and tics, can recur in adulthood if these patients are detected and treated during childhood.²¹ Certain late-onset problems have the potential to be extremely debilitating and to develop over time in both late-diagnosed and early-treated AwPKU cases after early treatment termination in childhood or adolescence.²²

Untreated PKU in children can result in severe intellectual and developmental deficits (IDDs), behavioural issues, and seizures.²³

Individuals with PKU who do not consume certain foods may experience mood swings and have delayed information processing.^24,25 

Resuming a PKU diet may help adults with high phenylalanine levels enhance their mental health and mitigate any potential harm to their central nervous systems.

Pregnancy complications

PKU pregnant women who do not adhere to a strict low-phenylalanine diet run the risk of giving birth to a child who has severe health issues, such as low birth weight, heart defects, microcephaly, or IDDs.²⁶ Pregnancy loss is more common in women with PKU who have uncontrolled phenylalanine levels.²³

Musculoskeletal complications

As a whole, the scant evidence indicates that kids with PKU have lower backbone mineral density (BMD) in comparison to kids in good health. Existing research, however, is unable to determine whether a higher incidence of clinical or morphometric vertebral fractures in childhood or later life is caused by lower spine BMD. Furthermore, it is unknown what causes low BMD in PKU.²⁷

Obesity 

Children and adolescents with phenylketonuria frequently experience excess weight. It is mostly brought on by a sedentary lifestyle and insufficient food consumption. To prevent related chronic diseases and to promote health by promoting ongoing good eating habits and regular exercise, it is crucial to identify nutritional abnormalities in children and adolescents with phenylketonuria as soon as possible.²⁸

Reproductive health

Many PKU women have unmet needs related to their sexual and reproductive health. Fears of becoming pregnant are common starting in adolescence, and for some women, these worries ultimately result in their decision to forgo having children. Interventions are required to help ensure healthy pregnancies and lessen the psychological effects of the mother’s PKU syndrome risk. Women with PKU's postpartum experiences are concerned.²⁹

Social factors

Major challenges that are challenging to overcome with traditional dietary control include socialization limitations, the impression of social isolation, and dietary stigma.²⁹

Cardiovascular complications

This study demonstrates that adult PKU patients have conventional risk markers for cardiovascular disease, such as elevated blood pressure, obesity, and an atherogenic lipoprotein profile. Furthermore, we observed substantial endothelial dysfunction, increased vascular stiffness, raised biochemical markers of inflammation and oxidative stress, and an increase in resting heart rate. The current plasma Phe concentrations show that dietary adherence modified risk factors and biochemical indicators (triglycerides, non-HDLc, HDL2c, and LDLc/HDLc).³⁰

Dermatological complications

Dermatological complications regarding skin and hair: The most defining cutaneous manifestation of PKU is the condition caused by a reduction in melanin production. While not all untreated individuals are fair, it can be particularly noticeable in Japanese and Black patients; treated people frequently exhibit usual pigmentation.

Other symptoms include eczema (including dermatitis atopic), sensitivity to light, a rise in the frequency of pyogenic infections, elevated keratosis pilaris incidence, reduced quantity of pigmented nevi and hair loss.

FAQs 

What would be the possible long-term complications of untreated PKU?

Learning problems may result from PKU if the brain and nerve system are harmed. Untreated PKU also manifests as behavioural issues, such as frequent tantrums and self-harming episodes.

How does PKU affect life expectancy?

PKU does not reduce life expectancy, either when therapy is received or not. Every state in the union requires newborns to be screened. Typically, PKU is detected by neonatal screening. If a child adheres to the diet to the letter, her outlook is excellent.

Summary

Phenylketonuria (PKU) is a genetic metabolic disorder caused by mutations in the PAH gene, leading to high levels of phenylalanine (Phe) in the blood and potential neurological and developmental complications if untreated. PKU's prevalence varies globally, with higher rates in regions with high consanguinity. Early diagnosis and strict lifelong treatment, including a low-phenylalanine diet and amino acid supplementation, are critical to prevent intellectual disability, neurological issues, and other complications. Neurological symptoms in untreated or poorly managed PKU can include developmental delays, seizures, and motor issues. Complications can also involve musculoskeletal problems, obesity, cardiovascular risks, and dermatological issues. Women with PKU face reproductive health concerns, and untreated PKU during pregnancy can lead to severe birth defects. Social isolation and dietary stigma also pose significant challenges for individuals with PKU.