Phenylalanine hydroxylase deficiency in children

Phenylketonuria (PKU) is a rare inherited metabolic disorder caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH), responsible for breaking down phenylalanine to Tyrosine (Tyr). Being a rare disease, the estimated global incidence is approximately 1 in 10,000 to 15,000 live births. However, the prevalence can vary significantly by geographic region and ethnic background [23]. The incidence among Egyptians was estimated to be 1: 2638 live births, with higher rates in Lower Egypt and South Sinai [24]. This higher rate is attributed to the high rate of consanguineous marriages in the country, that reaches 35.3% on average, especially among first cousins (86%) [25].

The PAH gene is located on chromosome 12, and over 1,000 pathogenic variants have been identified in this gene eventually leading to a reduction or complete absence of functional PAH enzyme [26]. High Phe concentrations may disrupt brain development, myelination, and neurotransmitter synthesis. The transport of large neutral amino acids (LNAAs) within the brain tissue is hindered by increased Phe concentration and this explains the deficiency of dopamine and serotonin in the brain tissue of PKU patients [27].

Because of widespread ոеwborn screening programs, overt clinical manifestations of РKU are rare. Neonates are asymptomatic until the initiation of feeds containing Phe (e.g., breast milk or standard infant formula). The serious manifestations of PKU include irreversible intellectual disability, developmental delays, seizures, behavioral abnormalities, microcephaly, and eczematous rash, decreased skin pigmentation and in some cases gait abnormalities [27].

The cornerstone in the diagnosis of PKU, is the direct estimation of Phe level in blood. The most useful laboratory method for screening for PKU is tandem mass spectrometry. In addition to being a high through output method, it can measure additional amino acids including tyrosine and acylcarnitine ester. A high concentration of Phe together with elevated Phe/tyrosine ratio suggests the diagnosis of PKU [28]. Enzyme assay is not performed to confirm the diagnosis, because PΑH activity is expressed only in the liver [27].

Once the biochemical diagnosis is established, treatment should be initiated as soon as possible to avoid irreversible brain damage. Lifetime dietary restriction of Phe has been the mainstay of treatment of PKU children [27]. The diet consists of Phe-free protein substitute in addition to normal (intact) protein calculated in reference to the age and body weight of each child and adjusted according to Phe tolerance. The intact protein includes breast milk, standard infant formula in neonates or vegetarian diet in older children [29].

Rocha and Macdonald, 2016 stated that the goal of dietary management is to reduce the blood phenylalanine concentration into the treatment range of 120–360 μmol/L (2–6 mg/dL) and to provide sufficient macronutrients and micronutrients essential for normal growth [29].

Sapropterin, a biologically active synthetic form of ΒH4, was approved by the US Food and Drug Administration (FDA) in December 2007 [30]. Ѕарrοptеriո may be used as an adjunct to dietary restriction in only ΡΚU patients who are responsive to ѕарrорtеriո [31].

The prognosis of PKU patients vary significantly depending on the timing of initiation of therapy and effectiveness of treatment. Early diagnosis and strict adherence to the phenylalanine-restricted diet from a young age can greatly improve outcomes. With appropriate management, individuals with PKU can often achieve normal or near-normal intellectual and cognitive development, as well as a good quality of life.

➡️Purpose and Scope

These guidelines have been developed to standardize the delivery of services and to implement guidance on diagnosis and management of PAH deficiency in children. It provides guidance and recommendations to primary health care providers, general practitioners, general pediatricians, family medicine physicians, neonatologists, nutritionists, psychologists, and nurses aiming at preventing morbidity and neurocognitive disabilities in PAH in children.