Materiały źródłowe

• #1 Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4567221/

  Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism caused by the deficiency of phenylalanine hydroxylase. This deficiency leads to the accumulation of Phe and its metabolites in tissues and body fluids of PKU patients. […] The main hypothesis is that Phe and its metabolites act as neurotoxins in the brain. Some pathomechanisms involving metabolic alterations are proposed and will be discussed below. […] Over the last years, oxidative damage to macromolecules has been investigated in HPA animal models and biological samples from PKU patients. It was demonstrated that high Phe levels are associated with DNA, protein, and lipid damage, as well with decreased antioxidant defenses in phenylketonuric patients. […] The decrease of these neurotransmitters levels could be related to the effect of high Phe concentration on amino acids transport through the blood-brain barrier (BBB) (such as Tyr and tryptophan – Trp) or on enzymes involved in neurotransmitters synthesis.

• #2 Genetic etiology and clinical challenges of phenylketonuria | Human Genomics | Full Text

  https://humgenomics.biomedcentral.com/articles/10.1186/s40246-022-00398-9

  This review discusses the epidemiology, pathophysiology, genetic etiology, and management of phenylketonuria (PKU). PKU, an autosomal recessive disease, is an inborn error of phenylalanine (Phe) metabolism caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene. […] Deficiency in the PAH enzyme or, in rare cases, the cofactor tetrahydrobiopterin results in high blood Phe concentrations, causing brain dysfunction. […] PAH is a tetrameric, iron-containing monooxygenase enzyme that catalyzes the irreversible hydroxylation of Phe to form tyrosine (Tyr). The hydroxylation of Phe requires BH4 as a cofactor in a rate-limiting step. […] PAH deficiency leads to the Phe accumulation in all body tissues (including the blood) and a relative tyrosine deficiency. Untreated PKU is associated with chronic HPA, microcephaly, mental retardation, epilepsy, hypopigmentation, growth delay, and eczema.

• #2 Genetic etiology and clinical challenges of phenylketonuria | Human Genomics | Full Text

  https://humgenomics.biomedcentral.com/articles/10.1186/s40246-022-00398-9

  The resulting deficiencies are responsible for the decreased synthesis of cerebral proteins in adults with PKU and contribute to neurotransmitter deficiencies in the brain. […] The absence of TATA boxes characterizes the promoter region of the PAH gene. However, GC boxes, CCAAT boxes, CACCC boxes, two activator protein sites, partial glucocorticoid response elements, and partial cyclic AMP response elements are present. […] Pathogenic variants most often cause PKU in the PAH gene (OMIM 612,349) inherited in an autosomal recessive pattern. […] The PAH gene’s coding sequence is 1359 base pairs, which encode 452 amino acid polypeptides with a molecular weight of ~52 kDa. […] Most variants were in the central domain (59.2%), followed by the N-terminal and the C-terminal of the PAH monomer (17.5% and 5.4%, respectively).

• #3 Phenylketonuria (PKU) – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/phenylketonuria/symptoms-causes/syc-20376302

  Phenylketonuria (fen-ul-key-toe-NU-ree-uh), also called PKU, is a rare inherited disorder that causes an amino acid called phenylalanine to build up in the body. PKU is caused by a change in the phenylalanine hydroxylase (PAH) gene. This gene helps create the enzyme needed to break down phenylalanine. […] A gene change (genetic mutation) causes PKU, which can be mild, moderate or severe. In a person with PKU, a change in the phenylalanine hydroxylase (PAH) gene causes a lack of or reduced amount of the enzyme that’s needed to process phenylalanine, an amino acid. […] A dangerous buildup of phenylalanine can develop when a person with PKU eats protein-rich foods, such as milk, cheese, nuts or meat, or grains such as bread and pasta, or aspartame, an artificial sweetener.

• #3 Genetic etiology and clinical challenges of phenylketonuria | Human Genomics | Full Text

  https://humgenomics.biomedcentral.com/articles/10.1186/s40246-022-00398-9

  The resulting deficiencies are responsible for the decreased synthesis of cerebral proteins in adults with PKU and contribute to neurotransmitter deficiencies in the brain. […] The absence of TATA boxes characterizes the promoter region of the PAH gene. However, GC boxes, CCAAT boxes, CACCC boxes, two activator protein sites, partial glucocorticoid response elements, and partial cyclic AMP response elements are present. […] Pathogenic variants most often cause PKU in the PAH gene (OMIM 612,349) inherited in an autosomal recessive pattern. […] The PAH gene’s coding sequence is 1359 base pairs, which encode 452 amino acid polypeptides with a molecular weight of ~52 kDa. […] Most variants were in the central domain (59.2%), followed by the N-terminal and the C-terminal of the PAH monomer (17.5% and 5.4%, respectively).

• #4 Phenylketonuria pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Phenylketonuria_pathophysiology

  Classical PKU is caused by a defective gene for the enzyme phenylalanine hydroxylase (PAH), which converts the amino acid phenylalanine to other essential compounds in the body. A rarer form of the disease occurs when PAH is normal but there is a defect in the biosynthesis or recycling of the cofactor 5,6,7,8-tetrahydrobiopterin (BH4) by the patient. This cofactor is necessary for proper activity of the enzyme. Other, non-PAH mutations can also cause PKU. […] The PAH gene is located on chromosome 12 in the bands 12q22-q24.1. More than four hundred disease-causing mutations have been found in the PAH gene. PAH deficiency causes a spectrum of disorders including classic phenylketonuria (PKU) and hyperphenylalaninemia (a less severe accumulation of phenylalanine). […] PKU is an autosomal recessive genetic disorder, meaning that each parent must have at least one defective allele of the gene for PAH, and the child must inherit two defective alleles, one from each parent. As a result, it is possible for a parent with PKU phenotype to have a child without PKU if the other parent possesses at least one functional allele of the PAH gene; but a child of two parents with PKU will always inherit two defective alleles, and therefore the disease.

• #5

  https://journals.lww.com/ijom/fulltext/2024/04000/mutation_analysis_of_pah_gene_in_phenylketonuria.2.aspx

  There are more than 1100 different pathogenic variants in the phenylalanine hydroxylase (PAH) gene that are responsible for phenylketonuria (PKU) diseases, and the spectrum of these mutations varies in different ethnic groups. […] The introduction of pathogenic variants in the PAH gene in each ethnic group provides valuable data regarding the understanding of the pathogenesis of the disease and can be helpful for prenatal diagnosis programs. […] PKU disease is usually caused by pathogenic variants in the PAH gene (ENSG00000171759), and in rare cases, failures in genes responsible for the synthesis or recycling of tetrahydrobiopterin (BH4), a cofactor for PAH enzyme, may also lead to hyperphenylalaninaemia. […] The PAH gene that is located on chromosome 12 q22q24.1 consists of 13 exons and occupies a region of about 171 kb in length.

• #6 Phenylketonuria (PKU) | Francesca Jimena Chevarría Gómez | Elio Academy

  https://elioacademy.org/student/23/francesca-gomez

  Approximately 60% of cases of this disorder arise from a missense mutation, leading to the encoding of a different amino acid. This alteration changes the tertiary structure of the protein, rendering the active site unable to bind to the substrate and the PAH enzyme non-functional. […] Research is currently underway on new therapies for PKU, including gene therapy. Gene therapy aims to modify genes to treat diseases by repairing or replacing defective genetic material. This involves introducing a therapeutic gene into the patient’s cells using viral or non-viral vectors. […] In the case of PKU, the goal is to introduce a functional PAH gene into patients with bi-allelic pathogenic variants. Clinical trials are ongoing using viral vectors such as AAVHSC15 and AAV2/8. However, data from these trials are not yet available.

• #7 Genetics and pathophysiology of phenylketonuria (PKU)

  https://hcp.biomarin.com/en-us/pku/overview/genetics-and-pathophysiology/

  Most cases (~98%) of phenylketonuria (PKU) are caused by variants in the gene encoding the phenylalanine hydroxylase (PAH) enzyme resulting in low enzymatic activity. […] PAH defects can range from mild folding defects in the protein to absence or deficiency of PAH expression. […] As PAH catalyzes the hydroxylation of Phe to tyrosine (Tyr), PAH deficiency impairs the conversion of Phe to Tyr. This causes the amino acid Phe to build up in the blood and brain leading to a range of intellectual disabilities, as well as neurological, neuropsychiatric, and psychosocial consequences. […] Elevated Phe in the brain affects normal white matter morphology and impairs neurotransmitter synthesis. […] High and/or variable Phe levels can have neurotoxic effects on the brain.

• #8 Phenylketonuria (PKU): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/945180-overview

  Phenylketonuria (PKU), less commonly known as phenylalanine hydroxylase (PAH) deficiency, is the most common inborn error of amino acid metabolism, arising from bi-allelic pathogenic variants in the gene that encodes PAH. A deficiency of the enzyme phenylalanine hydroxylase (PAH) impairs the body’s ability to metabolize the essential amino acid phenylalanine into tyrosine in the proximal step of the metabolic pathway. This leads to accumulation of phenylalanine in body fluids, and decreased tyrosine. […] In most patients, the classic type of PKU involves a deficiency of PAH that leads to increased levels of phenylalanine in the plasma (1200 mol/L; reference range, 35-120 mol/L). Phenylalanine hydroxylase catalyzes the conversion of L-phenylalanine to L-tyrosine, the rate-limiting step in the oxidative degradation of phenylalanine. This leads to accumulation of phenylalanine, which is transaminated to phenylpyruvate and other phenylketones. Tyrosine synthesis is therefore impaired, and so tyrosine, a precursor of melanin and catecholamines, is often low, without appropriate dietary supplementation and medical management.

• #9 Clinical Pathology Glossary: Phenylketonuria | ditki medical & biological sciences

  https://ditki.com/course/pathology/glossary/developmental-process/phenylketonuria

  Classic PKU defect in phenylalanine hydroxylase. […] Malignant PKU – defect in dihydrobiopterin reductase, which requires NADPH to convert dihydrobiopterin back to tetrahydrobiopterin. […] When phenylalanine accumulates at toxic levels, it transaminates into: […] Excess of phenylalanine […] Deficiency of tyrosine.

• #10 Phenylketonuria pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Phenylketonuria_pathophysiology

  The enzyme phenylalanine hydroxylase normally converts the amino acid phenylalanine into the amino acid tyrosine. If this reaction does not take place, phenylalanine accumulates and tyrosine is deficient. Excessive phenylalanine can be metabolized into phenylketones though the minor route, a transaminase pathway with glutamate. Metabolites include phenylacetate, phenylpyruvate and phenylethylamine. […] Phenylalanine is a large, neutral amino acid (LNAA). LNAAs compete for transport across the blood brain barrier (BBB) via the large neutral amino acid transporter (LNAAT). Excessive phenylalanine in the blood saturates the transporter. Thus, excessive levels of phenylalanine significantly decrease the levels of other LNAAs in the brain. But since these amino acids are required for protein and neurotransmitter synthesis, phenylalanine accumulation disrupts brain development in children, leading to mental retardation.

• #11

  https://www.omim.org/entry/261600?search=phenylketonuria&highlight=phenylketonuria

  Most missense mutations found in PKU result in misfolding of the phenylalanine hydroxylase protein, increased protein turnover, and loss of enzymatic function. Pey et al. (2007) studied the prediction of the energetic impact on PAH native-state stability of 318 PKU-associated missense mutations, using the protein-design algorithm FoldX. For the 80 mutations for which expression analyses had been performed in eukaryotes, in most cases they found substantial overall correlation between the mutational energetic impact and both in vitro residual activities and patient metabolic phenotype. This finding confirmed that the decrease in protein stability is the main molecular pathogenic mechanism in PKU and the determinant for phenotypic outcome. Metabolic phenotypes had been shown to be better predicted than in vitro residual activities, probably because of greater stringency in the phenotyping process. All the remaining 238 PKU missense mutations compiled in the PAH locus knowledgebase (PAHdb) were analyzed, and their phenotypic outcomes were predicted on the basis of the energetic impact provided by FoldX. Residues in exons 7-9 and in interdomain regions within the subunit appeared to play an important structural role and constitute hotspots for destabilization.

• #12

  https://www.omim.org/entry/261600?search=phenylketonuria&highlight=phenylketonuria

  Waters et al. (2000) characterized 4 PKU-associated PAH mutations that change an amino acid distant from the enzyme active site. Using 3 complementary in vitro protein expression systems and 3D structural localization, Waters et al. (2000) demonstrated a common mechanism, i.e., PAH protein folding is affected, causing altered oligomerization and accelerated proteolytic degradation, leading to reduced cellular levels of this cytosolic protein. Enzyme-specific activity and kinetic properties are not adversely affected, implying that the only way these mutations reduce enzyme activity within cells in vivo is by producing structural changes which provoke the cell to destroy the aberrant protein. The mutations were chosen because of their associations with a spectrum of in vivo hyperphenylalaninemia among patients. Waters et al. (2000) concluded that their in vitro data suggests that interindividual differences in cellular handling of the mutant but active PAH proteins contributes to the observed variability of phenotypic severity.

• #13

  https://www.omim.org/entry/261600?search=phenylketonuria&highlight=phenylketonuria

  Most PAH missense mutations impair enzyme activity by causing increased protein instability and aggregation. Gjetting et al. (2001) described an alternative mechanism by which some PAH mutations may render phenylalanine hydroxylase defective. They used database searches to identify regions in the N-terminal domain of PAH with homology to the regulatory domain of prephenate dehydratase (PDH), the rate-limiting enzyme in the bacterial phenylalanine biosynthesis pathway. Naturally occurring N-terminal PAH mutations are distributed in a nonrandom pattern and cluster within residues 46-48 (amino acids GAL) and 65-69 (amino acids IESRP), 2 motifs highly conserved in PDH. To examine whether N-terminal PAH mutations affect the ability of PAH to bind phenylalanine at the regulatory domain, wildtype and 5 mutant forms (including G46S, 612349.0055; A47V, 612349.0056; and I65T, 612349.0063) of the N-terminal domain (residues 2-120) of human PAH were expressed as fusion proteins in E. coli. Binding studies showed that the wildtype form of this domain specifically binds phenylalanine, whereas all mutations abolished or significantly reduced this phenylalanine-binding capacity. The data suggested that impairment of phenylalanine-mediated activation of PAH may be an important disease-causing mechanism of some N-terminal PAH mutations.

• #14 Genetic etiology and clinical challenges of phenylketonuria | Human Genomics | Full Text

  https://humgenomics.biomedcentral.com/articles/10.1186/s40246-022-00398-9

  HPA causes neuronal dendritic outgrowth and synaptic connectivity disturbances in vitro and in vivo animal experiments. […] HPA may alter the phenotypes of oligodendrocytes from myelinating to non-myelinating, but cultured oligodendrocytes from rats with HPA can lay down normal myelin sheaths. […] Phe may impair the synthesis of cholesterol through inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase activity or other brain lipids, thereby interfering with myelin production. However, the precise molecular mechanisms underlying the white (and gray) matter disturbances associated with elevated brain Phe concentrations remain unknown. […] In HPA, Phe-mediated competition for binding to an amino acid transporter LAT1 (also known as SLCA7A5) may impair the movement of aromatic acids (i.e., Phe, Tyr, and Trp) and other LNAAs (e.g., leucine, isoleucine, valine, methionine, threonine, and histidine) into the brain across the blood-brain barrier through sodium-independent transfer.

• #15 Phenylketonuria – Wikipedia

  https://en.wikipedia.org/wiki/Phenylketonuria

  PAH deficiency causes a spectrum of disorders, including classic phenylketonuria (PKU) and mild hyperphenylalaninemia (also known as „hyperphe” or „mild HPA”), a less severe accumulation of phenylalanine. […] Excessive phenylalanine levels tend to decrease the levels of other LNAAs in the brain. As these amino acids are necessary for protein and neurotransmitter synthesis, Phe buildup triggers the development of the brain, causing intellectual disability. […] Classic PKU affects myelination and white matter tracts in untreated infants; this may be one major cause of neurological problems associated with phenylketonuria. […] It was recently suggested that PKU may resemble amyloid diseases, such as Alzheimer’s disease and Parkinson’s disease, due to the formation of toxic amyloid-like assemblies of phenylalanine.

• #16 Phenylketonuria | Nature Reviews Disease Primers

  https://www.nature.com/articles/s41572-021-00267-0

  Phenylketonuria (PKU; also known as phenylalanine hydroxylase (PAH) deficiency) is an autosomal recessive disorder of phenylalanine metabolism, in which especially high phenylalanine concentrations cause brain dysfunction. […] Given the drawbacks of these approaches, other treatments are in development, such as mRNA and gene therapy. […] Even though PAH deficiency is the most common defect of amino acid metabolism in humans, brain dysfunction in individuals with PKU is still not well understood and further research is needed to facilitate development of pathophysiology-driven treatments. […] Pathogenesis of cognitive dysfunction in phenylketonuria: review of hypotheses. […] High plasma phenylalanine decreases cerebral protein synthesis. […] Reduced tyrosine brain influx relates to reduced cerebral protein synthesis.

• #17 Phenylketonuria (PKU) – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/inherited-disorders-of-metabolism/phenylketonuria-pku

  Phenylketonuria is a disorder of amino acid metabolism that causes a clinical syndrome of intellectual disability with cognitive and behavioral abnormalities caused by elevated serum phenylalanine. The primary cause is deficient phenylalanine hydroxylase activity. […] Excess dietary phenylalanine (ie, that not used for protein synthesis) is normally converted to tyrosine by phenylalanine hydroxylase; tetrahydrobiopterin (BH4) is an essential cofactor for this reaction. When one of several gene mutations results in deficiency or absence of phenylalanine hydroxylase, dietary phenylalanine accumulates; the brain is the main organ affected, possibly due to disturbance of myelination. […] PKU is caused by one of several gene mutations that result in deficiency or absence of phenylalanine hydroxylase so that dietary phenylalanine accumulates; the brain is the main organ affected, possibly because of disturbance of myelination.

• #18 Phenylketonuria (PKU): Pathogenesis and clinical findings | Calgary Guide

  https://calgaryguide.ucalgary.ca/phenylketonuria-pku-pathogenesis-and-clinical-findings/phenylketonuria_final/

  Biallelic mutations in PAH gene on chromosome 12q23.2 […] Loss of activity/deficiency of PAH […] Inability to convert Phe to Tyr […] Buildup of Phe and its metabolites transport of Phe via LAT-1 at the blood brain barrier […] PAH, using a BH4 cofactor, converts Phe to tyrosine, which is necessary to produce epinephrine, norepinephrine, dopamine and melanin. […] (Rare inherited disorders of BH4 synthesis/recycling cause elevated Phe and neurologic symptoms.) […] PKU is screened for at birth in most developed nations. […] In early-diagnosed, continuously treated patients, ID, microcephaly and neurologic features are not expected, but there is still an increased incidence of behavioral, emotional and social problems. […] Behavioral, emotional social problems (ADHD, mood disorders, aggression, self-esteem, social competency, autonomy) […] Intellectual disability (language, memory learning skills, executive function, IQ, school performance) […] Neurological findings (tremor, shaking, seizures, poor coordination) […] Microcephaly.

• #19 Phenylketonuria (PKU): Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/945180-overview

  The mechanism by which elevated phenylalanine levels cause intellectual disability is not known, although restriction of dietary phenylalanine ameliorates this effect if initiated within a few weeks of birth. A strong relation between control of blood phenylalanine levels in childhood and intelligence quotient (IQ) is recognized. […] Phenylalanine hydroxylase requires a nonprotein cofactor termed tetrahydrobiopterin (BH4). A small percentage of children with elevated phenylalanine levels exhibit normal PAH levels/function but have a deficiency in synthesis or recycling of BH4 known as tetrahydrobiopterin deficiency. This condition is in the differential diagnosis of elevated Phe levels in a new patient, and can result from biallelic mutations in the GCH1, PCB1, PTS, or QDPR genes. The BH4 cofactor is also required for hydroxylation of tyrosine (a precursor of dopamine) and tryptophan (a precursor of serotonin). Thus, individuals with BH4 cofactor deficiency can have additional neurologic problems that are not fully corrected by dietary phenylalanine reduction alone, but often require additional treatments that may not be fully effective.

• #20 Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4567221/

  Increased levels of Phe and related metabolites were also associated with impaired biosynthesis of antioxidants enzymes in PKU, connecting the impaired protein synthesis induced by Phe to disruption of redox homeostasis. […] In this context, energy metabolism impairment was reported in HPA animal models and patients. Significant decrease of succinate dehydrogenase (EC # 1.3.5.1) and mitochondrial respiratory chain complexes I-III activities were detected in cerebral cortex of rats subjected to experimental HPA. […] Taken together, these data indicate that disturbances in cell bioenergetics homeostasis may contribute to Phe neurotoxicity observed in PKU. […] Although the pathophysiological mechanisms of the brain damage found in phenylketonuric patients are not clearly understood yet, there are many evidences of metabolic alterations both in patients and in animal models. Such alterations include bioenergetics deficit, oxidative stress, impairment of lipid and protein metabolism, and disruption of calcium homeostasis and neurotransmitter synthesis in the brain.

• #21 Phenylketonuria: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/phenylketonuria/

  Phenylketonuria (commonly known as PKU) is an inherited disorder that increases the levels of a substance called phenylalanine in the blood. […] Variants (also called mutations) in the PAH gene cause phenylketonuria. The PAH gene provides instructions for making an enzyme called phenylalanine hydroxylase. This enzyme converts the amino acid phenylalanine into other important compounds in the body. PAH gene variants result in the production of altered versions of phenylalanine hydroxylase that cannot process phenylalanine effectively. As a result, this amino acid can build up to toxic levels in the blood and other tissues. Because nerve cells in the brain are particularly sensitive to phenylalanine levels, excessive amounts of this substance can cause brain damage. […] Classic PKU, the most severe form of the disorder, occurs in people who have very low levels of phenylalanine hydroxylase activity or who have no phenylalanine hydroxylase activity at all. People with untreated classic PKU have levels of phenylalanine high enough to cause severe brain damage and other serious health problems. Variants in the PAH gene that allow the enzyme to retain some activity result in milder versions of this condition, such as variant PKU or non-PKU hyperphenylalaninemia. […] Changes in other genes may influence the severity of PKU, but little is known about these additional genetic factors.

• #22 Overview of phenylketonuria – UpToDate

  https://www.uptodate.com/contents/overview-of-phenylketonuria

  Phenylketonuria (PKU; MIM #261600) is a disorder affecting the aromatic amino acid, phenylalanine. It results from a deficiency of phenylalanine hydroxylase (PAH) and, if untreated, results in irreversible intellectual disability among other clinical symptoms. […] PKU is caused by deficiency of PAH. This results in elevated blood and urine concentrations of phenylalanine and its metabolites, phenylacetate and phenyllactate. Tyrosine concentrations are typically in the normal range, although, occasionally, low concentrations are observed. […] Complete enzyme deficiency results in classic PKU, in which serum phenylalanine plasma concentrations in an untreated, newly diagnosed newborn infant exceed 20 mg/dL (1200 micromol/L). Residual enzyme activity causes moderate PKU (phenylalanine concentrations 900 to 1200 micromol/L), mild PKU (phenylalanine concentrations 600 to 900 micromol/L), mild hyperphenylalaninemia (HPA; phenylalanine concentrations 360 to 600 micromol/L), and benign mild HPA that typically does not require treatment (phenylalanine concentrations 120 to 360 micromol/L).

• #23 Phenylketonuria (PKU) – Rare Awareness Rare Education

  https://rareportal.org.au/rare-disease/phenylketonuria-pku/

  Malignant PKU is another type of PKU caused by the deficiency of a cofactor that helps metabolism of phe. This condition is also identified via newborn blood spot screening through elevated phe and requires further tests to confirm deficiency of the cofactor. Malignant PKU is not responsive to diet; however, it is treatable with medication. […] If not diagnosed and treated early, high levels of phe in the blood from PKU can cause developmental delays noticeable in the very first year of life, neurological complications including intellectual disability, hyperactivity and poor coordination, aggressive behaviour or emotional disturbances including anxiety, and, if left untreated, severe brain damage. […] Treatment consists of a life-long strict low-protein diet. The level of protein intake from foods is based on the extent of the individuals phe tolerance. To meet protein requirements, phe-free or low phe supplements need to be taken, which are also enriched with micronutrients to prevent malnutrition. Strict compliance with diet and maintaining phe concentrations within the recommended reference ranges ensures normal development and life expectancy. When PKU is diagnosed early and treated with diet and supplementation, children can reach their full potential.

• #24 Classic phenylketonuria | Newborn Screening

  https://newbornscreening.hrsa.gov/conditions/classic-phenylketonuria

  Without a working PAH gene, your babys body cannot make this enzyme, or it makes PAH enzymes that dont work well. […] If phenylalanine is not broken down, it can build up to harmful levels. Nerve cells in the brain are very sensitive to phenylalanine levels, so high levels of phenylalanine can cause brain damage.

• #25

  https://link.springer.com/article/10.1007/BF02179142

  Comprehensive studies on structure and function of the liver (biochemical profiles, light and electron microscopy, determination of phenylalanine hydroxylase activity) were performed in children with phenylketonuria (PKU). It was established that the liver is always involved in the pathological process. […] Comparison of results obtained with peculiarities of neuropsychiatric disorders revealed a dependence of the initial manifestations and the severity of PKU on the extent of enzyme deficiency. Amino acid disorders and abnormal lipid metabolism both contribute to the genesis of cerebral lesions.

• #26 Clinical burden of illness in patients with phenylketonuria (PKU) and associated comorbidities – a retrospective study of German health insurance claims data | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1153-y

  The higher comorbid burden in PKU patients is also supported by the significantly higher proportion of patients with CCI scores 3 compared with the control population. […] The observed difference in the prevalence of cardiovascular risk factors and diseases is reflected in the pattern of prescribed agents in this PKU population: 43.8% of the PKU population were receiving cardiovascular medicine vs 37.4% of the control population. […] Our study provides a snapshot of the comorbidities present in an older population (late-diagnosed) of patients with PKU and demonstrated a significant PR vs controls for both risk factors (disorders of lipoprotein metabolism and other lipidemias) and cardiovascular disease (chronic ischemic heart disease and atherosclerosis). Further studies in older populations of PKU patients are required to confirm this association and elucidate the etiology.

• #27 Clinical burden of illness in patients with phenylketonuria (PKU) and associated comorbidities – a retrospective study of German health insurance claims data | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1153-y

  The etiology of the comorbidities identified in this study cannot be ascertained from this type of study, but several interesting hypotheses can be generated based on knowledge of the underlying condition and the associated dietary management. […] The finding that late-diagnosed PKU patients exhibit a higher prevalence of CKD compared with their matched controls is an interesting finding and there is evidence to suggest that the PKU diet also may be a factor.

• #28 Phenylketonuria (PKU) – Children’s Health Issues – Merck Manual Consumer Version

  https://www.merckmanuals.com/home/children-s-health-issues/hereditary-metabolic-disorders/phenylketonuria-pku

  Phenylketonuria is caused by a lack of the enzyme needed to convert phenylalanine to tyrosine. […] Without the enzyme that converts it to tyrosine, called phenylalanine hydroxylase, phenylalanine builds up in the blood and is toxic to the brain, causing intellectual disability. […] A phenylalanine-restricted diet should continue for life, or intelligence may decrease and neurologic and mental problems may ensue.

• #29 Phenylketonuria: Causes, Symptoms, and Diagnosis

  https://www.healthline.com/health/phenylketonuria

  PKU is a genetic condition, so it cant be prevented. However, an enzyme assay can be done for people who plan on having children. An enzyme assay is a blood test that can determine whether someone carries the defective gene that causes PKU. The test may also be done during pregnancy to screen unborn babies for PKU. […] The long-term outlook for people with PKU is very good if they follow a PKU meal plan closely and shortly after birth. When diagnosis and treatment are delayed, brain damage may occur. This can lead to intellectual disabilities by the childs first year of life. Untreated PKU can also eventually cause: delayed development, behavioral and emotional problems, neurological problems, such as tremors and seizures.

• #30 Reversal of Hypopigmentation in Phenylketonuria Mice by Adenovirus-Mediated Gene Transfer | Pediatric Research

  https://www.nature.com/articles/pr199994

  Phenylketonuria (PKU) is caused by deficiency of phenylalanine hydroxylase (PAH) in the liver. […] Patients with PKU show profound mental retardation and hypopigmentation of skin, hair, and eyes due to increased amounts of phenylalanine in body fluids. […] The hydroxylation of tyrosine, catalyzed by tyrosinase, is the first step in the formation of melanin pigment. Tyrosinase is known to be competitively inhibited by increased amounts of L-phenylalanine, thus reducing melanin production. […] The reversal of hypopigmentation in PKU mice appears to be a direct consequence of lowered phenylalanine concentrations in body fluids after gene therapy. […] The therapeutic effects of gene transfer without FK506 lasted for only 7-10 d. Reelevation of the serum phenylalanine level was preceded by acute hepatitis associated with marked mononuclear cell infiltration and pronounced elevation of serum transaminases. […] To overcome the unfavorable immune responses, we administered an immunosuppressant, FK506, to the mice receiving gene transfer. […] In summary, we were able to reverse hypopigmentation, one of the major clinical phenotypes in PKU mice, by adenovirus-mediated gene transfer.

• #31

  https://www.medschool.lsuhsc.edu/genetics/louisiana_genetics_and_hereditary_health_care_pku_.aspx

  Phenylketonuria (PKU) is a genetic condition associated with abnormally high levels of phenylalanine in the body. Elevated phenylalanine leads to increased levels of phenylketones in the blood which are excreted in the urine, thus the name phenylketonuria. […] The metabolic pathway we are dealing with in PKU is the conversion of phenylalanine into another amino acid, tyrosine. The importance of this pathway is that it removes excess phenylalanine and it enables the production of sufficient tyrosine. […] Individuals with PKU have a genetic defect in the ability to produce PAH, therefore the phenylalanine they get from their diet keeps accumulating rather than being converted to tyrosine. […] The deficiency of PAH in a person with PKU is the result of a mutation or error in the gene that instructs our cells to make PAH.

• #32

  https://www.medschool.lsuhsc.edu/genetics/louisiana_genetics_and_hereditary_health_care_pku_.aspx

  Untreated maternal PKU is associated with a very high risk of mental retardation and other birth defects (such as congenital heart disease and small head size) to the baby. […] Before newborn screening was available, the vast majority of patients with PKU suffered mental retardation. Screening for PKU started over 30 years ago and has enabled early dietary treatment and normal IQs in the vast majority of patients.

• #33 Phenylketonuria (PKU)

  https://www.cham.org/HealthwiseArticle.aspx?id=hw44745

  Phenylketonuria (PKU) is a genetic condition in which the body has trouble breaking down an amino acid called phenylalanine, which is a part of protein. […] If PKU is not treated, phenylalanine can build up in the blood and lead to intellectual disability and problems with the central nervous system (brain and spinal cord). […] PKU is passed down through families. To have the disease, a baby must get (inherit) the PKU gene from both parents. […] The main treatment for phenylketonuria (PKU) is a lifelong reduced-protein diet. […] The medicine sapropterin (Kuvan) may help lower phenylalanine levels in some children who have PKU. […] People who have PKU need to follow a reduced-protein diet throughout their lives. […] If the level builds up, it can affect your IQ and your ability to learn, think, and understand. […] Babies born to people who have high levels of phenylalanine are at risk for having a very small head, intellectual disability, growth problems, and heart problems.

• #34 Comparative Effectiveness of Treatment for Phenylketonuria | Effective Health Care (EHC) Program

  https://effectivehealthcare.ahrq.gov/products/phenylketonuria/research-protocol

  Its mechanism of action is as a cofactor of the phenylalanine hydroxylase enzyme, thus increasing the activity level of the enzyme and leading to an increase in the amount of Phe that can be converted to tyrosine. […] The role of sapropterin dihydrochloride in pregnant women with PKU is still unclear but given the benefits of the drug in other groups of patients with PKU, this is a subpopulation of patients with PKU that merits further study. […] The guidelines from a National Institutes of Health Consensus Development Conference suggest that management, in addition to traditional approaches, should include home-testing of Phe levels for pregnant woman with PKU and outreach programs for pregnant woman with PKU and women with PKU who are of childbearing age to reinforce social support and positive attitudes about a controlled diet.

• #35 Phenylketonuria: a review of current and future treatments – Al Hafid – Translational Pediatrics

  https://tp.amegroups.org/article/view/8125/html

  Enzyme replacement therapy through viral delivery of protein fusions targeting the liver has been promising in recent years. […] The BH4 loading test is considered positive when initial plasma Phe concentrations decrease by at least 30% after 8 h or by 50% after 24 h. […] Treatment with the cofactor BH4 or sapropterin in BH4 responsive PKU patients has proven successful in significantly increasing Phe tolerance allowing patients to relax their diet and in some cases discontinuing the Phe free diet altogether. […] Enzyme substitution therapy using PAL has also been suggested as a possible therapeutic approach for PKU. […] The biological half-life of PAL was approximately 21 hours in several mammalian species after a single intravenous injection, but diminished significantly upon repeated administration.

• #36 Phenylketonuria (PKU) | Texas DSHS

  https://www.dshs.texas.gov/newborn-screening-program/newborn-screening-parent-resources/phenylketonuria-pku

  PKU is an inherited condition in which the body cannot break down and use phenylalanine, one of the amino acids in protein. […] PKU cannot be cured but can be treated if a special diet is started early in the newborn period. Current research indicates that the special diet should be continued at least through adolescence and possibly throughout life. A young woman with PKU will need strictly follow the diet restrictions both prior to and during pregnancy. […] The special PKU diet provides all protein, calories, vitamins and minerals needed for normal growth and development. […] It is very important that the special PKU diet be carefully followed at all times. […] The child with PKU requires diet control and regular blood tests but is otherwise a normal child and should be treated as such. […] Successful management of PKU involves not only the parents and physician but requires the cooperation of everyone who comes in contact with the child, including relatives, neighbors, friends, babysitters, teachers, and physicians.

• #37 Phenylketonuria (PKU)

  https://lakecountyin.gov/departments/health/nursing-clinic/diseases-and-conditions/genetic-disorders/phenylketonuria-pku

  Individuals with PKU must follow a lifelong diet low in phenylalanine, avoiding high-protein foods such as meat, dairy, eggs, and nuts. […] Since PKU affects the conversion of phenylalanine to tyrosine, supplementation with tyrosine may be necessary to support normal growth and development. […] Maintaining a low-phenylalanine diet throughout life is crucial for preventing neurological damage and ensuring optimal health.

• #38 Phenylketonuria (PKU) | Boston Children’s Hospital

  https://www.childrenshospital.org/conditions/phenylketonuria-pku

  Several medications can reduce or even eliminate the need for dietary treatment. These include: Sapropterin (Kuvan), a vitamin cofactor that helps the body break down phe. Phenylalanine ammonia lyase (PAL), a replacement enzyme that also breaks down phe. Approved in 2018 for adults with PKU, it is formulated as pegvaliase (Palynziq) and injected daily under the skin.

• #39 Comparative Effectiveness of Treatment for Phenylketonuria | Effective Health Care (EHC) Program

  https://effectivehealthcare.ahrq.gov/products/phenylketonuria/research-protocol

  In addition to the low-Phe diet, many patients take amino acid supplements, vitamins, and minerals daily to replace other essential amino acids and nutrients absent from the restricted diet. […] Patients with PKU may consume protein substitutes, but like the diet, they also have a poor taste. […] Such supplementation could include large neutral amino acids (LNAAs), which primarily decrease the Phe concentration in the brain by competing with Phe for transport across the blood-brain barrier. […] LNAAs inhibit Phe influx into the brain and lower the blood Phe concentration, thereby preventing neurological damage. […] In 2007, the U. S. Food and Drug Administration (FDA) approved sapropterin dihydrochloride (Kuvan, formerly known as Phenoptin) for the treatment of PKU under the stipulation that studies continue regarding the drugs efficacy and long-term safety. Current research on sapropterin dihydrochloride, the first pharmacologic treatment for PKU, suggests that it controls Phe concentrations and increases dietary Phe tolerance, potentially allowing a relaxation of the low-Phe diet (should be used in conjunction with the diet).

• #40 Gene Therapy for PKU: Using Viral Vectors to Treat Phenylketonuria – American Gene Technologies

  https://www.americangene.com/pipeline/phenylketonuria-pku/

  Lentivirus vectors for PKU therapy permanently insert a functional PAH gene in the person’s DNA. […] Our goal is to modify liver cells with lentivirus vectors and reconstitute the capacity for phenylalanine metabolism. […] Integrating lentivirus vectors are ideally suited for permanent genetic medicines because they deliver an integrated transgene that replicates with host DNA during every cell division and the genetic medicine dose increases in proportion to growth of the liver. […] Our lentivirus vector program in PKU is designed specifically for these goals and is progressing rapidly towards clinical development.

• #41 Phenylketonuria: a review of current and future treatments – Al Hafid – Translational Pediatrics

  https://tp.amegroups.org/article/view/8125/html

  The use of self-complementary AAV vectors resulted in normalization of hyperphenylalaninemia for up to 80 weeks in both males and females. […] The use of probiotics to produce and deliver the PAL enzyme has gained more attention, and studies are ongoing regarding the safety and efficacy of this approach.

• #42 Genetically engineered probiotic for the treatment of phenylketonuria (PKU); assessment of a novel treatment in vitro and in the PAHenu2 mouse model of PKU | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176286

  Phenylketonuria (PKU) is a genetic disease characterized by the inability to convert dietary phenylalanine to tyrosine by phenylalanine hydroxylase. […] Without PAH to convert phenylalanine (phe) into tyrosine, phe and its alternative metabolites accumulate to neurotoxic levels in the blood. […] The only effective treatment for all PKU patients is restriction of dietary phe. […] Development of new technology is therefore desired to provide less expensive and more patient friendly treatments. […] Using L. reuteri as a delivery system, PAL will reach the intestine intact to catabolize phe present in the intestinal lumen reducing phe entering the blood stream from the diet. […] The results support a potential therapeutic option for engineered probiotics to treat metabolic diseases such as PKU.

• #43 Phenylketonuria: a review of current and future treatments – Al Hafid – Translational Pediatrics

  https://tp.amegroups.org/article/view/8125/html

  Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism caused by a deficiency in the hepatic enzyme phenylalanine hydroxylase (PAH). […] A deficiency in PAH or its cofactor BH4, results in the accumulation of excess phenylalanine, whose toxic effects can cause severe and irreversible intellectual disability if untreated. […] Mutations in the PAH gene result in decreased catalytic activity affecting the catabolic pathway of phenylalanine. […] Gene therapy and enzyme replacement or substitution therapy have yielded more promising data in the recent years. […] The establishment of newborn screening programs along with the prompt institution of dietary treatment has prevented intellectual disability, however, neurophysiological and neuropsychological impairments may still persist in treated PKU patients.

• #44 Phenylketonuria (PKU) | Francesca Jimena Chevarría Gómez | Elio Academy

  https://elioacademy.org/student/23/francesca-gomez

  The genetic disorder PKU is one of the most extensively studied metabolic diseases. Recent advances have led to new treatments for PKU patients, and ongoing research is expected to continue. For instance, given that many neurological symptoms in PKU are linked to phenylalanine accumulation in the brain, research could focus on improving the delivery of enzymes or therapeutic agents across the blood-brain barrier.

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