Materiały źródłowe

• #1 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. […] The PAH enzyme, expressed predominantly in the liver (but also kidney and pancreas), is responsible for the conversion of Phe to tyrosine (Tyr) in a reaction that requires the co-substrate tetrahydrobiopterin (BH4). […] Thus, a small number of cases of hyperphenylalaninaemia (HPA) are caused by defects in BH4 metabolism or pathogenetic variants in the DNAJC12 gene. […] The prevalence of PKU varies widely among ethnicities and geographic regions. Worldwide, PKU has an estimated prevalence of 1 in 23,930 live births and affects about 0.45 million individuals, of whom at least two-thirds require treatment.

• #1 Genetic etiology and clinical challenges of phenylketonuria

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9295449/

  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. […] The PAH gene, mapped to chromosome 12 (12q22q24.2), is 90 kb in length with 13 exons. PKU is genetically heterogeneous, with more than 1,000 PAH variants reported in individuals with PKU worldwide. […] 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).

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

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

  Pathogenic variants most often cause PKU in the PAH gene (OMIM 612,349) inherited in an autosomal recessive pattern. […] The PAH gene, mapped to chromosome 12q23.2, spans 90 kb and consists of 13 exons that are not equally distributed, as the exons are more condensed in the second moiety of the gene. […] 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). […] Several reports have described BH4-related genes (for example, GCH1 GTPCH, PTS, PCBD1, QDPR, and SPR genes) linked to HPA. […] Although its proportion may be underestimated, genomic large deletion and duplication (in a 12.9% and 2.1%, respectively) in the PAH gene have been described in various ethnic populations. […] Evidence supports founder variants within the PAH and BH4-related genes among various ethnic populations.

• #3 Phenylketonuria (PKU): Symptoms, Causes & Treatment

  https://my.clevelandclinic.org/health/diseases/17816-phenylketonuria

  Phenylketonuria (PKU) is a genetic condition that causes elevated levels of a substance called phenylalanine to build up in your body. […] Mutations in both copies of the PAH gene causes phenylketonuria (PKU). The PAH gene gives your body instructions to make an enzyme (phenylalanine hydroxylase) that’s responsible for converting amino acids into components (proteins) that your body can use. […] Phenylketonuria (PKU) is a genetic condition that passes to children from their parents in an autosomal recessive pattern. This means that babies receive one copy of the mutated gene that causes PKU from each parent during conception.

• #4 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. […] The PAH enzyme, expressed predominantly in the liver (but also kidney and pancreas), is responsible for the conversion of Phe to tyrosine (Tyr) in a reaction that requires the co-substrate tetrahydrobiopterin (BH4). […] Thus, a small number of cases of hyperphenylalaninaemia (HPA) are caused by defects in BH4 metabolism or pathogenetic variants in the DNAJC12 gene. […] The prevalence of PKU varies widely among ethnicities and geographic regions. Worldwide, PKU has an estimated prevalence of 1 in 23,930 live births and affects about 0.45 million individuals, of whom at least two-thirds require treatment.

• #5 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. […] 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.

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

  https://emedicine.medscape.com/article/947781-overview

  Phenylketonuria (PKU) is an autosomal recessive disorder caused by pathogenic variants in the PAH gene, which expresses PAH. […] More than 900 different mutations in the PAH gene have been identified to date, and www.biopku.org is a growing resource for genotype-phenotype correlations or descriptions. […] The PAH gene shows great allelic variation, and pathogenic mutations have been described in all 13 exons of the PAH gene and its flanking region. […] Phenylketonuria displays a marked genotypic heterogeneity, both within populations and between different populations.

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

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

  Pathogenic variants most often cause PKU in the PAH gene (OMIM 612,349) inherited in an autosomal recessive pattern. […] The PAH gene, mapped to chromosome 12q23.2, spans 90 kb and consists of 13 exons that are not equally distributed, as the exons are more condensed in the second moiety of the gene. […] 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). […] Several reports have described BH4-related genes (for example, GCH1 GTPCH, PTS, PCBD1, QDPR, and SPR genes) linked to HPA. […] Although its proportion may be underestimated, genomic large deletion and duplication (in a 12.9% and 2.1%, respectively) in the PAH gene have been described in various ethnic populations. […] Evidence supports founder variants within the PAH and BH4-related genes among various ethnic populations.

• #8 Genetic etiology and clinical challenges of phenylketonuria

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9295449/

  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. […] The PAH gene, mapped to chromosome 12 (12q22q24.2), is 90 kb in length with 13 exons. PKU is genetically heterogeneous, with more than 1,000 PAH variants reported in individuals with PKU worldwide. […] 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).

• #8 Genetic etiology and clinical challenges of phenylketonuria

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9295449/

  Several reports have described BH4-related genes (for example, GCH1 GTPCH, PTS, PCBD1, QDPR, and SPR genes) linked to HPA. […] Although its proportion may be underestimated, genomic large deletion and duplication (in a 12.9% and 2.1%, respectively) in the PAH gene have been described in various ethnic populations. […] Evidence supports founder variants within the PAH and BH4-related genes among various ethnic populations. […] Pleiotropy can be described when one gene can influence two or more seemingly unrelated phenotypic traits. […] The PAH enzyme, expressed predominantly in the liver (and kidney and pancreas), is responsible for the converting Phe to Tyr in the presence of the co-substrate tetrahydrobiopterin (BH4).

• #9

  https://omim.org/entry/261600

  The first PKU mutation identified in the PAH gene was a single base change (GT-to-AT) in the canonical 5-prime splice donor site of intron 12 (612349.0001). Gene transfer and expression experiments demonstrated that the splice donor site mutation resulted in abnormal PAH mRNA processing and loss of PAH activity (DiLella et al., 1986). […] Most PAH missense mutations impair enzyme activity by causing increased protein instability and aggregation.

• #10 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. […] PAH deficiency presents a spectrum of severity. Most severe are individuals with complete enzyme deficiency, or classical PKU (blood phenylalanine (Phe) levels 1200 mol/L). […] 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. […] PKU is inherited as an autosomal recessive condition. Those who have only 1 PAH mutation (eg, parents of a child with phenylketonuria) are carriers and have none of the biochemical or clinical characteristics of PKU.

• #11 Phenylketonuria (PKU) Frequently Asked Questions (FAQs)

  https://hcp.biomarin.com/en-us/pku/hcp-resources/faqs/

  Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism caused by variants in the gene encoding the phenylalanine hydroxylase (PAH) enzyme. […] Most cases (~98%) of PKU are caused by variants in the gene encoding the enzyme, phenylalanine hydroxylase (PAH). PAH defects can range from mild folding defects in the protein to absence or deficiency of PAH expression. […] PKU is characterized by complete or partial deficiency of PAH enzymatic activity resulting in an inability to metabolize the amino acid Phe. […] As the PAH enzyme catalyzes the hydroxylation of Phe to tyrosine (Tyr), conversion of Phe to Tyr is impaired. This causes the Phe to build up in the blood and brain, leading to a range of intellectual disabilities, as well as neurological, neuropsychiatric, and psychosocial consequences.

• #11 Phenylketonuria (PKU) Frequently Asked Questions (FAQs)

  https://hcp.biomarin.com/en-us/pku/hcp-resources/faqs/

  If not adequately controlled, excess levels of Phe, which are toxic to the brain, disrupt normal neurophysiology. High Phe levels may lead to serious neurological and neuropsychological complications, affecting the way people with PKU think, feel, and act. […] Lowering Phe is recognized as the key strategy in managing PKU. […] Elevated levels of the Phe correlates with neuropsychological symptom severity, which generally improves with Phe reductions.

• #12 Phenylketonuria – Wikipedia

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

  Phenylketonuria is an inherited genetic disorder. It is caused by mutations in the PAH gene, which can result in inefficient or nonfunctional phenylalanine hydroxylase, an enzyme responsible for the metabolism of excess phenylalanine. This results in the buildup of dietary phenylalanine to potentially toxic levels. It is autosomal recessive, meaning that both copies of the gene must be mutated for the condition to develop. […] PKU is an autosomal recessive metabolic genetic disorder. As an autosomal recessive disorder, two PKU alleles are required for an individual to experience symptoms of the disease. For a child to inherit PKU, both parents must have and pass on the defective gene. […] PKU is characterized by homozygous or compound heterozygous mutations in the gene for the hepatic enzyme phenylalanine hydroxylase (PAH), rendering it nonfunctional. This enzyme is necessary to metabolize the amino acid phenylalanine (Phe) to the amino acid tyrosine (Tyr). When PAH activity is reduced, phenylalanine accumulates and is converted into phenylpyruvate (also known as phenylketone), which can be detected in the urine.

• #13 Phenylketonuria (PKU): Causes, Symptoms, Diagnosis, and Treatment • Yesil Health

  https://yesilhealth.com/your-health/phenylketonuria-pku-causes-symptoms-diagnosis-and-treatment/

  Phenylketonuria, commonly referred to as PKU, is a rare genetic disorder that affects the bodys ability to break down a specific amino acid called phenylalanine. […] PKU is caused by a mutation in the PAH gene, which codes for the enzyme phenylalanine hydroxylase. This enzyme is responsible for converting phenylalanine into another amino acid called tyrosine. Without this enzyme, phenylalanine builds up in the blood, causing damage to the brain and other organs. […] PKU is an autosomal recessive disorder, meaning that a person must inherit two copies of the mutated gene (one from each parent) to develop the condition. If a person inherits only one copy of the mutated gene, they will be a carrier of PKU but will not develop the condition themselves. […] PKU is caused by a mutation in the PAH gene, which codes for the enzyme phenylalanine hydroxylase. This enzyme is necessary for breaking down phenylalanine. Without it, phenylalanine builds up in the blood and can cause damage to the brain and other organs.

• #14 Phenylketonuria (PKU): Causes, Symptoms, Diagnosis, and Treatment • Yesil Health

  https://yesilhealth.com/your-health/phenylketonuria-pku-causes-symptoms-diagnosis-and-treatment/

  The mutation that causes PKU is usually inherited from ones parents. Its an autosomal recessive disorder, meaning that a person needs to inherit two copies of the mutated gene (one from each parent) to develop the condition. If a person inherits only one copy of the mutated gene, they will be a carrier of PKU but will not develop the condition themselves.

• #15 What causes phenylketonuria (PKU)? | NICHD – Eunice Kennedy Shriver National Institute of Child Health and Human Development

  http://www.nichd.nih.gov/health/topics/pku/conditioninfo/causes

  Even if both parents carry the mutated PAH gene, their child still may not develop PKU. This is because a childs parents each carry two versions of the PAH gene, only one of which they will pass on during conception. […] If both of a childs parents are carriers, there is a 25% chance that both parents will pass on the typical PAH gene. In this case, the child will not have the disorder. Conversely, there is also a 25% chance that the carrier parents will both pass along the mutated gene, causing the child to have PKU. However, there is a 50% chance that a child will inherit one typical gene from one parent and one atypical gene from the other parent, making the child a carrier.

• #16 Phenylketonuria

  https://www.nhs.uk/conditions/phenylketonuria/

  Phenylketonuria (PKU) is a rare but potentially serious inherited disorder. […] People with PKU cannot break down the amino acid phenylalanine, which then builds up in their blood and brain. This can lead to brain damage. […] The genetic cause (mutation) responsible for PKU is passed on by the parents, who are usually carriers and do not have any symptoms of the condition themselves. […] The way this mutation is passed on is known as autosomal recessive inheritance. This means a baby needs to receive 2 copies of the mutated gene to develop the condition 1 from their mother and 1 from their father. […] If you’re a carrier of the altered gene and you have a baby with a partner who’s also a carrier, your baby has a 1 in 4 chance of inheriting the condition.

• #17 Phenylketonuria (PKU) – CheckOrphan

  http://checkorphan.org/video/phenylketonuria-pku/

  Phenylketonuria (also known as Phenylalanine hydroxylase deficiency, and PKU) is an inborn error of metabolism involving impaired metabolism of the amino acid phenylalanine. Phenylketonuria is caused by absent or virtually absent phenylalanine hydroxylase (PAH) enzyme activity. […] PKU is an inherited disease. When an infant is diagnosed with PKU, it is never the result of any action of the parents or any environmental factor. Rather, for a child to inherit PKU, both of his or her parents must have at least one mutated allele of the PAH gene. Most parents who are carriers of PKU genes are not aware that they have this mutation because being a carrier causes no medical problems. To be affected by PKU, a child must inherit two mutated alleles, one from each parent.

• #18 What causes phenylketonuria (PKU)? | NICHD – Eunice Kennedy Shriver National Institute of Child Health and Human Development

  http://www.nichd.nih.gov/health/topics/pku/conditioninfo/causes

  PKU is caused by mutations in the gene that helps make an enzyme called phenylalanine hydroxylase, or PAH. This enzyme is needed to convert the amino acid phenylalanine into other substances the body needs. When this gene, known as the PAH gene, is defective, the body cannot break down phenylalanine. […] Many different PAH mutations result in problems with breaking down phenylalanine. Some mutations cause PKU, others cause non-PKU hyperphenylalaninemia, and others are silent mutations that do not have an effect. […] PKU is inherited from a persons parents. The disorder is passed down in a recessive pattern, which means that for a child to develop PKU, both parents have to contribute a mutated version of the PAH gene. If both parents have PKU, their child will have PKU as well. […] Sometimes, a parent does not have PKU but is a carrier, which means the parent carries a mutated PAH gene. If only one parent carries the mutated gene, the child will not develop PKU.

• #19 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. […] Most cases of PKU worldwide are caused by phenylalanine hydroxylase (PAH) deficiency. […] 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. Defects in BH4 metabolism account for approximately 2 percent of patients with elevated phenylalanine levels. […] 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).

• #20 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. […] The PAH enzyme, expressed predominantly in the liver (but also kidney and pancreas), is responsible for the conversion of Phe to tyrosine (Tyr) in a reaction that requires the co-substrate tetrahydrobiopterin (BH4). […] Thus, a small number of cases of hyperphenylalaninaemia (HPA) are caused by defects in BH4 metabolism or pathogenetic variants in the DNAJC12 gene. […] The prevalence of PKU varies widely among ethnicities and geographic regions. Worldwide, PKU has an estimated prevalence of 1 in 23,930 live births and affects about 0.45 million individuals, of whom at least two-thirds require treatment.

• #21 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. […] PAH deficiency presents a spectrum of severity. Most severe are individuals with complete enzyme deficiency, or classical PKU (blood phenylalanine (Phe) levels 1200 mol/L). […] 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. […] PKU is inherited as an autosomal recessive condition. Those who have only 1 PAH mutation (eg, parents of a child with phenylketonuria) are carriers and have none of the biochemical or clinical characteristics of PKU.

• #22 Phenylketonuria (PKU) | Britannica

  https://www.britannica.com/science/phenylketonuria

  The remainder of individuals affected by phenylketonuria have deficiencies in tetrahydrobiopterin (or BH4), a chemical cofactor required for phenylalanine hydroxylase activity. Autosomal recessive defects in enzymes that synthesize tetrahydrobiopterin or that restore its catalytic activity can lead to a general disorder called hyperphenylalaninemia, characterized by abnormally high levels of phenylalanine in the blood and urine.

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

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

  Pleiotropy can be described when one gene can influence two or more seemingly unrelated phenotypic traits. […] In PKU, the PAH-responsible gene may be harmful and beneficial, referred to as antagonistic pleiotropy. […] The BH4 synthetic analog sapropterin dihydrochloride (Kuvan, BioMarin Corporation, Tiburon, CA), approved by FDA, is indicated for the treatment of HPA in patients with PKU or BH4 deficiency. […] Pegvaliase is an enzyme substitution therapy using PEGylated recombinant Anabaena variabilis PAL to lower blood Phe levels to normal ranges irrespective of residual PAH. […] Gene therapy is generally concerned with modifying genes in cells to produce a therapeutic effect or treating disease by repairing or reconstructing defective genetic material.

• #24 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. […] The PAH enzyme, expressed predominantly in the liver (but also kidney and pancreas), is responsible for the conversion of Phe to tyrosine (Tyr) in a reaction that requires the co-substrate tetrahydrobiopterin (BH4). […] Thus, a small number of cases of hyperphenylalaninaemia (HPA) are caused by defects in BH4 metabolism or pathogenetic variants in the DNAJC12 gene. […] The prevalence of PKU varies widely among ethnicities and geographic regions. Worldwide, PKU has an estimated prevalence of 1 in 23,930 live births and affects about 0.45 million individuals, of whom at least two-thirds require treatment.

• #25 Genetic etiology and clinical challenges of phenylketonuria

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9295449/

  Several reports have described BH4-related genes (for example, GCH1 GTPCH, PTS, PCBD1, QDPR, and SPR genes) linked to HPA. […] Although its proportion may be underestimated, genomic large deletion and duplication (in a 12.9% and 2.1%, respectively) in the PAH gene have been described in various ethnic populations. […] Evidence supports founder variants within the PAH and BH4-related genes among various ethnic populations. […] Pleiotropy can be described when one gene can influence two or more seemingly unrelated phenotypic traits. […] The PAH enzyme, expressed predominantly in the liver (and kidney and pancreas), is responsible for the converting Phe to Tyr in the presence of the co-substrate tetrahydrobiopterin (BH4).

• #26 Phenylketonuria (PKU) | Lurie Children’s

  https://www.luriechildrens.org/en/specialties-conditions/phenylketonuria/

  Phenylketonuria (PKU) is a lifelong genetic disorder in which an enzyme that does not work properly prevents the body from metabolizing (or process) one of the normal building blocks of protein. […] PKU is a genetic disorder caused by changes (mutations) in the PAH gene that contains the instructions for the cells in our bodies to make an enzyme called phenylalanine hydroxylase (PAH). […] In PKU, the enzyme that would normally convert Phe to the amino acid tyrosine (Tyr) does not work properly. […] When Phe is not converted to Tyr, its levels rise in the blood and brain. High levels of Phe are toxic to the brain.

• #27 Phenylketonuria (PKU) Frequently Asked Questions (FAQs)

  https://hcp.biomarin.com/en-us/pku/hcp-resources/faqs/

  Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism caused by variants in the gene encoding the phenylalanine hydroxylase (PAH) enzyme. […] Most cases (~98%) of PKU are caused by variants in the gene encoding the enzyme, phenylalanine hydroxylase (PAH). PAH defects can range from mild folding defects in the protein to absence or deficiency of PAH expression. […] PKU is characterized by complete or partial deficiency of PAH enzymatic activity resulting in an inability to metabolize the amino acid Phe. […] As the PAH enzyme catalyzes the hydroxylation of Phe to tyrosine (Tyr), conversion of Phe to Tyr is impaired. This causes the Phe to build up in the blood and brain, leading to a range of intellectual disabilities, as well as neurological, neuropsychiatric, and psychosocial consequences.

• #28 About PKU | NPKUA

  https://www.npkua.org/about-pku/

  PKU is a rare metabolic disease thats inherited when a baby gets two genetic variants for PKU, one from each parent. […] PKU is caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH) that helps to break down the amino acid Phe. […] PKU affects the brain through increased levels of Phe in the blood. […] Toxic levels of Phe in the first few years of life can cause irreversible damage including neurological impacts and complications such as IQ loss, memory loss, seizures, learning disabilities, and emotional issues. […] Theres no cure yet, but new treatment options can help to manage blood Phe levels.

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

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

  Parents and siblings of children with PKU can be tested to find out whether they carry the gene that causes the disease. […] A phenylalanine-restricted diet should continue for life, or intelligence may decrease and neurologic and mental problems may ensue. […] Children who are born to mothers who have poorly controlled PKU (that is, they have high phenylalanine levels) during pregnancy are at high risk of developing an abnormally small head (microcephaly) and developmental problems. This condition is called maternal PKU.

• #30 Phenylketonuria | American Pregnancy Association

  https://americanpregnancy.org/healthy-pregnancy/birth-defects/phenylketonuria/

  Phenylketonuria (PKU) is a metabolic disease caused by a genetic mutation. […] Phenylketonuria (PKU) is a rare, autosomal recessive disease that prevents the body from breaking down one of the amino acids found in nearly all proteins: phenylalanine (Phe). […] It occurs when an abnormal or mutated PAH gene from both the mother and the father is passed on to the baby. […] Two mutated or deleted PAH genes causes PKU. […] The greatest risks come if a woman is untreated for PKU/does not follow a PKU diet and/or take Phe-reducing medications. […] If a woman goes untreated, she can present problems in pregnancies such as an increase in spontaneous miscarriages or delayed fetal growth. […] Additionally, pregnant women who have untreated PKU are more likely to have children with microcephaly, congenital heart disease, and facial abnormalities. […] If you have PKU and you know that your partner is a carrier, you may want to speak with a genetic counselor prior to trying to conceive.

• #31 Phenylketonuria Information | Mount Sinai – New York

  https://www.mountsinai.org/health-library/diseases-conditions/phenylketonuria

  Phenylketonuria (PKU) is a rare condition in which a baby is born without the ability to properly break down an amino acid called phenylalanine. […] PKU is inherited, which means it is passed down through families. If both parents carry a nonworking copy of the gene related to this condition, each of their children has a 25% (1 in 4) chance of developing the disease. […] Babies with PKU are missing an enzyme called phenylalanine hydroxylase. It is needed to break down the essential amino acid phenylalanine. […] Without the enzyme, levels of phenylalanine build up in the body. This buildup can harm the central nervous system and cause brain damage. […] An enzyme assay or genetic testing can determine if parents carry the gene for PKU. […] It is very important that women with PKU closely follow a strict low-phenylalanine diet both before becoming pregnant and throughout the pregnancy. Buildup of phenylalanine will damage the developing baby, even if the child has not inherited the full disease.

• #32 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. […] The PAH enzyme, expressed predominantly in the liver (but also kidney and pancreas), is responsible for the conversion of Phe to tyrosine (Tyr) in a reaction that requires the co-substrate tetrahydrobiopterin (BH4). […] Thus, a small number of cases of hyperphenylalaninaemia (HPA) are caused by defects in BH4 metabolism or pathogenetic variants in the DNAJC12 gene. […] The prevalence of PKU varies widely among ethnicities and geographic regions. Worldwide, PKU has an estimated prevalence of 1 in 23,930 live births and affects about 0.45 million individuals, of whom at least two-thirds require treatment.

• #33 Genetic etiology and clinical challenges of phenylketonuria

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9295449/

  Several reports have described BH4-related genes (for example, GCH1 GTPCH, PTS, PCBD1, QDPR, and SPR genes) linked to HPA. […] Although its proportion may be underestimated, genomic large deletion and duplication (in a 12.9% and 2.1%, respectively) in the PAH gene have been described in various ethnic populations. […] Evidence supports founder variants within the PAH and BH4-related genes among various ethnic populations. […] Pleiotropy can be described when one gene can influence two or more seemingly unrelated phenotypic traits. […] The PAH enzyme, expressed predominantly in the liver (and kidney and pancreas), is responsible for the converting Phe to Tyr in the presence of the co-substrate tetrahydrobiopterin (BH4).

• #34 PKU (Phenylketonuria) | familydoctor.org

  https://familydoctor.org/condition/phenylketonuria-pku/

  Phenylketonuria (PKU) is a rare genetic condition where babies are born unable to break down an amino acid called phenylalanine. This causes phenylalanine to build up. When phenylalanine levels get too high, it can damage the brain. This can lead to intellectual and developmental disabilities. […] PKU is an inherited disease. This means it’s passed down to the baby through the genes of the mother and father. It’s caused by mutations in the gene that helps make an enzyme called phenylalanine hydroxylase. This enzyme helps break down phenylalanine. When this gene doesn’t work right, the body can’t break down phenylalanine. It starts to build up and causes damage to nerve cells in the brain. […] In the United States, you’re at higher risk of having PKU if you’re of European or Native American descent.

• #35 What is Phenylketonuria? | University of Utah Health

  https://healthcare.utah.edu/the-scope/kids-zone/all/2015/05/what-phenylketonuria

  Babies get tested for many things right after they are born. […] It’s a rare birth defect and it pretty much means the body is not able to break down an amino acid called phenylalanine. […] The cause of PKU is completely genetic. For a child to be born with PKU both parents must have the PKU gene. […] A parent can have the PKU gene, but not have the disease and this is called being a carrier. […] If a pregnant woman with PKU does not follow a PKU diet during pregnancy, the baby may be born with intellectual disabilities, an abnormally small head, or even heard defects. […] PKU is much more common in Caucasians than any other ethnic population. […] Can you prevent PKU? No, you can not.

• #36 About PKU | NPKUA

  https://www.npkua.org/about-pku/

  PKU is a rare metabolic disease thats inherited when a baby gets two genetic variants for PKU, one from each parent. […] PKU is caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH) that helps to break down the amino acid Phe. […] PKU affects the brain through increased levels of Phe in the blood. […] Toxic levels of Phe in the first few years of life can cause irreversible damage including neurological impacts and complications such as IQ loss, memory loss, seizures, learning disabilities, and emotional issues. […] Theres no cure yet, but new treatment options can help to manage blood Phe levels.

• #37 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.

• #38 Phenylketonuria: Causes & Symptoms | StudySmarter

  https://www.studysmarter.co.uk/explanations/medicine/pathology-histology/phenylketonuria/

  An autosomal recessive pattern means that an individual must inherit two defective copies of a gene, one from each parent, to exhibit symptoms of the disease. […] For instance, if both parents are carriers of the PKU gene mutation, there is a 25% chance with each pregnancy that their child will inherit both mutated genes, resulting in PKU. […] The accumulation of phenylalanine in the body can have several adverse effects: […] Because phenylalanine is present in all protein-containing foods, individuals with PKU need careful dietary monitoring. […] Beyond the dietary management of PKU, emerging gene therapy and enzyme replacement therapies are being researched to address the underlying genetic cause. These therapies aim to introduce functional copies of the PAH gene or administer exogenous phenylalanine hydroxylase enzymes, offering potential future treatment avenues that could normalize phenylalanine levels without strict dietary restrictions.

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