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Nature Reviews. Disease Primers May 2021Phenylketonuria (PKU; also known as phenylalanine hydroxylase (PAH) deficiency) is an autosomal recessive disorder of phenylalanine metabolism, in which especially high... (Review)
Review
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. If untreated, this brain dysfunction results in severe intellectual disability, epilepsy and behavioural problems. The prevalence varies worldwide, with an average of about 1:10,000 newborns. Early diagnosis is based on newborn screening, and if treatment is started early and continued, intelligence is within normal limits with, on average, some suboptimal neurocognitive function. Dietary restriction of phenylalanine has been the mainstay of treatment for over 60 years and has been highly successful, although outcomes are still suboptimal and patients can find the treatment difficult to adhere to. Pharmacological treatments are available, such as tetrahydrobiopterin, which is effective in only a minority of patients (usually those with milder PKU), and pegylated phenylalanine ammonia lyase, which requires daily subcutaneous injections and causes adverse immune responses. 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.
Topics: Genetic Therapy; Humans; Infant, Newborn; Neonatal Screening; Phenylalanine; Phenylketonurias
PubMed: 34017006
DOI: 10.1038/s41572-021-00267-0 -
Lancet (London, England) Oct 2010Phenylketonuria is the most prevalent disorder caused by an inborn error in aminoacid metabolism. It results from mutations in the phenylalanine hydroxylase gene.... (Review)
Review
Phenylketonuria is the most prevalent disorder caused by an inborn error in aminoacid metabolism. It results from mutations in the phenylalanine hydroxylase gene. Phenotypes can vary from a very mild increase in blood phenylalanine concentrations to a severe classic phenotype with pronounced hyperphenylalaninaemia, which, if untreated, results in profound and irreversible mental disability. Neonatal screening programmes identify individuals with phenylketonuria. The initiation of a phenylalanine-restricted diet very soon after birth prevents most of the neuropsychological complications. However, the diet is difficult to maintain and compliance is often poor, especially in adolescents, young adults, and pregnant women. Tetrahydrobiopterin stimulates phenylalanine hydroxylase activity in about 20% of patients, and in those patients serves as a useful adjunct to the phenylalanine-restricted diet because it increases phenylalanine tolerance and allows some dietary freedom. Possible future treatments include enzyme substitution with phenylalanine ammonia lyase, which degrades phenylalanine, and gene therapy to restore phenylalanine hydroxylase activity.
Topics: Female; Humans; Infant, Newborn; Intellectual Disability; Neonatal Screening; Phenylketonurias; Pregnancy; Pregnancy Complications
PubMed: 20971365
DOI: 10.1016/S0140-6736(10)60961-0 -
Orphanet Journal of Rare Diseases Oct 2017Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts... (Review)
Review
Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method. Literature search, critical appraisal and evidence grading were conducted according to the SIGN (Scottish Intercollegiate Guidelines Network) method. The Delphi-method was used when there was no or little evidence available. External consultants reviewed the guidelines. Using these methods 70 statements were formulated based on the highest quality evidence available. The level of evidence of most recommendations is C or D. Although study designs and patient numbers are sub-optimal, many statements are convincing, important and relevant. In addition, knowledge gaps are identified which require further research in order to direct better care for the future.
Topics: Europe; Humans; Phenylketonurias; Practice Guidelines as Topic
PubMed: 29025426
DOI: 10.1186/s13023-017-0685-2 -
Orvosi Hetilap Nov 2017Starting from 1975 phenylketonuria is part of the newborn screening program in Hungary. Since then a generation, treated with special diet and medical foods right after... (Review)
Review
Starting from 1975 phenylketonuria is part of the newborn screening program in Hungary. Since then a generation, treated with special diet and medical foods right after neonatal diagnosis has reached adulthood. Thanks to early treatment initiation, children with phenylketonuria are able to lead life to the full. Consequently, phenylketonuria is no longer considered a pediatric disease. Follow up of adult patients with phenylketonuria is performed in internal medicine centers specialized in metabolic diseases. The outcome of the lifelong special treatment, and the particularities of phenylketonuria in adulthood are yet to be determined. The aim of our review is to present recent findings in phenylketonuria focusing mainly on the adult care. After long time the first international guidelines appeared, new therapies were put in use, and these current developments are expected to be implemented in daily practice in the near future. New challenges must be met such as maternal phenylketonuria, long term effects of dietotherapy and the sequelae of untreated phenylketonuria in adulthood. Orv Hetil. 2017; 158(46): 1857-1863.
Topics: Adult; Age Factors; Aging; Female; Health Services Accessibility; Humans; Long-Term Care; Male; Middle Aged; Phenylalanine; Phenylketonurias
PubMed: 29153021
DOI: 10.1556/650.2017.30888 -
Nature Reviews. Disease Primers May 2021
Topics: Humans; Phenylketonurias
PubMed: 34017004
DOI: 10.1038/s41572-021-00274-1 -
Annual Review of Nutrition 1987
Review
Topics: Humans; Infant; Infant Food; Infant Nutritional Physiological Phenomena; Infant, Newborn; Phenylalanine; Phenylketonurias
PubMed: 3300729
DOI: 10.1146/annurev.nu.07.070187.001001 -
Medicina 2019Phenylketonuria, also known as PKU, is the most frequent congenital inborn error of metabolism. The severe form or classic PKU untreated causes intellectual disability,...
Phenylketonuria, also known as PKU, is the most frequent congenital inborn error of metabolism. The severe form or classic PKU untreated causes intellectual disability, although with the early detection programs in the neonatal period, diagnosis and treatment prevent the appearance of the symptoms. Despite early diagnosis and treatment we have observed some neurotoxicity in treated PKU patients. We analyzed the factors involved apart from the toxicity due to the high cerebral concentrations of phenylalanine (Phe), the defects of synthesis of neurotransmitters, the alteration of cerebral myelination, the effect of the elevation of Phe in the processes of transport and distribution of neutral amino acids with an abnormal synthesis of brain proteins, plasma and cerebral tyrosine deficiency, the neurotoxicity of Phe metabolites, the defect of cholesterol biosynthesis or the increase of oxidative stress. White matter alterations in early treated PKU patients have an important role in neurological manifestations. The treatment of PKU is for life and is based on the reduction of foods containing Phe combined with the administration of a special formula or tetrahydrobiopterin (BH4) treatment. New therapeutic options will be analyzed.
Topics: Biopterins; Diet Therapy; Early Diagnosis; Humans; Neurons; Phenylalanine; Phenylketonurias; Tyrosine
PubMed: 31603834
DOI: No ID Found -
Clinica Chimica Acta; International... Jun 2024Phenylketonuria (PKU) is an autosomal recessive metabolic disorder resulting from deficient phenylalanine hydroxylase (PAH) enzyme activity, leading to impaired... (Review)
Review
Phenylketonuria (PKU) is an autosomal recessive metabolic disorder resulting from deficient phenylalanine hydroxylase (PAH) enzyme activity, leading to impaired phenylalanine (Phe) metabolism. This condition can lead to intellectual disability, epilepsy, and behavioural issues. Treatment typically involves strict dietary restrictions on natural protein intake, supplemented with chemically manufactured protein substitutes containing amino acids other than Phe. Various approaches, including casein glycomacropeptide (GMP), tetrahydrobiopterin (BH), phenylalanine ammonia-lyase (PAL) therapy, large neutral amino acid (LNAA) supplementation, enzyme therapy, gene therapy, and medical therapies, aim to prevent Phe transport in the brain to potentially treat PKU. Although newborn screening programs and early dietary interventions have enhanced outcomes of the potential treatment strategies, limitations still persist in this direction. These involve potent accuracy concerns in diagnosis due to the existence of antibiotics in blood of PKU patients, affecting growth of the bacteria in the bacterial inhibition assay. Monitoring involves complex methods for instance, mass spectrometry and high-pressure liquid chromatography, which involve shortcomings such as lengthy protocols and the need for specialized equipment. To address these limitations, adaptable testing formats like bio/nano sensors are emerging with their cost-effectiveness, biodegradability, and rapid, accurate, and sensitive detection capabilities, offering promising alternatives for PKU diagnosis. This review provides insights into current treatment and diagnostic approaches, emphasizing on the potential applications of the diverse sensors intended for PKU diagnosis.
Topics: Phenylketonurias; Humans; Biosensing Techniques
PubMed: 38734223
DOI: 10.1016/j.cca.2024.119725 -
Pediatrics in Review Mar 1986
Review
Topics: Child, Preschool; Humans; Infant; Infant, Newborn; Male; Phenylketonurias
PubMed: 3331441
DOI: 10.1542/pir.7-9-269 -
Practical Neurology Nov 2023
Topics: Humans; Siblings; Phenylketonurias
PubMed: 37487703
DOI: 10.1136/pn-2023-003815