Materiały źródłowe

• #1 Predictability and inconsistencies of cognitive outcome in patients with phenylketonuria and personalised therapy: the challenge for the future guidelines – PubMed

  https://pubmed.ncbi.nlm.nih.gov/31484718/

  Phenylketonuria (PKU) is a prototypical model of a neurodevelopmental metabolic disease that follows a cascade of pathological events affecting brain maturation and functioning. […] The aim of the present review is to focus on the inconsistencies in the clinical outcome of adult patients with ECTPKU unexplained by the biochemical markers adopted for the monitoring of the disease to date. […] In conclusion, individual vulnerability to the metabolic alterations of PKU contributes to the prognosis of PKU, also in patients with ECTPKU. […] The biological factors constitutive of this vulnerability are unknown (but have not been the object of many studies so far) and should be the target of further research as prerequisite for a personalised treatment aimed at avoiding burden and costs of overtreatment and clinical consequences and risks of undertreatment in patients with PKU.

• #2 The complete European guidelines on phenylketonuria: diagnosis and treatment | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-017-0685-2

  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. […] As high blood Phe concentrations are strongly related to neurocognitive outcome, existing treatments aim at decreasing blood Phe concentrations. […] Due to NBS and treatment commencement shortly after birth, patients fall within the broad normal range of general ability, attain more or less expected educational standards and lead independent lives as adults. […] As a consequence, PKU is considered a medical success story but neuropsychological deficits, behavioural and social issues occur in some patients, and (as a group) their mean neurocognitive always level is somewhat below their siblings or control groups from the general population.

• #3

  https://omim.org/entry/261600

  Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism resulting from a deficiency of phenylalanine hydroxylase (PAH; 612349), an enzyme that catalyzes the hydroxylation of phenylalanine to tyrosine, the rate-limiting step in phenylalanine catabolism. If undiagnosed and untreated, phenylketonuria can result in impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia (Zurfluh et al., 2008). […] Early diagnosis of phenylketonuria, a cause of mental retardation, is important because it is treatable by dietary means. Features other than mental retardation in untreated patients include a 'mousy’ odor; light pigmentation; peculiarities of gait, stance, and sitting posture; eczema; and epilepsy (Paine, 1957). […] Normal mentality is very rare among patients with phenylketonuria who have not received dietary therapy.

• #3

  https://omim.org/entry/261600

  Mildly depressed IQ is common in treated PKU. Griffiths et al. (2000) analyzed IQ scores collected from 57 British children with early-treated classic PKU using variants of the Wechsler intelligence scale for children (WISC) in relation to indicators of dietary control such as serum phenylalanine levels and socioeconomic factors. The authors found that, after correcting for socioeconomic status, phenylalanine control at age 2 was predictive of overall IQ, although early and continuous treatment did not necessarily lead to normalization of overall IQ. […] The authors stated that 'the difficulties of some patients to adjust their blood Phe level according to their target value although they comply with the dietary recommendations might be caused by low residual enzyme activity.’ […] In a retrospective study from birth in 13 patients with classic PKU, Barat et al. (2002) found greater variation of phenylalanine levels and a higher mean of cumulative variations in the 8 osteopenic patients than in 5 nonosteopenic patients.

• #3

  https://omim.org/entry/261600

  Waisbren et al. (2021) reported the long-term effects of sapropterin treatment on intellectual functioning and other outcomes in 62 children who started sapropterin before 6 years of age. Intellectual functioning (as measured by the full-scale intelligent quotient (FSIQ)) and growth rates were maintained over a follow-up period of 7 years and stayed in the normal range. Approximately 60% of patients maintained their blood phenylalanine levels in the therapeutic range of 120-360 micromol/L throughout the study.

• #4 Blood phenylalanine fluctuation in phenylketonuric children treated by BH4 or low-phenylalanine diet from birth | Scientific Reports

  https://www.nature.com/articles/s41598-023-36550-1

  The prognosis of phenylketonuria (PKU) is related to the quality of metabolic control all life-long. […] Fluctuations in blood phenylalanine (Phe) concentrations may be an important determinant of intellectual outcome in patients with early and continuously treated phenylketonuria (PKU). […] Additional time and patients are required to determine if the decrease in Phe fluctuation would positively impact the long-term outcome of PKU patients. […] PKU outcome research and clinical monitoring are focused on single or average blood Phe concentrations quantifying concurrent and historical exposure of the organism to Phe, the main cause of deleterious effects in PKU. […] In addition to absolute Phe exposure, variability or fluctuation of Phe levels has been claimed to have an independent negative effect on intellectual outcomes of patients.

• #5 Phenylketonuria: translating research into novel therapies – Ho – Translational Pediatrics

  https://tp.amegroups.org/article/view/3542/html

  Phenylketonuria (PKU) is an inborn error of metabolism of the amino acid phenylalanine. […] Newborn screening for PKU allows early intervention, avoiding irreparable neurological damage and intellectual disability that would arise from untreated PKU. […] It is hoped that continuing efforts into these studies will translate into a significant improvement in the physical outcome, as well as quality of life, for patients with PKU. […] The target level of Phe concentration varies according to the age of the patient. […] Early intervention and good dietary compliance are essential for cognitive outcome (measured as IQ) and for reducing the risk of neurological complications and behavioural problems in PKU patients. […] The level of diet adherence in patients with PKU is similar to that reported by the World Health Organization for patients with chronic disease complying with treatment recommendations.

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

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

  Early initiation of treatment for phenylketonuria (PKU) in the first few days of life is critical in preventing the severe manifestations of the disease. […] While a strict low-phenylalanine diet can help manage symptoms, mild cognitive deficits and mental health issues may still arise even with good dietary control. […] If treatment is not started until after 2 to 3 years of age, it may only effectively control extreme hyperactivity and seizures, with limited impact on cognitive outcomes. […] The prognosis for normal intelligence is excellent when patients are promptly placed on a low-phenylalanine diet within the first month of life and receive careful and frequent monitoring. […] However, some children may experience mild impairments in school functioning, particularly when dietary control is not optimal. Regular follow-up visits and adherence to dietary guidelines are necessary to optimize long-term health and cognitive outcomes for individuals with PKU.

• #7 Blood phenylalanine fluctuation in phenylketonuric children treated by BH4 or low-phenylalanine diet from birth | Scientific Reports

  https://www.nature.com/articles/s41598-023-36550-1

  Variation of Phe blood concentration over time is called phenylalanine fluctuation. […] Phe fluctuations have impact on long-term neurocognitive outcome and during pregnancy. […] Our study confirms that the Phe fluctuation is less important in the moderate PKU patients treated by BH4 which is logical as these patients have a higher Phe hydroxylase activity and this enzyme activity is increased by sapropterin treatment. […] A better control of Phe fluctuation may be associated with a higher IQ at adulthood. […] Therefore, it is possible that an improvement of Phe fluctuation in the first years of life could improve the neurocognitive outcome of PKU patients but larger and longer studies will be necessary to demonstrate it.

• #8 Molecular epidemiology and genotype–phenotype correlation in phenylketonuria patients from South Spain | Journal of Human Genetics

  https://www.nature.com/articles/jhg201316

  The aim of this study was to identify the most common genotypes in the phenylketonuria (PKU) population of Andalusia, assessing the correlation with the phenotype and the usefulness in predicting the response to treatment with tetrahydrobiopterin. […] Genotype is quite a good predictor of the phenotype and of the responsiveness to tetrahydrobiopterin, which is relevant for patient management and follow-up. […] A subset of the patients exhibit cofactor (BH4) responsiveness depending on the genotype. […] Genotypephenotype correlations have been extensively analyzed revealing they can be a strong and reliable predictive tool. […] However, there are siblings with identical genotype exhibiting slightly different phenotypes […] Regarding BH4 responsiveness, previous studies have shown that the genotype is the main determinant.

• #9 Tetrahydrobiopterin responsiveness in phenylketonuria: prediction with the 48-hour loading test and genotype | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-8-103

  How to efficiently diagnose tetrahydrobiopterin (BH4) responsiveness in patients with phenylketonuria remains unclear. This study investigated the positive predictive value (PPV) of the 48-hour BH4 loading test and the additional value of genotype. […] The 48-hour BH4 loading test in combination with a classified genotype is a good parameter in predicting true-positive BH4 responsiveness. We propose assessing genotype first, particularly in the neonatal period. Patients with two known putative null mutations can be excluded from BH4 testing. […] This study, in a large cohort of PKU patients, shows that the 48-hour BH4 loading test has a high PPV for true BH4 responsiveness. Furthermore, it shows that patients with genotypes including at least one mutation known to be associated with long-term BH4 responsiveness have a high rate of true response.

• #10 Phenylketonuria Information | Mount Sinai – New York

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

  The outcome is expected to be very good if the diet is closely followed, starting shortly after the child’s birth. […] If treatment is delayed or the condition remains untreated, brain damage will

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

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

  Phenylketonuria (PKU) is an inherited metabolic disorder that prevents the body from being able to break down the amino acid phenylalanine. If children born with PKU are not treated, phenylalanine in the blood can rise to levels that are harmful to the brain, interfering with brain development and causing intellectual disability. […] Fortunately, PKU is highly treatable with diet and/or medication. Following the prescribed treatment for PKU is a lifelong endeavor that requires support from family and your health care team. Children and adults who follow their treatment regimen can live full, active lives. […] If not treated during infancy and childhood, PKU can cause developmental delay and intellectual disability. However, children who start PKU treatment as newborns and continue through childhood are expected to have normal growth and development.

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

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

  Those who stop treatment later in childhood or as adults may develop cognitive and mental health symptoms, including attention deficits, mood-related issues, poor self-control, reduced ability to plan and prioritize tasks, and brain “fog.” However, these symptoms can be at least partly reversed by going back on treatment. […] PKU requires lifelong care, starting within the week or two after birth. The cornerstone of treatment is a specially prescribed diet that has very low levels of phenylalanine (phe). Because phe is found in nearly all proteins, the diet may limit or exclude meat, eggs, dairy products, legumes, and many grains. Many patients consume specially formulated low-protein foods and drink nutritional formulas. […] 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. […] PKU requires lifelong care, and our multidisciplinary team will work with you to achieve the best health available.

• #12 Phenylketonuria – Wikipedia

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

  Phenylketonuria affects about 1 in 12,000 babies. […] People who are diagnosed early and maintain a strict diet can have normal health and a normal life span. […] In general, however, outcomes for people treated for PKU are good. Treated people may have no detectable physical, neurological, or developmental problems at all. […] The damage done to the brain if PKU is untreated during the first months of life is not reversible. Affected children who are detected at birth and treated are much less likely to develop neurological problems or have seizures and intellectual disability, though such clinical disorders are still possible including asthma, eczema, anemia, weight gain, renal insufficiency, osteoporosis, gastritis, esophagus, and kidney deficiencies, kidney stones, and hypertension. […] Recent research suggests that neurocognitive, psychosocial, quality of life, growth, nutrition, and bone pathology are slightly suboptimal even for patients who are treated and maintain their Phe levels in the target range if their diet is not supplemented with other amino acids.

• #13 Phenylketonuria: translating research into novel therapies – Ho – Translational Pediatrics

  https://tp.amegroups.org/article/view/3542/html

  In spite of early intervention, children with PKU have lower intellectual functioning than their siblings and the general population, and poorer measures in other neurocognitive outcomes. […] Studies have also been carried out to determine how quality of life (QoL) in PKU patients is affected with a general perceived decreased in many aspects of QoL in both children and adults with PKU. […] Although the treatment with BH4 offers a safe and effective alternative for many patients with PKU, its appropriateness is limited to primarily patients with a milder biochemical phenotype. […] Different modes of therapy for PKU are now under development.

• #14 Outcomes of Phenylketonuria with Relevance to Follow-Up

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3509817/

  Currently, there is no international consensus on how patients with phenylketonuria (PKU) (or milder forms of hyperphenylalaninaemia) should be followed in clinical practice. […] A strong relationship has been established between the control of blood Phe concentrations during infancy and childhood and intelligence quotient (IQ). […] Although well-controlled patients reach a normal IQ, it may be lower than their siblings or classmates. […] Notwithstanding the relationship between blood Phe concentrations and outcome, it is to be resolved whether blood Phe concentrations can fully explain the total pathogenesis of brain pathophysiology in PKU. […] An additional target of significance among patients with PKU includes psychosocial outcome, of which too few studies have been conducted to date.

• #15

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

  Mildly depressed IQ is common in treated PKU. Griffiths et al. (2000) analyzed IQ scores collected from 57 British children with early-treated classic PKU using variants of the Wechsler intelligence scale for children (WISC) in relation to indicators of dietary control such as serum phenylalanine levels and socioeconomic factors. The authors found that, after correcting for socioeconomic status, phenylalanine control at age 2 was predictive of overall IQ, although early and continuous treatment did not necessarily lead to normalization of overall IQ. […] In a retrospective study from birth in 13 patients with classic PKU, Barat et al. (2002) found greater variation of phenylalanine levels and a higher mean of cumulative variations in the 8 osteopenic patients than in 5 nonosteopenic patients. Barat et al. (2002) suggested that serum phenylalanine variations may contribute to osteopenia in patients with classic PKU.

• #15

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

  Waisbren et al. (2021) reported the long-term effects of sapropterin treatment on intellectual functioning and other outcomes in 62 children who started sapropterin before 6 years of age. Intellectual functioning (as measured by the full-scale intelligent quotient (FSIQ)) and growth rates were maintained over a follow-up period of 7 years and stayed in the normal range. Approximately 60% of patients maintained their blood phenylalanine levels in the therapeutic range of 120-360 micromol/L throughout the study.

• #16 The complete European guidelines on phenylketonuria: diagnosis and treatment | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-017-0685-2

  In PKU, life-long, systematic follow-up is recommended independent of the degree of adherence and (non-) treatment choice, to screen for long-term complications at any life stage, and provide appropriate support to patients. […] The primary goal of treatment is normal neurocognitive and psychosocial functioning. […] The statements in this guideline recommend blood Phe as upper target levels where reported studies used means or mean of medians. […] The evidence for patients 12 years of age is strong indicating that a Phe concentration of 360 mol/l should be considered as the upper target Phe concentration. […] The evidence for patients 12 years of age is mainly indirect, as there are no studies investigating the effect of Phe levels during adolescence in patients who were in good metabolic control during childhood. […] The evidence, as strong or weak as it is, indicates 600 mol/l as the upper target level, while no study could be found to support an upper target blood Phe level of 360 mol/.

• #17 Phenylketonuria

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

  With early diagnosis and the correct treatment, most children with PKU are able to live healthy lives. […] As long as a person with PKU sticks to a low-protein diet throughout childhood, and their phenylalanine levels stay within certain limits, they’ll remain well and their brain function should be unaffected. […] Unlike in young children, there is not yet any evidence that high phenylalanine levels cause any permanent brain damage in adults with PKU. […] Provided that phenylalanine levels are strictly controlled during pregnancy, problems can be avoided and there’s no reason why a woman with PKU should not be able to have a normal, healthy baby. […] If your phenylalanine levels can be brought under control within the first few weeks of your pregnancy, the risk of damage to your baby should be small.

• #18 Molecular epidemiology and genotype–phenotype correlation in phenylketonuria patients from South Spain | Journal of Human Genetics

  https://www.nature.com/articles/jhg201316

  The present study with patients from south Spain reveals that having on both alleles a mutation not associated to BH4 response is a reliable predictor of the absence of BH4 responsiveness. […] In conclusion, a spectrum of 147 disease-causing mutations in Andalusian subjects with PAH deficiency was identified. A good correlation between the genotype and biochemical and BH4-responsive phenotype was observed.

• #19 Outcomes of Phenylketonuria with Relevance to Follow-Up

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3509817/

  A further main target is to ensure that there are no nutritional deficiencies that may give rise to possible physiological or neurological concerns. […] As with the lack of PKU studies assessing psychosocial outcomes, there is also a dearth in the number of studies that assess quality of life (QoL) in patients with PKU. […] This chapter tries to present a start for a follow-up programme. By no means, however, this chapter is aimed to present the one for all time follow-up programme.

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

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

  Phenylketonuria (PKU) is a lifelong condition and most people living with it lead healthy lives. […] After diagnosis, regular blood tests to monitor the level of phenylalanine in your blood are necessary. […] For those who are on a restrictive diet, many people benefit from working closely with a dietitian who can advise on the best foods to eat, what to avoid and how to get all the nutrients you need to stay healthy. […] If you have PKU and are pregnant, your provider and/or dietitian will create a diet plan that ensures you receive proper nutrition while lowering your baby’s risk for complications.

• #21 The complete European guidelines on phenylketonuria: diagnosis and treatment | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-017-0685-2

  The goal of these European guidelines is to offer a standard for diagnostics, treatment and care in PKU that would lead to optimal clinical and neuropsychological outcome without overtreatment and unnecessary costs. […] The evidence regarding initiation of treatment with blood Phe concentrations between 360 and 600 mol/l is inconsistent. […] The evidence that supports treatment is of suboptimal quality. […] The evidence that supports no treatment is of better quality. […] Overall it is unclear how many adults experience suboptimal outcomes that have impact on daily functioning. […] The risk of comorbidities makes dietary management more complex. […] The risk of low bone density has widely been acknowledged but the risk of bone fractures is still unclear. […] Evidence from a systematic review demonstrates that significant sub-optimal outcomes exist in ETPKU adults.

• #22 Phenylketonuria: translating research into novel therapies – Ho – Translational Pediatrics

  https://tp.amegroups.org/article/view/3542/4405

  Studies involving larger cohorts of patients revealed that BH4 supplementation is more effective in decreasing Phe levels in patients with milder forms of PKU, compared to those with the severe classical form. […] Although the treatment with BH4 offers a safe and effective alternative for many patients with PKU, its appropriateness is limited to primarily patients with a milder biochemical phenotype. […] Different modes of therapy for PKU are now under development. […] These treatment solutions may also be highly applicable to other genetic disorders of metabolism, and research into PKU therapies will have far-reaching consequences in the field of genetic medicine in the next few decades.

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