Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Phenylketonuria (PKU; MIM 261600) is an autosomal recessive metabolic disorder caused by a deficiency of phenylalanine hydroxylase (PAH; EC 1.14.16.1). Point mutations in the PAH gene are known to cause PKU in various ethnic groups, and large deletions or duplications account for up to 3% of the PAH mutations in some ethnic groups. However, a previous study could not identify approximately 14% of the mutant alleles by sequence analysis in Korean patients with PKU, which suggests that large deletions or duplication might be frequent causes of PKU in Koreans. To test this hypothesis, we performed multiplex ligation-dependent probe amplification (MLPA) for the identification of uncharacterized mutant alleles after PAH sequence analysis of 33 unrelated Korean patients with PKU. Bi-directional sequencing of the PAH exons and flanking intronic regions revealed 27 different mutations, including four novel mutations (two missense and two deletion mutations), comprising 57/66 (86%) mutant alleles. MLPA identified a large deletion that encompassed exons 5 and 6 in four patients, another large deletion that extended from exon 4 to exon 7 in one patient, and a duplication of exon 4 in one patient. Chromosomal walking characterized the deletion breakpoint of the most common large deletion that involved exons 5 and 6 (c.456_706+138del). The present study shows that the allelic frequency of exon deletion or duplication is 9% (6/66) in Korean PKU patients, which suggests that these mutations may be frequent causes of PKU in Korean subjects.
Exp Mol Med 2008 Oct 31
PMID:Mutation analysis of PAH gene and characterization of a recurrent deletion mutation in Korean patients with phenylketonuria. 1898 11

Phenylketonuria (PKU) is caused by mutations in the phenylalanine hydroxylase (PAH) gene, leading to deficient conversion of phenylalanine (Phe) to tyrosine and accumulation of toxic levels of Phe. A Phe-restricted diet is essential to reduce blood Phe levels and prevent long-term neurological impairment and other adverse sequelae. This diet is commenced within the first few weeks of life and current recommendations favor lifelong diet therapy. The observation of clinically significant reductions in blood Phe levels in a subset of patients with PKU following oral administration of 6R-tetrahydrobiopterin dihydrochloride (BH(4)), a cofactor of PAH, raises the prospect of oral pharmacotherapy for PKU. An orally active formulation of BH(4) (sapropterin dihydrochloride; Kuvan is now commercially available. Clinical studies suggest that treatment with sapropterin provides better Phe control and increases dietary Phe tolerance, allowing significant relaxation, or even discontinuation, of dietary Phe restriction. Firstly, patients who may respond to this treatment need to be identified. We propose an initial 48-h loading test, followed by a 1-4-week trial of sapropterin and subsequent adjustment of the sapropterin dosage and dietary Phe intake to optimize blood Phe control. Overall, sapropterin represents a major advance in the management of PKU.
Mol Genet Metab 2009 Apr
PMID:Optimizing the use of sapropterin (BH(4)) in the management of phenylketonuria. 1920 88

Phenylketonuria is an autosomal recessive disorder caused by a deficiency of phenylalanine hydroxylase. Transthyretin has been implicated as an indicator of nutritional status in phenylketonuria patients. In this study, we report that phenylalanine and its metabolite, phenylpyruvic acid, affect MAPK, changing transthyretin expression in a cell- and tissue-specific manner. Treatment of HepG2 cells with phenylalanine or phenylpyruvic acid decreased transcription of the TTR gene and decreased the transcriptional activity of the TTR promoter site, which was partly mediated through HNF4alpha. Decreased levels of p38 MAPK were detected in the liver of phenylketonuria-affected mice compared with wild-type mice. In contrast, treatment with phenylalanine increased transthyretin expression and induced ERK1/2 activation in PC-12 cells; ERK1/2 activation was also elevated in the brainstem of phenylketonuria-affected mice. These findings may explain between-tissue differences in gene expression, including Ttr gene expression, in the phenylketonuria mouse model.
Exp Mol Med 2010 Feb 28
PMID:Tissue-specific activation of mitogen-activated protein kinases for expression of transthyretin by phenylalanine and its metabolite, phenylpyruvic acid. 1994 78

Phenylalanine hydroxylase deficiency is a trait inherited in an autosomal recessive pattern; the associated phenotype varies considerably. This variation is mainly due to the considerable allelic heterogeneity in the phenylalanine hydroxylase enzyme locus. We examined the genotype-phenotype correlation in 54 phenylketonuria (PKU) patients from Minas Gerais, Brazil. Two systems were used. The first was a phenotype prediction system based on arbitrary values (AV) attributed to each mutation and the second was a correlation analysis. An AV was assigned to each mutation: AV = 1 for classical PKU mutation; AV = 2 for moderate PKU mutation; AV = 4 for mild PKU mutation, and AV = 8 for non-PKU hyperphenylalaninemia mutation. The observed phenotype for AV analysis was the clinical diagnosis established by the overloading phenylalanine test. Among the 51 PKU patients that we analyzed based on this trait, in 51% the predicted phenotype did not match the observed phenotype; the highest degree of concordance was found in patients with null/null genotypes. The genotype was observed to be a good predictor of the clinical course of the patients and significant correlations were found between phenylalanine values at first interview and predicted residual activity, genotype and arbitrary value sum.
Genet Mol Res 2010 Jan 05
PMID:Variations in genotype-phenotype correlations in phenylketonuria patients. 2008 65

Phenylketonuria (PKU) is characterized by elevated levels of phenylalanine (Phe) in plasma and cerebrospinal fluid of PKU patients, leading to mental retardation. The developmental delay in the cerebral cortex is one of the characteristic pathologic changes in untreated phenylketonuria patients. This is thought to be due to the toxic effects of Phe and/or its metabolites; however, the underlying mechanisms are as yet unknown. In this study, using a model system in which cultured cortical neurons were induced with Phe, we observed that Phe inhibited the longest neurite outgrowth and induced the neuronal death. We further demonstrated that the expression of BDNF mRNA and protein was significantly decreased by Phe, together with a decrease in extracellular signal-regulated kinase (ERK) and Akt phosphorylation activity. There was no change in expression of TrkB mRNA and protein. Considering the important role of BDNF in normal brain development and function, these L: -Phe-induced changes in BDNF in PKU brain may be a critical element of the neurological symptoms of PKU.
Mol Cell Biochem 2010 Jun
PMID:Effects of phenylalanine on the survival and neurite outgrowth of rat cortical neurons in primary cultures: possible involvement of brain-derived neurotrophic factor. 2010 19

Phenylketonuria (PKU) is a metabolic disorder that results in significant brain dysfunction if untreated. Although phenylalanine restricted diets instituted at birth have clearly improved PKU outcomes, neuropsychological deficits and neurological changes still represent substantial problems. The specific mechanisms by which Phe affects the brains of individuals with PKU are yet fully determined. The use of animal models in PKU research significantly broadens the possibilities for investigating these mechanisms. This report presents an overview of findings from animal studies on the mechanisms of Phe action in the PKU brain, discussing the importance of changes in protein synthesis, transport of large neutral amino acids across the blood-brain barrier, synthesis of monoamine neurotransmitters, activity of glutamate receptors, animal behavior, and translation of animal behavioral data to patients with PKU. This report shows that great progress has been made in past years and demonstrates the importance of further animal research to understand the neuropathological mechanisms underlying brain dysfunction in PKU. A better understanding of these mechanisms will guide the development of optimal treatment strategies for PKU.
Mol Genet Metab 2010
PMID:Animal models of brain dysfunction in phenylketonuria. 2012 63

Phenylketonuria (PKU) results in profound intellectual disability in untreated individuals and more subtle cognitive deficits in individuals treated early and continuously. The assessment of intellectual functioning has been an important outcome variable and the focus of extensive research. Since the implementation of neonatal PKU screening programs in the 1960s, research on intellectual functioning in individuals with PKU has played a significant and positive role in guiding therapy and improving results. This is a literature review examining the relationship between intellectual outcome and treatment parameters including initiation of treatment, duration of treatment, and blood phenylalanine (Phe) levels from infancy through adulthood. While current PKU treatment practices have eliminated severe neurological and cognitive impairment, evidence suggests that intellectual functioning, although typically within the average range when PKU is treated early and continuously, may not be maximized under the current definition of well-controlled PKU, which is based on blood Phe levels. Future research assessing intellectual and neurocognitive outcome in PKU will enhance the development of new treatment strategies.
Mol Genet Metab 2010
PMID:The role of intelligence in phenylketonuria: a review of research and management. 2012 65

Phenylketonuria (PKU) is a genetic disorder associated with disruption of prefrontal cortex (PFC) development and executive dysfunction. To date, however, there is little evidence directly linking these two sequelae of PKU. We utilized functional magnetic resonance imaging (fMRI) to evaluate prefrontal functioning in six individuals with early-treated PKU (ETPKU) during performance of an n-back working memory task and compared results with those of six age- and gender-matched neurologically intact individuals. In addition, we evaluated the possible presence of PKU-related disruptions in functional connectivity, as might be hypothesized based on prior reports of white matter injury in individuals with ETPKU. A number of brain regions, nearly half of which were located in the PFC, were found to show atypical neural activity in individuals with ETPKU during working memory performance. We also found decreased connectivity both within the PFC as well as between the PFC and other brain regions in individuals with ETPKU compared with controls. Results from this preliminary study suggest that both prefrontal dysfunction and disruptions in functional connectivity may contribute to PKU-related executive impairment. In addition to advancing our understanding of PKU, the current findings have a broader impact in that PKU is regularly used as a model of early prefrontal dysfunction in the study of other neurodevelopmental disorders (e.g., autism).
Mol Genet Metab 2010
PMID:Disruption of prefrontal function and connectivity in individuals with phenylketonuria. 2012 68

Despite having average intellectual abilities, academic difficulties are relatively common in children and adolescents with PKU. These academic difficulties may be a function of attention deficit hyperactivity disorder (ADHD), executive functioning deficits, and processing speed deficits, all of which are known to affect academic performance in non-PKU populations. This review focuses on what is currently known about academic performance in youth with PKU and offers suggestions for future research.
Mol Genet Metab 2010
PMID:ADHD, learning, and academic performance in phenylketonuria. 2012 71

Phenylketonuria (PKU) is an inborn error of metabolism, and its detrimental effects on neurocognitive functioning have been well studied. Early detection and treatment of PKU prevent the severe consequences of this disorder. However, even early- and well-treated patients experience hidden disabilities, including subtle deficits in executive functioning, mild reductions in mental processing speed, social difficulties, and emotional problems that may remain unnoticed for years. Poor executive function (EF) may impact treatment adherence and may lead to psychosocial deficits that are not always visible. These psychosocial aspects include social difficulties and psychosocial problems, such as forming interpersonal relationships, achieving autonomy, attaining educational goals, and having healthy emotional development. Studies report EF deficits in children and adults with early-treated PKU, which contribute significantly to the hidden disabilities in this population. In adults, hidden disabilities affect job performance and social relationships as a result of residual attention deficits, poor EF (e.g., planning, organizing), and reduced processing speed. An indirect relationship also exists between quality of life and EF impairment. In the absence of overt psychiatric symptoms, low level depressive or anxious symptom may be present. The interaction between the neurocognitive deficits and psychiatric symptoms puts this population of patients at significant risk for experiencing hidden disability. PKU is a disorder in which a less than optimal psychosocial outcome arises from the cumulative impact of relatively mild symptoms. The key to reducing risks associated with PKU is metabolic control throughout life.
Mol Genet Metab 2010
PMID:Psychosocial aspects of PKU: hidden disabilities--a review. 2012 73


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