Normal Clinical Outcome in Untreated Subjects with Mild Hyperphenylalaninemia

Weglage, Josef; Pietsch, Michael; Feldmann, Reinhold; Koch, Hans-Georg; Zschocke, Johannes; Hoffmann, Georg F.; Muntau-Heger, Anja; Denecke, Jonas; Guldberg, Per; Güttler, Flemming; Möller, Harald E.; Wendel, U.; Ullrich, Kurt; Harms, Erik

doi:10.1203/00006450-200104000-00015

Cited by 85 publications

(77 citation statements)

References 26 publications

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“…24 Many treatment centers in North America now initiate treatment at a PHE level of 360 µmol/l or higher; however, the evidence regarding clinical outcome in untreated patients with blood PHE levels between 360 and 600 µmol/l is mixed, with some studies demonstrating normal outcomes and others showing subtle neurocognitive deficits. [25][26][27][28] More research is needed…”

Section: Initiation Of Therapymentioning

confidence: 99%

Phenylalanine hydroxylase deficiency: diagnosis and management guideline

Vockley

Andersson

Antshel

et al. 2014

Genetics in Medicine

526

443

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Phenylalanine hydroxylase (PAH) deficiency, traditionally called phenylketonuria (PKU) due to characteristic phenylketones accumulating in the urine of affected individuals, has a significant place in history as the first inborn error of metabolism identified through population-based screening, initiating a new era in the diagnosis and treatment of genetic disorders. PKU was first described in 1934 by the Norwegian physician Asbjörn Fölling, but it was not until the mid-1950s that a patient with PAH deficiency was treated with a low phenylalanine (PHE) diet. Although this first patient already had irreversible Phenylalanine hydroxylase deficiency, traditionally known as phenylketonuria, results in the accumulation of phenylalanine in the blood of affected individuals and was the first inborn error of metabolism to be identified through population screening. Early identification and treatment prevent the most dramatic clinical sequelae of the disorder, but new neurodevelopmental and psychological problems have emerged in individuals treated from birth. The additional unanticipated recognition of a toxic effect of elevated maternal phenylalanine on fetal development has added to a general call in the field for treatment for life. Two major conferences sponsored by the National Institutes of Health held >10 years apart reviewed the state of knowledge in the field of phenylalanine hydroxylase deficiency, but there are no generally accepted recommendations for therapy. The purpose of this guideline is to review the strength of the medical literature relative to the treatment of phenylalanine hydroxylase deficiency and to develop recommendations for diagnosis and therapy of this disorder. Evidence review from the original National Institutes of Health consensus conference and a recent update by the Agency for Healthcare Research and Quality was used to address key questions in the diagnosis and treatment of phenylalanine hydroxylase deficiency by a working group established by the American College of Medical Genetics and Genomics. The group met by phone and in person over the course of a year to review these reports, develop recommendations, and identify key gaps in our knowledge of this disorder.Above all, treatment of phenylalanine hydroxylase deficiency must be life long, with a goal of maintaining blood phenylalanine in the range of 120-360 µmol/l. Treatment has predominantly been dietary manipulation, and use of low protein and phenylalanine medical foods is likely to remain a major component of therapy for the immediate future. Pharmacotherapy for phenylalanine hydroxylase deficiency is in early stages with one approved medication (sapropterin, a derivative of the natural cofactor of phenylalanine hydroxylase) and others under development. Eventually, treatment of phenylalanine hydroxylase deficiency will be individualized with multiple medications and alternative medical foods available to tailor therapy. The primary goal of therapy should be to lower blood phenylalanine, and any interventions, including medica...

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Section: Initiation Of Therapymentioning

confidence: 99%

Phenylalanine hydroxylase deficiency: diagnosis and management guideline

Vockley

Andersson

Antshel

et al. 2014

Genetics in Medicine

526

443

View full text Add to dashboard Cite

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“…Clinically, it corresponds to mild HPA. On a free diet, these patients (22% in the U.S., and 13% in the German study) do not need a low-Phe treatment for normal mental outcome [35].…”

Section: Deficiencymentioning

confidence: 79%

Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies

Blau

Hennermann

Langenbeck

et al. 2011

Molecular Genetics and Metabolism

198

168

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This article summarizes the present knowledge, recent developments, and common pitfalls in the diagnosis, classification, and genetics of hyperphenylalaninemia, including tetrahydrobiopterin (BH4) deficiency. It is a product of the recent workshop organized by the European Phenylketonuria Group in March 2011 in Lisbon, Portugal. Results of the workshop demonstrate that following newborn screening for phenylketonuria (PKU), using tandem mass-spectrometry, every newborn with even slightly elevated blood phenylalanine (Phe) levels needs to be screened for BH4 deficiency. Dried blood spots are the best sample for the simultaneous measurement of amino acids (phenylalanine and tyrosine), pterins (neopterin and biopterin), and dihydropteridine reductase activity from a single specimen. Following diagnosis, the patient's phenotype and individually tailored treatment should be established as soon as possible. Not only blood Phe levels, but also daily tolerance for dietary Phe and potential responsiveness to BH4 are part of the investigations. Efficiency testing with synthetic BH4 (sapropterin dihydrochloride) over several weeks should follow the initial 24-48-hour screening test with 20mg/kg/day BH4. The specific genotype, i.e. the combination of both PAH alleles of the patient, helps or facilitates to determine both the biochemical phenotype (severity of PKU) and the responsiveness to BH4. The rate of Phe metabolic disposal after Phe challenge may be an additional useful tool in the interpretation of phenotype-genotype correlation. This article summarizes the present knowledge, recent developments, and common pitfalls in the diagnosis, classification, and genetics of hyperphenylalaninemia, including tetrahydrobiopterin (BH4) deficiency. It is a product of the recent workshop organized by the European Phenylketonuria Group in March 2011 in Lisbon, Portugal. Results of the workshop demonstrate that following newborn screening for phenylketonuria (PKU), using tandem mass-spectrometry, every newborn with even slightly elevated blood phenylalanine (Phe) levels needs to be screened for BH4 deficiency. Dried blood spots are the best sample for the simultaneous measurement of amino acids (phenylalanine and tyrosine), pterins (neopterin and biopterin), and dihydropteridine reductase activity from a single specimen. Following diagnosis, the patient's phenotype and individually tailored treatment should be established as soon as possible. Not only blood Phe levels, but also daily tolerance for dietary Phe and potential responsiveness to BH4 are part of the investigations. Efficiency testing with synthetic BH4 (sapropterin dihydrochloride) over several weeks should follow the initial 24-48-hour screening test with 20 mg/kg/day BH4. The specific genotype, i.e. the combination of both PAH alleles of the patient, helps or facilitates to determine both the biochemical phenotype (severity of PKU) and the responsiveness to BH4. The rate of Phe metabolic disposal after Phe challenge may be an additional useful tool in the interp...

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“…The main goal of PKU treatment is to maintain blood Phe concentrations within a safe range through a Phe-restricted diet. A carefully maintained dietary regimen prevents mental retardation and other complications and allows optimum growth and development (6,7). During Phe-restricted diet treatment, some factors influence blood Phe concentrations.…”

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confidence: 99%

<i>Helicobacter pylori</i> Infection among Children with Phenylketonuria

2013

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SUMMARY: This study aimed to determine the frequency of Helicobacter pylori infections in children with phenylketonuria (PKU). Sixty-six children with PKU (35 boys, 31 girls; mean age, 8.2 ± 6.7 years) and 32 outpatient controls (15 boys, 17 girls; mean age, 9.6 ± 4.7 years) were studied. Socioeconomic factors did not differ between the two groups. The frequency of H. pylori infections was higher in patients with PKU (28.1z) than in healthy controls (9.4z). In particular, a higher frequency of infection was detected in patients with PKU with poor metabolic control (51.8z). The frequency of H. pylori infection in patients with PKU with good metabolic control was only 10.2z. There was no difference in the mean total WISC-R score between the poor and good metabolic control groups. A high frequency of H. pylori infection in children with PKU with poor metabolic control could be related to many factors. Advanced and standardized clinical studies on H. pylori infections in children with PKU are required.

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Normal Clinical Outcome in Untreated Subjects with Mild Hyperphenylalaninemia

Cited by 85 publications

References 26 publications

Phenylalanine hydroxylase deficiency: diagnosis and management guideline

Phenylalanine hydroxylase deficiency: diagnosis and management guideline

Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies

<i>Helicobacter pylori</i> Infection among Children with Phenylketonuria

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