Atypical cases of phenylketonuria

Dhondt, Jean-Louis; Farriaux, J. P.

doi:10.1007/bf00442055

Cited by 7 publications

(3 citation statements)

References 38 publications

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“…Phenylketonuria (PKU) is identified through national newborn screening programs [1]. The first efficient test for hyperphenylalaninemia (HPA) was a bacterial inhibition assay developed by Robert Guthrie [2].…”

Section: Newborn Screeningmentioning

confidence: 99%

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

Blau

Hennermann

Langenbeck

et al. 2011

Molecular Genetics and Metabolism

199

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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Section: Newborn Screeningmentioning

confidence: 99%

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

Blau

Hennermann

Langenbeck

et al. 2011

Molecular Genetics and Metabolism

199

168

View full text Add to dashboard Cite

show abstract

“…HPA is present only in the early neonatal period in these patients. PCD deficiency is considered as a benign disease, although one patient was reported as having mild neurological signs including tremor in the neonatal period and with tendency to hyper-or hypotonia and motor delay (Dhondt 2006).…”

Section: Discussionmentioning

confidence: 99%

Diagnosis of tetrahydrobiopterin deficiency using filter paper blood spots: further development of the method and 5 years experience

Opladen

Seda

Rassi

et al. 2011

J of Inher Metab Disea

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In every newborn with even mild hyperphenylalaninemia (HPA) tetrahydrobiopterin (BH 4 ) deficiencies need to be excluded as soon as possible. Differential diagnosis is most commonly performed by analysis of urinary neopterin and biopterin. In 2005 a new method for the measurement of neopterin, biopterin and other pterins in dried blood spot (DBS) on filter paper was introduced. In order to evaluate the usefulness of this method as a standard tool for differential diagnosis of HPAs we analyzed neopterin, biopterin, pterin and dihydropteridine reductase activity in DBS from 362 patients with HPA over the period of five years. Age-dependent reference values were established for the HPA population. Sixty-four patients with BH 4 deficiency (27 patients with 6-pyruvoyl-tetrahydropterin synthase deficiency, seven with GTP cyclohydrolase I deficiency, and 30 with dihydropteridine reductase) were identified. Reference values for neopterin and biopterin in DBS were calculated for each of the variants. 6-pyruvoyl-tetrahydropterin synthase and GTP cyclohydrolase I deficiency can be diagnosed by neopterin and biopterin analysis alone, while for diagnosis of dihydropteridine reductase deficiency additional determination of enzyme activity from the same DBS is essential. Regarding test sensitivity, the interpretation of neopterin and biopterin concentration per hemoglobin is more valid than the interpretation of neopterin and biopterin per liter. Percentage of biopterin, of the sum of neopterin and biopterin should always be calculated. In addition, determination of hemoglobin concentration is essential as a measure for efficient extraction of neopterin and biopterin. Although the measurement of neopterin and biopterin in urine is more sensitive due to the higher concentrations present, our data prove the usefulness of their measurement from DBS for the routine diagnosis of BH 4 deficiencies.

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“…In the same report (15), we have noted even larger increases in the content of metabolites of DA and 5-HT, which is considered to be index of the activities of DAergic and 5-HTergic neurons. Furthermore, administretion of 6R-BH 4 has been reported to improve clinical symptoms of malignant hyperphenylalaninemia (16) and Parkinson's disease (17), in which the activities of catecholamine and/or 5-HT-containing neurons in the brain are decreased because of decreased biosynthesis of catecholamine and/or 5-HT (18,19). These data, taken together, suggest that 6R-BH 4 enhances release of catecholamine and/or 5-HT from nerve terminals.…”

Section: Introductionmentioning

confidence: 99%

6R-L-erythro-5,6,7,8-Tetrahydrobiopterin and Dopamine Release

Miwa

Koshimura

1995

Pteridines

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SummaryWe previously reported that intracerebroventricular administration of 6,7,, a cofactor for aromatic amino acid hydroxylases and nitric oxide synthase, induces an increase in DOPA levels (as an index of DA biosynthesis) and in levels of DA metabolites (as an index of DA release) in the rat brain: the increase in DOPA levels was larger than that of DA metabolites, indicating that 6R-BH 4 enhances DA release. In the present study, we examined the effects of 6R-BH 4 on DA release in vivo from the striatum of male Wistar rats and its mechanism of action using brain microdialysis. When various concentrations of 6R-BJL, 6S-BJL (a diastereoisomer of 6R-BH 4 ) or 6-methyltetrahydropterin (6-MPJL) were added to the perfusion fluid of microdialysis probes, DA levels collected in dialysates increased in a concentration-dependent manner: the 6R-BJL-induced increase was far greater than the increase induced by 6S-BH4 or 6-MPJL. Biopterin had little effect on the DA levels. After i.p. injection of250 mg/kg ofa-methyl-p-tyrosine (a-MT; an inhibitor of tyrosine hydroxylase), most of the 6R-BH 4 -induced increase persisted but the increase induced by 6S-BJL or 6-MPH4 was abolished. The 6R-BH4 -induced increase in DA levels in dialysates was abolished after addition of tetrodotoxin (50 J.1M) to the perfusion fluid, but it persisted after i.p. injection of 100 mg/kg of nomifensine which completely inhibited DA reuptake. The increase in DA levels also persisted after administration of nitric oxide synthase inhibitors. The 6R-BJL-induced increase in DA levels was inhibited by co-administration of 6S-BJL or 6-MPJL. Administration of sepiapterin (an immediate precursor of 6R-BJL) increased tissue levels of reduced biopterin (mainly consisting of 6R-BJL) but not its extracellular levels monitored by brain microdialysis, indicating that it selectively increases the intracellular 6R-BJL levels. In contrast, administration of 6R-BH 4 increased both tissue levels of reduced biopterin and its extracellular levels, indicating that it increases both the intraand extra-cellular 6R-BH 4 leveles. DA levels in dialysates was elevated following administration of sepiaterin (an immediate precursor of 6R-BJL), but the elevation was abolished after pretreatment with a-MT. Furthermore, 6R-BJL increased firing rates of neurons in the dorsal motor nucleus of vagus monitored by a slice patch method. These results suggest that 6R-BJL has a DA releasing action independent of its cofactor for tyrosine hydroxylase and nitric oxide synthase, which is mediated by a specific recognition site for 6R-BH4 on DA neurons or related cells.

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Atypical cases of phenylketonuria

Cited by 7 publications

References 38 publications

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

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

Diagnosis of tetrahydrobiopterin deficiency using filter paper blood spots: further development of the method and 5 years experience

6R-L-erythro-5,6,7,8-Tetrahydrobiopterin and Dopamine Release

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