RESUMEN
BACKGROUND: Hyperphenylalaninemia is the most common genetic metabolic disease. Early treatment prevents brain injury effectively. The present study aimed to detect the exact amino acid status of patients with hyperphenylalaninemia before treatment. METHODS: Data of 116 newborn patients from our Newborn Screening Center and 161 older patients from our clinic before treatment were collected. The content of 17 amino acids in their blood was determined by tandem mass spectrometry and compared with normal controls. Relationship between phenylalanine and other amino acids in patients was analyzed using the smoothing curve fitting and threshold effect analysis. RESULTS: Most amino acids in the blood of patients were within the normal range; however, they were different significantly from those of the normal children. Newborn patients showed higher phenylalanine (346.30 vs 45.90 µmol/L), valine (121.50 vs 110.30 µmol/L), citrulline, ornithine and lower tyrosine (52.97 vs 66.12 µmol/L), threonine (68.68 vs 78.21 µmol/L), glutamine levels than observed in normal newborns. Older patients showed significantly higher phenylalanine (844.00 vs 51.82 µmol/L), valine (117.60 vs 110.90 µmol/L), histidine, serine and lower tyrosine (55.97 vs 67.31 µmol/L), threonine (35.94 vs 51.89 µmol/L), alanine, asparagine, glutamic acid, methionine, arginine, glycine, ornithine, glutamine content than found in matched normal children. Tyrosine, valine, ornithine, and threonine in newborn patients and tyrosine, glycine, glutamine, and threonine in older patients had a nonlinear correlation with phenylalanine levels with obvious threshold effect and clear inflection points. CONCLUSION: Significant difference was observed in the amino acid status between pretherapeutic hyperphenylalaninemia patients and normal children. Some amino acids showed notable threshold effect with phenylalanine level in a nonlinear pattern.
Asunto(s)
Aminoácidos/sangre , Fenilcetonurias/sangre , Fenilcetonurias/terapia , Estudios de Casos y Controles , Femenino , Humanos , Lactante , Recién Nacido , Dinámicas no Lineales , Fenilalanina Hidroxilasa/deficiencia , Fenilalanina Hidroxilasa/metabolismoRESUMEN
BACKGROUND: This study aimed to explore the value of applying a new pterin marker (isoxanthopterin) to the traditional urine pterin analysis to reduce the rate of mis-diagnosis of 6-pyruvoyltetrahydropterin synthase deficiency (PTPSD) and improve the accuracy of diagnosis. METHODS: We compared the urine neopterin (N), biopterin (B), isoxanthopterin (Iso), B% and Iso% levels between patients with phenylalanine hydroxylase deficiency and those with PTPSD, and found the most specific pterin biomarkers by ROC analysis. A positive cut-off value of urine pterins was determined. The effect of combined Iso% + B + B% in reducing PTPSD mis-diagnosis was evaluated, and the different urine pterin levels in PTPSD and false PTPSD (FPTPSD) were compared. The concordance of PTPSD diagnosis by the new pterin scheme and gene mutation analysis was determined. RESULTS: (1) Urinary B, B%, Iso and Iso% were significantly lower in PTPSD than those in phenylalanine hydroxylase-deficiency group (P < 0.01); (2) Iso%, B%, and B were the most specific markers; (3) The positive cut-off values of B, B%, Iso% for PTPSD were < 0.17 mmoL/moLCr, < 5.0%, and < 9.5%, respectively; (4) urinary B + B% + Iso% scheme significantly reduced the false-positive rate of PTPSD compared to traditional ones. The Iso% levels in FPTPSD group were higher than the ones in PTPSD group; (5) an accuracy of diagnosis for PTPSD was increased by 9-19% when Iso% was introduced to urinary pterin scheme. CONCLUSIONS: Iso% is helpful to reduce the rate of misdiagnosis of PTPSD in the diagnosis by urinary pterin analysis for hyperphenylalaninemias and improve the accuracy of diagnosis. This approach is worthy of further development and increased utilization.
Asunto(s)
Fenilcetonurias/diagnóstico , Liasas de Fósforo-Oxígeno/deficiencia , Xantopterina/orina , Biomarcadores/orina , Biopterinas/orina , Cromatografía Liquida , Diagnóstico Diferencial , Errores Diagnósticos/prevención & control , Humanos , Lactante , Neopterin/orina , Curva ROCRESUMEN
BACKGROUND: This study aimed to investigate the mutation spectrum of the QDPR gene, to determine the effect of mutations on dihydropteridine reductase (DHPR) structure/function, to discuss the potential genotypephenotype correlation, and to evaluate the clinical outcome of Chinese patients after treatment. METHODS: Nine DHPR-deficient patients were enrolled in this study and seven of them underwent neonatal screening. QDPR gene mutations were analyzed and confirmed by routine methods. The potential pathogenicity of missense variants was analyzed using Clustal X, PolyPhen program and Swiss-PDB Viewer 4.04_OSX software, respectively. The clinical outcomes of the patients were evaluated after long-term treatment. RESULTS: In 10 mutations of the 9 patients, 4 were novel mutations (G20V, V86D, G130S and A175R), 4 were reported by us previously, and 2 known mutations were identified. R221X was a hotspot mutation (27.7%) in our patients. Eight missense mutations probably had damage to protein. Six patients in this series were treated with a good control of phenylalanine level. The height and weight of the patients were normal at the age of 4 months to 7.5 years. Four patients, who underwent a neonatal screening and were treated early, showed a normal mental development. In 2 patients diagnosed late, neurological symptoms were significantly improved. CONCLUSIONS: The mutation spectrum of the QDPR gene is different in the Chinese population. Most mutations are related to severe phenotype. The determination of DHPR activity should be performed in patients with hyperphenylalaninemia. DHPR-deficient patients who were treated below the age of 2 months may have a near normal mental development.