Phenylalanine hydroxylase (PAH) deficiency is an autosomal recessive disorder that results in elevated concentrations of phenylalanine (Phe) in the blood. If left untreated, the accumulation of Phe can result in profound neurocognitive disability. The objective of this systematic literature review and meta-analysis was to estimate the global birth prevalence of PAH deficiency from newborn screening studies and to estimate regional differences, overall and for various clinically relevant Phe cutoff values used in confirmatory testing. The protocol for this literature review was registered with PROSPERO (International prospective register of systematic reviews). Pubmed and Embase database searches were used to identify studies that reported the birth prevalence of PAH deficiency. Only studies including numeric birth prevalence reports of confirmed PAH deficiency were included. From the 85 publications included in the review, 238 birth prevalence estimates were extracted. After excluding prevalence estimates that did not meet quality assessment criteria or because of temporal and regional overlap, estimates from 45 publications were included in the meta-analysis. The global birth prevalence of PAH deficiency, estimated by weighting regional birth prevalences relative to their share of the population of all regions included in the study, was 0.64 (95% confidence interval [CI] 0.53–0.75) per 10,000 births and ranged from 0.03 (95% CI 0.02–0.05) per 10,000 births in Southeast Asia to 1.18 (95% CI 0.64–1.87) per 10,000 births in the Middle East/North Africa. Regionally weighted global birth prevalences per 10,000 births by confirmatory test Phe cutoff values were 0.96 (95% CI 0.50–1.42) for the Phe cutoff value of 360 ± 100 µmol/L; 0.50 (95% CI 0.37–0.64) for the Phe cutoff value of 600 ± 100 µmol/L; and 0.30 (95% CI 0.20–0.40) for the Phe cutoff value of 1200 ± 200 µmol/L. Substantial regional variation in the birth prevalence of PAH deficiency was observed in this systematic literature review and meta-analysis of published evidence from newborn screening. The precision of the prevalence estimates is limited by relatively small sample sizes, despite widespread and longstanding newborn screening in much of the world.

/pdf/birth-prevalence-of-phenylalanine-hydroxylase-deficiency-a-1393zmtvs6.pdf

Birth prevalence of phenylalanine hydroxylase deficiency: a systematic literature review and meta-analysis.

The metabolism and function of phospholipids in Mitochondria

Background: Neonatal hyperphenylalaninemia (HPA) screening did not begin until 2009 in the Uygur population because of poor medical and economic conditions. This study intended to investigate HPA incidence rate and characterize mutation spectrum of phenylalanine hydroxylase ( PAH ) gene within the Uygur population. Methods: Cross-sectional data of National Direct Reporting System database from 2009 to 2016 were used to calculate incidence rate. All HPA positive newborns were diagnosed and confirmed by Sanger sequencing. A low Phe diet was implemented. Results: A total of 580,608 Uygur neonates were screened, 111 were diagnosed with HPA with an incidence rate of 1:5,230, 58 different mutations in PAH gene were detected. Eight novel variants were found, including two nonsense mutations (L11*, L197*), two splicing mutations (IVS12-2A > C, IVS13-1G > A), one frameshift mutation (K115 > Hfs) and three missense mutations (E368K, E370G, D435V), distributing in twenty patients. A104D was the most frequent mutation in this study, and the other hot spot of R413P was found in 4 patients in a same Uygur village with a carrier rate of 1:2.1. Conclusions: This is the first study to investigate HPA incidence rate in the Uygur population. Our study highlights regional differences in PAH genotypes and mutation rates.

/pdf/the-molecular-epidemiology-of-hyperphenylalaninemia-in-uygur-4gn7j8evs1.pdf

The molecular epidemiology of hyperphenylalaninemia in Uygur population: incidence from newborn screening and mutational spectra

Introduction Phenylketonuria (PKU) is an inborn error of metabolism characterized by pathogenic variants of the phenylalanine hydroxylase (PAH) gene with a resulting accumulation of phenylalanine (Phe) to neurotoxic levels. Diagnosis of PKU in the Latvian population began in 1985 and the present study's aim was to evaluate the available data on all PKU patients in Latvia. Materials and methods The medical records of 116 - DNA sample was available in 110 patients (102 nonrelated individuals) diagnosed with PKU in Latvia were obtained. Phe concentrations were measured in dried blood spots. Genomic DNA was analyzed for pathogenic variants in the PAH gene. Biochemical data were available through follow-up visits of the 83 patients. Results In 97% of patients (99 of 102), pathogenic variants were detected on both alleles. With an occurrence of 69.6%%, the most common pathogenic variant was the severe pathogenic variant p.Arg408Trp. The available data for 83 patients revealed that metabolic control was better in younger age groups and worse in adults. Conclusion Latvia exhibits a relatively homogeneous pool of disease-causing PKU alleles with a high prevalence of the classical severe form of PKU. Dietary compliance in all patients' groups is lower than expected, especially it is poor in adult age group.

Phenylketonuria in the Latvian population: Molecular basis, phenylalanine levels, and patient compliance.

BACKGROUND Tetrahydrobiopterin (BH4 ) deficiency is an autosomal recessive disorder, which is caused by an enzyme deficiency involved in its synthetic or metabolic pathways. Clinical symptoms may include microcephaly, hypoevolutism, severe ataxia, and seizures. The purposes of this study are to analyze the genotype-phenotype and the pedigree of the first case of BH4 deficiency in the Uygur of China. METHODS (a) This patient received tandem mass spectrometry, urinary neopterin and biopterin analysis, and determination of dihydropteridine reductase (DHPR) activity in dried blood spots. (b) Blood DNA samples of this patient and her three family members were collected for gene sequencing and mutation analysis. RESULTS (a) The basic urinary neopterin and biopterin were 1.07 mmol/mol Cr and 3.12 mmol/mol Cr, respectively, and biopterin percentage was 74.42%. The DHPR activity of this patient was 31.11% of normal control. (b) Sanger sequencing of PAH gene in this patient was negative but positive of her sister, which carries 2 heterozygous mutation c.781C>T and c.1238G>C. Next-generation sequencing on the patient identified a homozygous mutation in the quinoid dihydropteridine reductase (QDPR) gene at c.508G>A, which was confirmed by Sanger sequencing. CONCLUSION (a) The patient was the first case of clinical diagnosis of BH4 deficiency in the Uighur. And there are two types of hyperphenylalaninemia (HPA) in the same family. (b) The mild HPA patient with severe nervous system damage should pay more attention to the BH4 deficiency. (c) Using next-generation sequencing technology can increase the mutation detection rate when the hereditary diseases are highly suspected in clinic.

/pdf/gene-mutation-and-pedigree-analysis-of-tetrahydrobiopterin-22x4qiz3tj.pdf

Gene mutation and pedigree analysis of tetrahydrobiopterin deficiency in a Uygur family of China.

Neonatal metabolic acidosis (NMA) is a common problem, particularly in critically ill patients in neonatal intensive care units (NICUs). Complex etiologies and atypical clinical signs make diagnosis difficult; thus, it is crucial to investigate the underlying causes of NMA rapidly and provide disorder-specific therapies. Our study aims to provide an overview of the genetic causes of NMA in patients from NICUs. We performed next-generation sequencing (NGS) on neonates with NMA from January 2016 to December 2019. Clinical features, genetic diagnoses, and their effects on clinical interventions were collected for analysis. In the 354 enrolled patients, 131 (37%) received genetic diagnoses; 95 (72.5%) of them were autosomal recessively inherited diseases. Two hundred and fifteen variants spanning 57 genes were classified as pathogenic (P) or likely pathogenic (LP) in 131 patients. The leading cause was metabolic disorders due to 35 genes found in 89 patients (68%). The other 42 NMA patients (32%) with 22 genes had malformations and renal, neuromuscular, and immune-hematological disorders. Seven genes (MMUT, MMACHC, CHD7, NPHS1, OTC, IVD, and PHOX2B) were noted in more than four patients, accounting for 48.9% (64/131) of the identified P/LP variants. Forty-six diagnosed patients with uncorrected NMA died or gave up. In conclusion, 37% of neonates with metabolic acidosis had genetic disorders. Next-generation sequencing should be considered when investigating the etiology of NMA in NICUs. Based on early molecular diagnoses, valuable treatment options can be provided for some genetic diseases to achieve better outcomes.

/pdf/neonatal-metabolic-acidosis-in-the-neonatal-intensive-care-4caj2hg5ib.pdf

Neonatal Metabolic Acidosis in the Neonatal Intensive Care Unit: What Are the Genetic Causes?

MEGDEL syndrome and SATB2-associated syndrome (SAS) are both rare congenital disorders with poor prognoses caused by gene mutations. We present the case of a 2-day-old girl with an unexplained abnormal liver function, feeding problem, and dystonia. Using next-generation sequencing, we identified two novel mutations in SERAC1 and a mutation in SATB2. Now, she is 15 months old and has the characteristics of SAS, such as downslanting palpebral fissures and delayed primary dentition. Besides the typical phenotypes of MEGDEL syndrome, such as hypertonia, failure to thrive, deafness, and motor regression, she has progressive cholestasis and is prone to high serum lactate after rehabilitation training and hypoglycemia with low ketone under starving conditions. These phenotypes substantially differ from the transient liver function abnormalities and hypoglycemia reported in the literature.

/pdf/case-report-progressive-cholestasis-severe-phenotype-of-2y8q0yo70f.pdf

Case Report: Progressive Cholestasis: Severe Phenotype of MEGDEL Syndrome With SATB2-Associated Syndrome.

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Papers

The molecular epidemiology of hyperphenylalaninemia in Uygur population: incidence from newborn screening and mutational spectra

Neonatal Metabolic Acidosis in the Neonatal Intensive Care Unit: What Are the Genetic Causes?

Gene mutation and pedigree analysis of tetrahydrobiopterin deficiency in a Uygur family of China.

Case Report: Progressive Cholestasis: Severe Phenotype of MEGDEL Syndrome With SATB2-Associated Syndrome.