Molecular genetics of phenylketonuria and tetrahydrobiopterin deficiency in Jordan

Carducci, Claudia; Amayreh, Wajdi; Ababneh, Haneen; Mahasneh, Amjad; Rababah, Buthaina Al; Qaqa, Kefah Al; Aqeel, Momen Al; Artiola, Cristiana; Tolve, Manuela; D'Amici, Sirio; Shen, Nan; Yu, Yongguo; Hillert, Alicia; Himmelreich, Nastassja; Okun, Jürgen G.; Hoffmann, Georg F.; Blau, Nenad

doi:10.1002/jmd2.12130

Cited by 9 publications

(10 citation statements)

References 22 publications

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“…The frequency of PCD deficiency in the present study was 7.1%, exceeding the 2.6% reported in BIODEFdb (BIODEFdb), which could suggest that the frequency of the different BH4 disorders varies among populations ( Souza et al, 2018 ; Carducci et al, 2020 ; Bozaci et al, 2021 ; Gundorova et al, 2021 ; Ray et al, 2022 ). We only found one homozygous c.289G > A or p.(Glu97Lys) male patient.…”

Section: Discussioncontrasting

confidence: 86%

“…We are also a tertiary medical referral center for symptomatic patients suspected to have inborn metabolic diseases. In other populations with a high prevalence of BH4D, a high incidence of consanguinity or endogamy (57%) has been found as a possible explanation ( Carducci et al, 2020 ); remarkably, in the present study, there was a lower proportion of families with consanguinity or endogamy (4/14 families, 28.5%, Table 4 ). Moreover, the hypothesis of a founder effect for the c.331G>T or p.(Ala111Ser) variant in the southeastern region of Mexico ( Fernández-Lainez et al, 2018 ), could not be demonstrated here, but further studies are warranted in a larger number of patients.…”

Section: Discussionsupporting

confidence: 63%

“…This value of 9.8% for BH4D appears to be higher than that described worldwide (1–2%, Blau et al, 2018 ; Himmelreich et al, 2021 ). However, a higher prevalence of BH4D has also been reported in populations in other areas, such as Jordan (33%, Carducci et al, 2020 ), the southern region of China (15.1%, Yuan et al, 2021 ), and Iran (12.3%, Khatami et al, 2016 ). We speculate that the high frequency of BH4D in this sample of Mexican HPA patients could be related to bias, since our institution serves patients with abnormal NBS to perform confirmatory diagnosis, management, and medical follow-up.…”

Section: Discussionmentioning

confidence: 89%

“…This distinction is achieved by measuring the serum and urinary levels of neopterin, biopterin, and primapterin (pterin profile) and by evaluating dihydropteridine reductase (DHPR) activity ( Opladen et al, 2011 ). However, the current wide availability of molecular testing has simplified the differential diagnosis of HPA, including BH4D ( Carducci et al, 2020 ) ( Table 1 ). Sepiapterin reductase (SR) deficiency and autosomal dominant GCH1 -related disorder do not present elevated Phe, precluding their identification by NBS; hence, they can only be suspected by the clinical pictures in symptomatic patients ( Blau, 2001 ).…”

Section: Introductionmentioning

confidence: 99%

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Genotypic spectrum underlying tetrahydrobiopterin metabolism defects: Experience in a single Mexican reference center

et al. 2022

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Background: Pterin profiles or molecular analyses of hyperphenylalaninemia (HPA) caused by phenylalanine hydroxylase (PAH) deficiency or tetrahydrobiopterin deficiency (BH4D) are not always available in low- or middle-income countries, including Mexico, limiting information regarding the phenotypic and genotypic characteristics of patients exhibiting BH4D.Objective: To report the genotypes underlying BH4D and the clinical presentation in unrelated Mexican HPA pediatric patients with normal PAH genotypes who attended a single metabolic reference center in Mexico.Methods: Automated Sanger sequencing of the PTS, QDPR, and PCBD1 genes of 14 HPA patients was performed. Predicted effects on protein structure caused by missense variants were assessed by in silico protein modeling.Results and discussion: A high prevalence of BH4D was noted in our HPA cohort (9.8%, N = 14/142). Clinically relevant biallelic genotypes were identified in the PTS (N = 7/14 patients), QDPR (N = 6/14 patients), and PCBD1 (N = 1/14 patients) genes. Four novel QDPR variants [c.714dup or p.(Leu239Thrfs*44), c.106-1G>T or p.(?), c.214G>T or p.(Gly72*), and c.187_189dup or p.(Gln63dup)] were identified. In silico protein modeling of six missense variants of PTS [p.(Thr67Met), p.(Glu81Ala), and p.(Tyr113Cys)], QDPR [p.(Cys161Phe) and p.(Pro172Leu)], and PCBD1 [p.(Glu97Lys)] supports their pathogenicity. Progressive neurological symptoms (mainly intellectual and motor impairment and even death in three patients) were noted in all patients with biallelic QDPR genotypes and in 5/7 patients bearing biallelic PTS genotypes. The single homozygous PCBD1 p.(Glu97Lys) patient remains asymptomatic.Conclusion: A higher proportion of BH4D (9.8 vs. 1%–2% worldwide), attributable to a heterogeneous mutational spectrum and wide clinical presentation, was noted in our Mexican HPA cohort, with the PTS-related HPA disorder being the most frequent. Sequencing-based assays could be a reliable approach for diagnosing BH4D in our population.

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Section: Discussioncontrasting

confidence: 86%

Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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Genotypic spectrum underlying tetrahydrobiopterin metabolism defects: Experience in a single Mexican reference center

et al. 2022

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“…The first PKU screening project in Jordan was initiated in collaboration with the Ministry of Health (MOH) in 2006. The MOH in Jordan began the NBS program for PKU, congenital hypothyroidism (CH) in 2008, and Favism (G6PD-deficiency) in 2012 for all newborns, including Syrians and refugees from other countries [11]. Furthermore, we have only one specialized clinic in Jordan to monitor and treat PKU patients.…”

Section: Introductionmentioning

confidence: 99%

Epidemiology of Phenylketonuria Disease in Jordan: Medical and Nutritional Challenges

et al. 2022

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Background: Phenylketonuria (PKU) is the most frequent inborn error in amino acid metabolism caused by a deficiency of the phenylalanine hydroxylase enzyme (PAH). If PKU is left untreated, high concentrations of phenylalanine (Phe) accumulate in the blood, leading to severe brain dysfunction, neurodevelopmental, behavioral and psychological problems. Data concerning the epidemiology of PKU in Jordan are limited. The main objectives of our study were to determine the prevalence of PKU in Jordan, analyze the PKU phenotypes, and identify major challenges in providing dietary management to PKU patients. Methods: Data were collected utilizing the medical records of PKU patients attending the PKU clinic at the Ministry of Health in Amman, Jordan, between 2008 and 2021. Results: The total number of patients diagnosed with PKU was 294. The prevalence of PKU was estimated to be 1/5263. Most patients were Jordanians (90.8%), and 9.2% were non-Jordanians. More than half of the patients (56%) were diagnosed through the national newborn screening (NBS) program. Regarding the phenotypes of PKU, 46.6% had moderate PKU, whereas 42.9% had the classic type of PKU and only 8 (2.7%) had cofactor Tetrahydrobiopterin (BH4) deficiency (atypical PKU). According to the age of diagnosis, 66% of patients were diagnosed more than 30 days post-birth. Consanguinity was found in 87.4% of patients, and the majority of patients, 218 (74.2%), had first-degree consanguinity. The most common complication was mental retardation (31%). Most patients were committed to dietary management (83%) and developed fewer complications. Conclusion: In our study, we demonstrated the importance of the NBS program in the early identification and diagnosis of new PKU cases which allows the initiation of treatment and dietary management to prevent severe complications of PKU in Jordan.

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Classical phenylketonuria presenting as maternal PKU syndrome in the offspring of an intellectually normal woman

et al. 2023

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Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism resulting from a deficiency of phenylalanine hydroxylase (PAH). If untreated by dietary restriction of phenylalanine intake, impaired postnatal cognitive development results from the neurotoxic effects of excessive phenylalanine (Phe). Signs and symptoms include severe intellectual disability and behavior problems with a high frequency of seizures and variable microcephaly. Maternal PKU syndrome refers to fetal damage resulting in congenital abnormalities when the mother has untreated PKU during pregnancy. Here, we report an intellectually normal 32‐year‐old female who presented with recurrent pregnancy loss and two neonatal deaths with congenital heart disease, microcephaly, intrauterine growth restriction, and respiratory distress. She was diagnosed with PKU through exome sequencing performed for carrier testing with a homozygous pathogenic variant in the PAH gene, c.169_171del, p.(Glu57del) that is associated with classical PKU. Consistent with the genetic finding, she had a markedly increased plasma phenylalanine concentration of 1642 μmol/L (normal <100). This case demonstrates that recurrent pregnancy loss due to untreated maternal PKU may present as an initial finding in otherwise unsuspected classical PKU and illustrates that extreme degrees of variable expressivity may occur in classical PKU. Moreover, this case illustrates the value of genomic sequencing of women who experience recurrent pregnancy loss or neonatal anomalies.

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Molecular genetics of phenylketonuria and tetrahydrobiopterin deficiency in Jordan

Cited by 9 publications

References 22 publications

Genotypic spectrum underlying tetrahydrobiopterin metabolism defects: Experience in a single Mexican reference center

Genotypic spectrum underlying tetrahydrobiopterin metabolism defects: Experience in a single Mexican reference center

Epidemiology of Phenylketonuria Disease in Jordan: Medical and Nutritional Challenges

Classical phenylketonuria presenting as maternal PKU syndrome in the offspring of an intellectually normal woman

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