A common mutation in the<i>CBS</i>gene explains a high incidence of homocystinuria in the Qatari population

Elsaid, Mahmoud F.; Badii, Ramin; Bessisso, Mohammed S.; Shahbek, Noora; El-Ali, Mariam G.; El-Marikhie, Mariam; El-Zyoid, M.; Salem, Marwa S.; Bener, Abdülbari; Hoffmann, Georg F.; Zschocke, Johannes

doi:10.1002/humu.9436

Cited by 43 publications

(54 citation statements)

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“…One limitation is that CBS deficiency in the Qatari population is predominately caused by homozygosity for a frequent mutation (Bener and Hussain 2006;El-Said et al 2006;Zschocke et al 2009;Gan-Schreier et al 2010). Therefore our results are not necessarily transferable to other populations with different genetic backgrounds.…”

Section: Discussionmentioning

confidence: 99%

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Newborn Screening for Vitamin B6 Non-responsive Classical Homocystinuria: Systematical Evaluation of a Two-Tier Strategy

et al. 2016

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Background: In classical homocystinuria (HCU, MIM# 236200) due to the deficiency of cystathionine bsynthase (EC 4.2.1.22) there is a clear evidence for the success of early treatment. The aim of this study was to develop and evaluate a two-tier strategy for HCU newborn screening.Methods: We reevaluated data from our newborn screening programme for Qatar in a total number of 125,047 neonates including 30 confirmed HCU patients. Our hitherto existing screening strategy includes homocysteine (Hcy) measurements in every child, resulting in a unique dataset for evaluation of two-tier strategies. Reevaluation included methionine (Met) levels, Met to phenylalanine (Phe) ratio, and Hcy. Four HCU cases identified after database closure were also included in the evaluation. In addition, dried blood spot samples selected by Met values >P97 in the newborn screening programs in Austria, Australia, the Netherlands, and Taiwan were analyzed for Hcy.Results: Met to Phe ratio was found to be more effective for first sieve than Met, sorting out nearly 90% of normal samples. Only 10% of the samples would have to be processed by second-tier measurement of Hcy in dried blood spots. As no patient with HCU was found neither in the samples investigated for HCU, nor by clinical diagnosis in the other countries, the generalization of our two-tier strategy could only be tested indirectly.Conclusion: The finally derived two-tier algorithm using Met to Phe ratio as first-and Hcy as second-tier requires 10% first-tier positives to be transferred to Hcy measurement, resulting in 100% sensitivity and specificity in HCU newborn screening. Abbreviations CBSCystathionine b-synthase DBS Dried blood spots ESI-MS/ MS Electrospray ionization-tandem mass spectrometry HCU Classical homocystinuria Hcy Homocysteine

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Section: Discussionmentioning

confidence: 99%

“…We previously reported a high prevalence of about 1:3,000 in Qatar. In this highly consanguineous population HCU is caused primarily by homozygosity for the mutation p.R336C (c.1006C>T) in the CBS gene (Bener and Hussain 2006;El-Said et al 2006;Zschocke et al 2009;Gan-Schreier et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Newborn Screening for Vitamin B6 Non-responsive Classical Homocystinuria: Systematical Evaluation of a Two-Tier Strategy

et al. 2016

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“…For example, the incidence ranges between 1:6400 to 1:20,500 in European populations and between 1:1800 to 1:3000 in the Qatari population [2][3][4][5][6][7]. The true worldwide prevalence is likely underestimated because of undiagnosed cases [8].…”

Section: Introductionmentioning

confidence: 99%

“…The true worldwide prevalence is likely underestimated because of undiagnosed cases [8]. More than 190 mutations have been reported in the CBS gene [9], but within the Qatari population, homocystinuria (HCU) is caused predominately by a single mutation c.1006C > T (p.R336C) [6]. In Qatar, the high incidence of CBS deficiency and availability of effective treatment justifies a primary screen for all neonates.…”

Section: Introductionmentioning

confidence: 99%

A Rapid Screening Method for the Measurement of Neonatal Total Homocysteine in Dried Blood Spots by Liquid Chromatography-Tandem Mass Spectrometry

Maase

Skrinska

Younes

et al. 2017

IJNS

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Homocystinuria (HCU) due to cystathionine-β-synthase deficiency is generally regarded as a rare disease, but within the Qatari population has an incidence of 1 in 1800 live births. Most newborn screening methods for HCU using dried blood spots (DBS) rely on the detection of an elevated methionine level or a rapid screen for total homocysteine (tHCY). However, screening based on methionine levels alone lacks specificity and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) methods for tHCY exhibit variable results with high false positive rates. This report describes a LC-MS/MS method for detection of tHCY on DBS, with improved specificity. tHCY was extracted from DBS with a solution containing dithiothreitol and subsequently butylated with hydrochloric acid in n-butanol. The butyl esters were separated by liquid chromatography on a reverse-phase column and the homocysteine (HCY), detected by tandem mass spectrometry. The butyl ester of HCY eluted at 1.8 min. Total analysis time was 6.1 min per sample, including column flush and equilibration. This method allows for the quantification of tHCY over a linear range from 0.3 to 200 µM. Intraassay and interassay imprecision and recoveries were acceptable. Good concordance was observed with another LC-MS/MS method. Application of this method improves specificity and reduces false positive rates in screening for HCU.

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“…Although this disease is the most frequent disorder of sulphur and methionine metabolism, it is still considered a rare inborn error of metabolism with estimated prevalence between 1/20,000 and 344,000. However, in Qatar, its prevalence is extremely high, the highest in the world, of approximately 1/1,800 births (Mudd et al 1964;Mudd 1985;Naughten et al 1998;El-Said et al 2006;Zschocke et al 2009;Gan-Schreier et al 2010;Yap 2012). Clinically, CBS-deficient patients may present with ectopia lentis, osteoporosis, and skeletal deformities often associated with Marfanoid features, but most importantly with intellectual disability and life-threatening complications of the vascular system leading to premature death (Mudd 1985;Mudd et al 1985;Yap 2012).…”

Section: Introductionmentioning

confidence: 99%

Neurodevelopmental and Cognitive Outcomes of Classical Homocystinuria: Experience from Qatar

et al. 2014

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Background: Classical homocystinuria due to cystathionine b-synthase (CBS) deficiency (OMIM 236200) is a recessively inherited condition caused by mutations in the CBS gene. The founder mutation p.R336C accounts for almost all CBS deficiency in Qatar, affecting approximately 1 in 1,800 births, making it the most prevalent monogenic disease among the Qatari population. Untreated patients can have severe intellectual disability (ID), devastating multisystem complications and premature death. Current treatment is based on pharmacology therapy and life-long methionine-restricted diet, which is difficult to maintain particularly in late diagnosed individuals. Data on the neurodevelopmental and psychological impact of the disease on outcomes among Qatari patients are generally lacking and have not been studied.Objectives: To examine the cognitive, educational and psychological outcomes of classical homocystinuria on Qatari patients.Subjects and Methods: Thirty-two cases with classical homocystinuria and 25 sibling controls were recruited to evaluate the neurodevelopmental and cognitive outcomes. We reviewed the subjects' medical record and collected pertinent clinical and educational data from parents. Stanford-Binet Intelligence Test (Arabic translation -4th ed.) was used for cognitive (IQ) testing.

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A common mutation in theCBSgene explains a high incidence of homocystinuria in the Qatari population

Cited by 43 publications

References 10 publications

Newborn Screening for Vitamin B6 Non-responsive Classical Homocystinuria: Systematical Evaluation of a Two-Tier Strategy

Newborn Screening for Vitamin B6 Non-responsive Classical Homocystinuria: Systematical Evaluation of a Two-Tier Strategy

A Rapid Screening Method for the Measurement of Neonatal Total Homocysteine in Dried Blood Spots by Liquid Chromatography-Tandem Mass Spectrometry

Neurodevelopmental and Cognitive Outcomes of Classical Homocystinuria: Experience from Qatar

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