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Objective: To allow early recognition of cystathionine beta-synthase by newborn screening., Study Design: Total homocysteine was determined in dried blood spots with a novel, robust high-performance liquid chromatography method with tandem mass spectrometry. Quantification of homocysteine was linear over a working range up to 50 micromol/L. For mutation analysis, DNA was tested for 2 mutations common in Qatar., Results: Both methods proved to be suitable for high throughput processing. In 2 years, 7 infants with classic homocystinuria were identified of 12,603 native Qatari infants, yielding an incidence of 1:1800. Molecular screening would have missed 1 patient homozygous for a mutation not previously identified in the Qatari population. Over a period of 3 years, a total of 14 cases of classic homocystinuria were detected by screening of homocysteine from all newborn infants born in Qatar (n = 46 406). Homocysteine was always elevated, whereas methionine was elevated in only 7 cases., Conclusions: The study offers a reliable method for newborn screening for cystathionine beta-synthase deficiency, reaching a sensitivity of up to 100%, even if samples are taken within the first 3 days of life., (Copyright 2010 Mosby, Inc. All rights reserved.)

We report the results of molecular neonatal screening for homocystinuria (cystathionine beta-synthase deficiency) in neonates of Qatari origin, developed in conjunction with a novel biochemical screening approach. DNA was extracted from dried blood spots (DBS); the prevalent Qatari CBS gene mutation p.R336C (c.1006C>T) and a second mutation were tested with specific TaqMan assays. Over a period of 2 years we screened 12,603 neonates and identified six affected neonates homozygous for p.R336C. There were 225 heterozygous carriers for p.R336C. One additional child with homocystinuria detected through biochemical screening was homozygous for a mutation not previously identified in Qatar. Homocystinuria in the Qatari population has an incidence of 1:1,800, the highest in the world and even higher than previously estimated. Allele frequency of the mutation p.R336C is approximately 1%, displaying a significant deviation from Hardy Weinberg equilibrium. In conclusion, first-line molecular neonatal screening is technically feasible and may be developed as an option for presymptomatic identification of genetic disorders caused by specific mutations or a limited number of prevalent mutations. However, sensitivity for the diagnosis of disorders caused by various mutations is limited even in a homogeneous population such as Qatar.

Qatar is a country in the Gulf area and member of the Gulf Cooperation Council states. The country is populated by original Qatari tribes that amount to about 200,000 people and about 600,000 expatriates mainly from Arabic and Asian countries. Inbreeding over centuries and high rates of consanguinity in the Qatari population and in some groups of expatriates, in addition to large family sizes and rapid population growth, have contributed to a high frequency of autosomal recessive disorders. In December 2003 Hamad Medical Corporation in Doha and the University Children's Hospital of Heidelberg, Germany, started an extended state-wide neonatal screening programme for metabolic and endocrine disorders, with the laboratory situated in Heidelberg, Germany. All aspects of the screening process had to be adapted to the unique situation of the laboratory being 6000 km from the birthplace of the neonates. Within 32 months, samples of 25,214 neonates were screened. In 28 cases an endocrine or metabolic diagnosis was identified (incidence 1:901, in Germany 1:1728). In particular, a variety of monogenic metabolic diseases were prevalent, with 19 patients detected giving an incidence of metabolic diseases of 1:1327 (Germany 1:2517). Each euro spent on the screening programme saved more than 25 euros in health and social costs. The programme revealed a high incidence of treatable inborn metabolic diseases in the population of Qatar. A reliable screening for classical homocystinuria showing a unique incidence of >1:3000 and for sickle cell disease has now been added.