Molecular epidemiology and diagnosis study of common inborn errors of metabolism disorders in Oman and UAE: Phase 2

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Description

Inborn errors of metabolism disorders (IEMs) comprise a wide range of autosomal recessive disorders which show defects in metabolism of carbohydrates, amino acids, organic acids and fatty acids. This category of disorders even extends to include lysosomal storage diseases and mitochondrial disorders. Although the incidence of individual IEMs is relatively low, collectively IEMs affect more than 2% of all live newborns. This proportion is even much higher if we considered diseased children or the hospitalized population only (Baric et al., 2001). Reports from the Gulf region indicated that metabolic diseases constitute a significant cause of neonatal and infant death and mental retardation. However, prior to this project, only a handful of mutations responsible for IEM disorders have been identified and reported in the two populations (Abdulrazzaq et al., 2008; Ali et al., 2008). Hospital based studies in Oman indicated a relatively high prevalence of inborn errors of metabolism disorders (Joshi et al., 2002 Joshi and Venugopalan 2007). In one study, a total of 82 patients from 76 families were studied, of whom 33 (40%) were aged and lt;1 week at presentation. Disorders identified included different lysosomal storage disorders, organic acidureas, carbohydrate metabolic disorders, congenital lactic acidosis, urea cycle disorders, amino acidopathies, fatty acid oxidation defects and various other miscellaneous disorders (Joshi et al., 2002). In these patients parental consanguinity was twice as frequent in the study patients as in the general population. Recently, Joshi and Venugopalan (2007) analysed Tandem Mass Spectroscopy results of 166 neonates (90 males and 76 females) aged 1 and ndash;28 days (median age of 7 days) and found that the most common diseases diagnosed were MSDU, propionic acidemia, urea cycle diseases and isovaleric acidemia. A retrospective study on metabolic disorders at Al-Wasl Hospital in Dubai conducted by the Centre for Arab Genomic Studies Work Group (2006) between 1995 and 2004 indicated the presence of at least 30 inborn errors of metabolism disorders in the UAE including Phenylketonuria (PKU), Homocystinuria, Propionicacidemia, Maple Syrup Urine Disease (MSUD), Krabbe disease and Galactosemia (CAGS; WWW.CAGS.AE). In addition, the newborn screening programme in UAE revealed that PKU is the most common IEM disorder with incidence of 1:14,571 (Al-Hosani et al., 2008). Results from Phase 1 In phase 1 of this project, the two groups managed to identify more than seventy (70) IEM disorders causing mutations (see tables in the appendix for examples). Parts of those results have been published or submitted for publication in the following three manuscripts (manuscripts are attached): Hertecant JL, Ben-Rebeh I, Marah MA, Abbas T, Ayadi L, BenSalem S, Al-Jasmi FA, Al-Gazali L, Al-Yahyaee SA and Ali BR (2012) Clinical and molecular analysis of Isovaleric Acidaemia patients in the United Arab Emirates reveals remarkable phenotypes and four novel mutations in the IVD gene. European Journal of Medical Genetics. Under Review. Ben-Rebeh I, Hertecant, J, Al-Gazali L, Al-Jasmi F, Aburawi HE, Al-Yahyaee SA and Ali BR (2012) Identification of Mutations Underlying Twenty Inborn Errors of Metabolism in UAE population. Genetic Testing and Molecular Biomarkers, In Press Ali BR, Hertecant JL, Al-Jasmi F, Hamdan MA, Khuri S, Akawi NA and Al-Gazali L (2011) New and known mutations associated with Inborn Errors of Metabolism in a heterogeneous Middle Eastern population. Saudi Medical Journal, 32: 353-359. As can be seen from the published papers and the unpublished data presented in tables 1-7 of appendix B, we are pleased to report that we have identified many more mutations than we anticipated. Having said that, we have been also been receiving many more samples than originally expected and therefore we consider that the job is not fully completed yet. In addition, the disorders presented to us were more diverse and complex necessitating further efforts and resources to complete this project.

Layman's description

Inborn errors of metabolism disorders (IEMs) comprise a wide range of autosomal recessive disorders which show defects in metabolism of carbohydrates, amino acids, organic acids and fatty acids. This category of disorders even extends to include lysosomal storage diseases and mitochondrial disorders. Although the incidence of individual IEMs is relatively low, collectively IEMs affect more than 2% of all live newborns. This proportion is even much higher if we considered diseased children or the hospitalized population only (Baric et al., 2001). Reports from the Gulf region indicated that metabolic diseases constitute a significant cause of neonatal and infant death and mental retardation. However, prior to this project, only a handful of mutations responsible for IEM disorders have been identified and reported in the two populations (Abdulrazzaq et al., 2008; Ali et al., 2008). Hospital based studies in Oman indicated a relatively high prevalence of inborn errors of metabolism disorders (Joshi et al., 2002 Joshi and Venugopalan 2007). In one study, a total of 82 patients from 76 families were studied, of whom 33 (40%) were aged and lt;1 week at presentation. Disorders identified included different lysosomal storage disorders, organic acidureas, carbohydrate metabolic disorders, congenital lactic acidosis, urea cycle disorders, amino acidopathies, fatty acid oxidation defects and various other miscellaneous disorders (Joshi et al., 2002). In these patients parental consanguinity was twice as frequent in the study patients as in the general population. Recently, Joshi and Venugopalan (2007) analysed Tandem Mass Spectroscopy results of 166 neonates (90 males and 76 females) aged 1 and ndash;28 days (median age of 7 days) and found that the most common diseases diagnosed were MSDU, propionic acidemia, urea cycle diseases and isovaleric acidemia. A retrospective study on metabolic disorders at Al-Wasl Hospital in Dubai conducted by the Centre for Arab Genomic Studies Work Group (2006) between 1995 and 2004 indicated the presence of at least 30 inborn errors of metabolism disorders in the UAE including Phenylketonuria (PKU), Homocystinuria, Propionicacidemia, Maple Syrup Urine Disease (MSUD), Krabbe disease and Galactosemia (CAGS; WWW.CAGS.AE). In addition, the newborn screening programme in UAE revealed that PKU is the most common IEM disorder with incidence of 1:14,571 (Al-Hosani et al., 2008). Results from Phase 1 In phase 1 of this project, the two groups managed to identify more than seventy (70) IEM disorders causing mutations (see tables in the appendix for examples). Parts of those results have been published or submitted for publication in the following three manuscripts (manuscripts are attached): Hertecant JL, Ben-Rebeh I, Marah MA, Abbas T, Ayadi L, BenSalem S, Al-Jasmi FA, Al-Gazali L, Al-Yahyaee SA and Ali BR (2012) Clinical and molecular analysis of Isovaleric Acidaemia patients in the United Arab Emirates reveals remarkable phenotypes and four novel mutations in the IVD gene. European Journal of Medical Genetics. Under Review. Ben-Rebeh I, Hertecant, J, Al-Gazali L, Al-Jasmi F, Aburawi HE, Al-Yahyaee SA and Ali BR (2012) Identification of Mutations Underlying Twenty Inborn Errors of Metabolism in UAE population. Genetic Testing and Molecular Biomarkers, In Press Ali BR, Hertecant JL, Al-Jasmi F, Hamdan MA, Khuri S, Akawi NA and Al-Gazali L (2011) New and known mutations associated with Inborn Errors of Metabolism in a heterogeneous Middle Eastern population. Saudi Medical Journal, 32: 353-359. As can be seen from the published papers and the unpublished data presented in tables 1-7 of appendix B, we are pleased to report that we have identified many more mutations than we anticipated. Having said that, we have been also been receiving many more samples than originally expected and therefore we consider that the job is not fully completed yet. In addition, the disorders presented to us were more diverse and complex necessitating further efforts and resources to complete this project.
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