Sultan Qaboos University Med J, February 2014, Vol. 14, Iss. 1, pp. e42-49, Epub. 27TH Jan 14 Submitted 16TH Jun 13 Revisions Reqd. 28TH Jul & 19TH Sep 13; Revisions Recd. 7TH Aug & 6TH Oct 13 Accepted 10TH Oct 13 1Tawam Hospital, Al Ain, United Arab Emirates; 2Department of Paediatrics, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates *Corresponding Author e-mail: aljasmif@uaeu.ac.ae الطفرات الوراثية و نسبة شيوع األمراض االستقالبية عند اإلماراتيني دراسة من مركز األمراض االستقالبية مبستشفى توام – اإلمارات العربية املتحدة عائ�صة �ل�صام�صي, جوزيف هريتكنت, �صنية �حلماد, عبد �لقادر �صوعيد, فاطمة �جل�صمي abstract: Objectives: This study aimed to determine the mutation spectrum and prevalence of inborn errors of metabolism (IEM) among Emiratis. Methods: The reported mutation spectrum included all patients who were diagnosed with IEM (excluding those with lysosomal storage diseases [LSD]) at Tawam Hospital Metabolic Center in Abu Dhabi, United Arab Emirates, between January 1995 and May 2013. Disease prevalence (per 100,000 live births) was estimated from data available for 1995–2011. Results: In 189 patients, 57 distinct IEM were diagnosed, of which 20 (35%) entities were previously reported LSD (65 patients with 39 mutations), with a birth prevalence of 26.87/100,000. This study investigated the remaining 37 (65%) patients with other IEM (124 patients with 62 mutations). Mutation analysis was performed on 108 (87%) of the 124 patients. Five patients with biotinidase deficiency had compound heterozygous mutations, and two siblings with lysinuric protein intolerance had two homozygous mutations. The remaining 103 (95%) patients had homozygous mutations. As of this study, 29 (47%) of the mutations have been reported only in Emiratis. Two mutations were found in three tribes (biotinidase deficiency [BTD, c.1330G>C] and phenylketonuria [PAH, c.168+5G>C]). Two mutations were found in two tribes (isovaleric aciduria [IVD, c.1184G>A] and propionic aciduria [PCCB, c.990dupT]). The remaining 58 (94%) mutations were each found in individual tribes. The prevalence was 48.37/100,000. The most prevalent diseases (2.2–4.9/100,000) were biotinidase deficiency; tyrosinemia type 1; phenylketonuria; propionic aciduria; glutaric aciduria type 1; glycogen storage disease type Ia, and mitochondrial deoxyribonucleic acid depletion. Conclusion: The IEM birth prevalence (LSD and non-LSD) was 75.24/100,000. These results justify implementing prevention programmes that incorporate genetic counselling and screening. Keywords: Metabolism, Inborn Errors; Mutations; Prevalence; Founder Effect; United Arab Emirates. امللخ�ص: الهدف: هدفت �لدر��صة �إىل حتديد مدى �نت�صار �الأمر��س �ال�صتقالبية ومعرفة طفر�تها �لور�ثية الطريقة: ت�صمنت ت�صجيل كل �لطفر�ت �لو�رثية يف جميع �ملر�صى �لذين مت ت�صخي�صهم باالأمر��س �ال�صتقالبية )بعد ��صتبعاد �أمر��س �الختز�ن يف �جل�صيمات �حلالة ) �أمر��س �لتخزين �للي�صو�صومية( يف مركز �الأمر��س �ال�صتقالبية مب�صت�صفى تو�م بابوظبي – �الإمار�ت �لعربية �ملتحدة خالل �لفرتة من يناير 1995 �إىل مايو 2013 ومن ثم مت تقديرمعدل �نت�صار �الأمر��س �ال�صتقالبية )لكل 100,000 مو�ليد �أحياء( النتائج: مت ت�صخي�س 57 مر�صا من خمتلف �الأمر��س �ال�صتقالبية يف 189 مري�س منهم 20 )35%( من فئة �أمر��س �الختز�ن يف �جل�صيمات �حلالة )65 مري�س لديهم 39 طفرة ور�ثية( بن�صبة 26.87 لكل 100,000 .و �ل�صبعه و�لثالثون مري�صا �لباقون طفر�ت وجدت )87%( مري�صا �أ�صل 124 من يف 108 للطفر�ت حتليل مت ور�ثية(. طفرة لديهم 62 مري�صا 124( �حلالية در��صتنا مو�صع هم )65%( �لتحمل عدم مر�س لديهم �صقيقي يف �الأالئل متماثلة زيجوت طفرتي حتديد مت �لبيوتنيديز �نزمي عوز لديهم مر�صى خم�س يف �ملركبة �الأالئل متخالفة لربوتي �لليزين �أما باقي �ملر�صى 103 )%95( فوجدت لديهم طفر�ت زيجوت متماثلة �الأالئل. ومن �جلدير بالذكر �أن 29 )%47( طفرة ور�ثية مت ح�رشها يف �الإمار�تيي فقط �ىل �الآن. وجدت طفرتي يف 3 قبائل فقط )عوز �نزمي �لبيوتنيديز و بيلة �لفينل كيتونبينما وجدت طفرتي يف قبيلتي )�حم�صا�س �لدم �اليزوفالرييكي و �حم�صا�س �لدم �لربوبيونيكي( ووجد 58 )%94( طفرة يف عدد من �لقبائل �لفردية مبعدل �نت�صار 48.37 لكل 100,000. وكانت �أكرث �الأمر��س �صيوعا )4.9 –100,000/2.2( كاالآتي: عوز �نزمي �لبيوتنيديز وفرط تريوزين �لدم و بيلة �لفينل كيتون و �حم�صا�س �لدم �لربوبيونيكي و بيلة حم�س �لغلوتاريك �لنوع �الأول ود�ء �ختز�ن �لغليكوجي �لنوع �الأول �أ ونفاذ �حلم�س �لنووي �مليتوكوندري اخلال�صة: معدل �نت�صار�الأمر��س �ال�صتقالبية يف �ملو�ليد �الإمار�تيي )�أمر��س �الختز�ن يف �جل�صيمات �حلالة �أو غريها( يقدر بحو�يل ,100,000/75.24. هذه �لنتائج تربر تنفيذ �لرب�مج �لوقائية �لتي تت�صمن �ال�صت�صارة �لور�ثية و�مل�صح �جليني عند �لوالدة. مفتاح الكلمات: �أمر��س �ال�صتقالب يف �ملو�ليد؛ �لطفر�ت �جلينية؛ معدل �نت�صار؛ تاأثري موؤ�ص�س؛ �الإمار�ت �لعربية �ملتحدة. Mutation Spectrum and Birth Prevalence of Inborn Errors of Metabolism among Emiratis A study from Tawam Hospital Metabolic Center, United Arab Emirates Aisha Al-Shamsi,1 Jozef L. Hertecant,1 Sania Al-Hamad,2 Abdul-Kader Souid,2 *Fatma Al-Jasmi2 CLINICAL & BASIC RESEARCH Aisha Al-Shamsi, Jozef L. Hertecant, Sania Al-Hamad, Abdul-Kader Souid and Fatma Al-Jasmi Clinical and Basic Research | e43 Studies of the mutation spectrum and prevalence of IEM in the Middle East and North Africa (MENA) are still insufficient.1 These disorders, which are usually autosomal recessive, are more frequent in the MENA region due to “founder mutations” and consanguinity.2 The primary objective of this study was to provide data from the United Arab Emirates (UAE) that justify initiating prevention programmes, such as premarital screening and counselling. These data are also required to assess the impact of managing these patients within the UAE health systems. The population of Emiratis is ethnically diverse, claiming ancestry from the Arabian Peninsula, Persia, Baluchistan and East Africa. Emirati society consists of at least 70 distinct tribes. Despite the ethnic diversity, inter-tribal marriages are much less common than intra-tribal ones.3 In 2010, the UAE’s population was estimated at 8,264,070; 87% of this population was expatriate.4 In 2011, the total live birth in UAE was 83,950, of whom only 40% were Emiratis.5 The Center for Arab Genomic Studies reports 334 genetic diseases in the UAE, including IEM, congenital anomalies and mental retardation.6 Moreover, the prevalence and mutation spectrum of LSD in the UAE was recently reported and compared with published data from Western countries.7,9–11 This study was designed to report on other IEM entities among Emiratis. Methods This project was approved by the Al-Ain Medical Human Research Ethics Committee (protocol #12/59). The study’s population did not include patients who had received treatment exclusively abroad as they represent an unknown number of patients, nor did the study include the 22 patients managed at the Latifa Hospital in Dubai. For calculating the disease birth prevalence, all citizens of the UAE with IEM (excluding those with LSD) who were evaluated between January 1995 to December 2011 at Tawam Hospital, the only metabolic referral center in Abu Dhabi, were included. The mutation spectrum for non-LSD IEM included all patients evaluated from January 1995 to May 2013. The diagnosis of IEM was based on the clinical findings and screening tests, and was confirmed by biochemical and/or genetic studies. In many patients, the diagnosis was also supported by family studies. Direct genomic sequencing and multiplex ligation-dependent probe amplification (MLPA) studies for deletion/duplication mutations of IEM genes were performed by accredited genetic diagnostic laboratories. Novel variants were verified by extended family genetic testing as well as damage-prediction assessment using three different prediction tools: SIFT (Sorting Intolerant From Tolerant),12 PolyPhen-2 (Polymorphism Phenotyping Version 2)13 and MutationTaster.14 The estimated birth prevalence of each disease was calculated as the number of patients with a specific disease divided by the total number of Emirati live births in the UAE during the birth period (the time interval between the year of birth of the oldest patient and the year of birth of the youngest patient).10 The birth prevalence of a single patient was calculated as one divided by the number of total Emirati live births in the UAE between 1995 and 2011.11 The affected deceased siblings and fetuses that had not been evaluated at the Metabolic Center were not included in this study. The number Advances in Knowledge - The birth prevalence of inborn errors of metabolism (IEM) among Emiratis is 75.24 per 100,000 (1 per 1,329 live births). - Of the 62 mutations identified in this study, 29 (47%) have so far been reported only in Emiratis. - The most prevalent IEM in the United Arab Emirates (UAE) are biotinidase deficiency; tyrosinaemia type 1; phenylketonuria; propionic aciduria; glutaric aciduria type 1; glycogen storage disease type Ia, and mitochondrial deoxyribonucleic acid depletion. Application to Patient Care - The high prevalence of IEM in the UAE justifies implementing intensive prevention programmes that incorporate genetic counselling and screening. - The prevention of IEM requires premarital and prenatal testing, as well as counselling. - Early detection through newborn screening will improve patient outcomes, although prevention of these IEM is the ultimate goal. - Prevention programmes will decrease the burden of IEM on the UAE’s health system. Mutation Spectrum and Birth Prevalence of Inborn Errors of Metabolism among Emiratis A study from Tawam Hospital Metabolic Center, United Arab Emirates e44 | SQU Medical Journal, February 2014, Volume 14, Issue 1 of live births per year was obtained from the UAE National Bureau of Statistics but data were available only up to 2011.4 However, the mutation spectrum of patients who were diagnosed after 2011 was also included. Results Excluding those with LSD, 37 distinct IEM were diagnosed in the 124 patients between January 1995 and May 2013. Mutation analysis was performed on 108 (87%) patients. In 43 tribes, 62 mutations were found, with most of the reported mutations being homozygous. Five patients with biotinidase deficiency had compound heterozygous mutations, and two siblings with lysinuric protein intolerance had two homozygous mutations. The remaining 103 (95%) patients had homozygous mutations. As of the date of this study, 29 (47%) of the mutations had been reported only in Emiratis [Table 1]. Biotinidase deficiency (BTD, c.1330G>C) and phenylketonuria (PKU) (PAH, c.168+5G>C) occurred in three separate tribes. Isovaleric aciduria (IVD, c.1184G>A) and propionic aciduria (PCCB, c.990dupT) occurred in two separate tribes. The two tribes with propionic aciduria were originally from Oman. The remaining 58 (94%) mutations occurred in individual tribes [Table 1]. The 29 mutations unique to the UAE point to a “founder effect”. Diseases with a prevalence of 2.2–4.9 per 100,000 live births were biotinidase deficiency; tyrosinaemia type 1; PKU; propionic aciduria; glutaric aciduria type 1; glycogen storage disease type Ia; mitochondrial deoxyribonucleic acid (DNA) depletion; melanocortin 4 receptor deficiency, and chloride diarrhoea [Table 1]. Diseases with a prevalence of 1.1–1.9 per 100,000 live births were isovaleric aciduria; fructose 1,6-bisphosphatase deficiency; glutaric aciduria type II; lipoamide dehydrogenase deficiency; alpha- methylacyl-CoA racemase, and neonatal diabetes [Table 1]. Diseases with a prevalence of ≤0.98 per 100,000 live births were alkaptonuria; sulfite oxidase deficiency; nonketotic hyperglycinaemia; maple syrup urine disease; 3-methylcrotonylglycinuria; carbamoyl phosphate synthetase deficiency; citrullinaemia type 1; argininosuccinate lyase deficiency; lysinuric protein intolerance; cobalamin B deficiency; cobalamin C deficiency; pyridoxine- dependent seizures; medium-chain acyl-CoA dehydrogenase deficiency; carnitine deficiency; 3-ketothiolase deficiency; lipoamide dehyrogenase deficiency; adrenoleukodystrophy; Zellweger syndrome; bile acid disorder; progressive familial intrahepatic cholestasis; Crigler-Najjar syndrome; osteopetrosis, and butyrylcholinesterase deficiency [Table 1]. Discussion The UAE has a very high net migration rate, making it challenging to estimate the birth prevalence of a disease as a ratio of the entire population, so this study only estimated the birth prevalence of IEM among Emiratis.5 Intra-tribal marriages are dominant in the UAE, occurring in over 50% of unions. First-cousin marriages account for about 30% of those cases.3 The mutation spectrum and birth prevalence of LSD among Emiratis has recently been reported, focusing on other IEMs in the same population [Table 1].6,7 The main purpose of this study was to provide data that justify implementing prevention programmes, such as prenatal and premarital screening and counselling. The results show a birth prevalence for non-LSD IEM of 48.37 per 100,000 (1:2,067 live births) [Table 1], giving an overall IEM birth prevalence (LSD and non-LSD) of 75.24 per 100,000 (1:1,329 live births).7 This level of occurrence justifies the need for intensive prevention programmes. The data also point to the need for prenatal and premarital genetic testing and counselling. The overall disease prevalence of IEM in British Columbia, Canada, (1969–1996) is about 40 patients per 100,000 live births (1:2,500 live births); the prevalence in Italy (1985–1997) is 1:3,707 live births.15,16 The prevalence of classical IEM of amino acids, organic acids and fatty acid oxidation in Hong Kong is 1:4,122 live births.17 In our study, 62 distinct mutations were identified [Table 1]. Most mutations (95%) were homozygous, and 19 mutations were novel, not having been reported previously. As mentioned earlier, 29 (47%) have so far only been reported in Emiratis [Table 1]. The Centre for Arab Genomic Studies (CAGS) Aisha Al-Shamsi, Jozef L. Hertecant, Sania Al-Hamad, Abdul-Kader Souid and Fatma Al-Jasmi Clinical and Basic Research | e45 Table 1: Disorder, estimated prevalence, gene and mutation spectrum of non-lysomal storage disorders inborn errors of metabolism in the United Arab Emirates IEM OMIM# Genes/ RefSeq Mutations PKU† 261600 PAH NM_000277.1 n = 17 c.168+5G>C (splicing mutation)††; c.782G>A (p.R261G); c.970-2A>G**; c.1066-11G>A; c.755G>A** (p.R252Q)** Alkaptonuria§ 203500 HGD NM_000187.2 n = 1 c.174delA (p.R58fs) Tyrosinaemia type I† 276700 FAH NM_000137.2 n = 2 c.1156G>C (p.D386H); c.1A>G (p.M1V) Sulfite oxidase deficiency§ 606887 SUOX NM_000456.2 n = 1 c.650G>A (p.217R>Q) Nonketotic hyperglycinaemia§ 238300 GLDC NM_000170.2 n = 1 c.919G>T (p.E307*) Maple syrup urine disease§ 248600 DBT NM_001918.2 n = 1 c.1281+1 G>T Propionic aciduria† 606054 PCCA NM_000282.3 n = 2 c.1598_1601delTTGT (p.F533Wfs*5) PCCB NM_000532.3 n = 3 c.1142G>A (p.C381Y); c.990dupT (p.E331*)‡‡ 3-methylcrotonyl glycinuria§ 210200 MCCC1 NM_020166.2 n = 3 c.89+2_89+34del; c.1106C>G (p.P369R); c.694C>T (p.R232W) MCCC2 NM_022132.3 n = 1 c.735dupC (p.V247Gfs*2) Isovaleric aciduria‡ 243500 IVD NM_002225.3 n = 9 c.1193G>A (p.R398Q); c.295+5G>A; c.1175G>A (p.R392H); c.1184G>A**‡‡ (p.R395Q)**; c.1136_1138+4delTTGGTGA (p.F382fs)** Glutaric aciduria type I† 231670 GCDH NM_000159.2 n = 5 c.242C>T (p.P81L); c.427G>A (p.V143I); c.1204C>T (p.R402W) Carbamoyl phosphate synthetase deficiency§ 237300 CPS1 NM_001875.2 n = 1 c.1590dup (p.V531CfsX91)** Citrullinaemia type 1§ 603470 ASS1 NM_000050.4 n = 2 c.535T>C (p.W179R) Argininosuccinate lyase deficiency§ 207900 ASL NM_001024943.1 n = 1 c.332G>A (p.R111Q) Lysinuric protein intolerance§ 222700 SLC7A7 NM_001126105.2 n = 4 c.499+1G>C**; c.999G>C¶ (p.R333S); c.1005C>A¶ (p.F335L) Mutation Spectrum and Birth Prevalence of Inborn Errors of Metabolism among Emiratis A study from Tawam Hospital Metabolic Center, United Arab Emirates e46 | SQU Medical Journal, February 2014, Volume 14, Issue 1 Biotinidase deficiency† 253260 BTD NM_000060.3 n = 7 c.1330G>C (p.D444H)††; c.1207T>G (p.F403V); c.968A>G (p.H323R); c.1489C>T (p.P497S); c.557G>A (p.C186Y) Cobalamin B deficiency§ 251110 MMAB NM_052845.4 n = 1 c.197-1 G>T (intronic) Cobalamin C deficiency§ 277400 MMACHC NM_015506.2 n = 1 c.271insA (p.R91KfsX14) Pyridoxine-dependent seizures§ 266100 ALDH7A1 NM_001182.4 n = 1 deletion of exon 7 Fructose-1, 6-bisphosphatase deficiency‡ 611570 FBP1 NM_000507.2 n = 2 c.616_619delAAAG (p.K206fs*70)** Glycogen storage disease type Ia† 232200 G6PC NM_000151.2 n = 2 c.59A>G (p.Q20R) Glutaric aciduria type II‡ 231680 ETFDH NM_004453.2 n = 4 c.807A>C (p.Q269H) Medium-chain acyl- CoA dehydrogenase deficiency§ 607008 ACADM NM_000016.2 n = 1 c.985A>G (p.K329E) Carnitine deficiency§ 212140 SLC22A5 NM_003060.2 n = 1 c.248G>T (p.R83L) 3-ketothiolase deficiency§ 607809 ACAT1 NM_000019.3 n = 3 c.86_87dupTG (p.E30Wfs*11); c.854C>T (p.T285I) Lipoamide dehyrogenase deficiency‡ 238331 DLD NM_000108.3 n = 2 c.685G>T (p.G229C) Mitochondrial DNA depletion† 203700 POLG NM_002693.2 n = 7 c.3286C>T (p.R1096C) 251880 DGUOK NM_080916.1 n = 1 c.427 T>C (p.S143P) 609560 TK2 NM_004614.4 n = 2 c.173A>G (p.N58S) Adrenoleukodystrophy§ 300100 ABCD1 NM_000033.3 n = 1 c.309C>G (p.S103R) Zellweger syndrome§ 614862 PEX6 NM_000287.3 n = 1 c.611C>G (p.S204*)** Alpha-methylacyl-Co A racemase‡ 614307 AMACR NM_001167595.1 n = 3 c.877T>C (p.C293R) Bile acid synthesis disorder§ 235555 AKR1D1 NM_005989.3 (n = 1) c.781C>T (p.R261C)** Aisha Al-Shamsi, Jozef L. Hertecant, Sania Al-Hamad, Abdul-Kader Souid and Fatma Al-Jasmi Clinical and Basic Research | e47 has reported 29 published IEM in UAE (16 LSD and 13 other IEM). Only nine of the 13 non-LSD IEM entities are listed in Table 1. The remaining four disorders (argininaemia, mevalonic aciduria, homocystinuria and Menkes disease) occurred in the UAE, but data are lacking on whether these disorders exist in Emiratis or people of other nationalities. The 28 additional non-LSD IEM [Table 1] entities need to be included in the Catalogue of Transmission Genetics in Arabs database.8 Several IEM mutations in Middle Eastern populations have been reported.6,18–21 In the case of isovaleric aciduria, three mutations (p.R392H, p.R395Q and p.F382fs) were reported in four unrelated Emirati families and one mutation (p.E408K) in an Egyptian family.20 Alkaptonuria, due to the single nucleotide deletion of c.342delA (c.174delA), was reported in a family from Al Ain, UAE; the allelic prevalence was estimated at about 1%.21 In the UAE, screening began for PKU in 1995, for congenital hypothyroidism in 1998, sickle cell disease in 2002, congenital adrenal hyperplasia in 2005 and biotinidase deficiency in 2010.22–24 The Expanded National Neonatal Screening Programme, implemented in 2011, covers over 90% of all neonates. It includes amino acid disorders (PKU, maple syrup disease, citrullinaemia type I and argininosuccinic aciduria); organic acid disorders (isovaleric aciduria; HMG-CoA lyase deficiency; beta-ketothiolase deficiency; glutaric aciduria type I; propionic aciduria, and methylmalonic aciduria) and fatty acid oxidation disorders (medium-chain acyl-CoA dehydrogenase defici- ency). The registry for congenital anomalies and hereditary disorders, along with premarital genetic testing and counselling, were started in 1999.23 Biochemical studies can identify most IEM. The limitations to this approach, however, include the invasive sample collection (skin, liver or muscle biopsy), the limited availability of clinically accredited biochemical diagnostic laboratories and the need for relatively laborious analyses. Thus, the current clinical practice relies on combining biochemical and genetic studies. Identifying a mutation confirms the diagnosis, allows screening for asymptomatic family members, supports pre-implantation genetic programmes and may influence patient management. For example, Progressive familial intrahepatic cholestasis§ 601847 ABCB11 NM_003742.2 n = 1 c.1897A>C (p.T633P) Crigler-Najjar syndrome§ 606785 UGT-1 NM_000463.2 n = 1 c.1073A>G (p.N358S)** Melanocortin 4 receptor deficiency† 601665 MC4R NM_005912.2 (n = 2) c.485C>T (p.T162I) Chloride diarrhoea† 214700 SLC26A3 NM_000111.2 n = 3 c.559G>T (p.G187*) Osteopetrosis§ 259730 CA2 NM_000067.2 n = 2 c.232+1G>A Butyrylcholinesterase deficiency§ 177400 BCHE NM_000111.2 n = 1 c.293A>G (p.D98G) Neonatal diabetes mellitus‡ 176730 INS NM_001185098.1 n = 3 c.-331C>G IEM = inborn errors of metabolism; OMIM = Online Mendelian Inheritance in Man; RefSeq = National Center for Biotechnology Information Reference Sequence database; PKU = phenylketonuria; DNA = deoxyribonucleic acid. † Estimated birth prevalence of 2.2–4.9 per 100,000; ‡ Estimated birth prevalence of 1.1–1.9 per 100,000; § Estimated birth prevalence of <0.98 per 100,000; ¶ Both mutations found in the same patient in a homozygous state; ** Mutations reported so far only in Emiratis; †† The two mutations found in three separate tribes and ‡‡ the two mutations found in two separate tribes (the remaining mutations occurred in individual tribes); Bold = Novel mutations that have not previously been reported. Mutation Spectrum and Birth Prevalence of Inborn Errors of Metabolism among Emiratis A study from Tawam Hospital Metabolic Center, United Arab Emirates e48 | SQU Medical Journal, February 2014, Volume 14, Issue 1 PKU patients with c.168+5G>C, c.782G>A or c.970-2A>G typically respond to sapropterin, while patients with c.1066-11G>A or c.755G>A are unresponsive.25 In our practice, only ~50% of patients with c.168+5G>C responded to sapropterin and none of the patients with c.782G>A or c.970- 2A>G responded to this treatment. As shown in Table 1, the most prevalent diseases in the UAE are biotinidase deficiency; tyrosinaemia (type 1); PKU; propionic aciduria; glutaric aciduria type 1; glycogen storage disease type Ia; mitochondrial DNA depletion; melanocortin 4 receptor deficiency and chloride diarrhoea. Of the seven patients with biotinidase deficiency, most had a partial deficiency. When mutation analysis was performed on six patients, only one had a homozygous mutation with partial enzyme deficiency, while the other five carried compound heterozygous mutations (all born to parents of different tribes). Six of the seven patients were diagnosed by newborn screening after 2012, reflecting a high carrier frequency. Two siblings with lysinuric protein intolerance had two different homozygous mutations [Table 1]. The remaining patients had homozygous mutations. Ten novel missense mutations were reported in this study [Table 1], all in patients with clinical and/ or biochemical findings consistent with the disease. Future studies are needed to explain the functional effects associated with each of these mutations. Two mutations (involving biotinidase deficiency and PKU) each occurred in three separate tribes. Two mutations (involving isovaleric aciduria and propionic aciduria) each occurred in two separate tribes. The remaining 58 mutations (94%) each occurred in individual tribes [Table 1]. The need for effective premarital testing and counselling and prenatal/pre-implantation genetic diagnoses was highlighted by the 19 families with more than one affected child. This study reports 62 mutations. The 19 novel mutations that had not been previously reported are identified in Table 1 in bold. The 10 mutations that have been previously reported only in Emiratis are denoted by double asterisks in Table 1.17–20 The remaining 33 mutations are known mutations, which are available at the Human Gene Mutation Database.26 Identifying mutations allows the screening of asymptomatic family members and also supports pre-implantation genetic programmes. In the future, incorporating mutation analysis into newborn screenings as a second-tier test will decrease the number of false-positive cases and facilitate early treatment. Nevertheless, disease prevention remains the ultimate goal. This study has some limitations. First, the birth prevalence of IEM was estimated based only on patients who presented clinically or were referred by the National Newborn Screening Programme. Tawam Hospital is the UAE’s only referral center for metabolic diseases, and the 22 Emirati patients referred to Latifa Hospital were not included in this study. Thus it is possible that some patients who may have IEMs were not included in this study. Second, the UAE’s expanded National Newborn Screening Programme only started in 2011 so the population that has been screened for newborn IEM is limited. Third, patients who were born in 2012 and 2013 were not included in the calculation of disease prevalences since the total live births for those years were not yet available at the time of writing. Therefore, the reported IEM birth prevalences in Table 1 should be considered as rough estimations. Fourth, the IEM disorders in Table 1 were diagnosed primarily by biochemical studies, which is the gold-standard approach. The mutation analyses were done by an accredited laboratory and the novel missense variants were not investigated by functional assays, such as expression analyses. Preferably, chromosomes originating from Emirati tribes should be studied to verify whether the sequence variants represented polymorphisms versus disorders. Thus, the responsibility of some mutations for causing a disease may require future studies. Conclusion The estimated birth prevalence of IEM among Emiratis is 75.24 per 100,000 (1 per 1,329 live births). Distinct IEM (n = 57) and 101 mutations have been identified thus far. These data strongly point to the need for genetic counselling and screening. Identifying mutations unique to the UAE will allow for more effective pre-implantation genetic testing and premarital testing in order to prevent further cases from occurring within families. Early detection through newborn screening and treatment may prevent irreversible organ damage. Aisha Al-Shamsi, Jozef L. Hertecant, Sania Al-Hamad, Abdul-Kader Souid and Fatma Al-Jasmi Clinical and Basic Research | e49 However, in spite of the possibility of treatment, the prevention of genetic diseases should remain the ultimate goal. References 1. Tadmouri GO, Al Ali MT, Al-Haj Ali S, Al Khaja N. CTGA: The database for genetic disorders in Arab populations. Nucleic Acids Res 2006; 34:D602–6. 2. Teebi AS (Ed). Genetic Disorders Among Arab Populations (2nd ed). New York: Springer, 2010. P.612. 3. Al-Gazali L, Ali BR. Mutations of a country: A mutation review of single gene disorders in the United Arab Emirates (UAE). Hum Mutat 2010; 31:505–20. 4. United Arab Emirates National Bureau of Statistics. Methodology of estimating the population in UAE. From: w w w.uaestatistics .gov.ae/ReportPDF/Population%20 Estimates%202006%20-%202010.pdf Accessed: August 2013. 5. United Arab Emirates National Bureau of Statistics. Health 2011. From: www.uaestatistics.gov.ae/ EnglishHome/ReportDetailsEnglish/tabid/121/Default. aspx?ItemId=2180&PTID=104&MenuId=1 Accessed: Aug 2013. 6. Tadmouri GO. Genetic Disorders in Arab Populations. From: www.cags.org.ae/cbc02ga.pdf Accessed: May 2013. 7. Al-Jasmi FA, Tawfig N, Berniah A, Ali BR, Taleb M, Hertecant JL, et al. Prevalence and novel mutations of lysosomal storage disorders in United Arab Emirates: LSD in UAE. JIMD Rep 2013; 10:1–9. 8. Centre for Arab Genomic Studies. The Catalogue of Transmission Genetics in Arabs. From: http://www.cags. org.ae/ctga_search.html Accessed: May 2013. 9. Poupětová H, Ledvinová J, Berná L, Dvořáková L, Kožich V, Elleder M. The birth prevalence of lysosomal storage disorders in the Czech Republic: Comparison with data in different populations. J Inherit Metab Dis 2010; 33:387–96. 10. Poorthuis BJ, Wevers RA, Kleijer WJ, Groener JE, de Jong JG, van Weely S, et al. The frequency of lysosomal storage diseases in the Netherlands. Hum Genet 1999; 105:151–6. 11. Pinto R, Caseiro C, Lemos M, Lopes L, Fontes A, Ribeiro H, et al. Prevalence of lysosomal storage diseases in Portugal. Eur J Hum Genet 2004; 12:87–92. 12. Ng PC, Henikoff S. Predicting deleterious amino acid substitutions. Genome Res. 2001; 11:863–74. 13. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods 2010; 7:248–9. 14. Schwarz JM, Rödelsperger C, Schuelke M, Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 2010; 7:575–6. 15. Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics 2000; 105:e10. 16. Dionisi-Vici C, Rizzo C, Burlina AB, Caruso U, Sabetta G, Uziel G, et al. Inborn errors of metabolism in the Italian pediatric population: A national retrospective survey. J Pediatr 2002; 140:321–7. 17. Lee HC, Mak CM, Lam CW, Yuen YP, Chan AO, Shek CC, et al. Analysis of inborn errors of metabolism: Disease spectrum for expanded newborn screening in Hong Kong. Chin Med J (Engl) 2011; 124:983–9. 18. Ben-Rebeh I, Hertecant JL, Al-Jasmi FA, Aburawi HE, Al- Yahyaee SA, Al-Gazali L, et al. Identification of mutations underlying 20 inborn errors of metabolism in the United Arab Emirates population. Genet Test Mol Biomarkers 2012; 16:366–71. 19. Ali BR, Hertecant JL, Al-Jasmi FA, Hamdan MA, Khuri SF, Akawi NA, et al. New and known mutations associated with inborn errors of metabolism in a heterogeneous Middle Eastern population. Saudi Med J 2011; 32:353–9. 20. Hertecant JL, Ben-Rebeh I, Marah MA, Abbas T, Ayadi L, Ben Salem S, et al. Clinical and molecular analysis of isovaleric acidemia patients in the United Arab Emirates reveals remarkable phenotypes and four novel mutations in the IVD gene. Eur J Med Genet 2012; 55:671–6. 21. Abdulrazzaq YM, Ibrahim A, Al-Khayat AI, Nagelkerke N, Ali BR. R58fs mutation in the HGD gene in a family with alkaptonuria in the UAE. Ann Hum Genet 2009; 73:125– 30. 22. Al-Hosani H, Salah M, Saade D, Osman H, al-Zahid J. United Arab Emirates National Newborn Screening Programme: An evaluation 1998-2000. East Mediterr Health J 2003; 9:324–32. 23. Al Hosani H, Salah M, Abu-Zeid H, Farag HM, Saade D. The National Congenital Anomalies Register in the United Arab Emirates. East Mediterr Health J 2005; 11:690–9. 24. Al Hosani H, Salah M, Osman HM, Farag HM, Anvery SM. Incidence of haemoglobinopathies detected through neonatal screening in the United Arab Emirates. East Mediterr Health J 2005; 11:300–7. 25. Blau N, Yue W, Perez B. Databases of PKU and PND Variations. From: www.biopku.org/home/home.asp Accessed: Aug 2013. 26. Institute of Medical Genetics in Cardiff. The Human Gene Mutation Database. From: www.hgmd.org/ Accessed: Aug 2013.