SQU Med J, April 2010, Vol. 10, Iss. 1, pp. 80-83, Epub. 17th Apr 10 Submitted 2nd Sept 09 Revision Req. 23rd Nov 09. Revision Recd. 9th Dec. 09 Accepted 6th Jan 09 1Department of Medicine, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat, Oman; 2Department of Medicine, Sultan Qaboos University Hospital, Muscat, Oman; 3School of Medicine, University of Nottingham, UK *To whom correspondence should be addressed. Email: nickwood2@doctors.org.uk ِرّي الباِدِئ ِعنَْد النُّْضج احملدد سريريا عند البالغني كَّ داء السُّ الُعمانيني صغار السن غياب املوّرثات اجلينية الشائعة يف الغرب نيكوالس وودهاوس، أميمة الشفيع، علي املعمري، ناجي هاشم، فاطمة الريامي، ساندي رايبرن ال�شكري مر�س ال�رسيرية خ�شائ�شه ت�شابه الذي ال�شكر بداء امل�شابني ال�شن �شغار املر�شى من متزايدة اأعدادا ن�شنقبل الهدف: امللخ�ص: الباديء عند الن�شج حيث التاريخ االأ�رسي ي�شري اىل تاأثر م�ّرث اأحادي، مع غياب الدليل الذي ي�شري اىل وج�د داء ال�شكري من الن�ع االأول ذي ،1α - 4 ، والعامل الكبدي الن�ويα املناعة الذاتية. الهدف من هذه الدرا�شة حتديد م�ش�ؤولية الطفرات ال�راثية الثالثة )العامل الكبدي الن�وي واجلل�ك�كاينيز( االكرث �شي�عا بني املر�شى الغربيني من عدمه عند البالغني الُعمانيني �شغار ال�شن. الطريقة: متت الدرا�شة يف م�شت�شفى جامعة ال�شلطان قاب��س ب�شلطنة ُعمان، حيث مت اختيار ع�رسين مري�شا بالغا من �شغار ال�شن ممن لهم تاريخ اأ�رَسي باحتمالية الت�ريث مب�ّرث واحد بفرتة تقل عن )18( �شهرا، وكان مت��شط االأعمار )25( �شنة مع و�شيط من�شب كتلة اجل�شم )29(. اأجري التحري ل�ج�د م�شادات املناعة الذاتية �شد خاليا البنكريا�س اجلزيرية – ن�ع ب- و ناِزَعُ الَكْرُب�ك�ِشيل حلام�س اجلل�تاميك وكان �شلبيا. وافق اأربعة ع�رس مري�شا على اإجراء حتري فح�س الدم ال�راثي ومت اإر�شاله ل�حدة الربوفي�ش�ر هاتر�شلي يف كلية الطب بباك�شرت )اململكة املتحدة(، حيث مت فح�س احَلْم�ُس الرِّْيِبيُّ النََّ�ِوي َمْنُزوع االأوك�ِشجني للطفرات اجلينية يف االك�ش�ن )10-1( من انزمي ناِزَعُ الَكْرُب�ك�ِشيل حلام�س اجلل�تاميك واالك�ش�ن )10-2( من م�ّرثات (، الطفرات ال�راثية االأكرث �شي�عا يف اوروبا. النتائج: مل يتم العث�ر على اأي من 4α ( والعامل الكبدي الن�وي ) 1α (العامل الكبدي الن�وي الطفرات ال�راثية املذك�رة يف اأي من املر�شى. اخلال�صة: يف هذه املجم�عه ال�شغرية من املر�شى العمانيني البالغني �شغريي ال�شن الذين تطابق ج مل يتم العث�ر على اأي من الطفرات ال�راثية الثالث االأكرث �شي�عا يف الغرب. وهذا قد يك�ن ناجتا حالتهم ال�رسيرية داء ال�شكري الباِدُئ ِعْنَد النُّ�شْ من وج�د طفرات جديدة يف املر�شى العمانيني اأو اأن ه�ؤالء املر�شى يعان�ن من داء ال�شكري من الن�ع الثاين نتيجة لت�ريث بع�س امل�ّرثات التي ت�شكل خطرا يف اال�شابة املبكرة بداء ال�شكري من الن�ع الثاين الذي يتميز ب�ج�د مقاومة كبرية لالن�ش�لني ناجتة عن ال�شمنة . ج، طفرات، داء ال�شكري العائلي، البالغني ال�شغار، ُعمان. ِريُّ الباِدُئ ِعْنَد النُّ�شْ كَّ مفتاح الكلمات: داء ال�شكري – الن�ع الثاين، داء ال�شُّ abstract: Objectives: We are seeing a progressive increase in the number of young patients with clinically defined maturity onset diabetes of the young (MODY) having a family history suggestive of a monogenic cause of their disease and no evidence of autoimmune type 1 diabetes mellitus (T1DM). The aim of this study was to determine whether or not mutations in the 3 commonest forms of MODY, hepatic nuclear factor 4α (HNF4α), HNF1α and glucokinase (GK), are a cause of diabetes in young Omanis. Methods: The study was performed at Sultan Qaboos University Hospital (SQUH), Oman. Twenty young diabetics with a family history suggestive of monogenic inheritance were identified in less than 18 months; the median age of onset of diabetes was 25 years and the median body mass index (BMI) 29 at presentation. Screening for the presence of autoimmune antibodies against pancreatic beta cells islet cell antibody (ICA) and glutamic acid decarboxylase (GAD) was negative. Fourteen of them consented to genetic screening and their blood was sent to Prof. A. Hattersley’s Unit at the Peninsular Medical School, Exeter, UK. There, their DNA was screened for known mutations by sequencing exon 1-10 of the GCK and exon 2-10 of the HNF1α and HNF4α genes, the three commonest forms of MODY in Europe. Results: Surprisingly, none of the patients had any of the tested MODY mutations. Conclusion: In this small sample of patients with clinically defined MODY, mutations of the three most commonly affected genes occurring in Caucasians were not observed. Either these patients have novel MODY mutations or have inherited a high proportion of the type 2 diabetes mellitus (T2DM) susceptibility genes compounded by excessive insulin resistance due to obesity. Keywords: Diabetes Mellitus, Type II; Diabetes mellitus, maturity onset; MODY; mutations; Diabetes, familial; Young adults; Oman. Clinically-Defined Maturity Onset Diabetes of the Young in Omanis Absence of the common Caucasian gene mutations *Nicholas JY Woodhouse,1 Omayma T Elshafie,2 Ali S Al-Mamari,2 Nagi HS Mohammed,2 Fatma Al-Riyami,2 Sandy Raeburn3 brief communication Nicholas JY Woodhouse, Omayma T Elshafie,Ali S Al-Mamari, Nagi HS Mohammed,Fatma Al-Riyami and Sandy Raeburn Brief Communication | 81 Diabetes mellitus (DM), both types I and II, is common worldwide and now affects more than 5% of all obese adolescents;1-4 however, optimal investigation and management is still unclear. Doctors often struggle to provide the best therapy, especially in regions where lifestyle changes in the last one or two generations have contributed to the diabetogenic risk. In Oman, as in other countries of the Arabian Peninsula, type 2 diabetes (T2DM) especially and other complex, multifactorial disorders have reached epidemic levels.5 We are now seeing a progressive increase in the number of young Omani diabetics (<25 years) with a family history indicating a monogenic cause of their disease and who have no evidence of type 1 diabetes mellitus (T1DM). These patients have clinically defined maturity onset diabetes of the young (MODY), a disorder resulting from mutation in 6 different genes causing deficient insulin secretion. They are often misdiagnosed as T1DM and treated with insulin. However, some patients have mutations in the genes encoding HNF1α or β-cell potassium adenosine triphosphate (K-ATP) channels both of which respond well to low dose sylphonylurea (SU) therapy. To date, we have identified three such families (not included in the present study) who were able to discontinue insulin and continue on SU therapy alone. Clearly therefore, MODY exists in Oman and in this study we have screened an additional 14 patients for common MODY mutations. Methods Twenty young diabetics with a family history suggesting monogenic inheritance [Figure 1], and whose antibodies against pancreatic beta- cells islet cell antibodies (ICA) and glutamic acid decarboxylase (GAD)) were negative, were identified in less than 18 months. Of these 14 patients, whose characteristics are shown in Table 1, consented to genetic screening and their blood was sent to the Molecular Genetics Laboratory at the Peninsular Medical School, Exeter, UK. There, their DNA was screened for known mutations by sequencing exon 1-10 of the glucokinase gene and exon 2-10 of the HNF1α and HNF4α, the commonest forms of MODY in Europe6 using the DNA ABI PRISM® 3100 Genetic Analyzer, Results and Discussion In this small group of young Omani diabetics, we expected to find several with known MODY mutations, particularly as we have already identified 3 different MODY families responsive to SU therapy. Surprisingly, this was not the case and mutations in the three commonest forms of MODY were not observed, although all had family histories suggestive of a monogenic cause of their disease and no evidence of T1DM. How might this be explained? Either these patients had novel MODY mutations or have inherited one or more of the T2DM susceptibility genes. Novel mutations cannot be ruled out as, in a recent and larger Danish study, mutations were found in only half the patients with clinically defined MODY, as ours.7 Interestingly, patients with clinically defined MODY in Mexico and China8,9 have few of the documented mutations occurring in Caucasians which suggests that our Omani MODY patients may have novel gene mutations as well. However, we suspect that early onset T2DM is more likely, particularly as the median BMI in our study group was 29, an additional factor associated with early onset disease. MODY is a familial monogenic form of diabetes with autosomal dominant inheritance and high penetrance of 80–95%. In contrast to type 1 and type 2 diabetes, MODY usually develops below 25 years6,10 [Figure 2]. Currently there are 6 identified gene mutations, three of them, HNF1α, HNF4α and glucokinase, are common and account for >80% of MODY cases in Europe and North America, while others are rare (HNF1β, insulin promoter factor 1 and neurogenic differentiation factor 1).10 Some of the MODY patients will not Advances in Knowledge 1. It would appear that the maturity onset diabetes of the young mutations common in Caucasians are rare in Oman. Application to Patient Care 1. Families with mutations of the beta cells potassium ATP channels may be identified and thus the use of insulin avoided Clinically-Defined Maturity Onset Diabetes of the Young in Omanis Absence of the common Caucasian gene mutations 82 | QU Medical Journal, April 2010, Volume 10, Issue 1 have a known gene mutation (MODY X), but efforts are on going to determine the responsible mutations.10, 11 With young patients, the clinician should distinguish between T1DM (with autoimmune destructions of the beta-cells and insulin dependence), monogenic defects due to the maturity onset of diabetes in the young (MODY) and T2DM which is multifactorial.3,12,13 With their early age of onset, patients with single gene disorders such as MODY are often misdiagnosed as T1DM and inappropriately treated with insulin.12,14-16 This is unfortunate as patients with glucokinase deficiency (GKD) have few complications and rarely require treatment.13,17 Furthermore, patients with transcriptions factor mutations (such as HNF1α and neonatal Kir6.2) respond dramatically to sulphonylurea medication.14 Recently, we have successfully switched diabetics, from three families, from insulin of many years duration to oral SUs. Although monogenic DM in the UK is only estimated to occur in 1–2% of the diabetic population (i.e. up to 40,000 patients), in Oman the incidence of monogenic disease is probably much higher due to the higher rate of consanguinity. Mutagenesis screening is expensive so we are now actively screening candidate patients using a trial of SU therapy. Screening is carried out in patients aged <30 years who are taking insulin, have a positive family history and no GAD or ICA antibodies. Of the 10 patients studied so far 3 have gratifyingly responded to low dose SU therapy. This trial is currently in progress, together with screening of the patients for the T2DM susceptibility genes which are currently known to be associated with T2DM.18-21 References 1. Field LL. Type 1 Diabetes. In: T Bishop T, Sham P, Eds. Analysis of Multifactorial Disease. Oxford: Bios Scientific Publishers Ltd, 2000. 2. Hanson RL, Knowler WC. Type 2 diabetes mellitus and maturity onset diabetes of the young. In: T Bishop T, Sham P, Eds. Analysis of Multifactorial Disease. Oxford: Bios Scientific Publishers Ltd, 2000. 3. McCarthy M. Approaches to detemining the genetics basis of non-insulin-dependent diabetes mellitus. In: Day INM, Humphries SE, Eds. Genetics of Common Diseases: Future therapeutic and diagnostic possibilities. Oxford: Bios Scientific Publishers Ltd, 40s 65 60 31 30 Figure 1: Pedigree of index Omani patient. The numbers indicate the age at diagnosis 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 Age at Diagnosis Type 1 MODY Type 2 Legend: MODY = maturity onset diabetes of the young Figure 2: Age at onset with differnt types of diabetes Table 1: Details of the 14 patients with a family history suggesting a monogenic cause of their disease. Shown is the median and range of age and BMI at diagnosis. Four were taking insulin alone and 10 oral hypoglycaemic agents. Age at diagnosis/Yr Median Sex BMI Therapy GAD / ICA 20 (12-40) 10 M 29 INS Negative 4 F 20-41 OHA Negative Legend: BMI = body mass index; GAD = glutamic acid decarboxylase; ICA =islet cell antibody; INS = insulin; OHA = oral hypoglycaemic agents Nicholas JY Woodhouse, Omayma T Elshafie,Ali S Al-Mamari, Nagi HS Mohammed,Fatma Al-Riyami and Sandy Raeburn Brief Communication | 83 1997. 4. Pearson ER, Starkey BJ, Powell RJ, Gribble FM, Clark PM, Hattersley AT, et al. Genetic cause of hyperglycaemia and response to treatment in diabetes. Lancet 2003; 362:1275–81. 5. Hassan MO, Barwani S, Al-Yahyaee S, Al Haddabi S, Rizvi S, Jaffer A, et al. A family study in Oman: Large consanguineous, polygamous Omani Arab pedigrees. A planned model for the study of complex diseases. Community Genet 2005; 8:56–60. 6. Hattersley A, Bruining J, Shield J, Njolstad P, Donaghue K. The diagnosis and management of monogenic diabetes in children. Pediatr Diabetes 2006; 7:352–60. 7. 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Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families. Acta Diabetol 1997; 40:217–24. 18. Florez JC. Clinical review: the genetics of type 2 diabetes, a realistic appraisal in 2008. Clin Endocrinol Metab 2008: 93:4633. 19. Groop L, Lyssenko V. Genes and type 2 diabetes mellitus. Curr Diab Rep 2008; 8:192–7. 20. Lyssenko V, Groop L. Genome-Wide association study for the type 2 diabetes: clinical applications. Curr Opin Lipidol 2009; 20:87. 21. Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, et al. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 2008; 40:638–45.