- Email: [email protected]
Novel glucokinase gene mutation in the first Macedonian family tested for MODY
Accepted Manuscript Novel glucokinase gene mutation in the first Macedonian family tested for MODY M. Kocova, L. Elblova, S. Pruhova, J. Lebl, P. Dusatkova PII: DOI: Reference:
S0168-8227(16)31744-2 http://dx.doi.org/10.1016/j.diabres.2017.04.001 DIAB 6923
To appear in:
Diabetes Research and Clinical Practice
Received Date: Accepted Date:
6 December 2016 3 April 2017
Please cite this article as: M. Kocova, L. Elblova, S. Pruhova, J. Lebl, P. Dusatkova, Novel glucokinase gene mutation in the first Macedonian family tested for MODY, Diabetes Research and Clinical Practice (2017), doi: http:// dx.doi.org/10.1016/j.diabres.2017.04.001
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Novel glucokinase gene mutation in the first Macedonian family tested for MODY M. Kocova1, L. Elblova2, S. Pruhova2, J. Lebl2, P. Dusatkova2 1
University Pediatric clinic, Skopje, Republic of Macedonia
2
Department of Pediatrics, 2nd Faculty of Medicine, Charles University and University Hospital
Motol, V Uvalu 84, Prague, Czech Republic
Corresponding author Mirjana Kocova University Pediatric Clinic, Skopje 1000 Skopje Republic of Macedonia Phone: +389 2 3111713 Fax: +389 2 3716167 e-mail: [email protected]
1
Abstract We present a boy with mild hyperglycemia detected during an upper respiratory infection. Novel splicing mutation in the intron 1 of the GCK gene (c.45+1G>A) was detected, and was subsequently confirmed in his father. This is the first case of genetically confirmed Macedonian family with MODY. Key words: GCK-MODY, GCK mutation, mild hyperglycemia
2
Introduction Heterozygous inactivating mutations in the glucokinase (GCK) gene lead to a subtype of Maturity-Onset Diabetes of the Young (MODY) designated as GCK-MODY (1, 2) that is clinically characterized as persistent fasting hyperglycemia, negative pancreatic autoantibodies and optionally positive family history of diabetes/hyperglycemia (3). The GCK gene encodes enzyme glucokinase that plays crucial glucose processing role in the pancreatic beta cell. Glucokinase’s affinity to glucose is more than 20-times greater than hexokinase II (4) making it a sensitive sensor for glucose in the pancreatic beta cell. More than 700 mutations in the GCK gene causing GCK-MODY have been described so far (5) in many populations worldwide although reports from Western European countries prevail (6). However, the GCK-MODY population prevalence was estimated as 1.1 in 1,000 (7) indicating that majority of subjects is awaiting the correct diagnosis. Molecular genetic analyses of MODY patients are not widely accessible in economically challenged countries where a variety of known or novel mutations could have been detected. We describe the first case of genetically confirmed diagnosis of GCK-MODY in Macedonia caused by novel mutation in the GCK gene as a result of collaboration with a Czech institution performing molecular analysis.
3
Clinical observation and molecular work up A 2.5 year old boy presented epistaxis and increased thirst without glucosuria during an upper respiratory tract infection. His fasting blood glucose varied from 7.7 to 8.6 mmol/l, and he was referred for evaluation. The boy was born at term with a weight of 2800 grams (-1 SDS) and length 48 cm (-0.7 SDS). Family history revealed type 2 diabetes in a paternal grandfather who is on Metformin therapy with good metabolic control since the age of 36 years. At admission, both the height and weight of the boy were on 50% percentile. Fasting glucose levels were in the range 6.0-7.7 mmol/l. On OGTT his glycemia raised up to 13 mmol/l. HbA1c was 6.0% (42 mmol/mol) (normal range 4.4-6.2% and 25-44 mmol/mol, respectively). Fasting and postprandial insulinemias were within normal range (5 and 20 mU/l, respectively) as well as postprandial C-peptide (3.8-5.6 ng/ml). CGM (Guardian system, Medtronic) confirmed glycemia levels above the reference, particularly in the afternoon, however, the glycemia stability suggested further analyses to investigate MODY (Figure 1). Islet antibodies (GAD, IA, ICA and IAA2 were negative). . Diet with restriction of free carbohydrates was prescribed, daily and overnight measurements of glycemia and additional feedings if needed were recommended. The re-evaluation after six months revealed that the glucose levels measured at home ranged from 6.6 to 10.4 mmol/l, despite of the diet and physical activity. Additionally, mother reported that the probands’ father had hyperglycemia (the last measurement was 11.2 mmol/l postprandially), but he was
4
not under treatment and did not visit a specialist. Results of biochemical analyses in family members are summarized in Table 1. Molecular genetic testing of the GCK gene was performed using direct sequencing as described previously (8). In the patient and his father a novel heterozygous intronic substitution c.45+1G>A of the GCK gene was detected. This mutation was predicted to be disease causing by MutationTaster (9) and was not found neither in ExAC, nor in 1000 Genomes databases of polymorphisms. Moreover, another mutation at the same nucleotide position (c.45+1G>T) was published previously (10, 11). Mother and sister of the proband were negative for the respective mutation. Paternal grandfather was not available for analysis.
5
Discussion For the first time, we describe a family from Macedonia with genetically confirmed MODY, GCKMODY subtype. Moreover, hyperglycemia segregating within this family is caused by a novel mutation in the GCK gene (c.45+1G>A) that is predicted to disrupt exon – intron splicing. CGM is used mostly in patients with major forms of diabetes (12, 13). Small number of patients with MODY has been followed using CGM. The glucose curve recorded in our proband is similar to a patient with typical GCK-MODY reported previously (14). Increased demand for drinking was presented by the proband at the time of the first detection of hyperglycemia. However, polyuria and polydipsia are not typical clinical features for GCKMODY because patients generally display moderate fasting glycemia (3) which is below the renal threshold for glucose (15). Therefore, it is important not to misinterpret an increased demand for drinking during the common cold with fever for polydipsia as blood glucose over 10 mmol/l for a short period during common cold would not manifest by osmotic symptoms. Majority of patients with GCK-MODY do not know their diagnosis. We can find three reasons: first, because of the continuously mild phenotype (16), subjects are unaware of their hyperglycemia. Second, patients can be misdiagnosed as having major forms of diabetes (17). Third, genetic testing is financially demanding or inaccessible (7). In many, mostly Western European countries, the molecular genetic screening of the most common MODY genes is covered by research grants or public health insurance leading to higher mutation detection rate (18), whereas in some other countries including Macedonia these analyses may be less available. Because correct diagnosis of GCK-MODY has important consequences regarding 6
therapy, counseling and long-term follow-up, it is highly desirable to extend the genetic testing of MODY genes to other countries which also brings along cost-effectiveness (19). In the family reported here, the molecular-genetic diagnosis was possible to establish thanks to collaboration with Czech coauthors and their funding from the Czech Ministry of Health. GCK mutation in proband’s father could explain the low birth weight of the proband because it has been shown that GCK mutation carriers born to mothers without mutation displayed a reduced birth weight of approximately 500 grams because of changes in fetal insulin secretion (20). Moreover, it is likely that the grandfather had the same mutation and if it was detected, he might have not been treated with Metformin since the young adult age. In conclusion, we present a Macedonian patient with GCK-MODY caused by a novel mutation in the GCK gene. Improving the availability of molecular genetic analysis in Macedonia would improve precise diagnosis and appropriate medical approach in patients with GCK-MODY avoiding unnecessary therapy.
Conflict of interest: none
The molecular-genetic analysis was supported by the project for conceptual development of research organization 00064203/6001 (Ministry of Health, Czech Republic).
7
References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
12. 13.
14. 15. 16.
Froguel P, Vaxillaire M, Sun F, Velho G, Zouali H, Butel MO, et al. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature. 1992; 356:162-4. Hattersley AT, Turner RC, Permutt MA, Patel P, Tanizawa Y, Chiu KC, et al. Linkage of type 2 diabetes to the glucokinase gene. Lancet. 1992; 339:1307-10. Ellard S, Bellanne-Chantelot C, Hattersley AT. Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young. Diabetologia. 2008; 51:546-53. Cardenas ML, Cornish-Bowden A, Ureta T. Evolution and regulatory role of the hexokinases. Biochim Biophys Acta. 1998; 1401:242-64. Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. 2014; 133:1-9. Osbak KK, Colclough K, Saint-Martin C, Beer NL, Bellanne-Chantelot C, Ellard S, et al. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat. 2009; 30:1512-26. Chakera AJ, Spyer G, Vincent N, Ellard S, Hattersley AT, Dunne FP. The 0.1% of the population with glucokinase monogenic diabetes can be recognized by clinical characteristics in pregnancy: the Atlantic Diabetes in Pregnancy cohort. Diabetes Care. 2014; 37:1230-6. Pruhova S, Dusatkova P, Sumnik Z, Kolouskova S, Pedersen O, Hansen T, et al. Glucokinase diabetes in 103 families from a country-based study in the Czech Republic: geographically restricted distribution of two prevalent GCK mutations. Pediatr Diabetes. 2010; 11:529-35. Schwarz JM, Rodelsperger C, Schuelke M, Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods. 2013; 7:575-6. Flannick J, Beer NL, Bick AG, Agarwala V, Molnes J, Gupta N, et al. Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes. Nat Genet. 2013; 45:1380-5. Massa O, Meschi F, Cuesta-Munoz A, Caumo A, Cerutti F, Toni S, et al. High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI. Diabetes Study Group of the Italian Society of Paediatric Endocrinology and Diabetes (SIEDP). Diabetologia. 2001; 44:898-905. Maia FF, Araujo LR. Efficacy of continuous glucose monitoring system (CGMS) to detect huperglycemia and unrecognized hypoglycemia in type 1 diabetic patients. Diabetes Res Clin Pract. 2007; 75:30-4 Grazia A, Ruedy KJ, Riddlesworth TD, Kruger DF, Peters AL, Hirsch I et al. REPLACE-BG: A
Randomized Trial Comparing Continuous Glucose Monitoring With and Without Routine Blood Glucose Monitoring in Well-Controlled Adults With Type 1 Diabetes. Diabetes
Care. 2017; doi.org/10.2337/dc16-248214. Borowiec M, Mysliwiec M, Fendler W, Antosik K, Brandt A, Malecki M, et al. Phenotype variability and neonatal diabetes in a large family with heterozygous mutation of the glucokinase gene. Acta Diabetol. 2011; 48:203-8. Lawrence RD. Renal Threshold for Glucose: Normal and in Diabetics. Br Med J. 1940; 1:766-8. Pruhova S, Dusatkova P, Kraml PJ, Kulich M, Prochazkova Z, Broz J, et al. Chronic Mild Hyperglycemia in GCK-MODY Patients Does Not Increase Carotid Intima-Media Thickness. Int J Endocrinol. 2013; 2013:718254. 8
17. 18. 19. 20.
Petruzelkova L, Dusatkova P, Cinek O, Sumnik Z, Pruhova S, Hradsky O, et al. Substantial proportion of MODY among multiplex families participating in a Type 1 diabetes prediction programme. Diabet Med. 2016; 33:1712-6. Shields BM, Hicks S, Shepherd MH, Colclough K, Hattersley AT, Ellard S. Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia. 2010; 53:2504-8. Naylor RN, John PM, Winn AN, Carmody D, Greeley SA, Philipson LH, et al. Cost-Effectiveness of MODY Genetic Testing: Translating Genomic Advances Into Practical Health Applications. Diabetes Care. 2014; 37:202-9. Hattersley AT, Beards F, Ballantyne E, Appleton M, Harvey R, Ellard S. Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat Genet. 1998; 19:268-70.
9
Figure 1. Results from continuous glucose monitoring of the proband at the age of 3 years.
Table 1. Biochemical investigation of the family Family member
Preprandial/postprandial glycemia (mmol/l)
Insulinemia
Proband
6.6-7.8/10.4-13.1
2.3/20.0
5.6
6.0 , 41.7
Father
7.2/9.6
47.7
5.4
6.3 , 45.6
Mother
5.7/6.0
17.6
3.8
Sister
5.5/5.8
26.7
6.2
(uIU/ml)
10
Postprandial C-peptide (ng/ml)
HbA1c (%, mmol/mol)
Contributions of the authors:
1. Mirjana Kocova diagnosed and treated the patient, drafted the manuscript and edited the final version 2. Lenka Elblova participated in the molecular work up and edited the final version 3. Stefanka Pruhova participated in writing and editing 4. Jan Lebl edited the final version 5. Petra Dusatkova was instrumental in molecular analysis, discussion and editing of the manuscript All authors approved the final version of the manuscript
11
Highlights 1. We describe a novel GCK-MODY mutation in a Macedonian family, the very first family tested for GCK-MODY gene in the country 2. To our knowledge, It is a first GCK mutation detected in a child from the Balkan region 3. International collaboration and improved funding for genetic analysis in MODY patients might enlarge the detected number of mutations causing GCK-MODY
12
S0168-8227(16)31744-2 http://dx.doi.org/10.1016/j.diabres.2017.04.001 DIAB 6923
To appear in:
Diabetes Research and Clinical Practice
Received Date: Accepted Date:
6 December 2016 3 April 2017
Please cite this article as: M. Kocova, L. Elblova, S. Pruhova, J. Lebl, P. Dusatkova, Novel glucokinase gene mutation in the first Macedonian family tested for MODY, Diabetes Research and Clinical Practice (2017), doi: http:// dx.doi.org/10.1016/j.diabres.2017.04.001
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Novel glucokinase gene mutation in the first Macedonian family tested for MODY M. Kocova1, L. Elblova2, S. Pruhova2, J. Lebl2, P. Dusatkova2 1
University Pediatric clinic, Skopje, Republic of Macedonia
2
Department of Pediatrics, 2nd Faculty of Medicine, Charles University and University Hospital
Motol, V Uvalu 84, Prague, Czech Republic
Corresponding author Mirjana Kocova University Pediatric Clinic, Skopje 1000 Skopje Republic of Macedonia Phone: +389 2 3111713 Fax: +389 2 3716167 e-mail: [email protected]
1
Abstract We present a boy with mild hyperglycemia detected during an upper respiratory infection. Novel splicing mutation in the intron 1 of the GCK gene (c.45+1G>A) was detected, and was subsequently confirmed in his father. This is the first case of genetically confirmed Macedonian family with MODY. Key words: GCK-MODY, GCK mutation, mild hyperglycemia
2
Introduction Heterozygous inactivating mutations in the glucokinase (GCK) gene lead to a subtype of Maturity-Onset Diabetes of the Young (MODY) designated as GCK-MODY (1, 2) that is clinically characterized as persistent fasting hyperglycemia, negative pancreatic autoantibodies and optionally positive family history of diabetes/hyperglycemia (3). The GCK gene encodes enzyme glucokinase that plays crucial glucose processing role in the pancreatic beta cell. Glucokinase’s affinity to glucose is more than 20-times greater than hexokinase II (4) making it a sensitive sensor for glucose in the pancreatic beta cell. More than 700 mutations in the GCK gene causing GCK-MODY have been described so far (5) in many populations worldwide although reports from Western European countries prevail (6). However, the GCK-MODY population prevalence was estimated as 1.1 in 1,000 (7) indicating that majority of subjects is awaiting the correct diagnosis. Molecular genetic analyses of MODY patients are not widely accessible in economically challenged countries where a variety of known or novel mutations could have been detected. We describe the first case of genetically confirmed diagnosis of GCK-MODY in Macedonia caused by novel mutation in the GCK gene as a result of collaboration with a Czech institution performing molecular analysis.
3
Clinical observation and molecular work up A 2.5 year old boy presented epistaxis and increased thirst without glucosuria during an upper respiratory tract infection. His fasting blood glucose varied from 7.7 to 8.6 mmol/l, and he was referred for evaluation. The boy was born at term with a weight of 2800 grams (-1 SDS) and length 48 cm (-0.7 SDS). Family history revealed type 2 diabetes in a paternal grandfather who is on Metformin therapy with good metabolic control since the age of 36 years. At admission, both the height and weight of the boy were on 50% percentile. Fasting glucose levels were in the range 6.0-7.7 mmol/l. On OGTT his glycemia raised up to 13 mmol/l. HbA1c was 6.0% (42 mmol/mol) (normal range 4.4-6.2% and 25-44 mmol/mol, respectively). Fasting and postprandial insulinemias were within normal range (5 and 20 mU/l, respectively) as well as postprandial C-peptide (3.8-5.6 ng/ml). CGM (Guardian system, Medtronic) confirmed glycemia levels above the reference, particularly in the afternoon, however, the glycemia stability suggested further analyses to investigate MODY (Figure 1). Islet antibodies (GAD, IA, ICA and IAA2 were negative). . Diet with restriction of free carbohydrates was prescribed, daily and overnight measurements of glycemia and additional feedings if needed were recommended. The re-evaluation after six months revealed that the glucose levels measured at home ranged from 6.6 to 10.4 mmol/l, despite of the diet and physical activity. Additionally, mother reported that the probands’ father had hyperglycemia (the last measurement was 11.2 mmol/l postprandially), but he was
4
not under treatment and did not visit a specialist. Results of biochemical analyses in family members are summarized in Table 1. Molecular genetic testing of the GCK gene was performed using direct sequencing as described previously (8). In the patient and his father a novel heterozygous intronic substitution c.45+1G>A of the GCK gene was detected. This mutation was predicted to be disease causing by MutationTaster (9) and was not found neither in ExAC, nor in 1000 Genomes databases of polymorphisms. Moreover, another mutation at the same nucleotide position (c.45+1G>T) was published previously (10, 11). Mother and sister of the proband were negative for the respective mutation. Paternal grandfather was not available for analysis.
5
Discussion For the first time, we describe a family from Macedonia with genetically confirmed MODY, GCKMODY subtype. Moreover, hyperglycemia segregating within this family is caused by a novel mutation in the GCK gene (c.45+1G>A) that is predicted to disrupt exon – intron splicing. CGM is used mostly in patients with major forms of diabetes (12, 13). Small number of patients with MODY has been followed using CGM. The glucose curve recorded in our proband is similar to a patient with typical GCK-MODY reported previously (14). Increased demand for drinking was presented by the proband at the time of the first detection of hyperglycemia. However, polyuria and polydipsia are not typical clinical features for GCKMODY because patients generally display moderate fasting glycemia (3) which is below the renal threshold for glucose (15). Therefore, it is important not to misinterpret an increased demand for drinking during the common cold with fever for polydipsia as blood glucose over 10 mmol/l for a short period during common cold would not manifest by osmotic symptoms. Majority of patients with GCK-MODY do not know their diagnosis. We can find three reasons: first, because of the continuously mild phenotype (16), subjects are unaware of their hyperglycemia. Second, patients can be misdiagnosed as having major forms of diabetes (17). Third, genetic testing is financially demanding or inaccessible (7). In many, mostly Western European countries, the molecular genetic screening of the most common MODY genes is covered by research grants or public health insurance leading to higher mutation detection rate (18), whereas in some other countries including Macedonia these analyses may be less available. Because correct diagnosis of GCK-MODY has important consequences regarding 6
therapy, counseling and long-term follow-up, it is highly desirable to extend the genetic testing of MODY genes to other countries which also brings along cost-effectiveness (19). In the family reported here, the molecular-genetic diagnosis was possible to establish thanks to collaboration with Czech coauthors and their funding from the Czech Ministry of Health. GCK mutation in proband’s father could explain the low birth weight of the proband because it has been shown that GCK mutation carriers born to mothers without mutation displayed a reduced birth weight of approximately 500 grams because of changes in fetal insulin secretion (20). Moreover, it is likely that the grandfather had the same mutation and if it was detected, he might have not been treated with Metformin since the young adult age. In conclusion, we present a Macedonian patient with GCK-MODY caused by a novel mutation in the GCK gene. Improving the availability of molecular genetic analysis in Macedonia would improve precise diagnosis and appropriate medical approach in patients with GCK-MODY avoiding unnecessary therapy.
Conflict of interest: none
The molecular-genetic analysis was supported by the project for conceptual development of research organization 00064203/6001 (Ministry of Health, Czech Republic).
7
References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
12. 13.
14. 15. 16.
Froguel P, Vaxillaire M, Sun F, Velho G, Zouali H, Butel MO, et al. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature. 1992; 356:162-4. Hattersley AT, Turner RC, Permutt MA, Patel P, Tanizawa Y, Chiu KC, et al. Linkage of type 2 diabetes to the glucokinase gene. Lancet. 1992; 339:1307-10. Ellard S, Bellanne-Chantelot C, Hattersley AT. Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young. Diabetologia. 2008; 51:546-53. Cardenas ML, Cornish-Bowden A, Ureta T. Evolution and regulatory role of the hexokinases. Biochim Biophys Acta. 1998; 1401:242-64. Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet. 2014; 133:1-9. Osbak KK, Colclough K, Saint-Martin C, Beer NL, Bellanne-Chantelot C, Ellard S, et al. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat. 2009; 30:1512-26. Chakera AJ, Spyer G, Vincent N, Ellard S, Hattersley AT, Dunne FP. The 0.1% of the population with glucokinase monogenic diabetes can be recognized by clinical characteristics in pregnancy: the Atlantic Diabetes in Pregnancy cohort. Diabetes Care. 2014; 37:1230-6. Pruhova S, Dusatkova P, Sumnik Z, Kolouskova S, Pedersen O, Hansen T, et al. Glucokinase diabetes in 103 families from a country-based study in the Czech Republic: geographically restricted distribution of two prevalent GCK mutations. Pediatr Diabetes. 2010; 11:529-35. Schwarz JM, Rodelsperger C, Schuelke M, Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods. 2013; 7:575-6. Flannick J, Beer NL, Bick AG, Agarwala V, Molnes J, Gupta N, et al. Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes. Nat Genet. 2013; 45:1380-5. Massa O, Meschi F, Cuesta-Munoz A, Caumo A, Cerutti F, Toni S, et al. High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI. Diabetes Study Group of the Italian Society of Paediatric Endocrinology and Diabetes (SIEDP). Diabetologia. 2001; 44:898-905. Maia FF, Araujo LR. Efficacy of continuous glucose monitoring system (CGMS) to detect huperglycemia and unrecognized hypoglycemia in type 1 diabetic patients. Diabetes Res Clin Pract. 2007; 75:30-4 Grazia A, Ruedy KJ, Riddlesworth TD, Kruger DF, Peters AL, Hirsch I et al. REPLACE-BG: A
Randomized Trial Comparing Continuous Glucose Monitoring With and Without Routine Blood Glucose Monitoring in Well-Controlled Adults With Type 1 Diabetes. Diabetes
Care. 2017; doi.org/10.2337/dc16-248214. Borowiec M, Mysliwiec M, Fendler W, Antosik K, Brandt A, Malecki M, et al. Phenotype variability and neonatal diabetes in a large family with heterozygous mutation of the glucokinase gene. Acta Diabetol. 2011; 48:203-8. Lawrence RD. Renal Threshold for Glucose: Normal and in Diabetics. Br Med J. 1940; 1:766-8. Pruhova S, Dusatkova P, Kraml PJ, Kulich M, Prochazkova Z, Broz J, et al. Chronic Mild Hyperglycemia in GCK-MODY Patients Does Not Increase Carotid Intima-Media Thickness. Int J Endocrinol. 2013; 2013:718254. 8
17. 18. 19. 20.
Petruzelkova L, Dusatkova P, Cinek O, Sumnik Z, Pruhova S, Hradsky O, et al. Substantial proportion of MODY among multiplex families participating in a Type 1 diabetes prediction programme. Diabet Med. 2016; 33:1712-6. Shields BM, Hicks S, Shepherd MH, Colclough K, Hattersley AT, Ellard S. Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia. 2010; 53:2504-8. Naylor RN, John PM, Winn AN, Carmody D, Greeley SA, Philipson LH, et al. Cost-Effectiveness of MODY Genetic Testing: Translating Genomic Advances Into Practical Health Applications. Diabetes Care. 2014; 37:202-9. Hattersley AT, Beards F, Ballantyne E, Appleton M, Harvey R, Ellard S. Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat Genet. 1998; 19:268-70.
9
Figure 1. Results from continuous glucose monitoring of the proband at the age of 3 years.
Table 1. Biochemical investigation of the family Family member
Preprandial/postprandial glycemia (mmol/l)
Insulinemia
Proband
6.6-7.8/10.4-13.1
2.3/20.0
5.6
6.0 , 41.7
Father
7.2/9.6
47.7
5.4
6.3 , 45.6
Mother
5.7/6.0
17.6
3.8
Sister
5.5/5.8
26.7
6.2
(uIU/ml)
10
Postprandial C-peptide (ng/ml)
HbA1c (%, mmol/mol)
Contributions of the authors:
1. Mirjana Kocova diagnosed and treated the patient, drafted the manuscript and edited the final version 2. Lenka Elblova participated in the molecular work up and edited the final version 3. Stefanka Pruhova participated in writing and editing 4. Jan Lebl edited the final version 5. Petra Dusatkova was instrumental in molecular analysis, discussion and editing of the manuscript All authors approved the final version of the manuscript
11
Highlights 1. We describe a novel GCK-MODY mutation in a Macedonian family, the very first family tested for GCK-MODY gene in the country 2. To our knowledge, It is a first GCK mutation detected in a child from the Balkan region 3. International collaboration and improved funding for genetic analysis in MODY patients might enlarge the detected number of mutations causing GCK-MODY
12