Molekulargenetische Diagnostik bei Verdacht auf Maturity Onset Diabetes of the Young (MODY): Klinische Parameter zur Entscheidungshilfe

 

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Zusammenfassung

Hintergrund: Eine monogenetische Diabetesform wird im Kindes- und Jugendalter aufgrund der Variabilität der Klinik und der geringen Erfahrung der Diabetologen mit diesem Krankheitsbild oft nur zufällig diagnostiziert. Das Studienziel war, klinische Parameter zu evaluieren, die ein effizientes Screening ermöglichen.

Methoden: Patienten mit folgenden Parametern wurden molekulargenetisch untersucht: kein Nachweis diabetesspezifischer Antikörper bei Manifestation, positive Familienanamnese für Diabetes und niedriger Insulinbedarf (≤ 0,5 IE/kg/d) ein Jahr nach Therapiebeginn. Die drei häufigsten Gene für MODY wurden sequenziert: HNF-4alpha (MODY 1), Glukokinase (MODY 2), HNF1-alpha/TCF1 (MODY 3), sowie einmalig HNF-1beta/TCF2-Region (MODY 5). Bei 39 von 292 Patienten unter Insulintherapie konnten bei Manifestation keine Antikörper nachgewiesen werden, 8 (20,5 %) erfüllten die weiteren Kriterien.

Ergebnisse: Bei 5 Patienten (63 %) war der genetische Befund positiv (2 ¥ MODY 2, 2 ¥ MODY 3, 1 ¥ MODY 5). Bei Manifestation betrug das Alter im Mittel 10,6 ± 5,3 Jahre (2,6 – 15), das mittlere HbA_1c 8,4 ± 3,1 % (6,5 – 13,9). Die Diabetesdauer bis zum Zeitpunkt der Diagnose MODY betrug 3,3 ± 3,6 Jahre (0,8 – 9,6), der mittlere Insulinbedarf 0,44 ± 0,17 IE/kg/d (0,2 – 0,6). Patienten mit MODY 3 erhielten Repaglinid, bei MODY 2 wurde empfohlen, die Insulinbehandlung einzustellen.

Schlussfolgerung: Bei Patienten ohne Antikörper bei Manifestation, mit positiver Familienanamnese für Diabetes und niedrigem Insulinbedarf ist eine molekulargenetische Diagnostik auf MODY indiziert. Eine erhöhte Sensibilisierung und bessere Beobachtung der klinischen Parameter ermöglicht eine frühe molekulargenetische Untersuchung und Diagnose sowie eine adäquate Therapie.

Abstract

Background: Monogenic forms of diabetes are often diagnosed by chance, due to the variety of clinical presentation and limited experience of the diabetologists with this kind of diabetes. Aim of this study was to evaluate clinical parameters for an efficient screening.

Methods: Clinical parameters were: negative diabetes-specific antibodies at onset of diabetes, positive family history of diabetes, and low to moderate insulin requirements after one year of diabetes treatment. Molecular testing was performed through sequencing of the programming regions of HNF-4alpha (MODY 1), glucokinase (MODY 2) and HNF-1alpha/TCF1 (MODY 3) and in one patient the HNF-1beta/TCF2 region (MODY 5). 39 of 292 patients treated with insulin were negative for GADA and IA2A, and 8 (20.5 %) patients fulfilled both other criteria.

Results: Positive molecular results were found in five (63 %) patients (two with MODY 2, two with MODY 3, one with MODY 5). At diabetes onset, the mean age of the 5 patients with MODY was 10.6 ± 5.3 yrs (range 2.6 – 15 yrs), HbA1c was 8.4 ± 3.1 % (6.5 – 13.9 %), mean diabetes duration until diagnosis of MODY was 3.3 ± 3.6 yrs (0.8 – 9.6 yrs) with insulin requirements of 0.44 ± 0.17 U/kg/d (0.2 – 0.6 U/kg/d). Patients with MODY 3 were changed from insulin to repaglinide, those with MODY 2 were recommended discontinuing insulin treatment.

Conclusion: In patients with negative diabetes-specific antibodies at onset of diabetes, with a positive family history, and low to moderate insulin needs a genetic screening for MODY is indicated. Watchful consideration of these clinical parameters may lead to an early genetic testing, and to an adequate treatment.

Literatur

• 1 AMERICAN DIABETES ASSOCIATION . Type 2 diabetes in children and adolescents.  Diabetes Care. 2000;  23 381-389
  Google Scholar
• 2 AMERICAN DIABETES ASSOCIATION . Diagnosis and classification of diabetes mellitus.  Diabetes Care. 2009;  32 S62-S67
  Google Scholar
• 3 Bellanné-Chantelot C, Clauin S, Chauveau D. et al . Large genomic rearrangements in the hepatocyte nuclear factor-1beta (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5.  Diabetes. 2005;  54 3126-3132
  Google Scholar
• 4 Bingham C, Hattersley A T. Renal cysts and diabetes syndrome resulting from mutations in hepatocyte nuclear factor-1ß.  Nephrol Dial Transplant. 2004;  19 2703-2708
  Google Scholar
• 5 Bjorkhaug L, Sagen J V, Thorsby P. et al . Hepatocyte nuclear factor-1 alpha gene mutations and diabetes in Norway.  J Clin Endocrinol Metab. 2003;  88 920-931
  Google Scholar
• 6 Bloomgarden Z T. Type 2 diabetes in the young: the evolving epidemic.  Diabetes Care. 2004;  27 998-1010
  Google Scholar
• 7 Craig M E, Hattersley A, Donaghue K. International Society for Pediatric and adolescent Diabetes. ISPAD Clinical Practice Consensus Guidelines 2006 – 2007. Definition, epidemiology and classification.  Pediatr Diabetes. 2006;  7 343-351
  Google Scholar
• 8 Edghill E L, Bingham C, Ellard S, Hattersley A T. Mutations in hepatocyte nuclear factor -1beta and their related phenotypes.  J Med Genet. 2006;  43 84-90
  Google Scholar
• 9 Ellard S, Bellanné-Chantelot C, Hattersley A T. European Molecular Genetics Quality Network (EmQN) Mody group . Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young.  Diabetologia. 2008;  51 546-553
  Google Scholar
• 10 EURODIAB ACE Study Group . Variation and trends in incidences of childhood diabetes in Europe.  Lancet. 2000;  355 873-866
  Google Scholar
• 11 Fajans S S, Graeme I B, Polonsky K S. Molecular Mechanisms and clinical pathophysiology of maturity onset diabetes of the young.  N Engl J Med. 2001;  345 971-980
  Google Scholar
• 12 Harjutsalo V, Sjöberg L, Tuomilehto J. Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study.  Lancet. 2008;  371 1777-1782
  Google Scholar
• 13 Harries L W, Ellard S, Jones R W. et al . Abnormal splicing of hepatocyte nueclear factor-1beta in the renal cysts and diabetes syndrome.  Diabetologia. 2004;  47 937-942
  Google Scholar
• 14 Hattersley A, Bruining J, Shield J, Njolstad P, Donaghue K. International society for Pediatric and Adolescent Diabetes. ISPAD Clinical Practice Consensus Guidelines 2006 – 2007. The diagnosis and management of monogenic diabetes in children.  Pediatr Diabetes. 2006;  7 352-360
  Google Scholar
• 15 Horikawa Y, Iwasaki N, Hara M. et al . Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY.  Nature Genetics. 1997;  17 384-385
  Google Scholar
• 16 Meissner T, Marquard J, Schober E. Maturity-onset diabetes of the young (MODY).  Der Diabetologe. 2010;  6 219-230
  Google Scholar
• 17 Murphy R, Ellard S, Hattersley A T. Clinical implications of a molecular genetic classification of monogenic ß-cell diabetes.  Nat Clin Pract Endocrinol Metab. 2008;  4 200-213
  Google Scholar
• 18 Onkamo P, Vaananen S, Karvonen M, Tuomilehto J. Worldwide increase in incidence of type 1 diabetes- the analysis of the data on published incidence trends.  Diabetologia. 1999;  42 1395-1403
  Google Scholar
• 19 Pearson E R, Starkey B J, Powell R J, Gribble F M, Clark P M, Hattersley A T. Genetic cause of hyperglycaemia and response to treatment in diabetes.  Lancet. 2003;  362 1275-1281
  Google Scholar
• 20 Raile K, Klopocki E, Holder M. et al . Expanded clinical spectrum in hepatocyte nuclear factor 1b-maturity-onset diabetes of the young.  A J Clin Endocinol Metab. 2009;  94 2658-2664
  Google Scholar
• 21 Sabbah E, Savola K, Ebeling T. et al . Genetic, autoimmune, and clinical characteristics of childhood-and adult-onset type1 diabetes.  Diabetes Care. 2000;  23 1326-1332
  Google Scholar
• 22 Schnyder S, Mullis P E, Ellard S, Hattersley A T, Flück C E. Genetic Testing for glukokinase mutations in clinically selected patients with MODY: a worthwile investment.  Swiss Med Wkly. 2005;  135 352-356
  Google Scholar
• 23 Shepherd M, Pearson E R, Houghton J. et al . No deterioation in glycemic control in HNF1 alpha maturity-onset diabetes of the young following transfer from longterm insulin to sulphonylureas.  Diabetes Care. 2003;  26 3191-3192
  Google Scholar
• 24 Shepherd M, Shields B, Ellard S. et al . A genetic diagnosis of HNF1A diabetes alters treatment and improves glycaemic control in the majority of insulin-treated patients.  Diabet Med. 2009;  26 437-441
  Google Scholar
• 25 Stoffel M, Froguel P, Takeda J. et al . Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus.  Proc Natl Acad Sci USA. 1992;  89 7698-7702
  Google Scholar
• 26 Stride A, Hattersley A T. Different genes, different diabetes: lessons from maturity-onset diabetes of the young.  Ann Med. 2002;  34 207-216
  Google Scholar
• 27 Velho G, Blanché H, Vaxillaire M. et al . Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families.  Diabetologia. 1997;  40 217-224
  Google Scholar
• 28 Verge C F, Stenger D, Bonifacio E. et al . Combined use of autoantibodies (IA-2 autoantibody, GAD autoantibody, insulin autoantibody, cytoplasmic islet cell.  Diabetes. 1998;  47 1857-1866
  Google Scholar

Dr. Nicolin Datz

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