Mutations in GCK and HNF‐1α explain the majority of cases with clinical diagnosis of MODY in Spain

I Estalella, I Rica, GP De Nanclares… - Clinical …, 2007 - Wiley Online Library
I Estalella, I Rica, GP De Nanclares, JR Bilbao, JA Vazquez, JI San Pedro, MA Busturia…
Clinical endocrinology, 2007Wiley Online Library
Objective The aim of this study was to group patients with MODY (maturity‐onset diabetes of
the young) according to the genetic alterations underlying the disease and to investigate
their clinical characteristics. Patients and methods Molecular analysis of GCK (MODY2),
HNF‐1α (MODY3), HNF‐4α (MODY1) and HNF‐1β (MODY5) genes was performed by DNA
sequencing in 95 unrelated index probands (47M/48F; mean age 9· 9±5· 2 years) with
clinical diagnosis of MODY. After classification into MODY subtypes according to the genetic …
Summary
Objective  The aim of this study was to group patients with MODY (maturity‐onset diabetes of the young) according to the genetic alterations underlying the disease and to investigate their clinical characteristics.
Patients and methods  Molecular analysis of GCK (MODY2), HNF‐1α (MODY3), HNF‐4α (MODY1) and HNF‐1β (MODY5) genes was performed by DNA sequencing in 95 unrelated index probands (47M/48F; mean age 9·9 ± 5·2 years) with clinical diagnosis of MODY. After classification into MODY subtypes according to the genetic alterations, clinical characteristics were compared between the groups.
Results  Seventy‐six families were shown to carry mutations in GCK (34 of them previously unreported), eight families presented HNF‐1α mutations, and a large genomic rearrangement in HNF‐1β was found in a family. No alteration was found in HNF‐4α. Thus, relative frequencies in the group studied were 80% MODY2, 8·5% MODY3 and 1% MODY5. Comparison of clinical parameters according to genetic status showed significant differences between MODY2 and MODY3 patients in age at diagnosis (9·4 ± 5·4 years vs. 12·7 ± 4·6 years), diagnosis (impaired glucose tolerance vs. diabetes), diagnostic test used (OGTT vs. fasting glucose), treatment (diet and exercise vs. insulin/oral antidiabetic agents) and birth weight (2·96 ± 0·44 kg vs. 3·40 ± 0·67 kg).
Conclusion  Almost 90% of the MODY cases in the group studied are explained by mutations in the major genes GCK (MODY2) and HNF‐1α(MODY3), although differences in the relative prevalence of each form could be partly due to patient referral bias (paediatric vs. adult). In general, patients with MODY2 were diagnosed at an earlier age in life than MODY3 patients and had a milder form of diabetes. Moreover, the majority of patients with MODY2 mutations were treated with diet whereas half of MODY3 patients received pharmacological treatment.
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