Reclassification of diabetes etiology in a family with multiple diabetes phenotypes.
BACKGROUND: Maturity-onset diabetes of the young (MODY) is uncommon; however, accurate diagnosis facilitates personalized management and informs prognosis in probands and relatives. OBJECTIVE: The objective of the study was to highlight that the appropriate use of genetic and nongenetic investigatio...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2014
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| _version_ | 1797062218785751040 |
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| author | Kavvoura, F Raimondo, A Thanabalasingham, G Barrett, A Webster, A Shears, D Mann, N Ellard, S Gloyn, A Owen, K |
| author_facet | Kavvoura, F Raimondo, A Thanabalasingham, G Barrett, A Webster, A Shears, D Mann, N Ellard, S Gloyn, A Owen, K |
| author_sort | Kavvoura, F |
| collection | OXFORD |
| description | BACKGROUND: Maturity-onset diabetes of the young (MODY) is uncommon; however, accurate diagnosis facilitates personalized management and informs prognosis in probands and relatives. OBJECTIVE: The objective of the study was to highlight that the appropriate use of genetic and nongenetic investigations leads to the correct classification of diabetes etiology. CASE DISCUSSION: A 30-year-old European female was diagnosed with insulin-treated gestational diabetes. She discontinued insulin after delivery; however, her fasting hyperglycemia persisted. β-Cell antibodies were negative and C-peptide was 0.79 nmol/L. Glucokinase (GCK)-MODY was suspected and confirmed by the identification of a GCK mutation (p.T206M). METHODS: Systematic clinical and biochemical characterization and GCK mutational analysis were implemented to determine the diabetes etiology in five relatives. Functional characterization of GCK mutations was performed. RESULTS: Identification of the p.T206M mutation in the proband's sister confirmed a diagnosis of GCK-MODY. Her daughter was diagnosed at 16 weeks with permanent neonatal diabetes (PNDM). Mutation analysis identified two GCK mutations that were inherited in trans-p. [(R43P);(T206M)], confirming a diagnosis of GCK-PNDM. Both mutations were shown to be kinetically inactivating. The proband's mother, other sister, and daughter all had a clinical diagnosis of type 1 diabetes, confirmed by undetectable C-peptide levels and β-cell antibody positivity. GCK mutations were not detected. CONCLUSIONS: Two previously misclassified family members were shown to have GCK-MODY, whereas another was shown to have GCK-PNDM. A diagnosis of type 1 diabetes was confirmed in three relatives. This family exemplifies the importance of careful phenotyping and systematic evaluation of relatives after discovering monogenic diabetes in an individual. |
| first_indexed | 2024-03-06T20:42:23Z |
| format | Journal article |
| id | oxford-uuid:34b580bd-0707-43d2-b321-2b1f8ab4803f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:42:23Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:34b580bd-0707-43d2-b321-2b1f8ab4803f2022-03-26T13:27:38ZReclassification of diabetes etiology in a family with multiple diabetes phenotypes.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:34b580bd-0707-43d2-b321-2b1f8ab4803fEnglishSymplectic Elements at Oxford2014Kavvoura, FRaimondo, AThanabalasingham, GBarrett, AWebster, AShears, DMann, NEllard, SGloyn, AOwen, KBACKGROUND: Maturity-onset diabetes of the young (MODY) is uncommon; however, accurate diagnosis facilitates personalized management and informs prognosis in probands and relatives. OBJECTIVE: The objective of the study was to highlight that the appropriate use of genetic and nongenetic investigations leads to the correct classification of diabetes etiology. CASE DISCUSSION: A 30-year-old European female was diagnosed with insulin-treated gestational diabetes. She discontinued insulin after delivery; however, her fasting hyperglycemia persisted. β-Cell antibodies were negative and C-peptide was 0.79 nmol/L. Glucokinase (GCK)-MODY was suspected and confirmed by the identification of a GCK mutation (p.T206M). METHODS: Systematic clinical and biochemical characterization and GCK mutational analysis were implemented to determine the diabetes etiology in five relatives. Functional characterization of GCK mutations was performed. RESULTS: Identification of the p.T206M mutation in the proband's sister confirmed a diagnosis of GCK-MODY. Her daughter was diagnosed at 16 weeks with permanent neonatal diabetes (PNDM). Mutation analysis identified two GCK mutations that were inherited in trans-p. [(R43P);(T206M)], confirming a diagnosis of GCK-PNDM. Both mutations were shown to be kinetically inactivating. The proband's mother, other sister, and daughter all had a clinical diagnosis of type 1 diabetes, confirmed by undetectable C-peptide levels and β-cell antibody positivity. GCK mutations were not detected. CONCLUSIONS: Two previously misclassified family members were shown to have GCK-MODY, whereas another was shown to have GCK-PNDM. A diagnosis of type 1 diabetes was confirmed in three relatives. This family exemplifies the importance of careful phenotyping and systematic evaluation of relatives after discovering monogenic diabetes in an individual. |
| spellingShingle | Kavvoura, F Raimondo, A Thanabalasingham, G Barrett, A Webster, A Shears, D Mann, N Ellard, S Gloyn, A Owen, K Reclassification of diabetes etiology in a family with multiple diabetes phenotypes. |
| title | Reclassification of diabetes etiology in a family with multiple diabetes phenotypes. |
| title_full | Reclassification of diabetes etiology in a family with multiple diabetes phenotypes. |
| title_fullStr | Reclassification of diabetes etiology in a family with multiple diabetes phenotypes. |
| title_full_unstemmed | Reclassification of diabetes etiology in a family with multiple diabetes phenotypes. |
| title_short | Reclassification of diabetes etiology in a family with multiple diabetes phenotypes. |
| title_sort | reclassification of diabetes etiology in a family with multiple diabetes phenotypes |
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