Final Diagnosis -- Maturity-Onset Diabetes of the Young (MODY) -2
FINAL DIAGNOSIS: MATURITY-ONSET DIABETES OF THE YOUNG (MODY) -2
Maturity-Onset Diabetes of the Young (MODY):
- MODY is an autosomal, dominantly inherited form of diabetes that is characterized by an early age of onset (at least one affected family member with an onset before 25 years of age) and pancreatic beta-cell dysfunction.
- Linkage between microsatellite markers and disease was described in French and UK pedigrees and the first mutation was reported in 1992.
- MODY has been associated with defects in several genes; glucokinase (GCK) was the first MODY gene to be identified.
Pathogenesis in MODYs:
Distinguishing clinical characteristics between MODY and DM type 2:
- The prevalence of GCK-MODY is difficult to assess, as the mild hyperglycemia and the absence of symptoms means that patients are frequently not diagnosed. Large-scale population studies to assess the prevalence have not been done.
- In the Caucasian population, approximately 2% of the population will be diagnosed with gestational diabetes; of these, ~2-5% will have a GCK mutation. This would suggest a population prevalence of 0.04-0.10%. [Ellard et al., 2000].
- About 50 percent of women who are carriers may have gestational diabetes. Less than 50 percent of the carriers have overt diabetes.
- Neonatal diabetes mellitus (NDM), caused by homozygous inactivating mutation, is a rare disorder with an estimated incidence of 1:400,000 live births.
GCK Gene Structure:
GCK protein and the function:
- The glucokinase (GCK) gene encodes a 465 amino acid protein with a MW of 52 kDa, which is expressed in the pancreas, liver, and brain.
- The two isoforms of glucokinase differ by 13-15 amino acids at the N-terminal end of the molecule, which produces only a minimal difference in structure. The two isoforms have the same kinetic and functional characteristics.
- In liver, glucokinase acts as the gateway for the "bulk processing" of available glucose, while in the neuroendocrine cells, it acts as a sensor, triggering cell responses that affect body-wide carbohydrate metabolism.
- The presence of tissue-specific promoters allows differential regulation and transcription of different transcripts.
GCK mutations found in literatures
GCK mutation and phenotype:
- Heterozygous inactivating mutations are associated with mild hyperglycemia in children or gestational DM in women which are often subclinical and can be treated with diet alone.
- Homozygous inactivating mutation results in permanent neonatal diabetes and requires insulin treatment within the first month.
- Heterozygous activating GCK mutations have been reported to cause hypoglycemia.
- Over 190 mutations of the GCK gene have been identified in many populations, with the majority in France and Italy.
Genetic testing indications and benefits:
- Genetic testing indications:
- diabetes onset before age 25 in the absence of autoantibodies
- normal body weight
- family history of diabetes
- endogenous insulin production three years after diagnosis
- no evidence for insulin resistance
- no acanthosis nigricans
- Genetic testing benefits:
- to differentiate MODY from type I and II DM
- to determine MODY subtype for optimal management: diet (MODY2), sulfonylurea drugs (MODY3, MODY1), or insulin (MODY4, MODY5)
- to determine prognosis
- to identify family members at high risk for diabetes
- Gloyn AL. Human Mutation, 2003, V22: 353-362.
- Fajans S, et al, NEJM, 2001, Volume 345:971-980.
- Froguel et al., Nature, 1992, 356(6365): 162-4.
- Hattersley et al., Lancet,1992, 339(8805): 1307-10
Contributed by Zaibo Li, MD and Jeffery Kant, MD, PhD