Treatment of Monogenic Diabetes with HNF1A (MODY3) or HNF4A (MODY1) Mutation in Autosomal Dominant Symptomatic Familial Diabetes

Clinical Scenario

This protocol addresses monogenic diabetes caused by a heterozygous mutation in HNF1A (MODY3) or HNF4A (MODY1) — the autosomal dominant, familial forms presenting with postprandial or progressive hyperglycemia and known sensitivity to sulphonylureas. HNF1A-MODY is the most common form of monogenic diabetes resulting in familial symptomatic diabetes; heterozygous HNF1A mutations are approximately ten times more frequent than heterozygous HNF4A mutations.

Key Features of This Presentation

Autosomal dominant family history of symptomatic diabetes; postprandial or progressively worsening hyperglycemia; confirmed HNF1A or HNF4A gene mutation; and demonstrated or expected sensitivity to sulphonylurea therapy. Both HNF1A-MODY and HNF4A-MODY share sulphonylurea sensitivity as a defining pharmacogenomic characteristic.

Treatment Overview (Partial)

Sulphonylurea therapy is central to management, with specific formulation considerations when hypoglycemia arises — and a studied alternative agent class, evaluated in a randomised controlled trial, that has shown a favourable fasting glucose profile; the complete regimen, decision algorithm, and full options are in the structured protocol.

Instant Access to Structured Evidence-Based Regimens

References

HNF1A-MODY is the most common form of monogenic diabetes that results in familial symptomatic diabetes, with heterozygous HNF1A mutations being about 10 times more frequent than heterozygous mutations in HNF4A.
Some forms of MODY are sensitive to SU, such as HNF1A-MODY and HNF4A-MODY.
If there is hypoglycemia despite dose titration of a once or twice daily SU preparation, a slow-release preparation or meal time doses with a short-acting agent such as a meglitinide may be considered.
A randomized controlled trial comparing a glucagon-like peptide receptor agonist (GLP1RA) with a SU demonstrated lower fasting glucose in those treated with the GLP1RA.

DOI: 10.1111/pedi.13426

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