MODY due to hepatocyte nuclear factor 4-alpha mutations
Diabetes due to HNF4A mutations is less common than diabetes due to mutations of the HNF1A gene, but the clinical features are similar. The main clinical differences are that HNF4A-MODY is not associated with a low renal threshold for glucose and that foetal hyperinsulinism and neonatal hypoglycaemia is a feature. The condition is usually picked up when screening for HNF1A mutations is negative.
Mutations in the HNF4A gene represent about 10% of MODY cases in the UK . It was the first subtype of MODY identified, hence the previous name of MODY1, which is sometimes still used. It was identified by Stefan Fajans in Michigan, studying a very large MODY pedigree (the eponymous "RW" family). The number of affected family members meant that linkage techniques could be used to narrow down the area on chromosome 20 where the gene was located.
Clinical Features of HNF4A-MODY
The clinical features of HNF4A-MODY are very similar to HNF1A-MODY. The onset of diabetes is most commonly seen in 2nd-4th decade of life. The age of onset is said to be slightly later than HNF1A-MODY, but this was not marked in a cohort of European patients . It is C-peptide positive diabetes without features of insulin resistance or beta-cell autoimmunity. Typically, there is a strong family history of diabetes with at least two consecutive generations affected. Sensitivity to sulponylureas is also reported in patients with HNF4A-MODY.
Unlike HNF1A-MODY, low renal threshold for glucose is not observed and C-reactive protein is normal . Patients with HNF4A-MODY have lower HDL-cholesterol, apolipoprotein A2 and A1 comparing to mutation negative family members and normal triglycerides . They are at risk of vascular complications, especially if poorly controlled.
Relatively recently it was noted that there were reports of high birthweight and neonatal hypoglycaemia in babies from HNF4A-MODY families and investigation of 108 patients with HNF4A mutations confirmed that macrosomia due to hyperinsulism in utero and neonatal hypoglycaemia is a feature of HNF4A-MODY. 56% of babies had macrosomia (BW > 4kg) and the mean birthweight was 800g heavier than unaffected babies. About 14% had neonatal hypoglycaemia. Despite this, diabetes occurs later. It should be noted that this can occur whether the baby has inherited the mutation from either mother or father. This has implications for pregnancy management and all families with HNF4A-MODY should be counselled about possibility of neonatal hypoglycaemia.
Treatment of HNF4A-MODY.
Similarly to HNF1A-MODY this type of monogenic diabetes is also treated with low dose sulphonylurea agents, which are able to control glycaemia for many years.
^ Shields BM, Hicks S, Shepherd MH, Colclough K, Hattersley AT, Ellard S. Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia 2010.
^ Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, et al. Mutations in the hepatocyte nuclear factor 4 alpha gene in maturity-onset diabetes of the young (MODY1). Nature 1996;384:458-60.
^ Pearson ER, Pruhova S, Tack CJ, Johansen A, Castleden HA, Lumb PJ, et al. Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection. Diabetologia 2005;48(5):878-85.
^ Thanabalasingham G, Shah N, Vaxillaire M, Hansen T, Tuomi T, Gasperikova D, et al. A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes. Diabetologia 2011;54(11):2801-10.
^ Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med 2007;4(4):e118.