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Maturity-onset diabetes of the young type 1(MODY1)

MedGen UID:
377589
Concept ID:
C1852093
Disease or Syndrome
Synonyms: Diabetes mellitus MODY type 1; HNF4A-Related Maturity-Onset Diabetes of the Young Type 1; MILD JUVENILE DIABETES MELLITUS; MODY HNF4A related; MODY type 1; MODY, type I
SNOMED CT: Maturity onset diabetes of the young, type 1 (609562003); HNF4A (hepatocyte nuclear factor 4 alpha) monogenic diabetes mellitus (609562003); MODY1 (maturity onset diabetes of the young type 1) (609562003)
 
Gene (location): HNF4A (20q13.12)
 
Monarch Initiative: MONDO:0007452
OMIM®: 125850

Definition

Maturity-onset diabetes of the young (MODY) is a group of several conditions characterized by abnormally high levels of blood glucose, also called blood sugar. These forms of diabetes typically begin before age 30, although they can occur later in life. In MODY, elevated blood glucose arises from reduced production of insulin, which is a hormone produced in the pancreas that helps regulate blood glucose levels. Specifically, insulin controls how much glucose (a type of sugar) is passed from the blood into cells, where it is used as an energy source.

The different types of MODY are distinguished by their genetic causes. The most common types are HNF1A-MODY (also known as MODY3), accounting for 50 to 70 percent of cases, and GCK-MODY (MODY2), accounting for 30 to 50 percent of cases. Less frequent types include HNF4A-MODY (MODY1) and renal cysts and diabetes (RCAD) syndrome (also known as HNF1B-MODY or MODY5), which each account for 5 to 10 percent of cases. At least ten other types have been identified, and these are very rare.

HNF1A-MODY and HNF4A-MODY have similar signs and symptoms that develop slowly over time. Early signs and symptoms in these types are caused by high blood glucose and may include frequent urination (polyuria), excessive thirst (polydipsia), fatigue, blurred vision, weight loss, and recurrent skin infections. Over time uncontrolled high blood glucose can damage small blood vessels in the eyes and kidneys. Damage to the light-sensitive tissue at the back of the eye (the retina) causes a condition known as diabetic retinopathy that can lead to vision loss and eventual blindness. Kidney damage (diabetic nephropathy) can lead to kidney failure and end-stage renal disease (ESRD). While these two types of MODY are very similar, certain features are particular to each type. For example, babies with HNF4A-MODY tend to weigh more than average or have abnormally low blood glucose at birth, even though other signs of the condition do not occur until childhood or young adulthood. People with HNF1A-MODY have a higher-than-average risk of developing noncancerous (benign) liver tumors known as hepatocellular adenomas.

GCK-MODY is a very mild type of the condition. People with this type have slightly elevated blood glucose levels, particularly in the morning before eating (fasting blood glucose). However, affected individuals often have no symptoms related to the disorder, and diabetes-related complications are extremely rare.

RCAD is associated with a combination of diabetes and kidney or urinary tract abnormalities (unrelated to the elevated blood glucose), most commonly fluid-filled sacs (cysts) in the kidneys. However, the signs and symptoms are variable, even within families, and not everyone with RCAD has both features. Affected individuals may have other features unrelated to diabetes, such as abnormalities of the pancreas or liver or a form of arthritis called gout. [from MedlinePlus Genetics]

Clinical features

From HPO
Maturity onset diabetes mellitus in young
MedGen UID:
87433
Concept ID:
C0342276
Disease or Syndrome
Maturity-onset diabetes of the young is an autosomal dominant form of diabetes typically occurring before 25 years of age and caused by primary insulin secretion defects. Despite its low prevalence, MODY is not a single entity but represents genetic, metabolic, and clinical heterogeneity (Vaxillaire and Froguel, 2008). Genetic Heterogeneity of MODY MODY1 (125850) is caused by heterozygous mutation in the hepatocyte nuclear factor-4-alpha gene (HNF4A; 600281) on chromosome 20. MODY2 (125851) is caused by heterozygous mutation in the glucokinase gene (GCK; 138079) on chromosome 7. MODY3 (600496) is caused by heterozygous mutation in the hepatocyte nuclear factor-1alpha gene (HNF1A; 142410) on chromosome 12q24. MODY4 (606392) is caused by heterozygous mutation in the pancreas/duodenum homeobox protein-1 gene (PDX1; 600733) on chromosome 13q12. MODY5 (137920) is caused by heterozygous mutation in the gene encoding hepatic transcription factor-2 (TCF2; 189907) on chromosome 17q12. MODY6 (606394) is caused by heterozygous mutation in the NEUROD1 gene (601724) on chromosome 2q31. MODY7 (610508) is caused by heterozygous mutation in the KLF11 gene (603301) on chromosome 2p25. MODY8 (609812), or diabetes-pancreatic exocrine dysfunction syndrome, is caused by heterozygous mutation in the CEL gene (114840) on chromosome 9q34. MODY9 (612225) is caused by heterozygous mutation in the PAX4 gene (167413) on chromosome 7q32. MODY10 (613370) is caused by heterozygous mutation in the insulin gene (INS; 176730) on chromosome 11p15. MODY11 (613375) is caused by heterozygous mutation in the BLK gene (191305) on chromosome 8p23. MODY13 (616329) is caused by heterozygous mutation in the KCNJ11 gene (600937) on chromosome 11p15. MODY14 (616511) is caused by heterozygous mutation in the APPL1 gene (604299) on chromosome 3p14.
Flushing
MedGen UID:
5234
Concept ID:
C0016382
Sign or Symptom
Recurrent episodes of redness of the skin together with a sensation of warmth or burning of the affected areas of skin.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMaturity-onset diabetes of the young type 1

Professional guidelines

PubMed

Shepherd M, Shields B, Hammersley S, Hudson M, McDonald TJ, Colclough K, Oram RA, Knight B, Hyde C, Cox J, Mallam K, Moudiotis C, Smith R, Fraser B, Robertson S, Greene S, Ellard S, Pearson ER, Hattersley AT; UNITED Team
Diabetes Care 2016 Nov;39(11):1879-1888. Epub 2016 Jun 6 doi: 10.2337/dc16-0645. PMID: 27271189Free PMC Article

Recent clinical studies

Etiology

Wu HX, Chu TY, Iqbal J, Jiang HL, Li L, Wu YX, Zhou HD
J Clin Endocrinol Metab 2023 Oct 18;108(11):2970-2980. doi: 10.1210/clinem/dgad233. PMID: 37093977
Sheppard SE, Barrett B, Muraresku C, McKnight H, De Leon DD, Lord K, Ganetzky R
Am J Med Genet A 2021 Feb;185(2):566-570. Epub 2020 Nov 30 doi: 10.1002/ajmg.a.61978. PMID: 33251707Free PMC Article
Billings LK, Jablonski KA, Warner AS, Cheng YC, McAteer JB, Tipton L, Shuldiner AR, Ehrmann DA, Manning AK, Dabelea D, Franks PW, Kahn SE, Pollin TI, Knowler WC, Altshuler D, Florez JC; Diabetes Prevention Program Research Group
J Clin Endocrinol Metab 2017 Aug 1;102(8):2678-2689. doi: 10.1210/jc.2016-3429. PMID: 28453780Free PMC Article
Kleinberger JW, Maloney KA, Pollin TI
Am J Perinatol 2016 Nov;33(13):1319-1326. Epub 2016 Aug 29 doi: 10.1055/s-0036-1592078. PMID: 27571483Free PMC Article
Price JA, Fossey SC, Sale MM, Brewer CS, Freedman BI, Wuerth JP, Bowden DW
Diabetologia 2000 Mar;43(3):364-72. doi: 10.1007/s001250050055. PMID: 10768098

Diagnosis

Zhang J, Jiang Y, Li J, Zou H, Yin L, Yang Y, Yang L
Front Endocrinol (Lausanne) 2023;14:1237553. Epub 2023 Aug 29 doi: 10.3389/fendo.2023.1237553. PMID: 37711893Free PMC Article
Wu HX, Chu TY, Iqbal J, Jiang HL, Li L, Wu YX, Zhou HD
J Clin Endocrinol Metab 2023 Oct 18;108(11):2970-2980. doi: 10.1210/clinem/dgad233. PMID: 37093977
Çubuk H, Yalçın Çapan Ö
Protein J 2021 Jun;40(3):348-360. Epub 2021 May 5 doi: 10.1007/s10930-021-09991-8. PMID: 33950347
Kleinberger JW, Maloney KA, Pollin TI
Am J Perinatol 2016 Nov;33(13):1319-1326. Epub 2016 Aug 29 doi: 10.1055/s-0036-1592078. PMID: 27571483Free PMC Article
Fujiwara M, Namba N, Miura K, Kitaoka T, Hirai H, Kondou H, Shimotsuji T, Numakura C, Ozono K
Horm Res Paediatr 2013;79(4):220-6. Epub 2013 May 1 doi: 10.1159/000350520. PMID: 23652628

Therapy

Billings LK, Jablonski KA, Warner AS, Cheng YC, McAteer JB, Tipton L, Shuldiner AR, Ehrmann DA, Manning AK, Dabelea D, Franks PW, Kahn SE, Pollin TI, Knowler WC, Altshuler D, Florez JC; Diabetes Prevention Program Research Group
J Clin Endocrinol Metab 2017 Aug 1;102(8):2678-2689. doi: 10.1210/jc.2016-3429. PMID: 28453780Free PMC Article
Wiley F
Diabetes Self Manag 2016 Jul-Aug;33(4):36-7. PMID: 27491106

Prognosis

Zhang J, Jiang Y, Li J, Zou H, Yin L, Yang Y, Yang L
Front Endocrinol (Lausanne) 2023;14:1237553. Epub 2023 Aug 29 doi: 10.3389/fendo.2023.1237553. PMID: 37711893Free PMC Article
Katashima R, Matsumoto M, Watanabe Y, Moritani M, Yokota I
J Diabetes Res 2021;2021:7216339. Epub 2021 Oct 29 doi: 10.1155/2021/7216339. PMID: 34746319Free PMC Article
Sugawara K, Nomura K, Okada Y, Sugano A, Matsumoto M, Takarada T, Takeuchi A, Awano H, Hirota Y, Nishio H, Takaoka Y, Ogawa W
J Diabetes Investig 2019 May;10(3):680-684. Epub 2018 Dec 10 doi: 10.1111/jdi.12960. PMID: 30325586Free PMC Article
Vethe H, Bjørlykke Y, Ghila LM, Paulo JA, Scholz H, Gygi SP, Chera S, Ræder H
Sci Rep 2017 Jul 6;7(1):4780. doi: 10.1038/s41598-017-04979-w. PMID: 28684784Free PMC Article

Clinical prediction guides

Zhang J, Jiang Y, Li J, Zou H, Yin L, Yang Y, Yang L
Front Endocrinol (Lausanne) 2023;14:1237553. Epub 2023 Aug 29 doi: 10.3389/fendo.2023.1237553. PMID: 37711893Free PMC Article
Katashima R, Matsumoto M, Watanabe Y, Moritani M, Yokota I
J Diabetes Res 2021;2021:7216339. Epub 2021 Oct 29 doi: 10.1155/2021/7216339. PMID: 34746319Free PMC Article
Vethe H, Bjørlykke Y, Ghila LM, Paulo JA, Scholz H, Gygi SP, Chera S, Ræder H
Sci Rep 2017 Jul 6;7(1):4780. doi: 10.1038/s41598-017-04979-w. PMID: 28684784Free PMC Article
Raeder H, Bjørkhaug L, Johansson S, Mangseth K, Sagen JV, Hunting A, Følling I, Johansen O, Bjørgaas M, Paus PN, Søvik O, Molven A, Njølstad PR
Diabetes 2006 Jun;55(6):1899-903. doi: 10.2337/db05-1677. PMID: 16731861
Eeckhoute J, Formstecher P, Laine B
Mol Endocrinol 2001 Jul;15(7):1200-10. doi: 10.1210/mend.15.7.0670. PMID: 11435618

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