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Maturity-onset diabetes of the young type 3(MODY3)

MedGen UID:
324942
Concept ID:
C1838100
Disease or Syndrome
Synonyms: Diabetes mellitus MODY type 3; MODY type 3; MODY hepatocyte nuclear factor-1-alpha related; MODY, type III
SNOMED CT: Maturity-onset diabetes of the young, type 3 (609570008); MODY3 (maturity-onset diabetes of the young type 3) (609570008)
 
Gene (location): HNF1A (12q24.31)
 
Monarch Initiative: MONDO:0010894
OMIM®: 600496

Definition

MODY is a form of familial noninsulin-dependent diabetes mellitus (T2D; 125853) and is characterized by an early age of onset (childhood, adolescence, or young adulthood under 25 years) and autosomal dominant inheritance. For a phenotypic description and discussion of genetic heterogeneity of MODY, see 606391. [from OMIM]

Additional description

From MedlinePlus Genetics
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.

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.

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.

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.  https://medlineplus.gov/genetics/condition/maturity-onset-diabetes-of-the-young

Clinical features

From HPO
Type 2 diabetes mellitus
MedGen UID:
41523
Concept ID:
C0011860
Disease or Syndrome
WFS1 spectrum disorder (WFS1-SD) comprises classic WFS1 spectrum disorder and nonclassic WFS1 spectrum disorder. Classic WFS1-SD, a progressive neurodegenerative disorder, is characterized by onset of diabetes mellitus and optic atrophy before age 16 years. Additional complications may include one or more of the following: variable hearing impairment / deafness, diabetes insipidus, neurologic abnormalities, neurogenic bladder, and psychiatric abnormalities. Nonclassic WFS1-SD is less common than classic WFS1-SD. Phenotypes that appear to be milder than classic WFS1-SD include: optic atrophy and hearing impairment; neonatal diabetes, profound congenital deafness, and cataracts; isolated diabetes mellitus; isolated congenital cataracts; and isolated congenital, slowly progressive, and low-frequency (<2000 Hz) sensorineural hearing loss.
Hyperglycemia
MedGen UID:
5689
Concept ID:
C0020456
Disease or Syndrome
An increased concentration of glucose in the blood.
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.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMaturity-onset diabetes of the young type 3

Professional guidelines

PubMed

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Recent clinical studies

Etiology

Li LM, Jiang BG, Sun LL
Front Endocrinol (Lausanne) 2022;13:829565. Epub 2022 Mar 1 doi: 10.3389/fendo.2022.829565. PMID: 35299962Free PMC Article
Urbanová J, Brunerová L, Nunes MA, Brož J
Ceska Gynekol 2020 Winter;85(2):124-130. PMID: 32527107
Monsonego S, Clark H, Karovitch A, O'Meara P, Shaw T, Malcolm J
Can J Diabetes 2019 Dec;43(8):647-654. Epub 2019 Aug 2 doi: 10.1016/j.jcjd.2019.07.004. PMID: 31564623
Kleinberger JW, Maloney KA, Pollin TI
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Greaves WO, Bhattacharya B
Arch Pathol Lab Med 2008 Dec;132(12):1951-5. doi: 10.5858/132.12.1951. PMID: 19061298

Diagnosis

To C, Liu L, Satoskar RS, Thuluvath PJ
Dig Dis Sci 2022 Jun;67(6):2688-2690. Epub 2021 May 3 doi: 10.1007/s10620-021-07005-2. PMID: 33939153
Urbanová J, Brunerová L, Nunes MA, Brož J
Ceska Gynekol 2020 Winter;85(2):124-130. PMID: 32527107
Harryvan TJ, Tushuizen ME
Gastroenterology 2018 Jul;155(1):25-26. Epub 2018 Feb 1 doi: 10.1053/j.gastro.2017.12.031. PMID: 29410120
Fang C, Huang J, Huang Y, Chen L, Chen X, Hu J
Diabetes Res Clin Pract 2015 Aug;109(2):e5-7. Epub 2015 May 15 doi: 10.1016/j.diabres.2015.05.026. PMID: 26050565
Greaves WO, Bhattacharya B
Arch Pathol Lab Med 2008 Dec;132(12):1951-5. doi: 10.5858/132.12.1951. PMID: 19061298

Therapy

Li L, Gong L, Zheng A, Yang Q, Pu D, Zhang Y
Zhong Nan Da Xue Xue Bao Yi Xue Ban 2024 Jun 28;49(6):848-855. doi: 10.11817/j.issn.1672-7347.2024.230594. PMID: 39311780Free PMC Article
Urbanová J, Brunerová L, Nunes MA, Brož J
Ceska Gynekol 2020 Winter;85(2):124-130. PMID: 32527107
Sánchez Malo MJ, Arrudi Moreno M, Lou Francés GM
Endocrinol Diabetes Nutr (Engl Ed) 2019 Apr;66(4):271-272. Epub 2019 Feb 13 doi: 10.1016/j.endinu.2018.12.003. PMID: 30770229
Wiley F
Diabetes Self Manag 2016 Jul-Aug;33(4):36-7. PMID: 27491106
Heuvel-Borsboom H, de Valk HW, Losekoot M, Westerink J
Neth J Med 2016 Jun;74(5):193-200. PMID: 27323672

Prognosis

Takase K, Yokota H, Ohno A, Watanabe M, Kushiyama A, Kushiyama S, Yamagami S, Nagaoka T
Exp Eye Res 2023 Feb;227:109379. Epub 2023 Jan 3 doi: 10.1016/j.exer.2022.109379. PMID: 36608813
Urbanová J, Brunerová L, Nunes MA, Brož J
Ceska Gynekol 2020 Winter;85(2):124-130. PMID: 32527107
Lebenthal Y, Fisch Shvalb N, Gozlan Y, Tenenbaum A, Tenenbaum-Rakover Y, Vaillant E, Froguel P, Vaxillaire M, Gat-Yablonski G
Diabetes Res Clin Pract 2018 Jan;135:18-22. Epub 2017 Oct 28 doi: 10.1016/j.diabres.2017.10.024. PMID: 29107759
Heuvel-Borsboom H, de Valk HW, Losekoot M, Westerink J
Neth J Med 2016 Jun;74(5):193-200. PMID: 27323672
Greaves WO, Bhattacharya B
Arch Pathol Lab Med 2008 Dec;132(12):1951-5. doi: 10.5858/132.12.1951. PMID: 19061298

Clinical prediction guides

Hermann FM, Kjærgaard MF, Tian C, Tiemann U, Jackson A, Olsen LR, Kraft M, Carlsson PO, Elfving IM, Kettunen JLT, Tuomi T, Novak I, Semb H
Cell Stem Cell 2023 Jan 5;30(1):38-51.e8. Epub 2022 Dec 22 doi: 10.1016/j.stem.2022.12.001. PMID: 36563694
Cujba AM, Alvarez-Fallas ME, Pedraza-Arevalo S, Laddach A, Shepherd MH, Hattersley AT, Watt FM, Sancho R
Cell Rep 2022 Mar 1;38(9):110425. doi: 10.1016/j.celrep.2022.110425. PMID: 35235779Free PMC Article
Millan AL, Trobo SI, de Dios A, Cerrato García M, Pérez MS, Cerrone GE, Frechtel GD, López AP
Diabetes Metab Res Rev 2021 Feb;37(2):e3374. Epub 2020 Jul 20 doi: 10.1002/dmrr.3374. PMID: 32588935
Heuvel-Borsboom H, de Valk HW, Losekoot M, Westerink J
Neth J Med 2016 Jun;74(5):193-200. PMID: 27323672
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Recent systematic reviews

Liu J, Xiao X, Zhang Q, Yu M
J Diabetes 2023 Jun;15(6):519-531. Epub 2023 May 24 doi: 10.1111/1753-0407.13390. PMID: 37226652Free PMC Article

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