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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
Type 2 diabetes mellitus is distinct from maturity-onset diabetes of the young (see 606391) in that it is polygenic, characterized by gene-gene and gene-environment interactions with onset in adulthood, usually at age 40 to 60 but occasionally in adolescence if a person is obese. The pedigrees are rarely multigenerational. The penetrance is variable, possibly 10 to 40% (Fajans et al., 2001). Persons with type 2 diabetes usually have an obese body habitus and manifestations of the so-called metabolic syndrome (see 605552), which is characterized by diabetes, insulin resistance, hypertension, and hypertriglyceridemia. Genetic Heterogeneity of Susceptibility to Type 2 Diabetes Susceptibility to T2D1 (601283) is conferred by variation in the calpain-10 gene (CAPN10; 605286) on chromosome 2q37. The T2D2 locus (601407) on chromosome 12q was found in a Finnish population. The T2D3 locus (603694) maps to chromosome 20. The T2D4 locus (608036) maps to chromosome 5q34-q35. Susceptibility to T2D5 (616087) is conferred by variation in the TBC1D4 gene (612465) on chromosome 13q22. A mutation has been observed in hepatocyte nuclear factor-4-alpha (HNF4A; 600281.0004) in a French family with NIDDM of late onset. Mutations in the NEUROD1 gene (601724) on chromosome 2q32 were found to cause type 2 diabetes mellitus in 2 families. Mutation in the GLUT2 glucose transporter was associated with NIDDM in 1 patient (138160.0001). Mutation in the MAPK8IP1 gene, which encodes the islet-brain-1 protein, was found in a family with type 2 diabetes in individuals in 4 successive generations (604641.0001). Polymorphism in the KCNJ11 gene (600937.0014) confers susceptibility. In French white families, Vionnet et al. (2000) found evidence for a susceptibility locus for type 2 diabetes on 3q27-qter. They confirmed the diabetes susceptibility locus on 1q21-q24 reported by Elbein et al. (1999) in whites and by Hanson et al. (1998) in Pima Indians. A mutation in the GPD2 gene (138430.0001) on chromosome 2q24.1, encoding mitochondrial glycerophosphate dehydrogenase, was found in a patient with type 2 diabetes mellitus and in his glucose-intolerant half sister. Mutations in the PAX4 gene (167413) have been identified in patients with type 2 diabetes. Triggs-Raine et al. (2002) stated that in the Oji-Cree, a gly319-to-ser change in HNF1-alpha (142410.0008) behaves as a susceptibility allele for type 2 diabetes. Mutation in the HNF1B gene (189907.0007) was found in 2 Japanese patients with typical late-onset type 2 diabetes. Mutations in the IRS1 gene (147545) have been found in patients with type 2 diabetes. A missense mutation in the AKT2 gene (164731.0001) caused autosomal dominant type 2 diabetes in 1 family. A (single-nucleotide polymorphism) SNP in the 3-prime untranslated region of the resistin gene (605565.0001) was associated with susceptibility to diabetes and to insulin resistance-related hypertension in Chinese subjects. Susceptibility to insulin resistance has been associated with polymorphism in the TCF1 (142410.0011), PPP1R3A (600917.0001), PTPN1 (176885.0001), ENPP1 (173335.0006), IRS1 (147545.0002), and EPHX2 (132811.0001) genes. The K121Q polymorphism of ENPP1 (173335.0006) is associated with susceptibility to type 2 diabetes; a haplotype defined by 3 SNPs of this gene, including K121Q, is associated with obesity, glucose intolerance, and type 2 diabetes. A SNP in the promoter region of the hepatic lipase gene (151670.0004) predicts conversion from impaired glucose tolerance to type 2 diabetes. Variants of transcription factor 7-like-2 (TCF7L2; 602228.0001), located on 10q, have also been found to confer risk of type 2 diabetes. A common sequence variant, rs10811661, on chromosome 9p21 near the CDKN2A (600160) and CDKN2B (600431) genes has been associated with risk of type 2 diabetes. Variation in the PPARG gene (601487) has been associated with risk of type 2 diabetes. A promoter polymorphism in the IL6 gene (147620) is associated with susceptibility to NIDDM. Variation in the KCNJ15 gene (602106) has been associated with T2D in lean Asians. Variation in the SLC30A8 gene (611145) has been associated with susceptibility to T2D. Variation in the HMGA1 gene (600701.0001) is associated with an increased risk of type 2 diabetes. Mutation in the MTNR1B gene (600804) is associated with susceptibility to type 2 diabetes. Protection Against Type 2 Diabetes Mellitus Protein-truncating variants in the SLC30A8 (611145) have been associated with a reduced risk for T2D.
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
Am J Perinatol 2016 Nov;33(13):1319-1326. Epub 2016 Aug 29 doi: 10.1055/s-0036-1592078. PMID: 27571483Free PMC Article
Greaves WO, Bhattacharya B
Arch Pathol Lab Med 2008 Dec;132(12):1951-5. doi: 10.5858/132.12.1951. PMID: 19061298

Diagnosis

Urbanová J, Brunerová L, Nunes MA, Brož J
Ceska Gynekol 2020 Winter;85(2):124-130. PMID: 32527107
Valkovicova T, Skopkova M, Stanik J, Gasperikova D
Endocr Regul 2019 Apr 1;53(2):110-134. doi: 10.2478/enr-2019-0013. PMID: 31517624
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
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

Therapy

Christensen AS, Hædersdal S, Støy J, Storgaard H, Kampmann U, Forman JL, Seghieri M, Holst JJ, Hansen T, Knop FK, Vilsbøll T
Diabetes Care 2020 Sep;43(9):2025-2033. Epub 2020 Jul 13 doi: 10.2337/dc20-0408. PMID: 32661107Free PMC Article
Urbanová J, Brunerová L, Nunes MA, Brož J
Ceska Gynekol 2020 Winter;85(2):124-130. PMID: 32527107
Heuvel-Borsboom H, de Valk HW, Losekoot M, Westerink J
Neth J Med 2016 Jun;74(5):193-200. PMID: 27323672
Zhou K, Pedersen HK, Dawed AY, Pearson ER
Nat Rev Endocrinol 2016 Jun;12(6):337-46. Epub 2016 Apr 11 doi: 10.1038/nrendo.2016.51. PMID: 27062931
Østoft SH, Bagger JI, Hansen T, Pedersen O, Holst JJ, Knop FK, Vilsbøll T
Diabetes 2014 Aug;63(8):2838-44. Epub 2014 Mar 27 doi: 10.2337/db13-1878. PMID: 24677712

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
Cardenas-Diaz FL, Osorio-Quintero C, Diaz-Miranda MA, Kishore S, Leavens K, Jobaliya C, Stanescu D, Ortiz-Gonzalez X, Yoon C, Chen CS, Haliyur R, Brissova M, Powers AC, French DL, Gadue P
Cell Stem Cell 2019 Aug 1;25(2):273-289.e5. doi: 10.1016/j.stem.2019.07.007. PMID: 31374199Free PMC Article
Heuvel-Borsboom H, de Valk HW, Losekoot M, Westerink J
Neth J Med 2016 Jun;74(5):193-200. PMID: 27323672

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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