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Maturity-onset diabetes of the young type 2(MODY2)

MedGen UID:
87434
Concept ID:
C0342277
Disease or Syndrome
Synonyms: Diabetes mellitus MODY type 2; Diabetes mellitus, type II, autosomal dominant; MODY glucokinase-related; MODY type 2
SNOMED CT: Maturity onset diabetes of the young, type 2 (237604008); Diabetes mellitus autosomal dominant type II (237604008); Maturity onset diabetes in youth type II (237604008); Maturity onset diabetes in youth type 2 (237604008); GCK (glucokinase) monogenic diabetes mellitus (237604008); MODY2 (maturity onset diabetes of the young type 2) (237604008)
 
Gene (location): GCK (7p13)
 
Monarch Initiative: MONDO:0007453
OMIM®: 125851

Definition

MODY is a form of NIDDM (125853) characterized by monogenic autosomal dominant transmission and early age of onset. For a general phenotypic description and a discussion of genetic heterogeneity of MODY, see 606391. In a review of the various forms of MODY, Fajans et al. (2001) stated that glucokinase-related MODY2 is a common form of the disorder, especially in children with mild hyperglycemia and in women with gestational diabetes and a family history of diabetes. It has been described in persons of all racial and ethnic groups. More than 130 MODY-associated mutations have been found in the glucokinase gene. Heterozygous mutations in glucokinase are associated with a mild form of nonprogressive hyperglycemia that is usually asymptomatic at diagnosis and is treated with diet alone. The mild fasting hyperglycemia with blood glucose concentrations of 110 to 145 mg/deciliter and impaired glucose tolerance in most affected carriers may be recognized by biochemical testing at a young age, possibly as early as birth. About 50% of the women who are carriers may have gestational diabetes. Less than 50% of the carriers have overt diabetes; many of those who do are obese or elderly. Two percent of MODY2 patients require insulin therapy. Diabetes-associated complications are rare in this form of MODY. MODY was found in 13% of the Caucasian NIDDM families collected in France by Froguel et al. (1991). Gidh-Jain et al. (1993) found that GCK mutations accounted for 56% of MODY families in France. [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
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 2

Professional guidelines

PubMed

Fenner D, Odili S, Hong HK, Kobayashi Y, Kohsaka A, Siepka SM, Vitaterna MH, Chen P, Zelent B, Grimsby J, Takahashi JS, Matschinsky FM, Bass J
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Recent clinical studies

Etiology

Elias-Assad G, Saab R, Molnes J, Hess O, Abu-Ras R, Darawshi H, Rasmus Njølstad P, Tenenbaum-Rakover Y
Diabetes Res Clin Pract 2021 May;175:108791. Epub 2021 Apr 2 doi: 10.1016/j.diabres.2021.108791. PMID: 33812904
Hulín J, Škopková M, Valkovičová T, Mikulajová S, Rosoľanková M, Papcun P, Gašperíková D, Staník J
Physiol Res 2020 Dec 22;69(6):995-1011. Epub 2020 Nov 2 doi: 10.33549/physiolres.934487. PMID: 33129248Free 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

Diagnosis

Elias-Assad G, Saab R, Molnes J, Hess O, Abu-Ras R, Darawshi H, Rasmus Njølstad P, Tenenbaum-Rakover Y
Diabetes Res Clin Pract 2021 May;175:108791. Epub 2021 Apr 2 doi: 10.1016/j.diabres.2021.108791. PMID: 33812904
Liang H, Zhang Y, Li M, Yan J, Yang D, Luo S, Zheng X, Yang G, Li Z, Xu W, Groop L, Weng J
J Diabetes Investig 2021 Apr;12(4):501-509. Epub 2020 Sep 9 doi: 10.1111/jdi.13378. PMID: 32741144Free PMC Article
Hulín J, Škopková M, Valkovičová T, Mikulajová S, Rosoľanková M, Papcun P, Gašperíková D, Staník J
Physiol Res 2020 Dec 22;69(6):995-1011. Epub 2020 Nov 2 doi: 10.33549/physiolres.934487. PMID: 33129248Free PMC Article
Urbanová J, Brunerová L, Nunes MA, Brož J
Ceska Gynekol 2020 Winter;85(2):124-130. PMID: 32527107
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

Therapy

Li J, Shu M, Wang X, Deng A, Wen C, Wang J, Jin S, Zhang H
Front Endocrinol (Lausanne) 2021;12:700342. Epub 2021 Aug 5 doi: 10.3389/fendo.2021.700342. PMID: 34421822Free PMC Article
Li W, Zhang X, Sun Y, Liu Z
Pharmazie 2020 Jun 1;75(6):230-235. doi: 10.1691/ph.2020.0409. PMID: 32539915
Urbanová J, Brunerová L, Nunes MA, Brož J
Ceska Gynekol 2020 Winter;85(2):124-130. PMID: 32527107
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
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

Li J, Shu M, Wang X, Deng A, Wen C, Wang J, Jin S, Zhang H
Front Endocrinol (Lausanne) 2021;12:700342. Epub 2021 Aug 5 doi: 10.3389/fendo.2021.700342. PMID: 34421822Free PMC Article
Elias-Assad G, Saab R, Molnes J, Hess O, Abu-Ras R, Darawshi H, Rasmus Njølstad P, Tenenbaum-Rakover Y
Diabetes Res Clin Pract 2021 May;175:108791. Epub 2021 Apr 2 doi: 10.1016/j.diabres.2021.108791. PMID: 33812904
Liang H, Zhang Y, Li M, Yan J, Yang D, Luo S, Zheng X, Yang G, Li Z, Xu W, Groop L, Weng J
J Diabetes Investig 2021 Apr;12(4):501-509. Epub 2020 Sep 9 doi: 10.1111/jdi.13378. PMID: 32741144Free PMC Article
Hulín J, Škopková M, Valkovičová T, Mikulajová S, Rosoľanková M, Papcun P, Gašperíková D, Staník J
Physiol Res 2020 Dec 22;69(6):995-1011. Epub 2020 Nov 2 doi: 10.33549/physiolres.934487. PMID: 33129248Free PMC Article
Urbanová J, Brunerová L, Nunes MA, Brož J
Ceska Gynekol 2020 Winter;85(2):124-130. PMID: 32527107

Clinical prediction guides

Timsit J, Ciangura C, Dubois-Laforgue D, Saint-Martin C, Bellanne-Chantelot C
Front Endocrinol (Lausanne) 2021;12:802423. Epub 2022 Jan 5 doi: 10.3389/fendo.2021.802423. PMID: 35069449Free PMC Article
Liang H, Zhang Y, Li M, Yan J, Yang D, Luo S, Zheng X, Yang G, Li Z, Xu W, Groop L, Weng J
J Diabetes Investig 2021 Apr;12(4):501-509. Epub 2020 Sep 9 doi: 10.1111/jdi.13378. PMID: 32741144Free 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
George DC, Chakraborty C, Haneef SA, Nagasundaram N, Chen L, Zhu H
Theranostics 2014;4(4):366-85. Epub 2014 Jan 29 doi: 10.7150/thno.7473. PMID: 24578721Free PMC Article
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Clin Genet 2013 Jan;83(1):83-7. Epub 2012 Mar 26 doi: 10.1111/j.1399-0004.2012.01856.x. PMID: 22335469

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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