How Do I Diagnose Maturity Onset Diabetes of the Young in My Patients?

Kevin Colclough; Kashyap Patel

Clin Endocrinol. 2022;97(4):436-447.

Abstract and Introduction

Abstract

Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes diagnosed in young individuals that lack the typical features of type 1 and type 2 diabetes. The genetic subtype of MODY determines the most effective treatment and this is the driver for MODY genetic testing in diabetes populations. Despite the obvious clinical and health economic benefits, MODY is significantly underdiagnosed with the majority of patients being inappropriately managed as having type 1 or type 2 diabetes. Low detection rates result from the difficulty in identifying patients with a likely diagnosis of MODY from the high background population of young onset type 1 and type 2 diabetes, compounded by the lack of MODY awareness and education in diabetes care physicians. MODY diagnosis can be improved through (1) access to education and training, (2) the use of sensitive and specific selection criteria based on accurate prediction models and biomarkers to identify patients for testing, (3) the development and mainstream implementation of simple criteria-based selection pathways applicable across a range of healthcare settings and ethnicities to select the most appropriate patients for genetic testing and (4) the correct use of next generation sequencing technology to provide accurate and comprehensive testing of all known MODY and monogenic diabetes genes. The creation and public sharing of educational materials, clinical and scientific best practice guidelines and genetic variants will help identify the missing patients so they can benefit from the more effective clinical care that a genetic diagnosis brings.

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Table 1. The different genetic subtypes of MODY.
Gene	Clinical characteristics	Proportion of patients with suspected MODY and a genetic diagnosis^a	Mode of inheritance	Mutational mechanism	References
Genes associated with the classical MODY phenotype
HNF1A	Progressive insulin secretion defect with patients presenting as teenagers or young adults. Sensitive to low-dose sulphonylurea treatment. Glycosuria due to a low renal threshold for glucose. Neonatal hypoglycaemia reported in some patients. Increased risk of cardiovascular mortality despite a protective lipid profile.	33%	Autosomal dominant, very rarely recessive if mutations are hypomorphic for example p.Ala251Thr.	Loss of function (haploinsufficiency) resulting in an insulin secretion defect.	[4–6]
HNF4A	Progressive insulin secretion defect with patients presenting as teenagers or young adults. Sensitive to low-dose sulphonylurea treatment. Hyperinsulinism occurs in utero resulting in increased birthweight and risk of neonatal hypoglycaemia. The p.Arg63Trp mutation also causes a proximal tubulopathy and the p.Arg114Trp mutation is associated with a significantly reduced penetrance for diabetes.	14%	Autosomal dominant.	Loss of function (haploinsufficiency) resulting in an insulin secretion defect.	[4,7,8]
GCK	Glucose sensing is reset to a higher level resulting in mild fasting hyperglycaemia from birth (typically in the range of 5.5–8 mmol/L with HbA1c 40–60 mmol/mol) and small postprandial increase in glucose (<3 mmol) that does not increase risk of diabetes complications. Usually asymptomatic so often detected incidentally for example in pregnancy. Hyperglycaemia does not respond to or require treatment outside of pregnancy; treatment during pregnancy is determined by the GCKmutation status of the foetus.	22%	Autosomal dominant, although rare recessive cases occur with specific mutations that can result in a more severe phenotype similar to HNF MODY.	Loss of function (haploinsufficiency) causing a defect in glucose sensing by the beta cell.	[9,10]
INS	Highly penetrant subtype that resembles type 1 diabetes without autoimmunity. Insulin treatment can help reduce ER stress on beta cell and preserve insulin secretion.	2%	Autosomal dominant.	Toxic gain of function from misfolded proteins causing ER stress and beta cell death. The p.Arg46Gln mutation specifically causes diabetes due to loss of insulin activity.	[11,12]
ABCC8	Diabetes may occur as the relapsing stage of TNDM, or as isolated MODY when NDM is not penetrant. Patients with activating mutations are sensitive to sulphonylurea treatment, but not those with inactivating mutations.	4%	Autosomal dominant.	Gain of function (activating) missense mutations. Rarely, specific dominant loss of function (inactivating) missense mutations associated with congenital hyperinsulinism may cause MODY with reduced penetrance but the mechanisms driving this are not understood.	[13,14]
KCNJ11	Diabetes may occur as the relapsing stage of TNDM, or as isolated MODY when NDM is not penetrant. Patients are sensitive to sulphonylurea treatment.	2%	Autosomal dominant.	Gain of function (activating) missense mutations.	[15]
RFX6	Significantly reduced penetrance for diabetes. Hypothetical response to DPP4 inhibitors or GLP1 receptor agonists based on observation of lower GIP levels.	3%	Autosomal dominant.	Loss of function (haploinsufficiency). Nonsense, frameshift and splicing variants resulting in a null allele. Missense variants are yet to be associated with MODY.	[16]
PDX1	Diabetes with reduced/variable penetrance that is rarely treated with insulin.	<1%	Autosomal dominant.	Combination of haploinsufficiency and dominant negative effects. Specific frameshift mutations trigger translation reinitiation, generating two mutant proteins that lack either the DNA binding domain or the transactivation domain.	[17,18]
NEUROD1	Diabetes with reduced/variable penetrance that is rarely treated with insulin.	1%	Autosomal dominant.	Unclear—possible haploinsufficiency although specific missense mutations in the DNA binding domain may act in a dominant negative manner.	[19,20]
Genes associated with syndromic subtypes of monogenic diabetes that may result in referral for MODY genetic testing in the absence of typical characteristic nondiabetic features
HNF1B	Renal structural disease, urogenital tract malformations, hypomagnesaemia, gout, abnormal liver function, pancreatic hypoplasia, autism (HNF1Bdeletion cases). Severity of the renal phenotype is highly variable and patients may present with isolated MODY.	6%	Autosomal dominant.	Loss of function (haploinsufficiency). Whole gene deletions of HNF1Baccount for ~50% of all cases.	[21]
MT-TL1	Bilateral sensorineural deafness. Penetrance of deafness is highly variable due to variation in heteroplasmy in specific tissues and patients may present with isolated MODY.	8%	Mitochondrial (maternal).	m.3243A>G mutation.	[22]
CEL	Pancreatic lipomatosis and exocrine dysfunction.	<1%	Autosomal dominant.	Toxic gain of function from misfolded proteins caused by frameshift variants in the first 1–4 repeats of the VNTR region.	[23]
PAX6	Aniridia.	<1%	Autosomal dominant.	Loss of function (haploinsufficiency).	[24]
WFS1	Optic atrophy, deafness, bladder dysfunction, neurological problems. Islet autoantibody negative diabetes is usually the first presenting feature in childhood and this may trigger referral for MODY testing in the absence of any other features.	2%	Autosomal recessive. A specific missense mutation, p.Trp314Arg, causes autosomal dominant nonsyndromic WFS1-related diabetes.	Loss of function.	[25,26]
GATA6	Structural heart defects, pancreatic agenesis and neonatal diabetes. Very rarely patients can present with diabetes in childhood without structural defects of the heart and pancreas.	<1%	Autosomal dominant.	Loss of function (haploinsufficiency). Typically null mutations are identified and can arise de novo.	[27]
Putative MODY genes with limited evidence for gene-disease association
APPL1	Associated with a later age of onset, less severe disease and reduced penetrance for diabetes. Potentially risk variants for type 2 diabetes in combination with obesity rather than highly penetrant monogenic mutations.	<1%	Autosomal dominant.	Loss of function (haploinsufficiency).	[28]
Genes with refuted evidence for gene-disease association
PAX4	Potentially risk variants for type 2 diabetes in combination with obesity rather than highly penetrant monogenic mutations.	<1%	Autosomal dominant.	Loss of function (haploinsufficiency).	[29]
BLK
KLF11

Note: Genes are categorized into those that cause the classic MODY phenotype of isolated diabetes, those where the diabetes can resemble MODY but is part of a syndrome with characteristic nondiabetic features, and putative genes published as likely to cause MODY but require more evidence to definitively assign MODY gene status. HNF4A mutations are described using the reference sequence NM_175914.4 and may differ from descriptions in the literature.
Abbreviations: ER, endoplasmic reticulum; MODY, Maturity Onset Diabetes of the Young; NDM, neonatal diabetes mellitus; TNDM, transient neonatal diabetes mellitus; VNTR, variable number tandem repeat.
^aExeter of 297 patients with a genetic diagnosis of monogenic diabetes tested using targeted next generation sequencing of all known MODY genes due to a suspected diagnosis of MODY.

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How Do I Diagnose Maturity Onset Diabetes of the Young in My Patients?

Abstract and Introduction

Abstract

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