Mody how many cases are we missing

Lancet, Ledermann HM. Diabetologia, 12 Diabet Med, 5 Diabet Med, 7 Diabetologia, 4 Int J Mol Sci , 22 16 , 23 Aug Sci Rep , 11 1 , 09 Aug Front Endocrinol Lausanne , , 29 Jul Int J Mol Sci , 22 14 , 14 Jul JCI Insight , 6 13 , 08 Jul To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

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Abstract Read article for free, via Unpaywall a legal, open copy of the full text. Search articles by 'B M Shields'. Shields BM 1 ,. S Hicks Search articles by 'S Hicks'. Hicks S ,. Shepherd MH ,. K Colclough Search articles by 'K Colclough'. This secretory defect worsens over time due to progressive beta-cell dysfunction [ 17 ]. Diabetes mellitus manifests usually at the age of 6—25 years with mild osmotic symptoms polyuria, polydipsia or as asymptomatic postprandial hyperglycemia without ketosis or ketoacidosis [ 38 ].

In contrast to GCK -MODY, there is impairment of first and second-phase insulin secretion in individuals with HNF1A mutations [ 39 , 40 ], resulting more often in overt diabetes as opposed to the mild hyperglycemia seen in the first.

Environmental and genetic characteristics contribute to this heterogeneity [ 41 , 42 , 43 ]. Nevertheless, in general, diagnosis of HNF1A mutations may be suggested by the presence of clinical characteristics described on Table 3 [ 7 , 40 , 44 ]. In HNF1A -MODY the frequency of cardiovascular and microvascular complications is high and similar to that of patients with type 1 and type 2 diabetes [ 45 , 46 ].

Treatment depends on the age and HbA1c levels. Patients can initially be managed with diet but most patients will require pharmacological treatment. They are very sensitive to sulfonylureas which are usually more effective than insulin, particularly in children and young adults [ 47 ]. This treatment is usually effective for several decades, but in a case of severe decrease in beta-cell insulin production, insulin therapy is needed [ 48 ].

Patients are also often sensitive to sulfonylureas [ 50 ]. A family history of marked macrosomia or diazoxide responsive neonatal hyperinsulinism in the context of familial diabetes should raise the hypothesis of HNF4A -MODY [ 51 ].

HNF1B gene plays a role in the tissue-specific regulation of gene expression in liver, kidney, intestines, and pancreatic islets, therefore influencing their embryonic development [ 52 ].

Median age of onset of diabetes was 28 years old in a multicenter cohort of individuals. Patients present some degree of hepatic insulin resistance, explaining why approximately half of them do not respond to sulfonylureas, needing early insulin therapy [ 7 , 53 ]. A recent study evaluated 35 patients with HNF1B mutations, This subtype of MODY was thought to be rare when initially described, but since the diabetes phenotype is frequently associated with renal and urogenital malformations [ 57 ], search for MODY in patients with those features has demonstrated HNF1B to be more frequent, with a proportion of affected patients similar to HNF4A depending on the studied population [ 44 ].

Presence of urogenital tract malformations, renal failure not explainable by diabetes progression, renal cysts, renal dysplasia, or hypoplastic glomerulocystic kidney disease in association with diabetes may prompt direct investigation of HNF1B , without necessarily investigating more common types of MODY beforehand [ 8 ].

It is important to point out in this context that spontaneous de novo mutations are relatively frequent and the absence of a familial history of renal disease should not discourage testing for HNF1B mutations [ 58 ]. In addition to the marked heterogeneity of the urogenital phenotype observed in association with diabetes, many cases of HNF1B without diabetes have been described [ 59 ].

Considering the heterogenous phenotype of HNF1B , researchers have developed a score that could be used as a tool for clinicians to select patients with suspicion of HNF1B before genetic testing. One of these scores was developed based on the frequency of most typical findings considering clinical, biological, imaging, and familial characteristics.

Both positive cases had a score higher than 8 [ 62 ]. Clinical strategies to select patients for genetic test have benefited from inclusion of other clinical data in the past decade, with the added goal of excluding other common types of diabetes such as type 1 diabetes.

Superposition with type 2 diabetes has also to be considered, since monogenic diabetes does not usually show features of insulin resistance [ 63 ]. With typical MODY families identified, further exploration into the heterogeneity of type 1 and type 2 diabetes uncovered patients with MODY but not bearing typical clinical features, even when extended criteria have been used.

This has drawn especial attention to atypical cases of the two most common types of diabetes. In British individuals clinically labeled as type 1 diabetes, 20 had persistent residual beta-cell function outside the range usually expected for type 1 diabetes. In the same series, among patients clinically diagnosed as having type 2 diabetes, 80 met extended criteria for MODY.

This model is useful to improve the low sensitivity of the classical criteria, although its own definition precludes its utilization in non-European populations [ 64 ]. Even with extended clinical criteria, most variables have been traditionally used in discrete form, resulting in poor sensitivity. To cope with this limitation, a mathematical model was developed for patients of white European origin, who have been diagnosed with diabetes at age equal or less than Two-hundred and seventy-eight individuals with type 1 diabetes clinically defined as requiring insulin within 6 months of diagnosis , with type 2 diabetes clinically defined as not requiring insulin within 6 months of diagnosis , and probands with a genetic diagnosis of MODY GCK , HNF1A , and 55 HNF4A have been compared regarding simple and widely available clinical variables [ 21 ].

When comparing type 2 diabetes with MODY, the following variables were associated with MODY: lower age at diagnosis, BMI, HbA1c, and current age; having one diabetic parent; not being treated with insulin or oral antidiabetic agents; female sex. Accuracy as measured by area under ROC curve was 0.

Comparing type 1 diabetes with MODY, the latter was associated with: having one parent with diabetes; lower current age and HbA1c; higher age at diagnosis; female sex. Area under ROC curve was 0. Although promising, similar models need to be tested in other populations in order to gain wider acceptance in clinical use, since this specific model has been developed for European Caucasian individuals with diabetes diagnosed before 35 years old and has been validated only for the three most commons subtypes of MODY.

Moreover, even when the shift from individual gene Sanger sequencing to targeted-NGS is completed in most centers around the world, algorithms to select candidates to genetic testing would still be necessary in order to improve cost-effectiveness [ 65 , 66 , 67 ]. Many stepwise algorithms of etiologic diagnoses of hyperglycemia have been proposed [ 68 , 69 , 70 ]. Recently, Urakami et al. Nowadays, selection for molecular testing is based on nonspecific clinical characteristics such as age of onset, family background, and atypical presentation for the assumed etiology, although these criteria do not combine reasonable levels of specificity and sensitivity.

In this context, many researches have been persistently looking for biomarkers to assist selection of individuals who deserve further investigation.

Meanwhile, many candidates like apolipoprotein-M ApoM , aminoaciduria, complement components, and glycosuria have been tested, but have not translated into useful biomarkers [ 72 , 73 , 74 ]. An overview of the most studied biomarkers as well as its rationale and clinical limitations follow below.

Some studies have shown that common variants near the HNF1A gene are associated with small alterations in serum high-sensitive C-reactive protein hsCPR levels in healthy adults. First, C-reactive protein is coded by the CRP gene.

This gene bears binding sites specific for the HNF1A transcription factor. Second, although MODY can bear some clinical resemblance with type 2 diabetes, low-grade inflammatory process seen in type 2 diabetes, obesity, and cardiovascular disease does not participate in the pathophysiology of MODY.

Since the discriminating cutoff point occurs in very low levels of CRP, the utilization of a high-sensitivity assay is mandatory. In another British study, a cutoff point of 0. The rise in obesity and type 2 diabetes have made the number of individuals with a family history of diabetes increase. A recent French study assessed the added value of hsCRP to distinguish between these two conditions. Area under ROC-curve was 0. Szopa et al. Nevertheless, the model was not accurate enough to discriminate HNF1A patients without gene sequencing [ 68 ].

Although hsCRP is becoming a useful and promising marker for HNF1A, considering its extensive availability and low cost, clinicians should have in mind that it is a non-specific test, affected by several pathological conditions such as inflammation and acute infection, so caution should be exercised with its clinical significance until more data are available.

The measurement of C-peptide is used to assess endogenous insulin production in diabetic and non-diabetic individuals, despite treatment with insulin. Several methods of C-peptide measurement have been proposed.

Venous blood C-peptide levels can be measured in the random, fasting or stimulated state [ 74 ]. Fasting and random non-fasting C-peptide are simple, quick to perform, and correlate with diabetes type. C-peptide is a small linear peptide, which is susceptible to enzyme proteolytic cleavage, consequently, quickly centrifuging and freezing sample is usually required. The h urinary C-peptide 24 h UCP sample collection is non-invasive and stable for 72 h in boric acid but is time-consuming and requires good patient compliance.

Second-void fasting UCPCR was suggested as the optimum approach for the assessment of baseline endogenous C-peptide production using a spot urine test [ 82 ]. Both tests are inaccurate in chronic kidney disease and affected by variations in creatinine [ 81 , 82 ].

One important feature distinguishing type 1 diabetes from MODY is long-term evolution of residual pancreatic function. In type 1 diabetes, complete insulin deficiency ensues in most patients after 5 years of evolution [ 83 , 84 ].

In MODY, since there is no direct destruction of beta-cells, residual endocrine pancreatic function may be observed after several years of evolution, therefore, detectable serum C-peptide outside the honeymoon period may indicate a diagnosis of MODY. This can be especially useful in transcription factor MODY, which presents frequently as a differential diagnosis to type 1 diabetes.

In contrast, in type 2 diabetes, obesity-related insulin resistance may result in elevated levels of insulin and C-peptide [ 85 ]. Adults with diabetes duration equal or greater than 5 years were evaluated, including patients with monogenic diabetes, as well as clinically defined type 1 and type 2 diabetes. Considering that C-peptide is known to decline more rapidly in children than in adults, a study evaluated the use of UCPCR and its ability to discriminate pediatric diabetes subtypes even in short-duration diabetes.

Fasting C-peptide cutoff determined by ROC curve analysis was 0. A recent study assessed random C-peptide measurements in patients with antibody-negative diabetes. A cut-off level of 0. Thus, random C-peptide testing would be a potentially simple and affordable initial screening test for MODY in antibody-negative patients [ 89 ]. Biochemical parameters with autoimmune, demographic, physical characteristics, and the use of additional markers of pancreatic reserve may be critical to aid in the distinction between type 1 diabetes and MODY.

Further studies in larger samples with a broader ethnical distribution of patients with specific MODY mutations are indicated. Sulfonylurea sensitivity has been reported in MODY patients even before description of involved genes, including the first family described by Stephan Fajans [ 50 ].

Although better response of transcription factor MODY to sulfonylureas has been now solidly demonstrated, and many patients can be safely transferred back to oral medications even after many years of insulin therapy [ 16 ], it is frequent to encounter patients responding to sulfonylureas without a definite classification of diabetes, in clinical setting where molecular diagnosis is not readily available. While transferring patients to sulfonylurea based solely in a clinical diagnosis of MODY is not a validated approach, patients without mutations in the known genes responding to oral medications suggest other undiscovered causes of MODY which also respond to sulfonylureas.

Sulfonylurea responsiveness is not endorsed as a valid criterion for patient selection for genetic testing. Nevertheless, marked sensitivity and long-term effectiveness to sulfonylureas among patients with long diabetes duration could be a useful clue to optimize the recruitment process [ 92 ]. Type 1 diabetes is the most common form of diabetes in children and young adults. This issue often leads to an inadvertent use of insulin, which has important implications on quality of life, side effects, level of acceptance of illness, and costs.

In this context, the assessment of islet antibodies to rule out type 1 diabetes gains importance. A recent study assessed the prevalence of MODY in a nationwide population-based registry of childhood diabetes. It used next-generation sequencing for the most common affected genes only in children negative for both GAD and IA-2 autoantibodies. The prevalence of MODY in antibody-negative childhood diabetes reached almost 6.

One-third of these MODY cases had not been recognized by clinical criteria alone [ 94 , 95 ]. This approach effectively resulted in more patients with type 1 diabetes being identified and reduced the number of patients needing consideration for MODY testing. Therefore, evaluation of autoantibodies can be a useful tool to select patients for further investigation.

The correct MODY diagnosis is crucial for proper treatment and improvement in quality of life. Recent advances in next-generation sequencing technology have enabled the maximization of diagnosis performance of monogenic diabetes.

However, high costs of genetic testing and limited awareness of MODY as a relevant entity outside clinicians undermines accurate diagnosis. Moreover, paucity of studies in non-European populations especially African and Latino , as well as access to molecular diagnosis in those populations, is also a challenge [ 97 ]. Likewise, refining the selection of patients to undergo genetic testing, using clinical criteria and inexpensive biomarkers, readily available and validated in various populations, could positively impact cost-effectiveness of diagnosis, follow-up, and treatment.

MODY is a heterogeneous group of monogenic forms of diabetes. Although it has been initially defined as a clinical syndrome of early-onset diabetes, subtypes of MODY caused by mutations in specific genes now stand on their own as separate pathological entities. Moreover, strict enforcement of the classical criteria to screen for MODY mutations yields poor sensitivity levels, detrimental to an adequate screening strategy.

Clinical biomarkers have been studied to improve accuracy of recruitment for molecular diagnosis. Among them, models employing residual beta-cell function are the most promising, although they need to be further validated to other populations. This combined with advancements in molecular diagnosis technology and reduction of its costs may lead to more efficient detection of the great majority of undiagnosed MODY cases in the near future.

MODY: history, genetics, pathophysiology, and clinical decision making. Diabetes Care. Tattersall RB. Mild familial diabetes with dominant inheritance. Q J Med. A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young MODY3. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young MODY1.

Pediatr Diabetes. PubMed Article Google Scholar. Maturity-onset diabetes of the young MODY : how many cases are we missing? More than kin, less than kind: one family and the many faces of diabetes in youth. Arch Endocrinol Metabol. Maturity-onset diabetes of the young MODY is a clinically heterogeneous group of single-gene disorders.

Patients can present with mild fasting hyperglycemia for many years, whereas others have varying degrees of glucose intolerance for several years before the onset of persistent fasting hyperglycemia. MODY subtype, clinical phenotype and the most effective treatment options will differ depending on the defective gene and molecular characterization of the pathogenic variant is important. Confirmation by molecular genetic testing of the MODY subtype is important, as it enables correct diagnosis enabling treatment optimization and allowing monitoring of asymptomatic family members.

Disease summary:. Inheritance pattern:. The prevalence of MODY in racial and ethnic minorities may be underrepresented as many individuals with MODY remain undiagnosed and studies to date have largely involved white populations. Clinical symptoms:. Diagnostic criteria:. Autosomal dominant inheritance, with a vertical transmission of diabetes through at least 3 generations, and a similar phenotype shared by diabetic family members. Absence of insulin therapy at least 5 years after diagnosis or significant C-peptide levels even in a patient on insulin treatment.