Maturity-onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity

Maturity-onset diabetes of the young (MODY) can be defined by the clinical characteristics of early-onset Type 2 (non-insulin-dependent) diabetes and autosomal dominant inheritance. Mutations in four genes have been shown to cause MODY: glucokinase, hepatic nuclear factor 1 alpha (HNF1α), hepatic nuclear factor 4 alpha (HNF4α) and insulin protein factor 1 (IPF1). In white Caucasians it is now possible to define the gene in most patients with a clinical diagnosis of MODY. Each gene involved in MODY has its own specific clinical and physiological characteristics. Patients with mutations of the glucokinase gene have mild fasting hyperglycaemia throughout life, and rarely require medication or develop microvascular complications. The principle pathophysiology is stable beta-cell dysfunction characterized by reduced sensing of glucose by the pancreas. Patients with mutations in HNF1α have normal glucose tolerance in early childhood and usually present with symptomatic diabetes in their late teens or early adulthood. They show increasing hyperglycaemia and treatment requirements with frequent microvascular complications. The underlying defect is progressive beta-cell failure, with the early lesion characterized by failure to increase insulin secretion with increasing glucose levels. Patients with HNF4α and IPF1 mutations show a similar clinical picture to HNF1α although diabetes may be diagnosed later. There are other patients with MODY in whom the genetic defect is still unknown. Molecular genetic testing in patients with diabetes offers the possibility of making a firm diagnosis of MODY and allows prediction of the future clinical course. The role of predictive testing in non-diabetic subjects within families is uncertain at present. Preliminary evidence suggests that maintaining insulin sensitivity by avoiding obesity and regular physical exercise may help delay the onset of diabetes © 1998 John Wiley & Sons, Ltd.     

Maturity-onset diabetes of the young: a clinical history

A mild form of diabetes in young people was recognized in the pre-insulin era but was forgotten, probably because of Joslin’s dictum that all young people with diabetes should have insulin as a safeguard against complications. After the introduction of sulphonylureas in the 1950s it was found, most notably by Fajans and Conn at the University of Michigan, that tolbutamide could improve or normalize carbohydrate tolerance in some young non-obese mildly diabetic patients. These experiments were not primarily of genetic interest because diabetes was regarded as homogeneous with young and old patients forming part of the same continuum. The question was whether treatment could prevent young subjects with mild diabetes progressing to a total loss of insulin reserve. By 1973, Fajans had shown that the carbohydrate intolerance of 45 patients diagnosed under age 25 had not progressed after up to 16 years on sulphonylureas. Nearly all (43 out of 45) these subjects had a first degree relative with diabetes. In 1974, under the title ‘Mild familial diabetes with dominant inheritance’ Tattersall described three families in which diabetes, although diagnosed in adolescence, could be treated with sulphonylureas over 40 years later and was dominantly inherited. Collaboration between Fajans and Tattersall established that ‘chemical’ diabetes in Michigan was also predominantly inherited and distinct from classical ‘juvenile-onset’ diabetes. In Paris in 1973 Lestradet also described a non-insulin-dependent form of childhood diabetes and later established that it was dominantly inherited. In 1974, Tattersall and Fajans coined the acronym MODY which was defined as ‘fasting hyperglycaemia diagnosed under age 25 which could be treated without insulin for more than two years’. © 1998 John Wiley & Sons, Ltd.     

Maturity-onset diabetes of the young (MODY)

Maturity-onset diabetes of the young (MODY) is a rare but important differential diagnosis of diabetes presenting in childhood, adolescence or young adulthood. Common features of the 10 known MODY forms are autosomal dominant inheritance of mutations in genes involved, e.g. in the regulation of insulin secretion or β-cell development. The most common forms are MODY2 (glucokinase MODY) and MODY3 (HNF1A-MODY). Patients with MODY2 initially present with hyperglycemia during an incidental laboratory control without any clinical symptoms of diabetes and diet alone is usually sufficient for glycemic control. MODY3 is characterized by progressive hyperglycemia as a result of a decrease in insulin secretion capacity. Most patients are initially successfully treated with sulphonyl ureas but might later require insulin treatment. The other MODY forms occur much less frequently and can show specific clinical signs. Diagnosis of MODY has direct impact on the management of diabetes, genetic counselling and early diagnosing of diabetes in affected family members.     

Maturity-onset diabetes of the young (MODY)

This review summarized aspects of the widening scope, phenotypic expression, natural history, recognition, pathogeneses, and heterogenous nature of maturity-onset diabetes of the young (MODY), an autosomal dominant inherited subtype of NIDDM, which can be recognized at a young age. There are differences in metabolic, hormonal, and vascular abnormalities in different ethnic groups and even among Caucasian pedigrees. In MODY patients with low insulin responses, there is a delayed and decreased insulin and C-peptide secretory response to glucose from childhood or adolescence, even before glucose intolerance appears; it may represent the basic genetic defect. The nondiabetic siblings have had normal insulin responses for decades. The fasting hyperglycemia of some MODY has been treated successfully with sulfonylureas for more than 30 years. In a few, after years or decades of diabetes, the insulin and C-peptide responses to glucose are so low that they may resemble those of early Type I diabetes. The rate of progression of the insulin secretory defect over time does distinguish between these two types of diabetes. In contrast are patients from families who have very high insulin responses to glucose despite glucose intolerance and fasting hyperglycemia similar to those seen in patients with low insulin responses. In many of these patients, there is in vivo and in vitro evidence of insulin resistance. Whatever its mechanism, the compensatory insulin responses to nutrients must be insufficient to maintain normal carbohydrate tolerance. This suggests that diabetes occurs only in those patients who have an additional islet cell defect, i.e., insufficient beta cell reserve and secretory capacity. In a few MODY pedigrees with high insulin responses to glucose and lack of evidence of insulin resistance, an insulin is secreted which is a structurally abnormal, mutant insulin molecule that is biologically ineffective. No associations have been found between specific HLA antigens and MODY in Caucasian, black, and Asian pedigrees. Linkage studies of the insulin gene, the insulin receptor gene, the erythrocyte/Hep G2 glucose transporter locus, and the apolipoprotein B locus have shown no association with MODY. Vascular disease may be as prevalent as in conventional NIDDM. Because of autosomal dominant transmission and penetrance at a young age, MODY is a good model for further investigations of etiologic and pathogenetic factors in NIDDM, including the use of genetic linkage strategies to identify diabetogenic genes.     

Maturity-onset diabetes of the young (MODY)-related genetic variants in a Turkish patient cohort with early-onset diabetes: a cross-sectional study

International Journal of Diabetes in Developing Countries - There is no apparent data on the prevalence of maturity-onset diabetes of young (MODY) in adults in Turkey. We aimed to define the...     

Erratum: Maturity-onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity. Diabet Med 1998; 15(1): 15-24.

The abstract incorrectly referred to insulin promoter factor 1 as ‘insulin protein factor 1’ and the section entitled ‘Phenotype of HNF1α Mutations’ drew attention to Figure 4 rather than to Figure 2. We sincerely apologize to the author for these errors and to our readers for any confusion which may have been caused.     

Maturity-onset diabetes of the young (MODY): how many cases are we missing?

Aims/hypothesis  

Maturity-onset diabetes of the young is frequently misdiagnosed as type 1 or type 2 diabetes. A correct diagnosis of MODY is important for determining treatment, but can only be confirmed by molecular genetic testing. We aimed to compare the regional distribution of confirmed MODY cases in the UK and to estimate the minimum prevalence.     

beta-O-thalassemia from Algeria: genetic and molecular characterization

beta-Thalassemia is a major public health problem in Algeria. During a survey, a family including two cases of betaO-thalassemia was studied. The family study indicated that two of the affected siblings had homozygous beta-thalassemia; there were also both normal and heterozygous siblings, and both parents had beta-thalassemia trait. In the two cases of betaO-thalassemia there was no hemoglobin A in the peripheral blood, and no beta-globin chain synthesis in whole cell incubations. Hybridization of purified complementary DNA specific for alpha- and beta-globin messenger RNAs demonstrated less than 1% mRNAbeta relative to mRNAalpha in circulating reticulocytes, and for one case in total RNA from bone marrow. There is no apparent beta- globin gene deletion as determined by hybridization in globin cDNAbeta sequence excess. Therefore the Algerian cases studied are similar in molecular pathology to some Southern Italian and Asian cases described previously, and differ from other Italian and Chinese betaO- thalassemias, in which hybridizable mRNAbeta has been demonstrated, and from deltabetaO-thalassemia, which is caused by a gene deletion.     

Sudden cardiac death in the young: a clinical genetic approach

The sudden death of a young person is a devastating event for both the family and community. Over the last decade, significant advances have been made in understanding both the clinical and genetic basis of sudden cardiac death in the young. Many of the causes of sudden death in the young are due to genetic heart disorders, which can lead to both structural (e.g. hypertrophic cardiomyopathy) and arrhythmogenic (e.g. familial long QT syndrome) abnormalities. Most commonly, sudden cardiac death in the young can be the first presentation of an underlying heart problem, leaving the family at a loss as to why an otherwise healthy young person has died. Not only is this a tragic event for those involved, but it also presents a medical challenge to the clinician involved in the management of the surviving family members. Evaluation of families requires a multidisciplinary approach, which should include cardiologists, a clinical geneticist, a genetic counsellor and the forensic pathologist directly involved in the sudden death case. This multifaceted cardiac genetic service is crucial in the evaluation and management of the clinical, genetic, psychological and social complexities observed in families in which there has been a young sudden cardiac death.     

新的肝细胞核因子1β基因大片段缺失致青少年的成人起病型糖尿病5型一例

青少年的成人起病型糖尿病(MODY)5型在中国人群中较为罕见,且临床表现不典型,临床医师对其认识不足,极易误诊漏诊。本研究报道了一例MODY 5型患者,具有罕见的多脏器表型异常,包括背侧胰腺发育不全、肾萎缩、肾囊肿、肝功能异常、低镁血症等,经过基因检测,明确为肝细胞核因子1β基因外显子2~5杂合缺失导致,是一个特殊的自发基因变异,国内外均尚未见报道。本研究补充了我国该类患者的病例资料,建议对于无家族史,但存在早发糖尿病和肾脏疾病的患者应排查MODY 5,以明确分子诊断,实现精准医疗。     

Leishmaniasis in Turkey: molecular characterization of Leishmania from human and canine clinical samples

Human leishmaniasis, both visceral and cutaneous, and canine leishmaniasis have been reported in Turkey for centuries. However, the advent of new diagnostic tools during the last 30 years has led to the recognition that leishmaniasis is an important public health problem throughout the country. In most disease foci both canine and human leishmaniases exist together and identification of parasite species causing these diseases is a pre-requisite for understanding disease epidemiology. A total of 109 samples obtained from human and canine leishmaniasis cases were examined using internal transcribed spacer 1 PCR followed by restriction fragment length polymorphism analysis. Our results indicate that two species, Leishmania tropica and Leishmania infantum, are primarily responsible for cutaneous and visceral leishmaniasis, respectively, in Turkey. However, a new focus of human cutaneous leishmaniasis caused by L. infantum in Hatay region is described. This finding further stresses the importance of Leishmania species molecular characterization in prescribing appropriate therapy and understanding the disease's transmission in different endemic foci.     

Familial forms of diabetes insipidus: clinical and molecular characteristics

Over the past two decades, the genetic and molecular basis of familial forms of diabetes insipidus has been elucidated. Diabetes insipidus is a clinical syndrome characterized by the excretion of abnormally large volumes of diluted urine (polyuria) and increased fluid intake (polydipsia). The most common type of diabetes insipidus is caused by lack of the antidiuretic hormone arginine vasopressin (vasopressin), which is produced in the hypothalamus and secreted by the neurohypophysis. This type of diabetes insipidus is referred to here as neurohypophyseal diabetes insipidus. The syndrome can also result from resistance to the antidiuretic effects of vasopressin on the kidney, either at the level of the vasopressin 2 receptor or the aquaporin 2 water channel (which mediates the re-absorption of water from urine), and is referred to as renal or nephrogenic diabetes insipidus. Differentiation between these two types of diabetes insipidus and primary polydipsia can be difficult owing to the existence of partial as well as complete forms of vasopressin deficiency or resistance. Seven different familial forms of diabetes insipidus are known to exist. The clinical presentation, genetic basis and cellular mechanisms responsible for them vary considerably. This information has led to improved methods of differential diagnosis and could provide the basis of new forms of therapy.