Three novel mutations in MODY and its phenotype in three different Czech families.

AIMS/HYPOTHESIS: MODY (Maturity Onset Diabetes of the Young) is an autosomal dominant inherited type of diabetes with significant genetic heterogeneity. New mutations causing MODY are still being found. A genetically confirmed diagnosis of MODY allows application of individualized treatment based on the underlying concrete genetic dysfunction. Detection of novel MODY mutations helps provide a more complete picture of the possible MODY genotypes. MATERIALS AND METHODS: We tested 43 adult Czech patients with clinical characteristics of MODY, using direct sequencing of HNF1A (hepatocyte nuclear factor 1-alpha), HNF4A (hepatocyte nuclear factor 4-alpha) and GCK (glucokinase) genes. RESULTS: In three Czech families we identified three novel mutations we believe causing MODY-two missense mutations in HNF1A [F268L (c.802T>C) and P291S (c.871C>T)] and one frame shift mutation in GCK V244fsdelG (c.729delG). Some of the novel HNF1A mutation carriers were successfully transferred from insulin to gliclazide, while some of the novel GCK mutation carriers had a good clinical response when switched from insulin or oral antidiabetic drugs to diet. CONCLUSION: We describe three novel MODY mutations in three Czech families. The identification of MODY mutations had a meaningful impact on therapy on the mutation carriers.

[Contrast sensitivity and fluorescein angiography in evaluating the ocular changes in the relation to the diabetes mellitus type I compensation in young adult patients]. / Citlivost na kontrast a fluorescencní angiografie pri hodnocení ocních zmen v rámci posouzení kompenzace diabetes mellitus 1. typu u mladých dospelých pacientu.

UNLABELLED: The authors performed simultaneous contrast sensitivity examination (CS) and fluorescein angiography (FAG) in 42 patients older than 18 years of age; in 65% of them the duration of the diabetes mellitus type I (T1DM) was longer than 10 years. In these 27 patients, the diagnosis of non-prolipherative diabetic retinopathy (NPDR) was established by means of FAG in 44%, in contrast to only 19% by means of the direct ophthalmoscopy solely. The other findings (56%) were corresponding with diabetic preretinopathy (DpR) due to rare micro-aneurysms (establishes by means of FAG), and changes of the macular structure and pronounced dilation and tortuosity of the capillaries (by means of direct ophthalmoscopy). Out of the other 15 patients with T1DM duration of less than 10 years, the NPDR was established in 3 patients, and DpR confirmed in other 7 patients from the group. The authors compared the decrease in every single space frequency marked on the CS curvature for 31 eyes with NPDR and 39 eyes with DpR with the normal findings in patients without T1DM established in previous studies. Comparing NPDR with the norm, the authors found important and fundamental pathological defect of the CS (p = 0.0058). DpR comparing with the norm showed significant defect of the CS (p = 0.0197). Comparing NPDR and DpR, the difference was found in more noticeable pathological defect of the CS (p = 0.0228). The compensation of the metabolic state was evaluated from average year long values of the glycolated hemoglobin (Hb1Ac) in the last 10 years of the T1DM duration by means of DCCT method. The group of followed-up patients consisted of pairs of matched patients with NPDR and DpR of the same gender, time of beginning and duration of the metabolic disease. In the NPDR patients, the compensation was not good in 72% of this period, whereas in DpR patients the satisfactory compensation lasted for 53% of this period. During the follow up period, in NPDR the average Hb1Ac level was 8.49 +/- 0.88%, and in DpR this Hb1Ac value was 7.61 +/- 0.28%, with statistically significant difference (p = 0.0033). During the period, in DpR patients no serious complication was marked, in the NPDR group, the incipient diabetic nephropathy twice and slight diabetic neuropathy were noticed. The occasional pathological values of the microalbuminuria were not possible to correlate with beginning of the NPDR. CONCLUSION: The contrast sensitivity (CS) represents in the differential diagnosis of the NPDR and DpR a screening examination method. To specify the NPDR, the FAG is suitable and for both clinical entities specifies the extent of foveolar and perifoveolar involvement. Only the many years lasting follow up of Hb1Ac values documents the importance of long-term T1DM compensation in the prevention of pathological ocular changes development.

[The human lens' transparence changes in children, adolescents, and young adults with diabetes mellitus type I]. / Zmeny transparence cocky u detí, mladistvých a mladých dospelých s diabetes mellitus 1. typu.

Authors followed up the changes' development of the human lens' transparence in 213 children and young adult patients with diabetes mellitus type I. As initial changes of the lens' transparence they considered the posterior "Y" suture accentuation, because it was noticed in 44.4 % of lenses during the first 10 years of the metabolic disease duration, in contrast to 28.1 % representation of this dissociation in the control group of patients without diabetes (p = 0.012), and it was always markedly more often in patients with myopia. Substantial changes were detected predominantly during the sixth until the tenth year of duration of the basic disease as fine subcapsular opacities graded as first degree of lens transparency changes in 48 % of eyes. After 10 years of the disease duration, the lenses were never clear. Consequently, the changes in the transparency in the anterior subcapsular layer associated in 18 %. After 15 years of diabetes duration, we detected opacities in the anterior and posterior subcapsular layers of the lenses, graded as second degree of lenses transparence changes in 85 % of eyes. This subjective evaluating of lenses' opacity changes by means of the slit lamp examination was correlated with densitometric examination by means of Pentacam camera in a representative sample of 29 patients. In the first degree of lenses' transparence changes, the posterior subcapsular layer was affected in 50 %, and in the second degree, the opacities in this layer were found practically in 90 % of cases. False positive result in clear lenses or congenital opacities or "Y" suture was not detected. In general, the affected lens transparency did not basically influence the visual acuity and the decrease of contrast sensitivity was not statistically significant (p = 0.34). For the initial change of the lenses' transparency is also determining the patient's age at the onset of the diabetes mellitus type I. The changes are more common if the onset of the disease is after the fifteenth year of age as before that (p = 0.026). The authors also detected sporadic opacities in 4.2 % of eyes, probably of congenital origin (out of them, in two patients there was bilateral finding of the cerulean cataract) without visual acuity decrease.

[Glibenclamide instead of insulin: a new chance for MODY 3 type diabetes patients: case report]. / Glibenklamid místo inzulinu: nová sance pro pacienty s diabetem MODY 3: kazuistika.

MODY 3 belongs to monogenic forms of diabetes mellitus and is caused by monoallelic mutation in gene for transcription factor HNF-1alpha, essential for regulation of beta-cell function. Clinical presentation of MODY 3 is similar to that of type 1 diabetes. Although MODY 3 patients are not threatened by ketoacidosis, tight metabolic control is important for prevention of chronic diabetic complications. In the sibbling pair diabetes was manifested by osmotic symptoms resulting from hyperglycaemia at the age of 18 years (brother) resp. 15 years (sister) and both of them started being treated with intensified insulin treatment. Metabolic control of the brother was very tight with HbA1c 3.3 % but frequent hypoglycaemias occured. On the contrary metabolic control of the sister was very poor due to her non-compliance (HbA1c 10.9 %, IFCC). Molecular-genetic testing proved HNF-1alpha gene mutation (Arg200Gly). In accordance with the references treatment with sulphonylurea derivate glibenclamide was initiated [at the doses 1.25 (brother) resp. 7.5 (sister) mg/day] and insulin treatment was discontinued. The treatment change led to better quality of life and metabolic control in both the patients and suprisingly to the lower frequency of the hypoglycaemias in the brother (HbA1c decreased from 3.3 % to 2.8 % in three months in the brother resp. from 10.9 % to 10.0 % in two months in the sister). Molecular-genetic testing enables the change of treatment leading to better quality of life and metabolic control, although its longterm safety and efficacy will have to be confirmed.

[The contrast sensitivity test in early detection of ocular changes in children, teenagers, and young adults with diabetes mellitus type I]. / Test citlivosti na kontrast v casné detekci ocních zmen u detí, dospívajících a mladých dospelých s diabetes mellitus 1. typu.

UNLABELLED: The authors examined repeatedly every year 213 patients (97 boys and young men and 116 girls and young women, age ranged 6-36 years, median: 16.4 years). The diabetes mellitus type I duration at the first eye examination was 0.1 to 26 years (median: 5.9 years), and was diagnosed at the age 2-30 years (median 10.5 years). Changes of the posterior pole and their correlation to functional tests and to metabolic parameters were evaluated in five-years periods since the start of the study (within the fifth year of the study, between years 6-10, 11-15, and over 16 years of the study duration respectively). The beginning changes at the fundus were represented by means of dilatation of the capillaries with their possible obliteration and tortuosity, which was rare (7%) until the 5th year of the disease duration, between 6-10 years it was almost in a half of the patients (43 %), and after 10 years in was present in more than 90% of cases. Changes of the macular structure by means of the irregularity of foveolar reflex and relative retinal thickening without significant macular edema with increased pigmentation of this region appeared rarely after the fifth year (5%) and after 15th year of duration were present in more than two thirds of eyes (65%). Combination of these two findings was considered as diabetic preretinopathy (DpR), and was detected in 9% of eyes until 10 years of duration of diabetes. The number of hard exudates and microaneurysms gradually increased. Signs of non-prolipherative diabetic retinopathy were noticed in 0.5% of cases by means of ophthalmoscopical examination in patients with duration of diabetes type I less than 10 years. After that period, the non-prolipherative diabetic retinopathy was present in 19% of cases, and diabetic preretinopathy in 42%. The contrast sensitivity was examined by means of CSV-1000 instrument in 3, 6, 12 and 18 cycles/degree (c/deg) respectively. Normal values for children 6 years old and older were established in a previous study in a control group of children and teenagers without diabetes and with healthy eyes. In the age range 6 - 10 years the mean threshold values [log] are for: 3 c/deg 1.82; 6 c/deg 2.04; 12 c/deg 1.74; and 18 c/deg 1.29. Since the age of 11 years, normal mean threshold contrast sensitivity values [log] are for: 3 c/deg 1.92; 6 c/deg2.19; 12 c/deg 1.89; and 18 c/deg 1.42. No statistically significant difference was found in respective frequencies at the contrast sensitivity curve formulation. The marginal contrast level with standard deviation less than 0.15 log (range, 0.09 - 0.14), for all spatial frequencies represents for children aged 6 - 10 years the 5th stimulation target, and for those of 11 years of age and older the 6th stimulation target disc of the instrument. The value of pathologically decreased contrast sensitivity increased depending on the duration of the diabetes from 1.5% (up to 5 years of diabetes) to 23% after 15 years of diabetes. The lowest decrease of contrast sensitivity in pathological and border values of space frequencies was found in low-frequency 3 c/deg, which shows the evidence of perifoveolar involvement. No statistical significant difference was found among particular frequencies of low, middle, and higher contrast levels in pathological values of contrast sensitivity, but in case of counting in their border values, the statistical significant difference (p = 0.036) was established between the two frequencies 3 c/deg and 18 c/deg, which is giving the evidence of perifoveolar rather than exactly foveolar changes in scope of diabetes mellitus type I. The total decrease of contrast sensitivity values was determined by the increase of changes' number at the posterior pole by means of diabetic preretinopathy and non-prolipherative diabetic retinopathy mostly after 10 years of diabetes duration. Lowering of the contrast sensitivity by 65% is directly related to already mentioned changes of the macular region structure (MDM) and involvement of the foveola with preserved visual acuity. The decrease of the contrast sensitivity corresponded mostly with the posterior pole finding, and not with the diabetes duration, especially in middle and higher frequencies of 6, 12, and 18 c/deg. Changes in color vision by means of 15 Hue test were found in 7% of followed patients and those were not in direct connection with the disease, but were similar to changes in normal population. The decrease of contrast sensitivity values did not depend on the actual metabolic status of the basic disease (actual blood sugar and Hb A1c levels at the time of the ocular examination), nor with the one year level of compensation of diabetes (level of Hb A1c and microalbuminuria during the one year of the study. CONCLUSION: The contrast sensitivity examination by means of CSV-1000 device was not time consuming, non invasive for the patients and in case of good cooperation revealed the functional insufficiency of the retina, which was the sign of initial diabetic changes in foveolar and perifoveolar region structure.

Association of MHC class I chain related gene-A microsatellite polymorphism with the susceptibility to T1DM and LADA in Czech adult patients.

The results in this study suggest that microsatellite polymorphism within the transmembrane region of MIC-A gene is associated with genetic susceptibility to adult-onset of type 1 diabetes mellitus (T1DM), MIC-A5.1 allele, corrected P = 0.001, whereas it is not associated with latent autoimmune diabetes in adults (LADA) in Czech population. According to our findings, we can hypothesize that adult-onset T1DM and LADA may have partly different immunogenetic aetiopathogenesis.

Gustometry of diabetes mellitus patients and obese patients.

The sensation of adequate taste detection can be associated with satisfaction of food intake. The impairment of taste detection may be associated with the development of obesity. Taste detection is determined hereditarily, but it can be influenced also by the occurrence of neuropathy. To find an explanation for these phenomena, we investigated 73 patients with diabetes mellitus (DM) 2 (i.e., non-insulin-dependent DM); 11 patients with DM 1 (i.e., insulin-dependent DM); 12 obese patients (body-mass index >30) without DM; and 29 control patients. All subjects underwent electrogustometric examination with Hortmman's electrogustometer. During this examination, we obtained electrical thresholds of taste by stimulating appropriate parts of the tongue. We stimulated the apex, middle, and near tongue radix areas on both sides. The resulting value is the average on the left and right sides of the mentioned areas. We considered a value of less than 40 microA to be normal. Values in excess of 100 microA are considered as hypogeusia. Values between 40 and 100 microA are taken as borderline, and ageusia is in excess of 500 microA. According to these criteria, in the DM 2 group, we found 40% of patients with hypogeusia, whereas in the DM 1 group, we found 33% of patients; 25% of patients were in the obese group. Among normal subjects (people without obesity or DM), no hypogeusia was found. We found ageusia in 5% of patients with DM 2, in 3% of patients with DM 1, and in 14% of obese patients. Among normal subjects, we found no ageusia. These results support the hypothesis that diminished taste detection can evoke hyperphagia and later obesity.

[Type 1 diabetes mellitus in the aged]. / Diabetes mellitus I. typu ve vyssím veku.

Diabetes mellitus type I was till recently considered a disease affecting children and young adults. Research in the past several years provided evidence that this type of diabetes is found in all age groups and that the majority develops after the age of 35 years. Diagnostic possibilities of type I diabetes were markedly extended due to the introduction of radioimmunoassay of antibodies against glutamate decarboxylase. This examination has a 82% sensitivity and 100% specificity in diabetes. Diabetes mellitus in advanced age is manifested much less dramatically than in child age. It is found in non-obese subjects and usually its clinical manifestation is gradual. At first the patients are as a rule treated by diet. After several months usually sulphonylurea derivatives are started and only later insulin. If the diagnosis of diabetes mellitus type I is beyond doubt due to autoimmune disease, assessed preferably by antiGAD antibodies, immediate substitution therúpy with insulin is fully indicated. The latter can protect the residual function of B cells of the islets of Langerhans of the pancreas and contribute thus to the prevention of microvascular complications of diabetes mellitus.

[Autoimmunity and glutamate decarboxylase antibodies in the pathogenesis of type I diabetes mellitus in experimental and clinical practice]. / Autoimunita a protilátky proti glutamátdekarboxyláze v patogenezi diabetes mellitus I. typu v experimentu a klinické praxi.

Diabetes mellitus type 1 (DM type 1) is a chronic, organ specific autoimmune disease. Autoantibodies against the islets of Langerhans (ICA) are found in 71%, against insulin (IA) in 65% against glutamate decarboxylase (GAD) in 67-77% of children with DM type 1; in their close relatives and in patients with a more prolonged persistence of DM type 1 these antibodies and manifestations of cell-mediated autoreactivity are found less frequently also as a sign of the autoimmune character of DM type 1. In the pathogenesis of DM type 1 with the help of experimental mammalian models an idea on the genesis of the disease was obtained--activation of autoimmunity on the background of genetic sensitivity and environmental factors, the development of lymphocytic infiltration of the pancreatic islets (insulitis) destruction of pancreatic B-cells due to the cytotoxicity of T lymphocytes and the manifestation of DM type 1. According to this idea among the series of antigens of B-cells of the islets of Langerhans the dominant antigen is the isoform GAD65--under experimental conditions the specific response of T lymphocytes against GAD65 is found first, then follows extension of the reactivity also against other antigens of the islets. Understanding of the immune pathogenesis of DM type 1 makes it possible to apply the immunomodulating approach to the treatment of this condition which gave the first positive results in experimental work as well as in clinical practice.

[Actinomycosis of the ovary as a cause of cachexia in a young patient]. / Aktinomykóza ovaria jako prícina kachektizace u mladé pacientky.

The authors describe the case of a 40-year-old female patient treated for prolonged periods unsuccessfully with several antibiotics on account of a febrile condition of obscure aetiology and subsequently repeatedly subjected to laparotomy on account of intra-abdominal abscesses. The cause of the fever, abdominal pain and gradual cachectization was an abdominal form of actinomycosis. After establishment of the diagnosis the patient was successfully treated by long-term penicillin administration and recovered completely. The authors discuss experience reported in the literature and therapeutic possibilities in actinomycosis.