Molecularly confirmed pontocerebellar hypoplasia in a large family from Slovakia with four severely affected children.

BACKGROUND: Pontocerebellar hypoplasia type 1 (PCH1) is characterized by a central and peripheral motor dysfunction associated with anterior horn cell degeneration, similar to spinal muscular atrophy (SMA). OBJECTIVES: We analysed three probands (later discovered to be siblings) suspected to have severe SMA, however, not confirmed by genetic test. METHODS: Clinical-exome analysis (Illumina) was performed to identify causative variants, followed by Sanger sequencing confirmation in probands and other 10 family members. RESULTS: Homozygous pathogenic variant c.92G>C (p.(Gly31Ala)) in the Exosome Component 3 (EXOSC3) gene was found in all 3 probands, thus confirming the diagnosis of a severe form of PCH1B. The parents and six siblings were carriers, while one sibling was homozygous for a reference allele. This variant is frequent in the Czech Roma population, where it is considered a founder mutation. Haplotype analysis in this largest reported PCH1B family showed that our patients inherited from their father (of Roma origin) a haplotype identical to that found in the Czech Roma population, thus indicating these alleles have a common origin. CONCLUSION: This EXOSC3 variant is rare among the general population but most likely frequent also among Roma people in Slovakia. PCH1B should be considered for a differential diagnosis in infants manifesting SMA-like phenotype, especially if of Roma origin (Tab. 1, Fig. 1, Ref. 22). Text in PDF www.elis.sk Keywords: pontocerebellar hypoplasia, PCH1B, EXOSC3, SMA plus syndromes, pathogenic sequence variant.

Characterisation of Non-Pathogenic Premutation-Range Myotonic Dystrophy Type 2 Alleles.

Myotonic dystrophy type 2 (DM2) is caused by expansion of a (CCTG)n repeat in the cellular retroviral nucleic acid-binding protein (CNBP) gene. The sequence of the repeat is most commonly interrupted and is stably inherited in the general population. Although expanded alleles, premutation range and, in rare cases, also non-disease associated alleles containing uninterrupted CCTG tracts have been described, the threshold between these categories is poorly characterised. Here, we describe four families with members reporting neuromuscular complaints, in whom we identified altogether nine ambiguous CNBP alleles containing uninterrupted CCTG repeats in the range between 32 and 42 repeats. While these grey-zone alleles are most likely not pathogenic themselves, since other pathogenic mutations were identified and particular family structures did not support their pathogenic role, they were found to be unstable during intergenerational transmission. On the other hand, there was no observable general microsatellite instability in the genome of the carriers of these alleles. Our results further refine the division of CNBP CCTG repeat alleles into two major groups, i.e., interrupted and uninterrupted alleles. Both interrupted and uninterrupted alleles with up to approximately 30 CCTG repeats were shown to be generally stable during intergenerational transmission, while intergenerational as well as somatic instability seems to gradually increase in uninterrupted alleles with tract length growing above this threshold.

Excess diuresis and natriuresis during acute sleep deprivation in healthy adults.

The transition from wakefulness to sleep is associated with a pronounced decline in diuresis, a necessary physiological process that allows uninterrupted sleep. The aim of this study was to assess the effect of acute sleep deprivation (SD) on urine output and renal water, sodium, and solute handling in healthy young volunteers. Twenty young adults (10 male) were recruited for two 24-h studies under standardized dietary conditions. During one of the two admissions, subjects were deprived of sleep. Urine output, electrolyte excretions, and osmolar excretions were calculated. Activated renin, angiotensin II, aldosterone, arginine vasopressin, and atrial natriuretic peptide were measured in plasma, whereas prostaglandin E(2) and melatonin were measured in urine. SD markedly increased the diuresis and led to excess renal sodium excretion. The effect was more pronounced in men who shared significantly higher diuresis levels during SD compared with women. Renal water handling and arginine vasopressin levels remained unaltered during SD, but the circadian rhythm of the hormones of the renin-angiotensin-aldosterone system was significantly affected. Urinary melatonin and prostaglandin E(2) excretion levels were comparable between SD and baseline night. Hemodynamic changes were characterized by the attenuation of nocturnal blood pressure dipping and an increase in creatinine clearance. Acute deprivation of sleep induces natriuresis and osmotic diuresis, leading to excess nocturnal urine production, especially in men. Hemodynamic changes during SD may, through renal and hormonal processes, be responsible for these observations. Sleep architecture disturbances should be considered in clinical settings with nocturnal polyuria such as enuresis in children and nocturia in adults.

The effect of desmopressin on renal water and solute handling in desmopressin resistant monosymptomatic nocturnal enuresis.

PURPOSE: We sought to evaluate the effect of desmopressin on renal water and solute handling in children with monosymptomatic nocturnal enuresis and desmopressin resistant nocturnal polyuria compared to healthy controls. MATERIALS AND METHODS: A total of 12 patients with enuresis and nocturnal polyuria, normal bladder reservoir function and no response to desmopressin, and 10 age matched controls were enrolled in the study. Children were admitted to the hospital for a 48-hour protocol comprising urine collections and blood sampling. Sodium and water intake was standardized. During the second night children received 40 mug intranasal desmopressin. Parameters characterizing the renal water and solute handling were measured and compared between baseline nights and nights with desmopressin. RESULTS: Desmopressin markedly reduced nocturnal urine output in patients with enuresis, minimizing sodium, urea and overall solute excretion, despite the fact that these children were unresponsive to desmopressin at home. This effect on renal sodium handling was not mediated by atrial natriuretic peptide, angiotensin II, aldosterone or renin. Desmopressin did not influence urinary prostaglandin E(2) excretion. The antinatriuretic effect was seen only in patients with enuresis, and it was directly correlated with the reduction in urine output. CONCLUSIONS: Children with nocturnal enuresis and nocturnal polyuria who do not exhibit adequate response to desmopressin at home seem to respond well to the agent at the clinic. The effect of desmopressin in children with enuresis seems largely dependent on reductions in the amount of sodium excreted. Sodium regulating hormones remained unaffected by desmopressin, indicating a possible direct effect of the agent on renal sodium handling.

Role of NT-proBNP in detection of myocardial damage in childhood leukemia survivors treated with and without anthracyclines.

BACKGROUND: Exposure to anthracyclines (ANT) during childhood represents a high risk for development of late cardiotoxicity. Cardiotoxicity is usually detected only when clinical symptoms or progressive cardiac dysfunction have already occurred. Early detection of cardiotoxicity may lead to better therapeutic outcome. N-terminal pro-brain natriuretic peptide (NTproBNP) has been hypothesized to reflect increased left ventricular wall stress before development of echocardiographic abnormalities. The aim of this study was to detect cardiac abnormalities using plasma NTproBNP and echocardiography in asymptomatic childhood leukemia survivors treated with or without cardiotoxic anthracycline therapy. METHODS: Serum levels of NTproBNP were determined in 69 asymptomatic survivors of childhood leukemia treated with or without anthracyclines and in 44 apparently healthy controls. The survivors were divided into two treatment groups: 36 patients after chemotherapy containing anthracyclines (ANT) and 33 patients after chemotherapy without anthracyclines (nonANT). Levels of NTproBNP were measured by using the Elecsys 2010 immunoassay analyzer (Roche Diagnostics). Echocardiography using M-mode, two-dimensional and Doppler measurements were performed on the same day as blood samples were obtained for NTproBNP analysis in survivors. RESULTS: Serum levels of NTproBNP were significantly higher in the ANT group than in controls (median 51.52 vs 17.37 pg/ml; p=0.0026). Survivors exposed to ANT had significantly increased levels of NTproBNP compared with patients treated without ANT (median 51.52 vs 12.24 pg/ml; p=0.0002). Female exposed and unexposed survivors had significantly higher NTproBNP levels than males. Four of the 36 survivors (11%) treated with ANT and two of the 33 patients (6%) not exposed to ANT had abnormal NTproBNP levels. Although no patient had echocardiographic abnormalities, significant differences were found in values of left ventricular ejection fraction (LVEF) and deceleration time (DT) between survivors treated with or without anthracyclines. CONCLUSIONS: Higher levels of NTproBNP detected in childhood leukemia survivors after low anthracycline cumulative doses might reflect an initial stage of ANT cardiotoxicity before the development of echocardiographic abnormalities. Although the current studies support NTproBNP as one of the best available biochemical markers of late anthracycline cardiotoxicity, a possible strategy toward further improvement and combination with other cardiac biomarkers and novel echocardiographic methods should be explored in additional studies.

The role of bladder capacity in antidiuretic and anticholinergic treatment for nocturnal enuresis.

PURPOSE: We evaluated combination treatment with desmopressin and oxybutynin in patients with enuresis who did not respond to desmopressin monotherapy. Furthermore, we compared 2 methods of estimating bladder capacity and evaluated the ability of these methods to predict the response to desmopressin and oxybutynin. MATERIALS AND METHODS: A total of 60 children with a mean age +/- SD of 10.6 +/- 3.0 years who had monosymptomatic nocturnal enuresis completed the study. After a 2-week observation period maximal voided volume during free access to fluid intake was determined by a 2-day frequency-volume chart and maximal voided volume after water load was determined on a separate day. Patients then received 20 mug desmopressin intranasally at bedtime during 2 weeks. In nonresponders to desmopressin with less than a 50% decrease in wet nights 5 mg oxybutynin twice daily was added for another 2 weeks. RESULTS: Of the patients 41 (68%) showed more than 50% decrease in wet nights during the 2-week desmopressin treatment period (4.6 +/- 1.6 to 0.7 +/- 0.8, p <0.001). In desmopressin nonresponders combined treatment with desmopressin and oxybutynin resulted in a further decrease in wet nights (4.0 +/- 1.2 to 1.7 +/- 1.4, p <0.001). Maximal voided volume during free access to fluid intake was significantly higher in desmopressin responders than in nonresponders (244 +/- 111 vs 160 +/- 65 ml, p <0.001). In contrast, maximal voided volume after water load was not significantly different between desmopressin responders and nonresponders. CONCLUSIONS: The study indicates a role for oxybutynin in combination with desmopressin in children who are not responding to desmopressin monotherapy. Maximal voided volume during free access to fluid intake is a clinically useful predictor of the response to desmopressin but not to oxybutynin.

Reproducibility of contrast enhanced magnetic resonance renography in adolescents.

PURPOSE: We sought to determine the reproducibility of magnetic resonance imaging renography using 3 different mathematical models and 2 different approaches to convert the relative signal intensity into quantitative indices. Furthermore, we wanted to examine the influence of fluid intake on the obtained renal parameters. MATERIALS AND METHODS: A total of 10 healthy volunteers 13 to 16 years old were subjected to magnetic resonance imaging 3 times within 10 weeks, including an examination where fluid intake was increased. At each examination 0.1 mmol/kg gadolinium diethylenetriamine pentaacetic acid was administrated intravenously as a rapid bolus during a fast magnetic resonance renography sequence. Images were acquired in the coronal plan, and 1,200 images were recorded during approximately 7 minutes. Cortical data were analyzed to estimate absolute and differential function of renal parameters by converting signal intensities into quantitative units. RESULTS: Using the simple approach that a change in magnetic resonance imaging signal is linearly related to the change in gadolinium diethylenetriamine pentaacetic acid concentration, we found reproducibility in the range of 1% to 5% of all estimations of the differential renal function. The relative glomerular ultrafiltration (ml per minute per cm(3) kidney cortex) was calculated and a reproducibility of 7% was observed for relative glomerular ultrafiltration (using the model based on deconvolution). Increased hydration caused a significant change in most parameters. CONCLUSIONS: Contrast enhanced magnetic resonance renography is reproducible in the normal human kidney but excessive water intake has a significant influence on these parameters. Further studies are required to elucidate whether similar measurements can be applied to a kidney with impaired function.