Pathogenesis of enuresis: Towards a new understanding.

Enuresis was historically viewed as a primarily psychiatric disorder, but this understanding has changed dramatically since the end of the last century, when it became clear that somatic factors, such as nocturnal polyuria as a result of vasopressin deficiency, nocturnal detrusor overactivity and high arousal thresholds, all play a crucial role in enuresis pathogenesis. It has also become clear that enuresis is inherited in the majority of cases, although the correlation between genotype and enuretic phenotype is not straightforward. The standard view of enuresis as being the result of either (i) nocturnal polyuria and high arousal thresholds; or (ii) nocturnal detrusor overactivity and high arousal thresholds has become well-established, but further research now complicates the picture. First, psychological/psychiatric problems are overrepresented in enuresis, and might in a minority of cases have a causal or aggravating role. Second, nocturnal polyuria is not always linked to vasopressin deficiency. Third, nocturnal detrusor overactivity is in itself pathogenetically heterogeneous, and could be linked to constipation. Fourth, the sleep of enuretic children might be "deep," but possibly also disturbed (by obstructed airways or a distended or contracting bladder). These children might have high arousal thresholds because of the enuresis instead of the other way around. The same might possibly be said about nocturnal polyuria. Taking these new insights into account, a new model of enuresis pathogenesis is presented, which is more complicated but hopefully also more true than the standard consensus.

The epidemiology and factors associated with nocturnal enuresis among boarding and daytime school children in southeast of Turkey: a cross sectional study.

BACKGROUND: Nocturnal enuresis is an important problem among young children living in Turkey. The purpose of this study was to determine the possible differences in the prevalence of enuresis between children in boarding school and daytime school and the association of enuresis with sociodemographic factors. METHODS: This was a cross-sectional survey. A total of 562 self-administered questionnaires were distributed to parents from two different types of schools. One of them was a day-time school and the other was a boarding school. To describe enuresis the ICD-10 definition of at least one wet night per month for three consecutive months was used. Chi-square test and a logistic regression model was used to identify significant predictive factors for enuresis. RESULTS: The overall prevalence of nocturnal enuresis was 14.9%. The prevalence of nocturnal enuresis declined with age. Of the 6 year old children 33.3% still wetted their beds, while the ratio was 2.6% for 15 years-olds. There was no significant difference in prevalence of nocturnal enuresis between boys and girls (14.3% versus 16. 8%). Enuresis was reported as 18.5% among children attending day time school and among those 11.5% attending boarding school (p < 0.05). Prevalence of enuresis was increased in children living in villages, with low income and with positive family history (p < 0.05). After multivariate analysis, history of urinary tract infection (OR = 2.02), age (OR = 1.28), low monthly income (OR = 2.86) and family history of enuresis (OR = 3.64) were factors associated with enuresis. 46.4% of parents and 57.1% of enuretic children were significantly concerned about the impact of enuresis. CONCLUSION: Enuresis was more frequent among children attending daytime school when compared to boarding school. Our findings suggest that nocturnal enuresis is a common problem among school children, especially with low income, smaller age, family history of enuresis and history of urinary tract infection. Enuresis is a pediatric public health problem and efforts at all levels should be made such as preventive, etiological and curative.

Prevalence of enuresis and its association with attention-deficit/hyperactivity disorder among U.S. children: results from a nationally representative study.

OBJECTIVE: There are no published nationally representative prevalence estimates of enuresis among children in the United States using standardized diagnostic criteria. This study sets out to describe the prevalence, demographic correlates, comorbidities, and service patterns for enuresis in a representative sample of U.S. children. METHOD: The diagnosis of enuresis was derived from parent-reported data for "enuresis, nocturnal" collected using the computerized version of the Diagnostic Interview Schedule for Children (C-DISC 4.0) from a nationally representative sample of 8- to 11-year-old children (n = 1,136) who participated in the 2001-2004 National Health and Nutrition Examination Surveys. RESULTS: The overall 12-month prevalence of enuresis was 4.45%. The prevalence in boys (6.21%) was significantly greater than that in girls (2.51%). Enuresis was more common at younger ages and among black youth. Attention-deficit/hyperactivity disorder (ADHD) was strongly associated with enuresis (odds ratio 2.88; 95% confidence interval 1.26-6.57). Only 36% of the enuretic children had received health services for enuresis. CONCLUSIONS: Enuresis is a common condition among children in the United States. Few families seek treatment for enuresis despite the potential for adverse effects on emotional health. Child health care professionals should routinely screen for enuresis and its effects on the emotional health of the child and the family. Assessment of ADHD should routinely include evaluation for enuresis and vice versa. Research on the explanations for the association between enuresis and ADHD is indicated.

Genetic aspects and genetic epidemiology of parasomnias.

Parasomnias are undesirable phenomena associated with sleep. Many of them run in families, and genetic factors have been long suggested to be involved in their occurrence. This article reviews the present knowledge of the genetics of the major classical behavioral parasomnias as well as present results from genetic epidemiological studies. The level and type of evidence for genetic effects varies much from parasomnia to parasomnia. The genetic factors are best established in enuresis, with several linkages to chromosomal loci, but their functions are not so far known. Environmental causes and gene-environment interactions are most probably also of great importance in the origin of complex traits or disorders such as parasomnias.

Nocturnal enuresis.

Nocturnal enuresis is a common problem that can be troubling for children and their families. Recent studies indicate that nocturnal enuresis is best regarded as a group of conditions with different etiologies. A genetic component is likely in many affected children. Research also indicates the possibility of two subtypes of patients with nocturnal enuresis: those with a functional bladder disorder and those with a maturational delay in nocturnal arginine vasopressin secretion. The evaluation of nocturnal enuresis requires a thorough history, a complete physical examination, and urinalysis. Treatment options include nonpharmacologic and pharmacologic measures. Continence training should be incorporated into the treatment regimen. Use of a bed-wetting alarm has the highest cure rate and the lowest relapse rate; however, some families may have difficulty with this treatment approach. Desmopressin and imipramine are the primary medications used to treat nocturnal enuresis, but both are associated with relatively high relapse rates.

Actualización en el estudio y tratamiento de la enuresis primaria noctura / Update in the study and treatment of the nocturnal primary enuresis

La enuresis primaria nocturna no es una entidad nosológica sino un signo que está presente en un grupo heterogéneo de enfermedades. Constituye un problema de salud de amplia distribución, ya que está presente en todas las civilizaciones y áreas geográficas; afecta a todas las razas y estratos sociales con discreta predominancia en las clases menos favorecidas económicamente. A los 5 años de edad afecta al 15 por ciento de niños de ambos sexos con un predominio de 3:1 a favor del sexo masculino y es ligeramente más frecuente en zurdos. En Estados Unidos se calcula que hay de 5 a 7 millones de niños que padecen de enuresis nocturna primaria. En México no se cuenta con cifras exactas, pero considerando los datos proporcionados en el XII Censo de población realizado por el Instituto Nacional de Estadística, Geografía e Informática en el 2000, en México hay 2.250.886 niños de 5 años de edad, de ellos el 15 por ciento , es decir 337.633 padecen enuresis y considerando la población total de niños de 5 a 16 años de edad (26.031.931), es muy posible que en nuestro país haya aproximadamente de 4 a 5 millones de jóvenes que padecen de este problema médico el cual no solo afecta la salud física y emocional del paciente sino también a su propia familia y a la sociedad que le rodea

Does monosymptomatic enuresis exist? A molecular genetic exploration of 32 families with enuresis/incontinence.

OBJECTIVE: s To confirm linkage to microsatellite markers on chromosome 8q, 12q, 13q and 22q in families with nocturnal enuresis/incontinence segregating with an autosomal dominant pattern, and to determine if there is an association between the clinical subtype and these linked loci. PATIENTS AND METHODS: Families with at least three members with nocturnal enuresis in two generations were included in the study. The index patient was > or = 7 years old and had evidence of bladder dysfunction; all other family members were > or = 5 years old. Bladder dysfunction in the index patients was documented by video-urodynamics when indicated. A nycthemeral rhythm of diuresis was documented in all index patients. The clinical diagnosis of all family members was based on a questionnaire on voiding problems and micturition habits, uroflowmetry, measurement of functional bladder capacity and nocturnal diuresis. Linkage was analysed using an autosomal dominant model with a gene frequency equal to 0.05 and a penetrance of 0.9. RESULTS: Thirty-two families with nocturnal enuresis/incontinence (one with four, 25 with three and six with two generations) were included. The mean number of persons included per family was 10 and on average five members were symptomatic. Linkage of nocturnal enuresis to a region on chromosome 22q11 was found in nine families, to 13q13-14 in six and to 12q in four. There was no convincing evidence for linkage to chromosome 8q. Clinical findings in the proband and their family members with possible linkage to a given locus were heterogeneous, and hence no clear genotype/phenotype correlation could be postulated. CONCLUSION: These findings support the hypothesis of the genetic and phenotypic heterogeneity of nocturnal enuresis/incontinence. Putative linkage was confirmed to the same chromosomal loci as in previous studies of 'monosymptomatic' enuresis and different phenotypes were linked to the same loci.

Desmopressin for nocturnal enuresis in nephrogenic diabetes insipidus.

We have investigated two unrelated families, in which two children had inherited primary nocturnal enuresis, and nephrogenic diabetes insipidus caused by new mutations in the aquaporin-2 gene (AQP2). The mutant AQP2 proteins were inactive, suggesting that administration of desmopressin could not concentrate the urine in these patients. However, treatment with desmopressin resolved primary nocturnal enuresis completely. This observation questions the notion that desmopressin resolves primary nocturnal enuresis through pharmacological manipulation of renal concentrating ability only. Desmopressin might also act on extrarenal targets such as the central nervous system.

The aquaporin-2 water channel in autosomal dominant primary nocturnal enuresis.

PURPOSE: Nocturnal enuresis is one of the most common diagnoses in a pediatric clinic. Recently, linkage analysis revealed a 2-point lod score of 4.2 in 6 families with dominant primary nocturnal enuresis around the aquaporin-2 (AQP2) water channel locus. Since primary nocturnal enuresis is ameliorated by desmopressin, AQP2 expression is increased by desmopressin and AQP2 is essential for concentrating urine, we determined whether a mutation in the AQP2 gene could cause primary nocturnal enuresis in these families. MATERIALS AND METHODS: Genomic DNAs of several patients from the 6 families were analyzed for disease causing mutations in the 4 exons of the AQP2 genes. RESULTS: In 1 family a G to A transition in the intron 1 splice donor site was found but it was also found in healthy subjects. In another family a C to T transition in the intron 1 splice acceptor region was identified but it was often found in splice acceptor sites. In 2 families a C to T transition was identified in the coding region of exon 3 but this mutation did not lead to a changed amino acid. CONCLUSIONS: Since no mutation in the AQP2 coding sequence was found, while this is essential for involvement in dominant primary nocturnal enuresis, the AQP2 gene is excluded as a candidate for autosomal dominant PNE in these families in which the disease co-segregates with chromosome 12q.

Linkage study of a large Danish 4-generation family with urge incontinence and nocturnal enuresis.

PURPOSE: We studied a large 4-generation family in which night and day voiding problems segregated in an autosomal dominant pattern with a high penetrance. We mapped the gene(s) causing these forms of incontinence using a total genome scan approach. MATERIALS AND METHODS: The family comprises 74 subjects in 4 generations. The clinical phenotypes were evaluated by detailed questionnaires and frequency volume charts. Genetically, a genome scan approach with 500 polymorphic marker systems was used to localize a chromosome area for the trait(s) and to narrow down a candidate region. The 3 different genetic models studied were 1) a single gene causing either day, night or day and night incontinence; 2) a gene primarily causing night incontinence; and 3) 2 different genes each causing only day or night incontinence. RESULTS: For model 2 we found 2 areas that gave a high lod score on 2-point analysis (D4S2960, 4p16.1, Z = 3.66 and D12S86, 12q24.2, Z = 3.22) on chromosome 4p and 12q. With an estimated penetrance of 75% only 4p linkage was significant. Models 1 and 3 were excluded as causes due to lack of the affected haplotype in affected subjects. Based on manual haplotype and 2-point analyses, all other areas were excluded for linkage. CONCLUSIONS: The most likely genetic model in this kindred seems to be a gene located on chromosome 4p16.1 causing primarily nocturnal enuresis. However, involvement of chromosome 12q24.3 cannot be excluded for linkage. The dopamine receptors DRD5 and D1B are mapped to chromosome 4p16. These genes are candidate genes for nocturnal enuresis and urge incontinence.

No relationship between family history of enuresis and response to desmopressin.

PURPOSE: We determined the prevalence of positive family history of nocturnal enuresis in relation to response to desmopressin. MATERIALS AND METHODS: A total of 328 children with nocturnal enuresis and 53 normal children were interviewed to determine the presence of family history of nocturnal enuresis. Response to desmopressin was confirmed in some cases by home recordings of enuresis episodes during 2 baseline weeks and 2 weeks of 20 to 40 microg. desmopressin intranasally. RESULTS: Significantly more patients than normal children (75% versus 38%, p <0.001) reported a positive family history of enuresis (any relative). The high prevalence of a positive family history of nocturnal enuresis was present in severe/nonsevere or primary/secondary types of enuresis. Of the patients 141 completed 4 weeks of home recordings including 20 with a complete response (greater than 90% reduction in wet nights week), 25 with a partial response (50% to 90% reduction) and 96 with no response (less than 50% reduction). The prevalence of a positive family history (any relative) was no different among the response groups (80%, 84% and 78%, respectively). Similarly, family history, as defined by first order relatives only, showed no relation to treatment response. CONCLUSIONS: A positive family history of nocturnal enuresis is more prevalent in patients with enuresis than in normal children regardless of the nature of the nocturnal enuresis. In contrast to previous reports, a positive family history failed to predict a good response to desmopressin treatment. Hereditary factors are important to consider in desmopressin responding and desmopressin resistant cases.

The genetics of enuresis: a review.

PURPOSE: Formal studies of the genetics of enuresis have been performed since the 1930s and molecular genetics since 1995, both highlighting the importance of hereditary factors in the etiology of nocturnal enuresis. We summarize the current state of knowledge with respect to the genetics of nocturnal enuresis and its genotype-phenotype interactions. MATERIALS AND METHODS: A comprehensive review of the published data available on the genetic basis of enuresis was performed. RESULTS: Genetic factors are the most important in the etiology of nocturnal enuresis but somatic and psychosocial environmental factors have a major modulatory effect. Most commonly, nocturnal enuresis is inherited via an autosomal dominant mode of transmission with high penetrance (90%). However, a third of all cases are sporadic, and the difference between sporadic and familial forms is not known. Four gene loci associated with nocturnal enuresis have been identified but the existence of others is presumed (locus heterogeneity). All likely candidate genes have been excluded so far. There is no specific association among the different loci, type of wetting and other aspects of the phenotype. All subtypes of nocturnal enuresis (primary, secondary, combined day/night wetting) are susceptible to comparable genetic influences. Certain syndromes of day wetting follow their own genetic mechanisms but this association with the genetics of nocturnal enuresis is not known. CONCLUSIONS: Nocturnal enuresis is a common, genetic and heterogeneous disorder. The associations between genotype and phenotype are complex and are susceptible to environmental influences. Therefore, exact assessment of the clinical phenotype and identification of intermediary phenotypes or traits are needed. Future research will focus on the identification of genes, gene products and their interaction with environmental factors.

Treatment of primary monosymptomatic nocturnal enuresis with desmopressin: predictive factors.

OBJECTIVE: To investigate predictive factors for the outcome of treatment of primary monosymptomatic nocturnal enuresis (PMNE) with desmopressin. PATIENTS AND METHODS: Data from a large open multicentre study were analysed. The study comprised 399 children with PMNE who were recruited for long-term desmopressin treatment. Before treatment a history was taken and the children observed for 4 weeks. After a 6-week dose-titration period with desmopressin, the children were classified into four groups depending on the response rate. RESULTS: The children who improved during desmopressin treatment were older, had fewer wet nights during the observation period and had only one wet episode during the night, mostly after midnight. Many of them did not require the maximum dose of desmopressin to become dry. No hereditary factor for the response to desmopressin was found. CONCLUSION: Those most likely to be permanently dry with desmopressin treatment are older children who respond to 20 microg desmopressin and who do not wet frequently.

Parasomnias: co-occurrence and genetics.

In clinical practice, parasomnias are often found to run in families and to co-occur. Several studies have indicated a role of genetic factors in them. In 1990, a questionnaire (response rate, 77%) sent to the Finnish Twin Cohort, a representative population sample aged 33-60 years, surveyed the frequency of five parasomnias (sleepwalking, sleeptalking, enuresis, bruxism, and nightmares) in childhood and as adults. In assessing the phenotypic covariation and shared genetic effects between the parasomnias, we used polychoric correlations and structural equation modelling. In childhood (n = 5856 individuals), co-occurrence is highest in sleeptalking with sleepwalking (R = 0.73), nightmares (R = 0.50), and bruxism (R = 0.43). As adults (n = 8567), the results are similar (R = 0.56, 0.43, and 0.39, respectively). The analyses of shared genetic effects included 815 monozygotic and 1442 dizygotic twin pairs with complete responses on four parasomnias as adults. The strongest genetic covariation was found in sleeptalking with sleepwalking, sleeptalking with bruxism, and in sleeptalking with nightmares. The estimated proportions of shared genetic effects were 50, 30, and 26%, respectively. The present results indicate that parasomnias share some common genetic background.

Genetic and gender influences on nocturnal bladder control--a study of 2900 3-year-old twin pairs.

OBJECTIVE: The present study of over 2900 twin pairs born in England and Wales in 1994 examines the influences of genetics and gender on nocturnal bladder control at 3 years of age. MATERIALS AND METHOD: Parent report data was analysed in terms of means and components of variance, using a sex-limitation model to explore genetic and environmental variation within and between the sexes. RESULTS: Both genetics and gender are seen to influence acquisition: bladder control at 3 years is moderately heritable (24%), and girls show on average slightly increased acquisition compared with boys, even within opposite-sex pairs. The sex-limitation modelling showed an interaction between genetic influence and gender whereby nocturnal bladder control was significantly more heritable in boys (33%) than girls (10%). CONCLUSIONS: Both genetics and gender are important and interacting factors in the aetiology of nocturnal bladder control.

Prepulse inhibition of startle, intelligence and familial primary nocturnal enuresis.

UNLABELLED: Previous studies have shown a significant reduction of prepulse inhibition of startle in boys with primary nocturnal enuresis. Those enuretic boys who had higher IQs showed less prepulse inhibition. This study evaluates the association of prepulse inhibition and IQ in primary nocturnal enuresis in respect to family history of primary nocturnal enuresis. Prepulse inhibition of startle was studied in 83 boys with primary nocturnal enuresis and 57 non-enuretic boys using an interval of 120 ms between the onset of a 75 dB 1000 Hz tone and a 104 dB noise burst. Of the boys with primary nocturnal enuresis, 56 had a family history of primary nocturnal enuresis and 27 had no family history (no first-degree relative). Of the 57 non-enuretic boys, 42 also had no family history (no first-degree relative) of primary nocturnal enuresis, while 15 did have a positive family history. Associations between prepulse inhibition and IQ scores were compared among these four groups. Strong and significant associations between prepulse inhibition deficit and higher IQ scores in the enuretic group with familial primary nocturnal enuresis were unique in comparison to the other groups. CONCLUSIONS: The strong heritabilities of primary nocturnal enuresis, intelligence and prepulse inhibition suggest genetic mediation of the association of prepulse inhibition with intelligence in familial primary nocturnal enuresis.