A case of central diabetes insipidus due to neurophysin II gene abnormality diagnosed based on a family history of nocturnal enuresis.

The etiology of central diabetes insipidus (DI) is classified into (1) idiopathic, (2) familial, and (3) secondary. Of these, familial central diabetes insipidus shows an autosomal dominant inheritance. We herein report a case in which this disease was diagnosed based on a family history of nocturnal enuresis. A 40-year-old man had had symptoms of polydipsia, polyuria and nocturia since childhood and found that his daughter had the same symptoms. Despite reaching nine years old, his daughter's nocturnal enuresis still had not improved, resulting in her consulting a pediatrician. She was suspected of having familial neurohypophyseal diabetes insipidus (FNDI) based on her family history and was referred along with her father for a detailed examination and treatment. A hypertonic saline load test (HSLT) to evaluate the arginine vasopressin (AVP) reaction was performed in both the proband and his daughter. The results showed no increase in AVP levels in response to high plasma osmolality. The water deprivation test (WDT) revealed he was suffering from partial DI. Based on the above findings and considering the possibility of familial central diabetes insipidus, we performed a gene mutation analysis of AVP-neurophysin II (NPII). Both the father and daughter had an exon 2 abnormality in this gene (c232_234delGAG; pGlu78del), and this gene mutation is known to cause NPII protein abnormality, abolishing the function of AVP as a carrier protein. This case was considered to have provided an opportunity to understand the role of an NPII gene abnormality in familial central diabetes insipidus.

Effect of DRD4 Receptor -616 C/G Polymorphism on Thalamic GABA Levels in Pediatric Patients With Primary Nocturnal Enuresis.

BACKGROUND: The single nucleotide polymorphism (SNP) of dopamine D4 receptor (DRD4) promoter (-616; rs747302) is associated with abnormalities of the thalamus in children suffering from primary nocturnal enuresis (PNE). PURPOSE: To investigate the effect of DRD4 -616 C/G SNP on thalamic gamma-aminobutyric acid (GABA) levels in PNE children. STUDY TYPE: Prospective, observational. SUBJECTS: One hundred and seventy-six children with PNE and 161 healthy control children. FIELD STRENGTH/SEQUENCE: 3 T, three-dimensional T1-weighted turbo field echo sequence and MEscher-Garwood Point RESolved Spectroscopy (MEGA-PRESS) MRS sequence. ASSESSMENT: The MEGA-PRESS MRS sequence was used to measure thalamic GABA spectra. The thalamic GABA+ level was calculated using the Gannet 3.0 software package for each participant. A questionnaire was used to determine arousal from sleep (AS) scores. STATISTICAL TESTS: Comparisons of the AS scores and thalamic GABA+ levels were performed using the Mann-Whitney U test between C-allele carriers and GG homozygotes in the PNE and control groups. Spearman correlation analysis was performed to determine the association between AS scores and thalamic GABA levels in PNE children. RESULTS: Thalamic GABA levels in the PNE group were significantly higher than those in the healthy control group (0.178 (0.169-0.186) vs. 0.154 (0.146-0.164), Z = 8.526, Pcorrected < 0.001). The GABA levels in C-allele carriers were significantly higher than those in GG homozygotes in both the PNE and control groups (0.184 (0.181-0.193) vs. 0.170 (0.165-0.177), Z = 8.683, Pcorrected < 0.001; 0.166 (0.156-0.170) vs. 0.147 (0.141-0.152), Z = 9.445, Pcorrected < 0.001). GABA levels in the thalamus were also significantly and positively correlated with AS scores in C-allele carriers in the PNE group (r = 0.747, P < 0.05). DATA CONCLUSION: DRD4 -616 C allele may be associated with increased thalamic GABA+ levels, especially in C-allele carrying PNE children. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3.

Identification of genetic loci associated with nocturnal enuresis: a genome-wide association study.

BACKGROUND: Nocturnal enuresis (bedwetting) is a common disorder affecting 10-16% of 7-year-old children globally. Nocturnal enuresis is highly heritable, but its genetic determinants remain unknown. We aimed to identify genetic variants associated with nocturnal enuresis and explore its genetic architecture and underlying biology. METHODS: We did a genome-wide association study (GWAS) of nocturnal enuresis. Nocturnal enuresis cases were identified in iPSYCH2012, a large Danish population-based case cohort established to investigate mental disorders, on the basis of 10th revision of the International Statistical Classification of Diseases (ICD-10) diagnoses and redeemed desmopressin prescriptions in Danish registers. The GWAS was done in a genetically homogeneous sample of unrelated individuals using logistic regression with relevant covariates. All genome-wide significant variants were analysed for their association with nocturnal enuresis in an independent Icelandic sample from deCODE genetics. Standardised polygenic risk scores for attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder were constructed from summary statistics of large GWASs and analysed for association with nocturnal enuresis. FINDINGS: The GWAS included 3882 nocturnal enuresis cases and 31 073 controls. We found two loci at chromosome 6 and chromosome 13 significantly associated with nocturnal enuresis. Six genetic variants at the two loci (five variants at chromosome 6q16.2 and one variant at chromosome 13q22.3) surpassed the threshold for genome-wide significance (p<5 × 10-8). There were two lead variants: rs9376454 (chromosome 6q16.2), with an odds ratio (OR) of 1·199 (95% CI 1·135-1·267; p=9·91 × 10-11), and rs60721117 (chromosome 13q22.3), with an OR of 1·149 (1·095-1·205; p=1·21 × 10-8). All associated variants in the chromosome 6 locus were replicated (p<8 × 10-3) in the independent Icelandic cohort of 5475 nocturnal enuresis cases and 303 996 controls, whereas the associated variant in the chromosome 13 locus showed nominal significant association (p=0·031). The percentage of nocturnal enuresis phenotypic variance explained by the common genetic variants was 23·9-30·4%. Polygenic risk for ADHD was associated with nocturnal enuresis (OR 1·06, 95% CI, 1·01-1·10; p=0·011). Among the potential nocturnal enuresis risk genes mapped, PRDM13 and EDNRB have biological functions associated with known pathophysiological mechanisms in nocturnal enuresis, and SIM1 regulates the formation of the hypothalamic neuroendocrine lineage that produces arginine vasopressin, a well known nocturnal enuresis drug target. INTERPRETATION: This study shows that common genetic variants contribute considerably to nocturnal enuresis, and it identifies potential nocturnal enuresis risk genes with roles in sleep, urine production, and bladder function. Given that available treatments target these mechanisms, any of the identified genes and their functional gene networks are potential drug targets. FUNDING: The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Stanley Foundation.

Increased potassium excretion in children with monosymptomatic nocturnal enuresis: could it be related to Kir 4.1- KCNJ10 gene polymorphism?

BACKGROUND AND OBJECTIVES: There are controversial results in the literature regarding urinary electrolytes, especially potassium, in enuretic children. KCNJ10 channel protein, a member of the Kir 4.1 family is expressed in renal distal tubules and has an important function in renal ion transport. We investigated whether KCNJ10 gene polymorphisms are associated with clinical and laboratory findings of a group of Turkish children with monosymptomatic primary nocturnal enuresis (MNE). METHOD: Ninety-seven MNE children and 100 healthy controls were tested for three single nucleotide polymorphisms (SNPs) in the KCNJ10 gene. The transversions in SNPs were G to A for intron 1(SNP1), G to A for exon 2 (SNP2), and T to C transition for promoter (SNP3). All SNPs were genotyped by PCR-restriction fragment length polymorphism. RESULTS: SNP3 in promoter of KCNJ10 gene showed strong association with MNE children for distribution of genotype and allele frequency, while SNP1 in intron 1 and SNP2 in exon 2 were noninformative. The distribution of TT, TC, and CC genotypes for SNP3 was 66%, 26.8% and 7.2% respectively in MNE compared with 38%, 59% and 3% respectively in controls (p < 0.0001). In enuretic children, TT genotype was higher and there was an increased potassium excretion in children with TT genotype (P < 0.05). CONCLUSION: We conclude that KCNJ10 gene promoter polymorphism may have a role on potassium excretion in Turkish MNE children. This is the first study in literature evaluating KCNJ10 gene polymorphism in this patient population. Future studies investigating the other SNPs, mutations or altered regulation of Kir4.1 in larger samples would help clarify the role (s) of KCNJ10 gene in enuresis.

BDNF and NGF gene polymorphisms and urine BDNF-NGF levels in children with primary monosymptomatic nocturnal enuresis.

INTRODUCTION: The pathophysiology and genetic influences in nocturnal enuresis have not been fully elucidated. Delayed neuronal maturation has been suggested as a pathogenetic mechanism in primary monosymptomatic nocturnal enuresis (PMNE). Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are neurotrophins affecting maturation of the nervous system. OBJECTIVE: The aim of this preliminary study was to investigate BDNF and NGF gene polymorphisms and urine levels of BDNF and NGF in children with PMNE as a first time. STUDY DESIGN: The single-nucleotide polymorphisms of BDNF (rs6265:G > A:Val66Met; rs8192466:C > T:Thr2Ile) and NGF (rs6330:C > T:Ala35Val, rs11466112:C > T:Arg221Trp) were investigated by comparing 104 children with PMNE and 140 healthy control subjects. Children with non-PMNE were excluded. DNA isolation and detection of polymorphisms were performed by real-time polymerase chain reaction. In addition, urine BDNF and NGF levels of 47 PMNE and 29 healthy children were measured by enzyme-linked immunosorbent assay method and normalized to urine creatinine (Cr) concentration for comparisons. RESULTS: There were no differences in genotype and allele frequencies of BDNF rs6265 and NGF rs6330 polymorphisms between patients with PMNE and the control group (P > 0.05). No mutant alleles were found in BDNF rs8192466 and NGF rs11466112 polymorphisms in either group. Children with PMNE had higher urine BDNF/Cr (0.020 ± 0.010 vs 0.010 ± 0.002; P = 0.008) and NGF/Cr ratio (3.01 ± 1.87 pg/mg vs 1.77 ± 0.26 pg/mg; P = 0.002) compared with the control subjects. However, no significant differences were found in BDNF/Cr and NGF/Cr values between GG, GA, and AA genotypes of BDNF rs6265 polymorphism and CC and CT genotypes of NGF rs6330 polymorphism (P > 0.05). DISCUSSION: In this study, no association of BDNF and NGF gene polymorphisms with PMNE was found, and urine neurotrophin concentrations were not directly influenced by investigated polymorphisms. Although, previously increased urine neurotrophin secretion has been found in detrusor overactivity, bladder inflammation, and dysfunctional voiding, this preliminary results also showed an increase in neurotrophins in PMNE. Higher urine neurotrophin levels may be related to delayed and continued neuronal maturation or increased production of neurotrophins in the bladder. The increased urine neurotrophins in PMNE may be an indicator of increased sensory nerve excitability of the bladder, contributing to the development of enuresis. CONCLUSION: This study showed that investigated neurotrophin gene polymorphisms did not make a significant contribution to the development of PMNE, but urine levels of neurotrophin gene products were higher in PMNE. Owing to the complexity and heterogeneity of genotype-phenotype relationships in enuresis, further studies are needed in PMNE.

Effect of DRD4 receptor -616 C/G polymorphism on brain structure and functional connectivity density in pediatric primary nocturnal enuresis patients.

The dopamine D4 receptor (DRD4) promoter (-616; rs747302) has been associated with primary nocturnal enuresis (PNE); however, its relationship with neuroimaging has not been investigated. Therefore, we assessed the effects of the DRD4 -616 C/G single nucleotide polymorphism on the gray matter volume (GMV) and functional connectivity density (FCD) during resting-state functional magnetic resonance imaging in children with PNE using voxel-based morphometry and FCD methods. Genomic and imaging data were obtained from 97 children with PNE and 105 healthy controls. DRD4 -616 C/G was genotyped. Arousal from sleep (AS) was assessed on a scale of 1-8. Both the main effect of genotype and the group (PNE/control)-by-genotype interaction on GMV and FCD were calculated. Our results showed that C-allele carriers were associated with a higher AS, decreased GMV and FCD in the pregenual anterior cingulate cortex; children with PNE carrying the C allele exhibit decreased GMV and FCD in the thalamus; however, controls carrying the C allele exhibit increased FCD in the posterior cingulate cortex. These effects of genetic variation of the DRD4 locus may help us understand the genetic susceptibility of the DRD4 -616 C allele to PNE.

The Time of Spontaneous Resolution of Monosymptomatic Nocturnal Enuresis (MNE) Is Familial.

PURPOSE: To investigate whether or not the age of spontaneous resolution of monosymptomatic nocturnal enuresis (MNE) was familial. PATIENTS AND METHODS: A questionnaire was administered to more than 1,500 people, and 100 appropriate participants were identified from four referral hospitals. We included the participants who had MNE and whose parents also had MNE with spontaneous resolution. Then the association between the spontaneous resolution time of MNE in parents and that in their children was investigated. RESULTS: The mean ages of spontaneous resolution were 10.7 (10-30 years), 9.4 (6-17 years) and 10.9 (6-18 years) in participants, their mothers and their fathers, respectively. According to the statistical analysis, there was a positive correlation between participants and both their mothers and fathers (p < 0.05). In addition, it was revealed that familial MNE history based on first- and second-degree relatives, in addition to their parents, was also associated with the increased spontaneous resolution age of MNE (p < 0.05). According to our results, gender and parents' education status were not statistically associated with the spontaneous resolution (p > 0.05). CONCLUSION: As a conclusion, the age of spontaneous resolution of MNE is familial. Although the exact reasons of spontaneous resolution still remain a mystery; further genetic investigations may be able to resolve this mystery.

Possible impact of comorbid conditions on the persistence of nocturnal enuresis: results of a long-term follow-up study.

PURPOSE: To describe the natural history of patients with nocturnal enuresis (NE) during a 10-year period and to evaluate possible impact of comorbid conditions on the persistence of NE. MATERIALS AND METHODS: Ninety-five children (male to female ratio [M:F] 65:30), aged at first visit between 6 and 21 years were included in this study. Of study subjects 75 had primary monosymptomatic nocturnal enuresis (PMNE), 3 had secondary monosymptomatic nocturnal enuresis (SMNE) and 17 had non-mono­symptomatic nocturnal enuresis (NMNE). Demographic and NE-related details were assessed from electron­ic medical records and by telephone interview at the times 3, 6, 12 months and 3, 5, 10 years after the first examination. Sixty-seven of 95 patients were enrolled, of whom 57 had PMNE (M:F ratio 39:18, mean age 9.35 ± 2.81 years, mean age at improvement 11.5 ± 4.08 years), 8 had NMNE (M:F ratio 4:4, mean age 10.1 ± 2.64 years, mean age at improvement 12.6 ± 1.68 years) and 2 had SMNE (M:F ratio 1:1, mean age 12 years, mean age at improvement 13.5 ± 2.12 years). RESULTS: The mean duration of follow up was 7.2 ± 2.5 years. All of the 67 children had 5 years follow up. Only 29 of 67 patients (19 with PMNE, 8 with NMNE and 2 with SMNE) had 10 years follow up and 4 of 19 with PMNE were still affected by NE. Out of 57 patients with PMNE 12 (2/12 with language disorders, 1/12 varicocele and 1/12 cryptorchidism) and out of 8 patients with NMNE 1 were still enuretic while all patients with SMNE were in remission. CONCLUSION: We observed that language disorders and testicular pathology in NE children could be comor­bidities associated with persistence of NE and treatment resistance.

Chronobiology of micturition: putative role of the circadian clock.

PURPOSE: Mammals urinate less frequently during the sleep period than the awake period. This is modulated by a triad of factors, including decreased arousal in the brain, a decreased urine production rate in the kidneys and increased functional bladder capacity during sleep. The circadian clock is genetic transcription-translation feedback machinery. It exists in most organs and cells, termed the peripheral clock, which is orchestrated by the central clock in the suprachiasmatic nucleus of the brain. We discuss the linkage between the day and night change in micturition frequency and the genetic rhythm maintained by the circadian clock system, focusing on the brain, kidney and bladder. MATERIAL AND METHODS: We performed an inclusive review of the literature on the diurnal change in micturition frequency, urine volume, functional bladder capacity and urodynamics in humans and rodents, relating this to recent basic biological findings about the circadian clock. RESULTS: In humans various behavioral studies demonstrated a diurnal functional change in the kidney and bladder. Conversely, patients with nocturnal enuresis and nocturia showed impairment in this triad of factors. Rats and mice, which are nocturnal animals, also have a micturition frequency rhythm that is decreased during the day, which is the sleep phase for them. Mice with a genetically defective circadian clock system show impaired physiological rhythms in the triad of factors. The existence of the circadian clock has been proven in the brain, kidney and bladder, in which thousands of circadian oscillating genes exist. In the kidney they include genes involved in the regulation of water and major electrolytes. In the bladder they include connexin 43, a gene associated with the regulation of bladder capacity. CONCLUSIONS: Recent progress in molecular biology about the circadian clock provides an opportunity to investigate the genetic basis of the micturition rhythm or impairment of the rhythm in nocturnal enuresis and nocturia. If this approach is to be translated clinically, a strategy is to analyze and treat the triad of micturition factors as separate parts of 1 problem. The other way could be to cope with this triad of problems simultaneously, if possible, by treating the circadian physiological rhythm itself. The discoveries reviewed point toward further investigation of the micturition rhythm by basic and translational chronobiology.

Anti-diuretic hormone and genetic study in primary nocturnal enuresis.

OBJECTIVE: To investigate whether primary nocturnal enuresis (PNE) is related to a disturbance in anti-diuretic hormone (ADH) secretion pattern at night which may be genetically inherited. SUBJECTS AND METHODS: This study included 121 children aged 6-18 years with PNE and 45 matched healthy children as controls. Enuretic children were subjected to genetic evaluation and cytogenetic assessment (n = 99). Assay of ADH levels (9-11 am & 9-11 pm) was performed for cases (n = 99) and controls. RESULTS: There was a positive family history in 82.4% (autosomal dominant in 35.4% and autosomal recessive in 64.6%). ADH morning and evening values were reversed in cases vs controls with significant difference in morning level. Reversal of circadian rhythm was present in 71.7% of cases and normal rhythm in 28.3% of them. Morning and evening ADH levels revealed significant difference between patients with reversed rhythm and those with normal one, and with controls. Mode of inheritance had no influence on hormonal level. Chromosomal abnormality was detected in 3 cases with reversed ADH rhythm, involving chromosome 22 in two of them. CONCLUSION: PNE could be attributed in part to reversed ADH circadian rhythm which may be linked to chromosome 22.

Prevalence of nocturnal enuresis and associated factors in schoolchildren in Western Turkey.

INTRODUCTION: The prevalence of nocturnal enuresis (NE) in pediatric populations varies between 1% to 20%. The aim of this study was to determine the prevalence of NE in schoolchildren living in Tekirdag, a city in Western Turkey. MATERIALS AND METHODS: We distributed a questionnaire to 11324 schoolchildren aged 7 to 14 years who were living in Tekirdag. The questionnaires were filled in by the children's parents. The main study endpoints were the prevalence of NE, and its association with sociodemographic factors of the children and their parents. RESULTS: The results from 9210 children (81.4%) who returned fully completed questionnaires were included in the study. The prevalence of NE was 7.5%. Another 579 children (6.2%) had NE that had resolved at the time of study. Prevalence rates decreased with increasing age, reaching 1.4% by age 14 years. NE was more prevalent among boys than girls, but the rates became similar by age 12 years. There was a strong relationship between NE and family history of childhood NE. More than half of the parents who had a child with NE were using traditional techniques for treatment. CONCLUSIONS: The prevalence of NE in schoolchildren in Tekirdag, a city in Western Turkey was 7.5%. Having a family history of childhood NE was the one of main risk factors for NE.

Involvement of urinary bladder Connexin43 and the circadian clock in coordination of diurnal micturition rhythm.

Nocturnal enuresis in children and nocturia in the elderly are two highly prevalent clinical conditions characterized by a mismatch between urine production rate in the kidneys and storage in the urinary bladder during the sleep phase. Here we demonstrate, using a novel method for automated recording of mouse micturition, that connexin43, a bladder gap junction protein, is a negative regulator of functional bladder capacity. Bladder connexin43 levels and functional capacity show circadian oscillations in wild-type mice, but such rhythms are completely lost in Cry-null mice having a dysfunctional biological clock. Bladder muscle cells have an internal clock, and show oscillations of connexin43 and gap junction function. A clock regulator, Rev-erbα, upregulates connexin43 transcription as a cofactor of Sp1, using Sp1 cis-elements of the promoter. Therefore, circadian oscillation of connexin43 is associated with the biological clock and contributes to diurnal changes in bladder capacity, which avoids disturbance of sleep by micturition.

Behavioural genetics of childhood disorders.

After a general introduction into genetic risk factors for child psychiatric disorders, four specific child psychiatric disorders with a strong genetic component, namely, Autism Spectrum Disorders, Attention Deficit / Hyperactivity Disorder, Nocturnal Enuresis, and obesity, are discussed in detail. Recent evidence of linkage, candidate gene, and genome-wide association studies are presented. This chapter ends with a prospectus on further research needs.

Family history of nocturnal enuresis and urinary incontinence: results from a large epidemiological study.

PURPOSE: Nocturnal enuresis is a common, genetically heterogeneous disorder. Family, twin and segregation analyses have demonstrated a high heritability. Molecular genetic linkage studies have identified several loci on different chromosomes. Much less is known about the genetics of daytime urinary incontinence. In this study we identify familial patterns in a large, representative sample of children with nocturnal enuresis and daytime urinary incontinence. MATERIALS AND METHODS: Participants were a cohort of more than 8,000 children enrolled in the population based Avon Longitudinal Study of Parents and Children, a prospective longitudinal study of an original birth cohort of nearly 14,000 children. Parents completed postal questionnaires asking about their own nocturnal enuresis and urinary incontinence. At the age of 7½ years extensive data on nocturnal enuresis and urinary incontinence of their children were obtained. RESULTS: At the age of 7½ years the prevalence of nocturnal enuresis was 15.5%. Infrequent nocturnal enuresis affected 12.8% of children and severe nocturnal enuresis (2 or more episodes weekly) affected 2.6%. The prevalence of urinary incontinence was 7.8%, and 6.8% had infrequent and 1.0% had severe daytime urinary incontinence. Of the 11,650 mothers who provided data on their own nocturnal enuresis and urinary incontinence 8.8% had nocturnal enuresis and 0.7% had daytime urinary incontinence. Of the 7,897 fathers 9.6% had nocturnal enuresis and 0.3% had daytime urinary incontinence. There were significant associations between parental and child nocturnal enuresis, and parental and child urinary incontinence. Specifically the odds ratios for severe child nocturnal enuresis were 3.63 times higher in maternal and 1.85 times higher in paternal nocturnal enuresis. The odds ratios for severe child urinary incontinence were 3.28 times higher in maternal and 10.1 times higher in paternal urinary incontinence. The associations were less pronounced between parental nocturnal enuresis and child urinary incontinence, as well as between parental urinary incontinence and child nocturnal enuresis. CONCLUSIONS: Formal genetic risks exist for nocturnal enuresis and urinary incontinence, especially in severe incontinence. The magnitude of effects for child nocturnal enuresis and urinary incontinence is comparable. While the heritability of nocturnal enuresis is well-known, the familiarity of urinary incontinence has been underestimated.

Rs 6313 polymorphism in 5-hydroxytryptamine receptor 2A gene association with polysymptomatic primary nocturnal enuresis.

BACKGROUND: Tricyclic antidepressants (TCA) were used to treat nocturnal enuresis (NE) for decades of years although their real mechanisms are unknown. Recently, some case studies demonstrated the efficacy of selective serotonin reuptake inhibitors (SSRI) in the treatment of NE. Both TCA and SSRI have similar influences on serotonin transmission. This study was aimed at evaluating whether 5-hydroxytryptamine receptor 2A (5HTR2A) gene is associated with NE. METHODS: We analyzed rs6313 polymorphism in 5HTR2A gene of 213 Taiwanese children (116 NE cases and 97 healthy control subjects) using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: There were no significant differences when comparing the genotypes and allelic frequencies of rs6313 polymorphism in 5HTR2A gene between patients with NE and control subjects. However, when subsequently comparing 5HTR2A genotypes and allelic frequencies in NE child with different phenotypes, genotypes TT and TC appeared higher risks of polysymptomatic NE compared with CC (odds ratio (OR)=10.71, 95% confidence interval (CI)=2.66-43.12; OR=2.68, 95% CI=0.67-10.75, respectively; P=0.0002); and allele T also revealed higher frequencies of polysymptomatic NE compared with allele C (OR=3.7, 95% CI=2.01-6.79, P=0.000015). CONCLUSIONS: This is the first study that shows the association between 5HTR2A gene polymorphisms and polysymptomatic NE. These results provide further evidence suggesting that genetic variations at 5HTR2A may influence NE treatment response.

Nocturnal enuresis: a suggestive endophenotype marker for a subgroup of inattentive attention-deficit/hyperactivity disorder.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) and enuresis co-occur at a higher rate than expected; the cause for this is unclear. STUDY DESIGN: Diagnostic and demographic variables were compared in 344 children ages 6 to 12 years, with and without enuresis, recruited in an ADHD genetic study. Sleep variables were investigated in a subgroup of 44 enuretic children with age- and sex-matched nonenuretic controls. The association of enuresis with single nucleotide polymorphisms located in regions reported in linkage with enuresis was explored. RESULTS: The prevalence rate of nocturnal enuresis was 16.9% for the entire cohort. There were no differences in sex, age, socioeconomic status, intelligence quotient, medication treatment, or comorbidities. The enuresis group had a higher likelihood of inattentive symptoms than the nonenuretic group. Night wakings and ability of children to wake themselves in the morning were both significantly decreased in children with enuresis compared with control children in the Child Sleep Habits Questionnaire Night Wakings subscale. No significant association was found with chromosomal regions previously reported in linkage with enuresis. CONCLUSIONS: Deficits in arousal may contribute to both enuresis and inattentive ADHD. Nocturnal enuresis may be a useful clinical marker in identifying a subgroup of the inattentive phenotype in ADHD genetic studies.