Search

CDKL5 deficiency disorder (CDD) was first identified as a cause of human disease in 2004. Although initially considered a variant of Rett syndrome, CDD is now recognised as an independent disorder and classified as a developmental epileptic encephalopathy. It is characterised by early-onset (generally within the first 2 months of life) seizures that are usually refractory to polypharmacy. Development is severely impaired in patients with CDD, with only a quarter of girls and a smaller proportion of boys achieving independent walking; however, there is clinical variability, which is probably genetically determined. Gastrointestinal, sleep, and musculoskeletal problems are common in CDD, as in other developmental epileptic encephalopathies, but the prevalence of cerebral visual impairment appears higher in CDD. Clinicians diagnosing infants with CDD need to be familiar with the complexities of this disorder to provide appropriate counselling to the patients' families. Despite some benefit from ketogenic diets and vagal nerve stimulation, there has been little evidence that conventional antiseizure medications or their combinations are helpful in CDD, but further treatment trials are finally underway. [ABSTRACT FROM AUTHOR]

Objective: What effect does regular exercise have on oxidative stress in people with Down syndrome?Design: Systematic review with meta-analyses.Methods: A systematic review with meta-analyses was conducted. Six databases were searched from inception until August 2017. Studies where included if participants with Down syndrome (any age) had completed an exercise program of at least 6 weeks duration and at least one biomarker measured the generation or removal of reactive oxidative species. Data were extracted using a customised form. Risk of bias was assessed using the Cochrane Collaboration's Risk of Bias assessment tool. Effect sizes were calculated and meta-analyses completed for clinically homogeneous data using a random effects model.Results: Seven studies (11 articles) involving 144 inactive participants investigated the effect of moderate intensity aerobic exercise. No pattern emerged for how most biomarkers responded with non-significant pooled effect sizes and high levels of heterogeneity observed. The exception was catalase which increased significantly after exercise (standardised mean difference 0.39, 95%CI 0.04-0.75; I2 15%). Available studies were at high risk of bias. Two of five studies that measured more than one biomarker reported a decrease in oxidative stress with increased antioxidant activity after exercise but the other three (including one small randomised controlled trial) reported increased oxidative stress with variable change in antioxidant activity.Conclusions: There remains uncertainty about the effect of exercise on oxidative stress in people with Down syndrome.Review Registration: PROSPERO CRD42016048492. [ABSTRACT FROM AUTHOR]

Objective: To compare quality of life (QOL) across diagnoses associated with intellectual disability, construct QOL profiles and evaluate membership by diagnostic group, function and comorbidities.Method: Primary caregivers of 526 children with intellectual disability (age 5-18 years) and a diagnosis of cerebral palsy, autism spectrum disorder, Down syndrome, CDKL5 deficiency disorder or Rett syndrome completed the Quality of Life Inventory-Disability (QI-Disability) questionnaire. Latent profile analysis of the QI-Disability domain scores was conducted.Results: The mean (SD) total QOL score was 67.8 (13.4), ranging from 60.3 (14.6) for CDD to 77.5 (11.7) for Down syndrome. Three classes describing domain scores were identified: Class 1 was characterised by higher domain scores overall but poorer negative emotions scores; Class 2 by average to high scores for most domains but low independence scores; and Class 3 was characterised by low positive emotions, social interaction, and leisure and the outdoors scores, and extremely low independence scores. The majority of individuals with autism spectrum disorder and Down syndrome belonged to Class 1 and the majority with CDKL5 deficiency disorder belonged to Class 3. Those with better functional abilities (verbal communication and independent walking were predominately members of Class 1 and those with frequent seizures were more often members of Class 2 and 3.Conclusion: The profiles illustrated variation in QOL across a diverse group of children. QOL evaluations illustrate areas where interventions could improve QOL and provide advice to families as to where efforts may be best directed. [ABSTRACT FROM AUTHOR]

Objective: To assess the direct annual health care costs for children and adolescents with Down syndrome in Western Australia and to explore the variation in health care use including respite, according to age and disease profile. Study design: Population-based data were derived from a cross-sectional questionnaire that was distributed to all families who had a child with Down syndrome as old as 25 years of age in Western Australia. Results: Seventy-three percent of families (363/500) responded to the survey. Mean annual cost was $4209 Australian dollars ($4287 US dollars) for direct health care including hospital, medical, pharmaceutical, respite and therapy, with a median cost of $1701. Overall, costs decreased with age. The decline in costs was a result of decreasing use of hospital, medical, and therapy costs with age. Conversely, respite increased with age and also with dependency. Health care costs were greater in all age groups with increasing dependency and for an earlier or current diagnosis of congenital heart disease. Annual health care costs did not vary with parental income, including cost of respite. Conclusions: Direct health care costs for children with Down syndrome decrease with age to approximate population costs, although costs of respite show an increasing trend. [Copyright &y& Elsevier]

Abstract: This study measured use and cost of health sector and related services in Rett syndrome and effects of socio-demographic, clinical severity and genetic factors on costs. The study population consisted of individuals with Rett syndrome registered with the Australian Rett Syndrome Database in 2004. Descriptive analysis was used to examine patterns of resource use and costs, and logistic regression to analyse factors associated with higher costs. We found the use of health sector and related resources varied by type of resource. Mean annual cost per case was $21,158 (range $238–$85,776). High cost items included long-term residential care, therapy services out of school and paid home and community care. Factors associated with increasing odds of being above the median cost were clinical severity and the p.R255X mutation. Compared with the youngest cases, cases in the 5–14 year age group and the 15–24 year age group were at lower odds of being above the median cost. Needs relating to health sector and related resources can result in considerable costs for individuals with Rett syndrome. Many households caring for dependents with Rett syndrome are like to be facing undue financial pressures from the additional costs of disability. [ABSTRACT FROM AUTHOR]

Abstract: This study assessed factors that could influence equipment and respite services use among Australian families caring for a girl/woman with Rett syndrome and examined relationships between use of these resources and the health of female caregivers. Data was sourced from questionnaires completed by families (n =170) contributing to the Australian Rett Syndrome Database in 2004 and 2006. Regression analysis was used to assess relationships between child factors (age, mobility, clinical severity and behaviour), family factors (accessibility and socio-economic factors) and the use of equipment and respite services in 2004, and relationships between resource use in 2004 and health of female caregivers as measured by the SF-12 in 2006. In 2004, the majority (88.3%) of families used at least one piece of equipment with more equipment use associated with greater mobility restrictions. Home respite services were used by 54.9% of families and overnight respite services by 47.6% of families. Use of more home respite services was associated with severely restricted levels of mobility and mothers having a vocational or university qualification. Use of more overnight respite services was associated with increasing age of the girl/woman with Rett syndrome and mothers being employed while use of less overnight respite services was associated with increasingly difficult behaviours in the girl/woman. In 2006, female caregivers had a mean mental health score of 41.1 (95% CI 38.9–43.3) and no relationships with previous resource use were identified. The mean physical health score of female caregivers was 48.7 (95% CI 46.8–50.5) and lower scores were associated with the use of equipment and overnight respite services. Equipment was a widely used resource whereas respite services, particularly overnight services, were used less widely. Further investigation of the reasons for this and alternative support strategies is indicated. [ABSTRACT FROM AUTHOR]

Abstract: This study aimed to investigate the trajectories over time of health status and health service use in Rett syndrome by mutation type. Data were obtained from questionnaires administered over 6 years to 256 participants from the Australian Rett Syndrome Database. Health status (episodes of illness and medication load) and health service use (general practitioner and specialist visits and hospital stays) were summarized into composite scores with principal component analysis. Linear and mixed regression models examined effects of mutation type and other variables on these scores over time. For some mutations (such as p.R255X and p.R168X) health status was poorer at a younger age and improved over time, while for p.R133C it was better at a younger age and deteriorated with time. For those with p.R133C health service use was lowest at a younger age and highest at 25 years. With other mutations, such as p.R255X, p.R270X, p.R294X, C terminal and p.R306C, health service use was higher at a younger age, but dropped off considerably by 25 years of age. Health service use generally declined in parallel with deterioration in health status, although this pattern differed by mutation type, demonstrating important variability in the course of Rett syndrome. [ABSTRACT FROM AUTHOR]

Abstract: The etiology of autism spectrum disorders is unknown but there are claims of increasing prevalence in many countries. Despite more than a decade of epidemiological investigation, it is still unclear whether the rising trend in prevalence reflects a true increase or changes in diagnostic trends and improvements in case ascertainment. This paper discusses changes in diagnostic criteria, decreasing age at diagnosis, improved case ascertainment, diagnostic substitution, and social and cultural influences on the overall effects on prevalence, including the role of an ASD diagnosis as a gateway to funding. The evidence suggests that the increased prevalence of autism spectrum disorder can be partly supported by each of these factors, but remains largely unquantified due to a variety of other global and local factors. The question of how much of a real increase in prevalence has occurred remains crucially important to understand the classification, epidemiology and etiology of autism spectrum disorders but can only be answered if controlling these other factors. [Copyright &y& Elsevier]

Abstract: Rett syndrome (RTT) is a rare genetic disorder within the autistic spectrum. This study compared socio-demographic, clinical and genetic characteristics of the international database, InterRett, and the population-based Australian Rett syndrome database (ARSD). It also explored the strengths and limitations of InterRett in comparison with other studies. A literature review compared InterRett with RTT population-based and case-based studies of 30 or more cases that investigated genotype and/or phenotype relationships. Questionnaire data were used to determine case status and to investigate the comparability of InterRett and ARSD. Twenty-four case series, five population-based studies and a MECP2 mutation database were identified of which 21 (70%) collected phenotype and genotype data. Only three studies were representative of their underlying case population and many had low numbers. Of 1114 InterRett subjects, 935 born after 1976 could be verified as Rett cases and compared with the 295 ARSD subjects. Although more InterRett families had higher education and occupation levels and their children were marginally less severe, the distribution of MECP2 mutation types was similar. The InterRett can be used with confidence to investigate genotype phenotype associations and clinical variation in RTT and provides an exemplary international model for other rare disorders. [Copyright &y& Elsevier]

Objective: To identify the relationship between characteristics of the child with Down syndrome and the health of their mother. Study design: Families with a child/young adult with Down syndrome (<25 years) provided information related to the health of the child, functioning and behavior, and the health and well-being of the mother (n = 250). Results: The mean physical health score of mothers was 50.2 (SD = 9.6). Factors associated with lower mean physical health scores were as follows: child having a current heart problem (P = .036), a higher body mass index (P = .006), and higher (poorer) scores on the Developmental Behavior Checklist. Better physical health scores were seen in mothers whose children required no help/supervision in learning new skills (P = .008) and domestic tasks (P = .014). The mean mental health score of mothers was 45.2 (SD = 10.6), significantly lower than the norm of 50 (P < .0001). Associated child factors included current ear problems (P = .079), muscle/bone problems (P = .004), >4 episodes of illness in past year (P = .016), and higher scores on the DBC (P < .0001). Conclusions: The most important predictors of maternal health were children''s behavioral difficulties, everyday functioning and current health status. Mothers of children with Down syndrome appear to experience poorer mental health and may require greater support and services to improve behavior management skills for their child and their own psychological well-being. [Copyright &y& Elsevier]

Abstract: Background: Rett syndrome is a neurodevelopmental disorder mainly affecting females. It is principally caused by mutations in the MECP2 gene. Seizures occur in about 80% of subjects but there has been little research into the factors contributing to their frequency. Aims: To investigate seizure frequency in Rett syndrome and its relationship with other factors, including genetic characteristics and the use of anti-epileptic drugs. Methods: Information on daily seizure occurrence and health service utilization and monthly anti-epileptic drug use was provided on 162 Rett syndrome cases for a calendar year. Age at onset of seizures, developmental history and other clinical and genetic characteristics were obtained from a contemporaneously completed questionnaire and from the Australian Rett Syndrome Database. Negative binomial regression was used to investigate factors associated with seizure rates. Results: Seizure rates were highest in the 7–12 year age group. They were lower in those with p.R294X, p.R255X mutations and C terminal mutations. Those who had early developmental problems and poorer mobility had higher seizure rates as did those with greater clinical severity and poorer functional ability. Many different combinations of medications were being used with carbamazepine, sodium valproate and lamotrigine either singly or in combination with another being the most common. Conclusions: Seizure frequency in Rett syndrome is age-dependent, more common in those with more severe early developmental problems and influenced by mutation type. [Copyright &y& Elsevier]

Objectives: To investigate risk factors for seizure onset in Rett syndrome. Study design: Information on presence and age at onset of seizures, perinatal and developmental history, and genetic status was abstracted on 275 cases in the Australian Rett Syndrome Database. Cox and Weibull regression were used to investigate and provide a model for predicting the effects of genetic and developmental factors on age at seizure onset. Results: Seizures were reported in 81% of 275 cases; the median age of onset was 48 months. Not having gained the ability to walk (P = .003) and developmental problems in the first 10 months of age (P = .04) were associated with an almost 2-fold increased risk of seizures. Cases without a detectable MECP2 mutation had a higher risk of seizure onset up to 4 years of age (P < .001) but a lower risk after 4 years (P = .08). Conclusions: Seizure onset in Rett syndrome is associated with early developmental factors and with genotype. Information on these factors can be used to predict age at seizure onset after diagnosis. [Copyright &y& Elsevier]

Purpose: The aim of the study is to investigate the relationship between common maternal conditions and intellectual disability (ID) of unknown cause in the offspring. Methods: Information about the maternal health of children with and without ID was obtained by using record linkage. For mothers with specific medical conditions, proportions of children with mild to moderate ID, severe ID, and autism spectrum disorder (ASD) with ID were compared with those who did not have ID. Results: There was an increased risk for mild to moderate ID in children of mothers with asthma (odds ratio [OR], 1.52; confidence interval [CI], 1.26–1.83]), diabetes (OR, 1.69; CI, 1.26–2.27), a renal or urinary condition (OR, 2.09; CI, 1.39–3.14), and epilepsy (OR, 3.53; CI, 2.56–4.84). ASD risk was increased for children of women with diabetes (OR, 2.89; CI, 1.28–6.51) and epilepsy (OR, 4.57; CI, 1.69–12.31). For anemia (n = 1101), there was an increased risk for severe ID (OR, 5.26; CI, 2.16–12.80). Conclusions: The increased risk for ID in offspring of mothers with such conditions as asthma and diabetes is particularly important for disadvantaged or ethnic populations, for whom these conditions are more prevalent and may be less well managed. [Copyright &y& Elsevier]

Objective: To examine the prevalence, cumulative incidence, and survival in an Australian cohort with Rett syndrome (RTT). Study design: The Australian Rett Syndrome Database is a longitudinal data collection that included 276 verified female cases at the end of 2004. Survival was calculated using the Kaplan-Meier product limit method, and cumulative incidence was determined using the complement of the Kaplan-Meier method. Results: Most cases (88.4%) have had MECP2 mutation testing, with positive results in 73%. The prevalence of RTT was .88 per 10,000 females in 5- to 18-year-olds, and the cumulative incidence was 1.09 per 10,000 females by 12 years of age. The cumulative incidence by the age of 5 years increased from .39 per 10,000 in the 1980 to 1984 cohort to .76 per 10,000 in birth cohorts beyond 1984. Survival was 77.8% at 25 years, compared with 99.96% survival in the Australian female population. Pneumonia (10/25) was the most common cause of death. Conclusions: The availability of genetic testing has contributed to the changing pattern and timing of RTT diagnosis in Australia. Girls with RTT have worse survival compared with the general female population. When more data are available, it will be possible to evaluate the relationship between survival and specific MECP2 mutations. [Copyright &y& Elsevier]

The social determinants of intellectual disability (ID) are poorly understood, particularly in Australia. This study has investigated sociodemographic correlates of ID of unknown cause in Western Australian born children. Using record linkage to the Western Australian Maternal & Child Health Research Database, maternal sociodemographic characteristics of children with ID (of unknown cause) born between 1983 and 1992 (n = 2871) were compared with those of children without ID (n = 236,964). Socioeconomic indices for areas based on the census district of mother's residence were also included in the analysis. Aboriginal mothers (OR = 2.83 [Ci: 2.52, 3.18]), teenagers (OR = 2.09 [CI: 1.82, 2.40]) and single mothers (OR=2.18 [CI: 1.97, 2.42]) were all at increased risk of having a child with mild or moderate ID. Children of mothers in the most socioeconomically disadvantaged 10% had more than five times the risk of mild and moderate ID compared with those in the least disadvantaged 10% (OR = 5.61 [CI: 4.42, 7.12]). Fourth or later born children were also at increased risk (OR = 1.82 [CI: 1.63, 2.02]). The results of the study have implications both for further aetiological investigation as well as service provision for children with ID. Furthermore, many of the sociodemographic correlates identified in this study, particularly in the mild/moderate category of ID, are potentially modifiable, opening up opportunities for primary prevention. [ABSTRACT FROM AUTHOR]

Objective: To describe birth prevalence of rare craniofacial anomalies and associations with antenatal and perinatal factors.Study Design: All live and stillbirths in Western Australia between 1980 and 2010 were identified from the Western Australian Birth Registrations and the Midwives Notification System (also provides information on antenatal and perinatal factors). Rare craniofacial anomalies (craniosynostosis, craniofacial microsomia, and others [Pierre Robin, Van der Woude, and Treacher Collins syndrome]) were ascertained from the Western Australian Register of Developmental Anomalies and linked to other data sources. Trends in prevalence, adjusted for sex and Indigenous status, were investigated by Poisson regression and presented as annual percent change (APC). Strengths of association of related factors were assessed using multivariable log-binomial regression adjusted for sex, Indigenous status, birth year, socioeconomic disadvantage, and remoteness and reported as risk ratios with 95% CIs.Results: There was a temporal increase in prevalence of metopic synostosis (APC 5.59 [2.32-8.96]) and craniofacial microsomia (Goldenhar syndrome) (APC 4.43 [1.94-6.98]). Rare craniofacial anomalies were more likely among infants born preterm, as twins or greater-order multiples, with growth restriction, to older parents, to mothers undertaking fertility treatments, and with pre-existing medical conditions, specifically epilepsy, diabetes, or hypothyroidism. Prenatal identification of rare craniofacial anomalies was uncommon (0.6%).Conclusions: Our findings indicate a steady increase over time in prevalence of metopic synostosis and craniofacial microsomia (Goldenhar syndrome). Possible associations of fertility treatments and pre-existing maternal medical conditions with rare craniofacial anomalies require further investigation. [ABSTRACT FROM AUTHOR]

Information on the hospital service use among individuals with CDKL5 Deficiency Disorder, an ultrarare developmental epileptic encephalopathy, is limited, evidence of which could assist with service planning. Therefore, using baseline and longitudinal data on 379 genetically verified individuals in the International CDKL5 Disorder Database, we aimed to investigate rates of seizure-related and other hospitalizations and associated length of stay in this cohort. Outcome variables were lifetime count of family-reported hospitalizations and average length of stay both for seizure- (management and/or investigative) and non-seizure-related causes. These variables were examined according to gender, age group, genetic variant group, and lifetime number of antiseizure medications. Using negative binomial regression associations were expressed as incidence rate ratios and geometric mean ratios for hospitalization rates and length of stay, respectively. There were 2880 hospitalizations over 2728.4 person-years with two thirds seizure related. Infants were much more likely to be hospitalized than older individuals, with decreasing effect sizes with increasing age. Males had slightly higher rates of hospitalizations for seizure-related management and for non-seizure-related admissions. Lifetime use of six or more antiseizure medications was associated with a higher hospitalization rate for seizure management than use of three or fewer medications. The median length of stay was five days for seizure and nonseizure reasons. There is an urgent need for much better seizure management in CDKL5 deficiency disorder given the hospitalization burden especially in the preschool age group and the multiplicity of antiseizure medications being used. [ABSTRACT FROM AUTHOR]

Objective: To investigate the longitudinal stability of hand function in Rett syndrome and to analyze further the relationships between stability of hand function and genotype, age, and walking ability.Study Design: Longitudinal video data of functional abilities of individuals with genetically confirmed Rett syndrome were collected by families of individuals registered with the Australian Rett Syndrome Database. A total of 120 individuals provided 290 recordings from which 170 observation pairs were available for comparison. The Rett Syndrome Hand Function Scale was used to classify a level of hand function observed in each video on a range from unable to grasp, pick up, and hold objects to skillful manipulation of large and small objects.Results: Approximately one-third of the population lost some hand function over time. Younger children (<6 years) rather than adults were at greater risk of deterioration in hand function. Clinical severity, as indicated by walking ability or genotype, played a lesser role. There was no identified pattern between genotype and the stability of hand function skills. Rather, mutations associated with milder (p.Arg133Cys, p.Arg294∗) and greater (p.Arg106Trp, p.Thr158Met) clinical severity were both associated with greater risks of decline.Conclusions: Genotype was a lesser predictor of loss of hand function beyond the early regression period, and younger children were particularly vulnerable to further loss of hand function compared with adults. [ABSTRACT FROM AUTHOR]

Objective: To examine the frequency of hospital admissions before and after gastrostomy insertion in children with severe intellectual disability.Study Design: We conducted a retrospective cohort study using linked health administrative and disability data from Western Australia (WA) and New South Wales (NSW). Children born between 1983 and 2009 in WA and 2002 and 2010 in NSW who had a gastrostomy insertion performed (n = 673 [WA, n = 325; NSW, n = 348]) by the end of 2014 (WA) and 2015 (NSW) were included. Conditional Poisson regression models were used to evaluate the age-adjusted effect of gastrostomy insertion on acute hospitalizations for all-cause, acute lower respiratory tract infections (LRTI), and epilepsy admissions.Results: The incidence of all-cause hospitalizations declined at 5 years after procedure (WA cohort 1983-2009: incidence rate ratio, 0.70 [95% CI, 0.60-0.80]; WA and NSW cohort 2002-2010: incidence rate ratio, 0.63 [95% CI, 0.45-0.86]). Admissions for acute LRTI increased in the WA cohort and remained similar in the combined cohort. Admissions for epilepsy decreased 4 years after gastrostomy in the WA cohort and were generally lower in the combined cohort. Fundoplication seemed to decrease the relative incidence of acute LRTI admissions in the combined cohort.Conclusions: Gastrostomy was associated with health benefits including reduced all-cause and epilepsy hospitalizations, but was not protective against acute LRTI. These decreases in hospitalizations may reflect improved delivery of nutrition and medications. [ABSTRACT FROM AUTHOR]

Objective: To describe the long-term neurodevelopmental and cognitive outcomes for children born preterm.Study Design: In this retrospective cohort study, information on children born in Western Australia between 1983 and 2010 was obtained through linkage to population databases on births, deaths, and disabilities. For the purpose of this study, disability was defined as a diagnosis of intellectual disability, autism, or cerebral palsy. The Kaplan-Meier method was used to estimate the probability of disability-free survival up to age 25 years by gestational age. The effect of covariates and predicted survival was examined using parametric survival models.Results: Of the 720 901 recorded live births, 12 083 children were diagnosed with disability, and 5662 died without any disability diagnosis. The estimated probability of disability-free survival to 25 years was 4.1% for those born at gestational age 22 weeks, 19.7% for those born at 23 weeks, 42.4% for those born at 24 weeks, 53.0% for those born at 25 weeks, 78.3% for those born at 28 weeks, and 97.2% for those born full term (39-41 weeks). There was substantial disparity in the predicted probability of disability-free survival for children born at all gestational ages by birth profile, with 5-year estimates of 4.9% and 10.4% among Aboriginal and Caucasian populations, respectively, born at 24-27 weeks and considered at high risk (based on low Apgar score, male sex, low sociodemographic status, and remote region of residence) and 91.2% and 93.3%, respectively, for those at low risk (ie, high Apgar score, female sex, high sociodemographic status, residence in a major city).Conclusions: Apgar score, birth weight, sex, socioeconomic status, and maternal ethnicity, in addition to gestational age, have pronounced impacts on disability-free survival. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the prevalence and risks of developmental disability (autism spectrum disorder, intellectual disability, and cerebral palsy) in Western Australian children of different groups of foreign-born women.Study Design: Western Australian population-based linked data of 764 749 singleton live births from 1980 to 2010 were used to compare disability outcomes among children of foreign-born, Australian-born non-Indigenous, and Indigenous women. The risk of disability was assessed using multinomial logistic regression.Results: Overall, the prevalence of any disability was lowest for the children of foreign-born mothers. From 1980 to 1996 but not from 1997 to 2010, children born to mothers from foreign-born low-income countries had an increased relative risk of autism spectrum disorder with intellectual disability, and children born to foreign-born mothers from upper-middle-income countries had an increased risk of cerebral palsy with intellectual disability. After adjusting for smoking, the relative risks of intellectual disability and cerebral palsy with intellectual disability were markedly decreased in children of Australian-born Indigenous mothers.Conclusions: Although we did not find among children born to foreign-born women an increased prevalence across all the measured developmental outcomes, we did observe an increased risk of autism spectrum disorder with intellectual disability and cerebral palsy with intellectual disability for mothers of some foreign-born groups. Our findings related to smoking in the Indigenous population underscore its possible role on the causal pathway to intellectual disability. Maternal migration is considered a factor on the causal pathway to intellectual disability. Maternal migration may be either a risk or a protective factor on the causal pathway to developmental disabilities and the direct role of migration is inconclusive in our study. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate how age-related trends in nutritional status, physical health, and parental well-being in females with Rett syndrome may be related to gastrostomy placement and to examine the impact of the procedure on mortality.Study Design: We included 323 females from the Australian Rett Syndrome Study and analyzed their demographic, genetic, and child and parental health data collected from over 6 waves of follow-up questionnaire between 2000 and 2011. We used mixed-effects models to estimate the association between repeated measures of outcomes and age, gastrostomy placement and their interaction and Cox proportional hazards regression models to estimate relative risks of mortality for individuals with gastrostomy.Results: Nearly one-third (30.3%) of the cases underwent gastrostomy placement. Nutritional status based on weight, height, and body mass index (BMI) improved over time, and BMI was greater in individuals with gastrostomy placement than in those without (adjusted β = 0.87, 95% CI 0.02-1.73). There was no association between gastrostomy placement and individual's physical health outcomes or parental physical and mental health, nor did the age trend of these outcomes vary by gastrostomy insertion status. Nevertheless, among those at risk of suboptimal weight, the all-cause mortality rate was greater in those who had gastrostomy placement compared with those who had not (hazard ratio 4.07, 95% CI 1.96-8.45).Conclusion: Gastrostomy placement was associated with improvement in BMI in females with Rett syndrome, but its long-term impact on individuals and their families is unclear. [ABSTRACT FROM AUTHOR]

Objectives: To quantify the independent risks of neonatal (0-28 days), postneonatal (29-364 days), 1- to 5- and 6- to 30-year mortality by gestational age and investigate changes in survival over time in an Australian birth cohort.Study Design: Maternal and birth related Western Australian population data (1980-2010) were linked to the state mortality data using a retrospective cohort study design involving 722 399 live-born singletons infants.Results: When compared with 39- to 41-week born infants, the adjusted risk ratio for neonatal mortality was 124.8 (95% CI 102.9-151.3) for 24-31 weeks of gestation, 3.4 (95% CI 2.4-4.7) for 35-36 weeks of gestation, and 1.4 (95% CI 1.1-1.8) for 37-38 weeks of gestation. For 24-31 weeks of gestation infants, the adjusted hazard ratio for postneonatal mortality (29-364 days) was 13.9 (95% CI 10.9-17.6), for 1- to 5-year mortality 1.4 (95% CI 0.7-3.0) and for 6- to 30-year mortality 1.3 (95% CI 0.8-2.3). The risk of neonatal and postneonatal mortality for those born preterm decreased over time.Conclusions: In Western Australia, late preterm and early term infants experienced higher risk of neonatal and postneonatal mortality when compared with their full-term peers. There was insufficient evidence to show that gestational length was independently associated with mortality beyond 1 year of age. Neonatal and postneonatal mortality improved with each decade of the study period. [ABSTRACT FROM AUTHOR]

Objectives: To investigate survival up to early adulthood for children with intellectual disability and compare their risk of mortality with that of children without intellectual disability.Study Design: This was a retrospective cohort study of all live births in Western Australia between January 1, 1983 and December 31, 2010. Children with an intellectual disability (n = 10 593) were identified from the Western Australian Intellectual Disability Exploring Answers Database. Vital status was determined from linkage to the Western Australian Mortality database. Kaplan-Meier product limit estimates and 95% CIs were computed by level of intellectual disability. Hazard ratios (HRs) and 95% CIs were calculated from Cox proportional hazard regression models adjusting for potential confounders.Results: After adjusting for potential confounders, compared with those without intellectual disability, children with intellectual disability had a 6-fold increased risk of mortality at 1-5 years of age (adjusted HR [aHR] = 6.0, 95%CI: 4.8, 7.6), a 12-fold increased risk at 6-10 years of age (aHR = 12.6, 95% CI: 9.0, 17.7) and a 5-fold increased risk at 11-25 years of age (aHR = 4.9, 95% CI: 3.9, 6.1). Children with severe intellectual disability were at even greater risk. No difference in survival was observed for Aboriginal children with intellectual disability compared with non-Aboriginal children with intellectual disability.Conclusions: Although children with intellectual disability experience higher mortality at all ages compared with those without intellectual disability, the greatest burden is for those with severe intellectual disability. However, even children with mild to moderate intellectual disability have increased risk of death compared with unaffected children. [ABSTRACT FROM AUTHOR]

Objective: To calculate the survival of people with Down syndrome over the past 60 years and the influence of major perinatal factors by using linked population-based data.Study Design: A data linkage between 2 Western Australian (WA) data sets (the Register for Developmental Anomalies and the Intellectual Disability Exploring Answers database) was used to identify 772 children born with Down syndrome in WA from 1980-2010. Perinatal and mortality data were extracted from the WA Midwives Information System and WA death registrations and compared with the remaining WA population born during that same era. An additional 606 children with Down syndrome living in WA prior to 1980 were available from a disability services database and were used for predicting survival into adulthood.Results: Overall, for cases born 1953-2010, 88% (95% CI 86%, 90%) survived to 5 years of age, 87% (95% CI 85%, 89%) to 10 years, and 83% (95% CI 80%, 85%) to 30 years. Children live-born with Down syndrome were significantly more likely (all P > .001) to have mothers older than 35 years (32.7% vs 13.4%), a gestational age less than 37 weeks (23.8% vs 7.9%), a cesarean delivery (28.9% vs 23.0%), and a birth weight less than 2500 g (20.4% vs 6.1%). Down syndrome survival was reduced in the presence of a cardiovascular defect, younger gestational age, low birth weight, or earlier birth years.Conclusions: Improved survival for children born with Down syndrome over the last 60 years has occurred incrementally, but disparities still exist for children who are preterm or have low birth weight. [ABSTRACT FROM AUTHOR]

Objectives: To compare the prevalence of parent reported medical conditions and rates of health service utilization in school-aged children with Down syndrome in Western Australia in 1997 and 2004. Study design: We compared two cross-sectional surveys completed by parents of children with Down syndrome identified from population-based sources in 1997 (n = 210) and 2004 (n = 208). Surveys collected information on family demographics, medical conditions, health issues, and service utilization. The analysis described medical conditions in 2004 and compared frequencies in both years. Regression analyses compared medical conditions and health utilisation in the two cohorts. Results: In 2004, children with Down syndrome had greater odds of having a bowel condition (OR, 1.69; 95%, 1.16 to 2.45; P = .01), were less likely to have a current problem due to their cardiac condition (OR, 0.32; 95% CI, 0.15 to 0.68, P = .003), and demonstrated an overall reduction in episodic illnesses and infections. The use of GP services (incidence rate ratio [IRR] = 0.91; 95% CI, 0.83 to 1.00, P = .05) and combined medical specialist visits (IRR = 0.92; 95% CI, 0.84 to 1.01; P = .09) were reduced in 2004, as were overnight hospital admissions (IRR = 0.60; 95% CI, 0.37 to 0.96; P = .03) and length of stay (IRR = 0.33; 95% CI, 0.24 to 0.44; P < .001). Conclusions: The health status of children with Down syndrome has varied over time with reductions in current cardiac problems, episodic illnesses, and health service use. Research is now needed to investigate the impact of these changes on the overall health and quality of life of children and families living with Down syndrome. [ABSTRACT FROM AUTHOR]

Abstract: Background: Rett syndrome is a neurodevelopmental disorder mostly affecting females and caused by mutations in the MECP2 gene. Originally the syndrome was characterised as having a normal prenatal and perinatal period with later regression. Previous work has speculated that the girl with Rett syndrome may not be normal at birth. Aims: to examine whether early development between birth and ten months varies by genotype in Rett syndrome. Methods: cases were sourced from two databases, the Australian Rett Syndrome Database (est. 1993) and the newly formed InterRett - IRSA Rett Phenotype Database. Data available on 320 cases included information provided by parents on perinatal problems, early developmental behaviour and mobility. Problem scores, mobility scores and a total composite score for each mutation were generated and compared. Results: overall, 58% of respondents noted unusual behaviour during the first six months and 70.6% from the period between 6 and 10 months of life. Statistically significant differences were detected between some of the common mutations. Infants with R294X (P=0.05) and R133C (P=0.03) were less likely than those with R255X to have problems in the perinatal period. The most severe profile overall for early development was associated with mutations R255X and R270X. Conclusion: This is the largest study to date examining the effects of individual mutations in Rett syndrome. With the ongoing case ascertainment and expansion of InterRett, sample size will increase rapidly and provide improved statistical power for future analyses. Results from this study will contribute to understanding the mechanism of early development in Rett syndrome and determining if and at which time(s) early intervention might be feasible. [Copyright &y& Elsevier]

Objectives: To investigate the prevalence, trends, and characteristics of maltreatment and assault related hospital admissions and deaths among children; and identify common injuries and conditions associated with these admissions using routinely collected morbidity and mortality data. Methods: A retrospective cohort study of all children aged 0-17 years in Western Australia from 1980 to 2005 was identified from linked de-identified population level data. Annual trends in prevalence of assault and maltreatment related admissions were calculated and child characteristics were investigated using logistic regression models. Results: Assault admissions more than doubled from 2.8 per 10,000 children in 1981 to 6.1 per 10,000 in 2005 (p <0.0001) and maltreatment admissions rose from 0.7 per 10,000 children in 1981 to 1.3 per 10,000 in 2005 (p <0.0001). Males aged greater than 12 years were at greater risk of an assault, while children aged less than 6 years were more likely to be at risk of maltreatment as well as those from greater disadvantaged backgrounds. Aboriginal children were more likely to be identified with assault and maltreatment compared to non-Aboriginal children. Common indicators of assault admissions included injuries of the skull and facial bones, intracranial, wrist, hand, and abdominal injuries. Children with maltreatment-related admissions were more likely to have superficial head or abdominal injuries and a high proportion had infectious and parasitic diseases, particularly intestinal infections. Many of these cases were associated with factors influencing health status, particularly socioeconomic and psychosocial circumstances. Conclusions: There has been a steady increase in the prevalence of assault and maltreatment related admissions. Specific child characteristics and injuries associated with child assault and maltreatment-related admissions have been identified using routinely collected morbidity data and may be utilized as potential indicators for identifying and monitoring child abuse and neglect. Practice implications: Broadening child maltreatment surveillance to children's admissions for assault and maltreatment is an important public health initiative which can be improved by the increased use of external cause codes. Health data is collected using international coding standards enhancing comparability across states and countries and has clinical implications in highlighting injuries associated with child abuse and neglect. [Copyright &y& Elsevier]

Objective: The behavioral phenotype of neurogenetic disorders associated with intellectual disability often includes psychiatric comorbidity. The objectives of this systematic review and meta-analysis were to systematically review the prevalence of psychiatric disorders and symptoms in children and adolescents with these disorders and compare phenotypic signatures between syndromes.Method: MEDLINE and PsycINFO databases were searched for articles from study inception to December 2018. Eligible articles were peer reviewed, were published in English, and reported prevalence data for psychiatric disorders and symptoms in children and adolescents aged 4 to 21 years using a formal psychiatric assessment or a standardized assessment of mental health symptoms. Pooled prevalence was determined using a random-effects meta-analysis in studies with sufficient data. Prevalence estimates were compared with general population data using a test of binomial proportions.Results: Of 2,301 studies identified for review, 39 articles were included in the final pool, which provided data on 4,039 children and adolescents. Ten syndromes were represented, and five were predominant: Down syndrome, 22q11.2 deletion syndrome, fragile X syndrome, Williams syndrome, and Prader-Willi syndrome. The Child Behavior Checklist was the most commonly used assessment tool for psychiatric symptoms. The pooled prevalence with total scores above the clinical threshold was lowest for Down syndrome (32% [95% confidence interval, 19%-44%]) and highest for Prader-Willi syndrome (74% [95% CI, 65%-82%]) with each syndrome associated with significantly higher prevalence than in the general population. Parallel trends were observed for the internalizing and externalizing domains and social subscale scores.Conclusion: Differential vulnerability for psychiatric phenotype expression across the disorders was observed. Syndromes with higher levels of social ability or competence appear to offer relative protection against developing psychopathology. This preliminary finding merits further exploration. [ABSTRACT FROM AUTHOR]

Alcohol exposure during pregnancy has been associated with altered brain development and facial dysmorphology. While Autism Spectrum Disorder (ASD) is not specifically related to distinct facial phenotypes, recent studies have suggested certain facial characteristics such as increased facial masculinity and asymmetry may be associated with ASD and its clinical presentations. In the present study, we conducted a preliminary investigation to examine facial morphology in autistic children with (n = 37; mean age = 8.21 years, SD = 2.72) and without (n = 100; mean age = 8.37 years, SD = 2.47) prenatal alcohol exposure. Using three-dimensional facial scans and principal component analysis, we identified a facial shape associated with prenatal alcohol exposure in autistic children. However, variations in the alcohol-related facial shape were generally not associated with behavioral and cognitive outcomes. These findings suggest that while early exposure to alcohol may influence the development of facial structures, it does not appear to be associated with ASD phenotypic variability. Importantly, although these findings do not implicate a role for prenatal alcohol exposure in the etiology of ASD, further research is warranted to investigate the link between prenatal alcohol exposure and facial morphology differences among neurodevelopmental conditions. [ABSTRACT FROM AUTHOR]

Objective: Familial recurrence risk is an important population-level measure of the combined genetic and shared familial liability of autism spectrum disorder (ASD). Objectives were to estimate ASD recurrence risk among siblings and cousins by varying degree of relatedness and by sex.Method: This is a population-based cohort study of livebirths from 1998 to 2007 in California, Denmark, Finland, Israel, Sweden and Western Australia followed through 2011 to 2015. Subjects were monitored for an ASD diagnosis in their older siblings or cousins (exposure) and for their ASD diagnosis (outcome). The relative recurrence risk was estimated for different sibling and cousin pairs, for each site separately and combined, and by sex.Results: During follow-up, 29,998 cases of ASD were observed among the 2,551,918 births used to estimate recurrence in ASD and 33,769 cases of childhood autism (CA) were observed among the 6,110,942 births used to estimate CA recurrence. Compared with the risk in unaffected families, there was an 8.4-fold increase in the risk of ASD following an older sibling with ASD and a 17.4-fold increase in the risk of CA following an older sibling with CA. A 2-fold increase in the risk for cousin recurrence was observed for the 2 disorders. There also was a significant difference in sibling ASD recurrence risk by sex.Conclusion: The present estimates of relative recurrence risks for ASD and CA will assist clinicians and families in understanding autism risk in the context of other families in their population. The observed variation by sex underlines the need to deepen the understanding of factors influencing ASD familial risk. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental encephalopathy caused by pathogenic variants in the gene CDKL5. This unique disorder includes early infantile onset refractory epilepsy, hypotonia, developmental intellectual and motor disabilities, and cortical visual impairment. We review the clinical presentations and genetic variations in CDD based on a systematic literature review and experience in the CDKL5 Centers of Excellence. We propose minimum diagnostic criteria. Pathogenic variants include deletions, truncations, splice variants, and missense variants. Pathogenic missense variants occur exclusively within the kinase domain or affect splice sites. The CDKL5 protein is widely expressed in the brain, predominantly in neurons, with roles in cell proliferation, neuronal migration, axonal outgrowth, dendritic morphogenesis, and synapse development. The molecular biology of CDD is revealing opportunities in precision therapy, with phase 2 and 3 clinical trials underway or planned to assess disease specific and disease modifying treatments. [ABSTRACT FROM AUTHOR]

Background: Pathologic mutations in cyclin-dependent kinase-like 5 cause CDKL5 deficiency disorder, a genetic syndrome associated with severe epilepsy and cognitive, motor, visual, and autonomic disturbances. This disorder is a relatively common genetic cause of early-life epilepsy. A specific severity assessment is lacking, required to monitor the clinical course and needed to define the natural history and for clinical trial readiness.Methods: A severity assessment was developed based on clinical and research experience from the International Foundation for CDKL5 Research Centers of Excellence consortium and the National Institutes of Health Rett and Rett-Related Disorders Natural History Study consortium. An initial draft severity assessment was presented and reviewed at the annual CDKL5 Forum meeting (Boston, 2017). Subsequently it was iterated through four cycles of a modified Delphi process by a group of clinicians, researchers, industry, patient advisory groups, and parents familiar with this disorder until consensus was achieved. The revised version of the severity assessment was presented for review, comment, and piloting to families at the International Foundation for CDKL5 Research-sponsored family meeting (Colorado, 2018). Final revisions were based on this additional input.Results: The final severity assessment comprised 51 items that comprehensively describe domains of epilepsy; motor; cognition, behavior, vision, and speech; and autonomic functions. Parental ratings of therapy effectiveness and child and family functioning are also included.Conclusions: A severity assessment was rapidly developed with input from multiple stakeholders. Refinement through ongoing validation is required for future clinical trials. The consensus methods employed for the development of severity assessment may be applicable to similar rare disorders. [ABSTRACT FROM AUTHOR]

Background: Reduced gestational age and low birthweight are associated with an increased risk of neonatal infections. However, the long-term risk of infection, especially in late preterm infants or those at near-normal birthweight, is unknown. We estimated whether rates of infection-related admissions to hospital for children in Western Australia were associated with age, gestational age, birthweight, and birth length.Methods: We did a population-based, data-linkage study using total-linked, registry data from the Western Australia Birth Register of all liveborn, non-Indigenous Australian singleton births recorded from Jan 1, 1980, to Dec 31, 2010. We followed up individuals from birth-related hospital discharge to age 18 years, death, or end of 2010, and linked to data about subsequent admissions to hospital or death registrations. Gestational age was assessed from both the last menstrual period and from estimates based on ultrasonography. We categorised birthweight by 500 g bands and birth length by 5 cm bands, and approximated the reference ranges for both to the 50th percentile. Because size at birth and gestational age are strongly associated, we calculated Z scores for gestational-specific and sex-specific birthweight, birth length, and ponderal index. Our primary outcomes were the number and type of infection-related admissions to hospital. We used multilevel negative binomial regression to generate rate ratios (RR) for such admissions, identified by codes from the International Classification of Diseases, versions 9 and 10-AM. We adjusted the RRs for maternal age at delivery, birth year, birth season, parity, sex, 5-min Apgar score, delivery method, socioeconomic status, and bronchopulmonary dysplasia.Findings: Of 719 311 liveborn singletons included in the analysis and followed up for 8 824 093 person-years, 365 867 infection-related admissions to hospital occurred for 213 683 (30%) children. Of the 719 311 children included in the analysis, 137 124 (19%) had one infection-related admission to hospital, 43 796 (6%) had two, 16 679 (2%) had three, and 16 084 (2%) had four or more. The 365 867 admissions to hospital included a diagnosis of infection of the upper respiratory tract for 174 653 (48%), the lower respiratory tract for 74 297 (20%), the gastrointestinal tract for 44 755 (12%), and a viral infection for 37 213 (10%). Infection-related rates of admissions to hospital increased by 12% for each week reduction in gestational age less than 39-40 weeks (RR 1·12, 95% CI 1·12-1·13), by 19% for each 500 g reduction in birthweight less than 3000-3500 g (1·19, 1·18-1·21), and by 41% for each 5 cm reduction in birth length less than 45-50 cm (1·41, 1·38-1·45). Gestational age-specific and sex-specific birthweight Z scores lower than the 25th to 50th percentile and birth length Z scores lower than the 10th to 25th percentile were associated with increased rates of infection-related admissions to hospital (eg, 1st-5th percentile RR 1·15, 95% CI 1·12-1·19, and 1·11, 1·07-1·14, respectively). Ponderal index Z scores lower than the 25th to 50th percentile were also associated with increased rates of infection-related admissions (eg, 1st-5th percentile RR 1·08, 95% CI 1·04-1·12). A gestational age of 41 weeks or later, a birthweight or birth length Z score above the 50th percentile, or a ponderal index Z score between the 75th and 95th percentile, were associated with modestly reduced rates of infection-related admissions to hospital.Interpretation: Children who were born with reduced gestational age, birthweight, and birth length have persistently increased rates of infection-related admissions to hospital until age 18 years. Pregnancy outcomes should be optimised to prevent infection occurring in this population, especially in resource-limited settings where suboptimum intrauterine growth and moderate prematurity are common.Funding: Australian National Health and Medical Research Council. [ABSTRACT FROM AUTHOR]

Mothers of a child with intellectual disability (ID) have more psychiatric disorders after the birth of their child than other mothers. However, it is unclear if this is because they have more psychiatric disorders before the birth or if the increase is related to the burden of caring for the child. We aimed to calculate the rate of new psychiatric disorders in mothers after the birth of their eldest child with ID born between 1983 and 2005 and to compare these with rates in women with a child with no ID or autism spectrum disorder (ASD) born during the same period. By linking data from Western Australian population-based registries, we selected women with no psychiatric history who survived the birth of their live-born child (N = 277,559) and compared rates of psychiatric disorders for women with a child with ID and women without a child with or ASD. Negative binomial regression with STATA 12 was used for all analyses. Mothers of children with mild-moderate ID of unknown cause had around two to three and a half times the rate of psychiatric disorders of mothers of children without ID or ASD. Mothers of children with Down syndrome and no pre-existing psychiatric disorder showed resilience and had no impairments in their mental health. Interventions and services are needed for mothers of other children with ID to improve their mental health. Further research is implicated to explore the mental health of mothers of children with ID and a pre-existing psychiatric disorder. [ABSTRACT FROM AUTHOR]

Abstract: Background: Rett syndrome is a severe genetic neurodevelopmental disorder mainly affecting females. The aim of this study was to describe pubertal development in a population-based cohort of females with Rett syndrome. Methods: To assess pubertal trajectory we used six waves of data provided by parents of girls and women, recruited through the Australian population-based Rett Syndrome Database. The age at which adrenarche, thelarche or menarche occurred was used as the parameter for time to event (survival) analysis. The relationships between BMI, mutation type and the trajectories were investigated, using Cox proportional hazards. Results: One quarter of girls reached adrenarche by 9.6years, half by 11years and three quarters by 12.6years. Half reached menarche by 14years (range 8–23). Being underweight was associated with later age at adrenarche, thelarche and menarche, while higher BMI (overweight) was associated with earlier onset. In general, girls with C-terminal deletions and early truncating mutations reached pubertal stages earlier and those with the p.R168X mutation reached them later. Conclusion: The pubertal course in Rett syndrome may be abnormal, sometimes with early adrenarche but delayed menarche. These features may be genotype dependent and may have varying relationships with growth and bone acquisition. [Copyright &y& Elsevier]

Children born to parents with intellectual disability (ID) have been shown as disproportionally represented in child protection services however with limited population-based research. To investigate child protection involvement for children born to mothers with ID in Western Australia using linked administrative data. A cohort of 1106 children born to a mother with ID and a comparison group of 9796 children of mothers without ID were identified in Western Australia. Cox regression analyses stratified by maternal Aboriginal status were conducted to investigate risk of child involvement with child protection services and care placement. Interaction with child age, intellectual disability status, and maternal mental health and substance use was investigated. Children born to a mother with ID were both at higher risk of having contact with child protection services (HR: 4.35 (3.70–5.12)) and placement in out-of-home care (HR: 6.21 (4.73–8.17)). For non-Aboriginal children, the risks of child protection involvement and placement for those born to mothers with ID were 7 times and 12 times higher than those of mothers without ID. The risk was lower for Aboriginal children, at 1.8 and 1.9 times, respectively. Infants born to mothers with ID were at higher risk of child protection involvement compared to other age groups. Maternal mental health and substance use moderated the increased risk. Intellectual disability alone is not sufficient justification for removal of children from their parents. The challenge for family services is ensuring that resources are adequate to meet the family's needs. • This is a population-based linked data study enabling a large representative sample. • Children of mothers with ID had 6 times higher risk of child protection involvement. • Maternal mental health and substance use contacts moderated the increased risk. [ABSTRACT FROM AUTHOR]

Abstract: Rett syndrome (RTT) is a severe neurological disorder, affecting mainly females. It is generally caused by mutations in the MECP2 gene. Sleep problems are thought to occur commonly in Rett syndrome, but there has been little research on prevalence or natural history. An Australian population-based registry of cases born since 1976 has been operating since 1993, with current ascertainment at 300. The Australian Rett Syndrome Database (ARSD) consists of information about Rett syndrome cases including their functional ability, behaviour, sleep patterns, medical conditions and genotype. The cases range in age from 2 to 29years. The aim of this study was to investigate the type and frequency of sleep problems, relationships with age and MECP2 mutation type and to evaluate changes over time. Parents or carers of the subjects with Rett syndrome were asked to complete a questionnaire about sleep problems on three separate occasions (2000, 2002 and 2004). Regression modelling was used to investigate the relationships between sleep problems, age and mutation type. Sleep problems were identified in over 80% of cases. The prevalence of night-time laughter decreased with age and the prevalence of reported night-time seizures and daytime napping increased with age. The prevalence of sleep problems was highest in cases with a large deletion of the MECP2 gene and in those with the p.R294X or p.R306C mutations. Sleep problems are common in Rett syndrome and there is some variation with age and mutation type. [Copyright &y& Elsevier]

: ObjectivesThe purpose of this study was to understand the clinical and molecular features of familial hypertrophic cardiomyopathy (HCM) in which a mitochondrial abnormality was strongly suspected.: BackgroundDefects of the mitochondrial genome are responsible for a heterogeneous group of clinical disorders, including cardiomyopathy. The majority of pathogenic mutations are heteroplasmic, with mutated and wild-type mitochondrial deoxyribonucleic acid (mtDNA) coexisting within the same cell. Homoplasmic mutations (present in every copy of the genome within the cell) present a difficult challenge in terms of diagnosis and assigning pathogenicity, as human mtDNA is highly polymorphic.: MethodsA detailed clinical, histochemical, biochemical, and molecular genetic analysis was performed on two families with HCM to investigate the underlying mitochondrial defect.: ResultsCardiac tissue from an affected child in the presenting family exhibited severe deficiencies of mitochondrial respiratory chain enzymes, whereas histochemical and biochemical studies of the skeletal muscle were normal. Mitochondrial DNA sequencing revealed an A4300G transition in the mitochondrial transfer ribonucleic acid (tRNA)Ile gene, which was shown to be homoplasmic by polymerase chain reaction/restriction fragment length polymorphism analysis in all samples from affected individuals and other maternal relatives. In a second family, previously reported as heteroplasmic for this base substitution, the mutation has subsequently been shown to be homoplasmic. The pathogenic role for this mutation was confirmed by high-resolution Northern blot analysis of heart tissue from both families, revealing very low steady-state levels of the mature mitochondrial tRNAIle.: ConclusionsThis report documents, for the first time, that a homoplasmic mitochondrial tRNA mutation may cause maternally inherited HCM. It highlights the significant contribution that homoplasmic mitochondrial tRNA substitutions may play in the development of cardiac disease. A restriction of the biochemical defect to the affected tissue has important implications for the screening of patients with cardiomyopathy for mitochondrial disease. [Copyright &y& Elsevier]

Background: Preterm birth is a known risk factor for infant development but it is less clear whether fetal growth restriction (FGR) and early term birth between 37 and 39 weeks gestation are associated with risks for infant development.Aims: This study investigated risk factors for adverse developmental outcomes at 12 months of age in a population-based birth cohort.Study Design: Cohort study.Subjects: Participants in the Raine Study, which recruited 2900 women at 18 weeks of gestation (Gen1) and followed up infants longitudinally (Gen2). At 12 months, 1773 mothers provided developmental data for their infants.Outcome Measure: The Ages and Stages Questionnaire (ASQ) was used to measure gross and fine motor, communication, adaptability and personal social development. Multivariate logistic regression analyses were used to estimate associations between FGR, gestational age, sex, breast feeding, parental age, socioeconomic factors and developmental delay at 12 months of age as measured with the ASQ.Results: The risk of any delay at 12 months of age, as well as gross motor, fine motor and adaptive delay, was slightly increased for infants born FGR. Preterm and early term birth and male sex were associated with poorer development at 12 months. Breast feeding was protective of developmental status.Conclusions: Developmental assessment using the ASQ of infants with FGR was mostly comparable to those born without FGR at 12 months, although finer-grained neurobehavioural assessments may yield capacity for earlier identification of developmental risk. Our data provide weight to the argument that surveillance of early term infants could enable earlier intervention for children at risk. [ABSTRACT FROM AUTHOR]