Lyn Colvin

Describing the phenotype in Rett syndrome using a population database

Background: Mutations in the MECP2 gene have been recently identified as the cause of Rett syndrome, prompting research into genotype-phenotype relations. However, despite these genetic advances there has been little descriptive epidemiology of the full range of phenotypes. Aims: To describe the variation in phenotype in Rett syndrome using four different scales, by means of a population database. Methods: Using multiple sources of ascertainment including the Australian Paediatric Surveillance Unit, the development of an Australian cohort of Rett syndrome cases born since 1976 has provided the first genetically characterised population based study of Rett syndrome. Follow up questionnaires were administered in 2000 to families and used to provide responses for items in four different severity scales. Results: A total of 199 verified cases of Rett syndrome were reported between January 1993 and July 2000; 152 families provided information for the follow up study. The mean score using the Kerr scale was 22.9 (SD 4.8) and ranged from 20.5 in those under 7 years to 24.2 in those over 17 years. The mean Percy score was 24.9 (SD 6.6) and also increased with age group from 23.0 to 26.9. The mean Pineda score was 16.3 (SD 4.5) and did not differ by age group. The mean WeeFIM was 29.0 (SD 11.9), indicating extreme dependence, and ranged from 18 to 75. Conclusion: We have expanded on the descriptive epidemiology of Rett syndrome and shown different patterns according to the severity scale selected. Although all affected children are severely functionally dependent, it is still possible to identify some variation in ability, even in children with identified MECP2 mutations.

Twins born following assisted reproductive technology: perinatal outcome and admission to hospital

BACKGROUND Compared with spontaneously conceived (SC) singletons, adverse perinatal outcome, neonatal intensive care unit (NICU) admission and hospital admission in infancy are more common in those born following Assisted Reproductive Technology (ART). Similar comparisons for twins have shown conflicting results. METHODS We investigated perinatal outcome and hospital admission during the first 3 years of life for all twin children born in Western Australia between 1994 and 2000 [700 ART, 4097 SC]. RESULTS ART twins had a greater risk of adverse perinatal outcome including preterm birth, low birthweight and death compared with SC twins of unlike-sex. In their first year of life, ART twins had a longer birth admission; were 60% more likely to be admitted to a NICU; and had a higher risk of hospital admission. The increased risk of hospital admission continued in the second and third year but was not statistically significant in the third year. CONCLUSIONS Couples undertaking ART should be aware that in addition to the known increased perinatal risks associated with a twin birth, ART twins are more likely than SC twins to be admitted to a NICU and hospitalized in the first 3 years of life.

Environmental risk factors by gender associated with attention-deficit/hyperactivity disorder.

BACKGROUND: Early environmental risk factors associated with attention-deficit/hyperactivity disorder (ADHD) have been increasingly suggested. Our study investigates the maternal, pregnancy, and newborn risk factors by gender for children prescribed stimulant medication for treatment of ADHD in Western Australia. METHODS: This is a population-based, record linkage case–control study. The records of all non-Aboriginal children and adolescents born in Western Australia and aged <25 years who were diagnosed with ADHD and prescribed stimulant medication (cases = 12 991) were linked to the Midwives Notification System (MNS) to obtain maternal, pregnancy, and birth information. The control population of 30 071 children was randomly selected from the MNS. RESULTS: Mothers of children with ADHD were significantly more likely to be younger, be single, have smoked in pregnancy, have labor induced, and experience threatened preterm labor, preeclampsia, urinary tract infection in pregnancy, or early term delivery irrespective of the gender of the child, compared with the control group. In the fully adjusted model, a novel finding was of a possible protective effect of oxytocin augmentation in girls. Low birth weight, postterm pregnancy, small for gestational age infant, fetal distress, and low Apgar scores were not identified as risk factors. CONCLUSIONS: Smoking in pregnancy, maternal urinary tract infection, being induced, and experiencing threatened preterm labor increase the risk of ADHD, with little gender difference, although oxytocin augmentation of labor appears protective for girls. Early term deliveries marginally increased the risk of ADHD. Studies designed to disentangle possible mechanisms, confounders, or moderators of these risk factors are warranted.

Refining the phenotype of common mutations in Rett syndrome

Rett syndrome (RTT; MIM No 312750) is a neurodevelopmental disorder mainly affecting girls, with an incidence of 1:10 000 female births.1 The clinical features of the syndrome were first described in a series of publications2–5 during the decade after it was first reported in English language journals.6 At that time, in the absence of a biological marker, criteria to assist with the diagnosis were developed by an international working group.7 These criteria relate to the typical characteristics which are: normal prenatal and perinatal period and apparently normal development for the first six months of life; deceleration in head growth; loss of hand and communication skills between six and 30 months; apparent severe psychomotor retardation; acquisition of stereotypical hand movements; and evidence of gait or truncal apraxia between one and four years. These necessary criteria were supplemented by a set of supportive but not mandatory criteria, which help to delineate the phenotype further. These include breathing dysfunction, EEG abnormalities, seizures, spasticity, peripheral vasomotor disturbance, scoliosis, growth retardation, and hypotrophic small feet. In 1999 the association between Rett syndrome and mutations in the methyl-CpG binding protein 2 (MECP2; MIM No 300005) located on Xq28 was first identified.8 In the last decade there had already been much commentary about the expanding clinical spectrum of Rett syndrome and the occurrence of atypical forms.9 This culminated in 2001 in a meeting to revise the existing diagnostic criteria.10 It is now clear that, although this condition must be considered a severe neurodevelopmental disorder, there is still considerable variation in both functioning and associated morbidity, even in those cases with confirmed MECP2 mutations. We have been able to demonstrate this variability11 using a tool to measure functional ability12 and three clinical scales. The first was developed by …

Correlation between clinical severity in patients with Rett syndrome with a p.R168X or p.T158M MECP2 mutation, and the direction and degree of skewing of X-chromosome inactivation

Introduction: Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder that is usually associated with mutations in the MECP2 gene. The most common mutations in the gene are p.R168X and p.T158M. The influence of X-chromosome inactivation (XCI) on clinical severity in patients with RTT with these mutations was investigated, taking into account the extent and direction of skewing. Methods: Female patients and their parents were recruited from the UK and Australia. Clinical severity was measured by the Pineda Severity and Kerr profile scores. The degree of XCI and its direction relative to the X chromosome parent of origin were measured in DNA prepared from peripheral blood leucocytes, and allele-specific polymerase chain reaction was used to determine the parental origin of mutation. Combining these, the percentage of cells expected to express the mutant allele was calculated. Results: Linear regression analysis was undertaken for fully informative cases with p.R168X (n = 23) and p.T158M (n = 20) mutations. A statistically significant increase in clinical severity with increase in the proportion of active mutated allele was shown for both the p.R168X and p.T158M mutations. Conclusions: XCI may vary in neurological and haematological tissues. However, these data are the first to show a relationship between the degree and direction of XCI in leucocytes and clinical severity in RTT, although the clinical utility of this in giving a prognosis for individual patients is unclear.

Dispensing patterns and pregnancy outcomes for women dispensed selective serotonin reuptake inhibitors in pregnancy

BACKGROUND The safety of selective serotonin reuptake inhibitors (SSRIs) during pregnancy remains uncertain. The purpose of this study was to investigate dispensing patterns and pregnancy outcomes for women dispensed an SSRI in pregnancy. METHODS Using data linkage of population-based health datasets from Western Australia and a national pharmaceutical claims dataset, our study included 123,405 pregnancies from 2002 to 2005. There were 3764 children born to 3703 women who were dispensed an SSRI during their pregnancy. RESULTS A total of 42.3% of the women were dispensed an SSRI in each trimester, and 97.6% of the women used the same SSRI throughout the first trimester without switching. The women who were dispensed an SSRI were more likely to give birth prematurely (adjusted odds ratio [aOR], 1.4; 95% confidence interval [CI], 1.2-1.7), to have smoked during the pregnancy (OR, 1.9; 95% CI, 1.8-2.1), and parity>1 (OR, 1.7; 95% CI, 1.5-1.8). The singletons were found to have a lower birth weight than expected when other factors were taken into account (OR, 1.2; 95% CI, 1.1-1.3). There was an increased risk of major cardiovascular defects (OR, 1.6; 95% CI, 1.1-2.3). The children of women dispensed citalopram during the first trimester had an increased risk of vesicoureteric reflux (OR, 3.1; 95% CI, 1.3-7.6). Children born to women dispensed sertraline had a higher mean birth weight than those born to women dispensed citalopram, paroxetine, or fluoxetine. This pattern was also seen in birth length. CONCLUSIONS Most women were dispensed the same SSRI throughout their pregnancy. We have confirmed previous findings with an increased risk of cardiovascular defects and preterm birth. New findings requiring confirmation include an increased risk of vesicoureteric reflux with the use of citalopram.

Patients with the R133C mutation: is their phenotype different from patients with Rett syndrome with other mutations?

Rett syndrome is an X linked dominant neurodevelopmental disorder with an incidence of 1:10 000 females in Australia.1 It is characterised by apparently normal development between 6 and 18 months, followed by a period of regression with loss of purposeful hand use, deceleration of head growth, and onset of repetitive, stereotypic hand movements.2 Affected people also manifest gait ataxia and apraxia, autistic features, epileptic seizures, respiratory dysfunction, autonomic dysfunction, and decreased somatic growth.2,3 In recent years it has become apparent that the phenotypic range of this disorder is much wider than previously thought. Some patients may have a milder phenotype and retain the ability to walk or speak and others have an earlier onset and more severe features. People who have some but not all of the necessary criteria have been categorised as atypical4 or as one of six variant forms.5 Rett syndrome has now been shown to be associated with mutations in the methyl-CpG-binding protein 2 (MeCP2).6 For many genetic disorders, the next stage in research after the identification of the gene involves describing the relation between genotype and phenotype, and the phenotypic diversity produced by different mutations in the same gene. Some research has found that people with missense MECP2 mutations may have a milder phenotype than those with truncating mutations.7,8 Weaving et al 9 found that age at onset of hand stereotypies was later and speech and height (but not head growth) were slightly more normal in those with missense mutations whereas Nielsen et al 10 found no difference in severity between these mutation types. In the study of Amir et al 11 breathing abnormalities were found to be more common with truncating mutations and scoliosis more common with missense mutations. Hoffbuhr et al 12 concluded that patients …

Pharmacovigilance in pregnancy using population-based linked datasets

National dispensing data for subsidised prescription medicines have recently been approved for linkage to the population‐based health datasets in Western Australia (WA), creating the capacity to study how these medicines are used and their impact on pregnancy outcomes.

Hospitalisations from birth to 5 years in a population cohort of Western Australian children with intellectual disability

Aims: To describe the hospitalisation history in the first five years of life for all children born in Western Australia (WA) between 1983 and 1992 and diagnosed with intellectual disability (ID). Methods: Unit record linkage of the WA Midwives Collection, WA Intellectual Disability Database, and the WA Hospital Morbidity Dataset provided the population database of WA born children with and without ID. Affected children were divided into those co-affected with autism spectrum disorders (ASD), and those whose ID had or had no known biomedical cause. Those without a biomedical cause were further subdivided into mild–moderate and severe categories. Results: On average, ID affected children were more likely than non-affected children to be admitted to hospital (RR: 1.64; 95% CI 1.6 to 1.7), on more occasions (5.3 versus 2.2 admissions), for longer (29.6 versus 8.3 days), and for a larger range of clinical diagnoses. The only exception was the group of children co-diagnosed with ASD whose hospitalisation profile resembled more that of non-affected children. Conclusions: This total population study is unique because of the availability of the system of linkable population registers and administrative health databases in WA. The results indicated that this vulnerable population of children with ID has substantial medical needs. This paper points to the need for authorities to develop supportive programmes for this population especially in the current climate of de-medicalisation of ID. More research is not only needed on the welfare of the affected children but also on the impact of the substantial medical and other needs of affected children on the rest of their immediate and extended families.

Linking a pharmaceutical claims database with a birth defects registry to investigate birth defect rates of suspected teratogens

Data linkage of population administrative data is being investigated as a tool for pharmacovigilance in pregnancy in Australia. Records of prescriptions of known or suspected teratogens dispensed to pregnant women have been linked to a birth defects registry to determine if defects associated with medicine exposure can be detected.