Jennepher Downs

The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy

The clinical understanding of the CDKL5 disorder remains limited, with most information being derived from small patient groups seen at individual centres. This study uses a large international data collection to describe the clinical profile of the CDKL5 disorder and compare with Rett syndrome (RTT). Information on individuals with cyclin-dependent kinase-like 5 (CDKL5) mutations (n=86) and females with MECP2 mutations (n=920) was sourced from the InterRett database. Available photographs of CDKL5 patients were examined for dysmorphic features. The proportion of CDKL5 patients meeting the recent Neul criteria for atypical RTT was determined. Logistic regression and time-to-event analyses were used to compare the occurrence of Rett-like features in those with MECP2 and CDKL5 mutations. Most individuals with CDKL5 mutations had severe developmental delay from birth, seizure onset before the age of 3 months and similar non-dysmorphic features. Less than one-quarter met the criteria for early-onset seizure variant RTT. Seizures and sleep disturbances were more common than in those with MECP2 mutations whereas features of regression and spinal curvature were less common. The CDKL5 disorder presents with a distinct clinical profile and a subtle facial, limb and hand phenotype that may assist in differentiation from other early-onset encephalopathies. Although mutations in the CDKL5 gene have been described in association with the early-onset variant of RTT, in our study the majority did not meet these criteria. Therefore, the CDKL5 disorder should be considered separate to RTT, rather than another variant.

Early Determinants of Fractures in Rett Syndrome

OBJECTIVES. The goals were to compare the fracture incidence in Rett syndrome with that in the general population and to investigate the impact of genotype, epilepsy, and early motor skills on subsequent fracture incidence in girls and young women with Rett syndrome. METHODS. The Australian Rett syndrome study, a population-based study operating since 1993, investigated Australian subjects with Rett syndrome born since 1976. The 234 (81.2%) of 288 verified cases in the Australian Rett syndrome database in 2004 whose families had completed follow-up questionnaires and provided information about fracture history were included in the analyses. The main outcomes were fracture incidence in the Rett syndrome population and fracture risk according to genotype, presence of epilepsy, and early motor profile. RESULTS. Fracture incidence in this cohort was 43.3 episodes per 1000 person-years, nearly 4 times greater than the population rate. Risk was increased specifically in cases with p.R270X mutations and in cases with p.R168X mutations. Having epilepsy also increased fracture risk, even after adjustment for genotype. CONCLUSIONS. Girls and young women with Rett syndrome are at increased risk of fracture. Those with mutations found previously to be more severe and those with epilepsy have an increased propensity toward fractures. Improved understanding of the risk factors for fracture could contribute to better targeting of interventions to decrease fracture incidence in this vulnerable population.

Gross Motor Profile in Rett Syndrome as Determined by Video Analysis

Movement impairment is a fundamental but variable component of the Rett syndrome phenotype. This study used video supplemented by parent report data to describe the gross motor profile in females with Rett syndrome (n=99) and to investigate the impact of age, genotype, scoliosis and hand stereotypies. Factor analysis enabled the calculation of general and complex gross motor skills scores. Most subjects were able to sit, slightly less than half were able to walk and a minority were able to transfer without assistance. General gross motor skills declined with age and were poorer in those who had surgically treated scoliosis but not conservatively managed scoliosis. Complex gross motor skills did not decline with age and were better in those without scoliosis. Those with a p.R133C, p.R294X, or a p.R255X mutation appear to have better motor skills overall than those with a p.R270X or large deletion mutation. Motor scores were not related to the frequency of hand stereotypies. This information is useful for the clinician and family when planning support strategies and interventions.

Twenty years of surveillance in Rett syndrome: what does this tell us?

BackgroundThe clinical characteristics of children diagnosed with Rett syndrome are well described. Survival and how these characteristics persist or change in adulthood are less well documented. This study aimed to describe overall survival and adult health in those with Rett syndrome.MethodsUsing the Kaplan-Meier method, we estimated survival of individuals registered with the Australian Rett syndrome Database (ARSD) who had been followed for up to 20 years (n = 396). We then conducted logistic and linear regression analyses investigating epilepsy, musculoskeletal, gastrointestinal, autonomic dysfunction and behaviour of individuals aged 18 years and over using cross sectional cohorts from the ARSD (n = 150) and the international database InterRett (n = 273).ResultsThe likelihood of survival was 77.6% at 20 years, 71.5% at 25 years and 59.8% at 37 years. The median age of the combined cross-sectional cohort was 25 years (range 18 to 54 years), the majority (71%) were living in their parental home and the remainder being cared for in group homes or other institutions. Just over half walked either independently (18%) or with assistance (43%). The majority (86%) had scoliosis with 40% of those having undergone corrective surgery. Almost two-thirds (64%) of the women were taking anti-epileptic medications at the time of data collection. Constipation was highly prevalent (83%) and many experienced bloating (53%). Biliary dyskinesia, inflammation or infection of the gallbladder was reported for 20 women (5%) and of those 13 had undergone gallbladder surgery. Sleep disturbance was relatively common (63%), and adverse mood events and anxiety were slightly more prevalent in those aged 26-30 years in comparison to the younger and older age groups. Other frequently reported medical conditions included urinary tract infections, pneumonia and other respiratory conditions.ConclusionsSurvival in Rett syndrome has now been estimated with the most accurate follow up to date. During adulthood, continuation of multidisciplinary services and programs is necessary to optimise health and wellbeing.

Valproate and risk of fracture in Rett syndrome

Objectives Some associations between antiepileptic drugs (AEDs) and fracture risk have been reported in the general population. This study investigated the relationships between fracture risk and commonly used AEDs in Rett syndrome, a genetic disorder associated with intellectual and physical disability. Study design Cases (n=233) were sourced from the population-based Australian Rett Syndrome Database and longitudinal data were used. The Cox proportional hazard model was used to analyse relationships between fracture and prescribed AEDs, mobility, epilepsy diagnosis and genotype. Results After controlling for mobility, epilepsy diagnosis and genotype, use of valproate increased the risk of fracture threefold after at least 1 year (HR 3.56; 95% CI 1.85 to 6.82) and after 2 or more years (HR 3.02; 95% CI 1.90 to 4.80). There was a lesser increased risk (HR 1.99; 95% CI 0.99 to 4.02) with lamotrigine in the first year of use but not for subsequent years of use. Carbamazepine slightly decreased the risk (HR 0.60; 95% CI 0.35 to 1.02) after 2 or more years of use. Conclusions The effect of valproate on bone health should be considered when managing epilepsy in Rett syndrome. Multiple mechanisms could be contributing to this effect.

Gastrointestinal dysmotility in Rett syndrome.

Objectives: Through evidence review and the consensus of an expert panel, we developed recommendations for the clinical management of gastroesophageal reflux disease, constipation, and abdominal bloating in Rett syndrome. Methods: Based on review of the literature and family concerns expressed on RettNet, initial draft recommendations were created. Wherein the literature was lacking, 25 open-ended questions were included. Input from an international, multidisciplinary panel of clinicians was sought using a 2-stage modified Delphi process to reach consensus agreement. Items related to the clinical assessment and management of gastroesophageal reflux disease, constipation, and abdominal bloating. Results: Consensus was achieved on 78 of 85 statements. A comprehensive approach to the assessment of gastroesophageal reflux and reflux disease, constipation, and abdominal bloating was recommended, taking into account impairment of communication skills in Rett syndrome. A stepwise approach to the management was identified with initial use of conservative strategies, escalating to pharmacological measures and surgery, if necessary. Conclusions: Gastrointestinal dysmotility occurs commonly in Rett syndrome. These evidence- and consensus-based recommendations have the potential to improve care of dysmotility issues in a rare condition and stimulate research to improve the present limited evidence base.

The Natural History of Scoliosis in Females with Rett Syndrome

Study Design. Population-based longitudinal observational study. Objective. To describe the prevalence of scoliosis in Rett syndrome, structural characteristics and progression, taking into account the influences of age, genotype, and ambulatory status. Summary of Background Data. Scoliosis is the most common orthopedic comorbidity in Rett syndrome yet very little is known about its natural history and influencing factors such as age, genotype, and ambulatory status. Methods. The infrastructure of the Australian Rett Syndrome Database was used to identify all cases with confirmed Rett syndrome in Australia and collect data on genotype and walking status. We identified radiological records and described the Cobb angle of each curve. Time to event analysis was used to estimate the median age of onset of scoliosis and the log-rank test to compare by mutation type. Latent class group analysis was used to identify groups for the trajectory of walking status over time and a multilevel linear model used to assess trajectories of scoliosis development by mutation type and walking status. We used a logistic regression model to estimate the probability of developing a scoliosis with a Cobb angle >60° at 16 years in relation to Cobb angle and walking status at 10 years of age. Results. The median age of scoliosis onset was 11 years with earliest onset in those with a p.Arg255* mutation or large deletion. Scoliosis was progressive for all mutation types except for those with the p.Arg306Cys mutation. Scoliosis progression was reduced when there was capacity to walk independently or with assistance. Cobb angle and walking ability at age 10 can be reliably used to identify those who will develop a very severe scoliosis by age 16. Conclusion. These data on prognosis of scoliosis inform clinical decision making about the likelihood of progression to very severe scoliosis and the need for surgical management. Level of Evidence: 4

Impact of scoliosis surgery on activities of daily living in females with Rett syndrome.

Background: Scoliosis is a common orthopaedic complication of Rett syndrome, and surgery is commonly used to reduce asymmetry in cases with severe scoliosis. Methods: Data from questionnaires administered to caregivers biennially from 2000 to 2006 were used to describe functional skill levels in subjects with Rett syndrome, and within-subject change in 16 subjects with scoliosis surgery were compared with within-subject change in 186 pairs of data from 86 subjects with conservatively managed scoliosis. Postsurgical assessment was conducted after a mean of 17.8 months. Results: Surgery was associated with improved activities of daily living as measured by the WeeFIM for subjects who were wheelchair bound (P = 0.05). Mobility levels, social interaction, communication skills, and the frequency of daytime napping remained similar for the group as a whole. Conclusions: Improvements in activities of daily living are likely to represent an increase in the quality of life for subjects and caregivers and were mainly found in subjects who were wheelchair bound, indicating that those who were more severely affected were able to benefit from this intervention. Level of Evidence: Therapeutic study: level III

The diagnostic odyssey to Rett syndrome: The experience of an Australian family†

The diagnosis of a rare disorder is dependent on the clinician’sparticular knowledge and experience, and can be challengingwhen the presentation of the disorder is variable [Zurynski et al.,2008; Fehr et al., 2010]. Under- or misdiagnosis commonlyoccurs and there can be long time lags between the family’s firstconcerns and the formal diagnosis [Fehr et al., 2011]. When adiagnosis is received, families have a clearer understanding oftheir child’s condition and can then participate in a greaterlevelofplanningforcurrentandfutureneeds.Intheaccompanyingpaper, the diagnostic journeys of families in China who have adaughter with Rett syndrome were found to be complexand challenging [Lim et al., 2012]. Such scenarios can occurelsewhere in the world. This paper illustrates the experiences ofone of us (MK) in the search for a diagnosis for her daughter inAustralia.‘‘Nearly 10 years ago, my life took an extraordinary turn whenIbecameamotherforthefirsttimeattheageof31years.Iwas,andI guess I still am, the type of person who needs everything to beperfectand running accordingto plan.Ihad allthe testsexpectantmums usually haveand Iadmitthat Iused to bethe person sayingthatifIwereevertohaveachildwithsomesortofbirthdefectthatI didn’t think I’d be able to cope. At the time, my own fatherwas deteriorating and succumbing to the symptoms of a rareneurological disorder called Progressive Supra Nuclear Palsy(PSP or Steele Richardson syndrome), which eventually claimedhis life within 4 years of diagnosis.My daughter was almost 2 years of age when my fatherpassed away, and at that time I knew there was somethingnot quite right with her development, so my search for answersbegan. My daughter had been diagnosed with having GlobalDevelopmental Delay. After having seen what my mother hadendured nursing my father through illness, the thought ofraising a child with a disability or illness was, quite literally,gut wrenching. However, my father always taught me that‘‘knowledgeispower’’’andasIhadnoideawithwhatIwasdealingat the time, how, without knowing what was happening to her,could I offer my child what she needed? Global DevelopmentalDelay was simply not an answer I could accept and I figured thatif I was never going to find out what was wrong, it wouldn’t befor lack of trying.My daughter was eventually diagnosed with the neurologicaldisorder Rettsyndromeamonth afterher 3rdbirthday.Forover ayearpriortodiagnosis,shehadbeentestedforarangeofgeneticandmetabolicdisordersthatIjustknewshedidn’thave.Unfortunately,at the time, specialists we consulted were not up to date with thevariancesofclinicalsymptomsingirlssufferingwithRettsyndromeand they were persistent in looking to other disorders for answers.I would like to tell you our story.Mydaughterhadinitiallybeenaveryplacidbabyandsheseemedto progress well in that she began speaking and clapping hands ondemandfromwhenshewasjust3monthsold,however,bythetimeshe was 6 months we had noticed she was physically delayed. Shedidn’t sit up competently on her own until she was 12 months.She never crawled conventionally, instead she bottom shuffled tomove around. She didn’t bear weight until she was 13 months andthen there was the constant hand mouthing that has been presentthroughout her life.We’d had several appointments with pediatricians and healthnurses who kept assuring us how it’s most common for largerbabies to be physically delayed. Then, one day she wouldn’t talkor repeat words as she had done every other day. At first Ithought

Longitudinal hand function in Rett syndrome

Loss of hand function is a core feature of Rett syndrome. This article describes longitudinal hand function at 3 time points for 72 subjects participating in the Australian Rett Syndrome Database. Approximately 40% of subjects with some grasping abilities lost skill over the 3- to 4-year period between video assessments. In these subjects, a decrease in hand function was seen less frequently in girls 13 to 19 years old than in those younger than 8 years, in subjects with some mobility compared with those who were wheelchair bound, and in those who had previously been able to finger feed. Relationships with the magnitude of change reflected these findings. Change in hand function did not vary with clinical severity. The results for all subjects were similar to results obtained when analysis was restricted to those with a pathogenic mutation. Variability in the longitudinal course of hand function in Rett syndrome was observed.