Helen Leonard

Rett Syndrome: Revised Diagnostic Criteria and Nomenclature

Rett syndrome (RTT) is a severe neurodevelopmental disease that affects approximately 1 in 10,000 live female births and is often caused by mutations in Methyl‐CpG‐binding protein 2 (MECP2). Despite distinct clinical features, the accumulation of clinical and molecular information in recent years has generated considerable confusion regarding the diagnosis of RTT. The purpose of this work was to revise and clarify 2002 consensus criteria for the diagnosis of RTT in anticipation of treatment trials.

Mutations of CDKL5 Cause a Severe Neurodevelopmental Disorder with Infantile Spasms and Mental Retardation

Rett syndrome (RTT) is a severe neurodevelopmental disorder caused, in most classic cases, by mutations in the X-linked methyl-CpG-binding protein 2 gene (MECP2). A large degree of phenotypic variation has been observed in patients with RTT, both those with and without MECP2 mutations. We describe a family consisting of a proband with a phenotype that showed considerable overlap with that of RTT, her identical twin sister with autistic disorder and mild-to-moderate intellectual disability, and a brother with profound intellectual disability and seizures. No pathogenic MECP2 mutations were found in this family, and the Xq28 region that contains the MECP2 gene was not shared by the affected siblings. Three other candidate regions were identified by microsatellite mapping, including 10.3 Mb at Xp22.31-pter between Xpter and DXS1135, 19.7 Mb at Xp22.12-p22.11 between DXS1135 and DXS1214, and 16.4 Mb at Xq21.33 between DXS1196 and DXS1191. The ARX and CDKL5 genes, both of which are located within the Xp22 region, were sequenced in the affected family members, and a deletion of nucleotide 183 of the coding sequence (c.183delT) was identified in CDKL5 in the affected family members. In a screen of 44 RTT cases, a single splice-site mutation, IVS13-1G-->A, was identified in a girl with a severe phenotype overlapping RTT. In the mouse brain, Cdkl5 expression overlaps--but is not identical to--that of Mecp2, and its expression is unaffected by the loss of Mecp2. These findings confirm CDKL5 as another locus associated with epilepsy and X-linked mental retardation. These results also suggest that mutations in CDKL5 can lead to a clinical phenotype that overlaps RTT. However, it remains to be determined whether CDKL5 mutations are more prevalent in specific clinical subgroups of RTT or in other clinical presentations.

Intellectual disability co-occurring with schizophrenia and other psychiatric illness: population-based study

BACKGROUND The epidemiology of intellectual disability co-occurring with schizophrenia and other psychiatric illness is poorly understood. The separation of mental health from intellectual disability services has led to a serious underestimation of the prevalence of dual diagnosis, with clinicians ill-equipped to treat affected individuals. AIMS To estimate the prevalence of dual diagnosis and describe its clinical profile. METHOD The Western Australian population-based psychiatric and intellectual disability registers were cross-linked (total n=245,749). RESULTS Overall, 31.7% of people with an intellectual disability had a psychiatric disorder; 1.8% of people with a psychiatric illness had an intellectual disability. Schizophrenia, but not bipolar disorder and unipolar depression, was greatly over-represented among individuals with a dual diagnosis: depending on birth cohort, 3.7-5.2% of those with intellectual disability had co-occurring schizophrenia. Pervasive developmental disorder was identified through the Intellectual Disability Register and is therefore limited to individuals with intellectual impairment. None the less, pervasive developmental disorder was more common among people with a dual diagnosis than among individuals with intellectual disability alone. Down syndrome was much less prevalent among individuals with a dual diagnosis despite being the most predominant cause of intellectual disability. Individuals with a dual diagnosis had higher mortality rates and were more disabled than those with psychiatric illness alone. CONCLUSIONS The facility to combine records across administrative jurisdictions has enhanced our understanding of the epidemiology of dual diagnosis, its clinical manifestations and aetiological implications. In particular, our results are suggestive of a common pathogenesis in intellectual disability co-occurring with schizophrenia.

Investigating genotype–phenotype relationships in Rett syndrome using an international data set

Background: Rett syndrome is an uncommon neurodevelopmental disorder with an incidence of 1:9,000 live female births. The principal genetic cause was first reported in 1999 when the association with mutations in the methyl-CpG-binding protein 2 (or MECP2) gene was identified. This study uses data from a large international database, InterRett, to examine genotype–phenotype relationships and compares these with previous findings in a population-based cohort. Method: The data set for these analyses was derived from a subset of InterRett cases with subject information collected from the family, the clinician, or both. Individual phenotypic characteristics and clinical severity using three scales were compared among those with eight known recurrent pathogenic MECP2 mutations as well as those with C-terminal deletions (n = 272). Results: Overall, p.R270X and p.R255X were the most severe and p.R133C and p.R294X were the mildest mutations. Significant differences by mutation were seen for individual phenotypic characteristics such as hand use, ambulation, and language. Conclusions: This multicenter investigation into the phenotypic correlates of MECP2 mutations in Rett syndrome has provided a greater depth of understanding than hitherto available about the specific phenotypic characteristics associated with commonly occurring mutations. Although the modifying influence of X inactivation on clinical severity could not be included in the analysis, the findings confirm clear genotype–phenotype relationships in Rett syndrome and show the benefits of collaboration crucial to effective research in rare disorders. GLOSSARY: ANOVA = analysis of variance; ARSD = Australian Rett Syndrome Database; IQR = interquartile range.

Guidelines for reporting clinical features in cases with MECP2 mutations

An international group recommends that papers relating phenotypes to genotypes involving mutations in the X chromosome gene MECP2 should provide a minimum data set reporting the range of disturbances frequently encountered in Rett Syndrome. A simple scoring system is suggested which will facilitate comparison among the various clinical profiles. Features are described which should prompt screening for MECP2 mutations.

Autism spectrum disorders in young children: effect of changes in diagnostic practices.

BACKGROUND It is unclear whether the increase in autism over the past two decades is a real increase or due to changes in diagnosis and ascertainment of autism spectrum disorders (ASDs), which include autism, Asperger syndrome and pervasive developmental disorder not otherwise specified (PDD-NOS). The aim of this study was to examine the trends in ASD over time in Western Australia (WA) and the possible effects and contribution of changes in diagnostic criteria, age at diagnosis, eligibility for service provision based on ASD diagnoses and changes in diagnostic practices. METHODS A population-based study was conducted among the cohort of children born in WA between 1983 and 1999 and diagnosed with ASD between the age of 2 and 8 years up to December 31, 2004. The trend in ASD diagnosis over the study period was assessed by investigating birth cohort and period effects, and examining whether these were modified by age of diagnosis. ASD diagnosis corresponding with changes in diagnostic criteria, funding and service provision over time were also investigated. A subgroup analysis of children aged <or=5 years was also conducted to examine trends in the incidence and age of diagnosis of ASD and intellectual disability (ID) and to investigate the role of changes in diagnostic practices. RESULTS The overall prevalence of ASD among children born between 1983 and 1999 and diagnosed by age 8 was 30 per 10,000 births with the prevalence of autism comprising 21 per 10,000 births. The prevalence of ASD increased by 11.9% per annum, from 8 cases per 10,000 births in 1983 to 46 cases per 10,000 births in 1999. The annual incidence of ASD, based on newly diagnosed ASD cases in each year from 1985 to 2002, increased over the study period. The increase in incidence of ASD appeared to coincide with changes in diagnostic criteria and availability of funding and services in WA, particularly for children aged <5 years. The age-specific rates of autism and PDD-NOS increased over time and the median age of diagnosis for autism decreased from 4 to 3 years of age throughout the 1990s. For children aged <or=5 years the incidence of ASD diagnosis increased significantly from 1992, with an average annual increase of 22%. Similar findings were found for autism. In the corresponding years the incidence of diagnosis of severe ID fell by 10% per annum and mild-moderate ID increased by 3% per annum. CONCLUSIONS The rise in incidence of all types of ASDs by year of diagnosis appears to be related to changes in diagnostic and service provision practices in WA. In children aged <or=5 years, diagnosis of severe ID decreased, but mild-moderate ID increased during the study period. A true increase in ASD cannot be ruled out.

Effects of MECP2 mutation type, location and X-inactivation in modulating Rett syndrome phenotype.

Rett syndrome (RTT) is a clinically defined disorder that describes a subset of patients with mutations in the X‐linked MECP2 gene. However, there is a high degree of variability in the clinical phenotypes produced by mutations in MECP2, even amongst classical RTT patients. In a large‐scale screening project, this variability has been examined by looking at the effects of mutation type, functional domain affected and X‐inactivation. Mutations have been identified in 60% of RTT patients in this study (25% of whom were atypical), including 23 novel mutations and polymorphisms. More mutations were found in classical patients (63%) compared to atypical patients (44%). All of the pathogenic mutations were de novo in patients for whom parent DNA was available for screening. A composite phenotype score was developed, based on the recommendations for reporting clinical features in RTT of an international collaborative group. This score proved useful for summarising phenotypic severity, but did not correlate with mutation type, domain affected or X‐inactivation, probably due to complex interactions between all three. Other correlations suggested that truncating mutations and mutations affecting the methyl‐CpG‐binding domain tend to lead to a more severe phenotype. Skewed X‐inactivation was found in a large proportion (43%) of our patients, particularly in those with truncating mutations and mutations affecting the MBD. It is therefore likely that X‐inactivation does modulate the phenotype in RTT.

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.

Physical and Mental Health in Mothers of Children with Down Syndrome

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 childrens 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.

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.