Sue Fyfe

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.

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.

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 …

Predictors of Scoliosis in Rett Syndrome

Scoliosis is a common clinical manifestation of Rett syndrome, a neurodevelopmental disorder that almost exclusively affects girls. Following apparently normal development, these girls typically regress and lose previously attained cognitive, social, and motor skills. Severe intellectual and physical disabilities remain throughout life. Mutations in the methyl-CpG-binding protein 2 gene, MECP2, are detected in approximately 80% of cases and are associated with phenotypic variability. Population-based data on Australian cases were used to study the association between early developmental and genetic factors and the onset of scoliosis. The median age at scoliosis onset was 9.80 years, and three quarters of subjects had developed scoliosis by 13 years of age. Children with compromised early development before 6 months, those who were less mobile at 10 months, and those who never walked were more likely to have an earlier onset of scoliosis. When seven common point mutations and large genomic and C-terminal deletions were compared, the R294X mutation appeared to provide some protective effect against the development of scoliosis. (J Child Neurol 2006;21: 809—813; DOI 10.2310/7010.2006.00183).

Guidelines for Management of Scoliosis in Rett Syndrome Patients Based on Expert Consensus and Clinical Evidence

Study Design. Modified Delphi technique. Objective. To develop guidelines for the clinical management of scoliosis in Rett syndrome through evidence review and consensus expert panel opinion. Summary of Background Data. Rett syndrome is a rare disorder and clinical expertise is thus with small case series. Scoliosis is a frequent association and the evidence base dealing with scoliosis management in this syndrome is limited. Parents of affected girls and women have expressed needs for more information about scoliosis and Rett syndrome. Methods. An initial draft of scoliosis guidelines was created based on literature review and open-ended questions where the literature was lacking. Perspectives of four parents of Rett syndrome patients informed this initial draft. Access to an online and a Microsoft Word formatted version of the draft were then sent to an international, multidisciplinary panel of clinicians via e-mail with input sought using a 2-stage modified Delphi process to reach consensus agreement. Items included clinical monitoring and intervention before the diagnosis of scoliosis; monitoring after the diagnosis of scoliosis; imaging; therapy and conservative management; bracing; and preoperative, surgical, and postoperative considerations. Results. The first draft contained 71 statements, 65 questions. The second draft comprised 88 items with agreement to strong agreement achieved on 85, to form the final guideline document. A comprehensive, life-span approach to the management of scoliosis in Rett syndrome is recommended that takes into account factors such as physical activity, posture, nutritional and bone health needs. Surgery should be considered when the Cobb angle is approximately 40° to 50° and must be supported by specialist management of anesthesia, pain control, seizures, and early mobilization. Conclusion. Evidence- and consensus-based guidelines were successfully created and have the potential to improve care of a complex comorbidity in a rare condition and stimulate research to improve the current limited evidence base.

Clinical guidelines for management of bone health in Rett syndrome based on expert consensus and available evidence

Objectives We developed clinical guidelines for the management of bone health in Rett syndrome through evidence review and the consensus of an expert panel of clinicians. Methods An initial guidelines draft was created which included statements based upon literature review and 11 open-ended questions where literature was lacking. The international expert panel reviewed the draft online using a 2-stage Delphi process to reach consensus agreement. Items describe the clinical assessment of bone health, bone mineral density assessment and technique, and pharmacological and non-pharmacological interventions. Results Agreement was reached on 39 statements which were formulated from 41 statements and 11 questions. When assessing bone health in Rett syndrome a comprehensive assessment of fracture history, mutation type, prescribed medication, pubertal development, mobility level, dietary intake and biochemical bone markers is recommended. A baseline densitometry assessment should be performed with accommodations made for size, with the frequency of surveillance determined according to individual risk. Lateral spine x-rays are also suggested. Increasing physical activity and initiating calcium and vitamin D supplementation when low are the first approaches to optimizing bone health in Rett syndrome. If individuals with Rett syndrome meet the ISCD criterion for osteoporosis in children, the use of bisphosphonates is recommended. Conclusion A clinically significant history of fracture in combination with low bone densitometry findings is necessary for a diagnosis of osteoporosis. These evidence and consensus-based guidelines have the potential to improve bone health in those with Rett syndrome, reduce the frequency of fractures, and stimulate further research that aims to ameliorate the impacts of this serious comorbidity.

Functional status, medical impairments, and rehabilitation resources in 84 females with Rett syndrome: a snapshot across the world from the parental perspective

PURPOSE Rett syndrome is a neurological disorder almost exclusively affecting females. Information on its genetic basis has recently become available. However there is little information on the burden and impact of this disorder on the family despite the apparent variability in phenotype. The purpose of this study was to obtain information on the burden and impact of Rett syndrome by examining the functional abilities, medical needs and use of medical, therapy and accommodation services in the sample. METHOD We used the internet to access an opportunistic sample of parents of 86 females with Rett syndrome. Data on functional status (using the Wee FIM in questionnaire format) morbidity patterns and use of services were collected. RESULTS The response indicated that the instrument used would be appropriate for tracking these parameters in a population-based cohort. Subjects with Rett syndrome in this pilot sample were completely or partially dependent in all functional domains and significantly more so than children with Down syndrome. CONCLUSION The complexity of dependency with need for quality medical surveillance throughout adolescence and adulthood requires accessible centres of excellence linking families and skilled professionals. We plan to use this instrument to obtain a more comprehensive profile of the health, functioning and service use of a total population of children with Rett syndrome.

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.

Feeding experiences and growth status in a Rett syndrome population.

Objectives: Feeding difficulties in Rett syndrome are complex and multifactorial. In this study, we describe the feeding experiences in Rett syndrome and examine the factors affecting growth. Materials and Methods: Using questionnaire data related to a population-based cohort, ages 2 to 29 years (n = 201), we measured the feeding experiences, growth, and factors affecting growth (enteral nutritional support, mutations, mobility, breath-holding, hyperventiliation) in subjects with Rett syndrome. Results: The mean weight, height, and body mass index z scores in subjects with Rett syndrome were below that of their age group and decreased steadily with age. Twenty percent of subjects had enteral nutrition support, and it was more common in the older age group. Those with truncating mutations had significantly less enteral nutrition support than the other mutation groups. Furthermore, those with low mobility had lower mean body mass index z scores than those with higher mobility, and increased frequency of breath-holding and hyperventilation also was associated with lower body mass index z scores. Conclusions: Routine monitoring of growth should continue to determine the severity of nutritional problems in Rett syndrome. Active nutritional management is recommended to ensure females affected with Rett syndrome have the best opportunity to reach their growth potential.

InterRett, a model for international data collection in a rare genetic disorder.

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 thirty 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 twenty one (70%) collected phenotype and genotype data. Only three studies were representative of their underlying case population and many had low numbers. Of one thousand one hundred and fourteen InterRett subjects, nine hundred and thirty five born after 1976 could be verified as Rett cases and compared with the two hundred and ninety five 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.