PhD study conducted by Jane Lunding Larsen, PhD student, MEd in Educational Psychology 

In this PhD-project we focus on both the positive and the negative psychological aspects of the parenting role in parents of individuals with Rett syndrome and similar multiple disabilities. We do this through the concepts of compassion fatigue and compassion satisfaction, which are concepts originally used in relation to professionals working with people who are seriously ill, suffering, or traumatized. This particular parenting role is a lifelong responsibility and we therefore focus on whether there are certain time points or situations in the child’s or the parents’ lives that seems to be more stressful or vulnerable for the parents. 

The PhD-project consist of three studies: 1) A scoping review which is systematically mapping the existing knowledge and the knowledge gaps about parents of individuals with multiple disabilities, compassion fatigue/satisfaction and similar concepts. 2) A qualitative interview study investigating what creates and affects the parenting role positively and negatively. 3) A quantitative questionnaire study investigating the extend and the patterns of the positive and the negative psychological aspects of the parents of individuals with multiple disabilities.

The project is expected to be completed in 2024.

Research project conducted in collaboration between Australia and Denmark. Contact person in Denmark is Michelle Stahlhut, PhD.

As health professionals we wish to conduct the best evidence-based practice. However, our knowledge is limited when it comes to people with severe multiple disabilities such as Rett syndrome. Thus, there is a great need for trials that focus on increasing physical activity and at the same time support the family and the local environment surrounding the person with Rett syndrome. The aim of this project was to examine the effect of a physical activity Telehealth programme. This was a randomized waitlist-controlled trial. 

Participants included 38 children and adults with Rett syndrome aged 6-41 years. All participants were able to walk either independently or with assistance. Participants from the control group engaged in their usual care routines for 12 weeks whereas the intervention group participated in a goal-based Telehealth programme for 12 weeks. The purpose of the Telehealth programme was to increase ’uptime’ – which is defined as time in standing and walking activities. Each participant was followed by a physiotherapist from the research team during the entire programme. The physiotherapist assessed the participant’s gross motor skills, daily routines and activities and environment. Between 2-4 goals were co-designed with parents and service providers using Goal Attainment Scaling. Each goal was evaluated and adjusted at fortnightly video calls. All ’uptime’ activities took place in the usual settings of the participant (home, school/day care centre, community). Sedentary time and number of daily steps were assessed at baseline, after 12 weeks and after 24 weeks.

Results showed a 2.7% reduction in sedentary time in the intervention group and the daily step count increased with 265 steps. In the control group sedentary time was reduced with 1.3% and the daily step count increased with 105 steps. No significant differences were found between the intervention and control group. The research project did show small improvements in ’uptime’ even during the CVID-19 pandemic during which it took place. Even though we didn’t find statistically significant results we can’t preclude that these changes were of clinical importance for the participants. All participants had very limited walking ability and a very low physical activity level at baseline.

What we have learned from the study:

The research project was completed in the fall 2022.

Experiences from the project and strategies to work with physical activity and participation will be further disseminated on a webpage that is expected to launch in December 2022/January 2023. 

We found that more than 60% of the women were able to walk outside their homes and 75% were household ambulators. Only 11% were not able to walk at all. However, nearly 70% could not transfer from sitting to standing position without support. There were profound difficulties communicating, but 85% of the women could either consistently point with their hand or eyes to things of their interest.

We concluded that adult women with RTT are very dependent on caregivers who maintain and rehabilitate their functional abilities. They can often walk short distances unassisted but do have trouble transferring and thus getting up from a chair on their own. They have severe problems communicating and they often perform subtle signs that can be difficult to recognize. 

The project taught us that:

We then did a longitudinal study where we focused on gross motor abilities to address if a possible decline in motor skills in adults with RTT can be explained by the presence of common medical conditions as epilepsy, breathing disturbance, and scoliosis. We used data from the Danish RTT database, from medical files, and videos from visits at our national Center for Rett syndrome were reviewed. The study included 24 individuals aged 30-66 years at last visit after a follow-up period of 6-12 years. 

Results showed a clinically observable and significant decline in gross motor skills using the Rett syndrome Gross Motor Scale (RSGMS) with a tendency of less decline in the individuals with the best motor abilities. The frequencies of comorbidities were high. Decline in RSGMS score was associated with the presence of epilepsy and severe scoliosis that had been conservatively managed. 

The results emphasized that: 

• Adult women with RTT are at risk of decline in gross motor skills and need lifelong rehabilitation and promotion of active lifestyles 
• There is a need for lifelong medical follow-up
• Epilepsy plays a significant role in the adult RTT life
• Management of severe scoliosis in the younger years has impact on the motor abilities in adulthood.

The research projects were completed in 2016 and 2020.

PhD study conducted by Bitten Schönewolf-Greulich, PhD and MD, Clinical Geneticist

Rett syndrome (RTT) is a severe neurobiological developmental syndrome. The diagnosis is clinical, consensus criteria were last described in 2010, and genes described as causative have been MECP2, CDKL5 and FOXG1. Symptoms include initial normal development and then regression until severe intellectual disability with loss of speech and hand use and development of hand stereotypies. Some patients might have characteristic clinical RTT symptoms, but do not fulfill the clinical diagnostic RTT criteria for typical or atypical RTT or do not have a pathogenic variant in the known RTT genes; they are known as “Rett-like”.

In recent years, new advanced techniques within the field of clinical genetics have been developed. In the Danish National Rett Center 147 patients are known, of whom 33 patients with RTT, atypical or Rett-like symptoms remained without a conclusive diagnosis. In all these patients, the project aimed to apply the latest genetic methods to perform analyses on the molecularly unclarified patients and to investigate phenotype-genotype correlations.

The main purposes of the project was: Identification of new genes or genetic mechanisms causing Rett-like syndromes, identification of pathogenic variants in known disease-causing genes in patients with Rett-like syndromes and collecting knowledge of atypical RTT and Rett-like symptoms as neurological regression, stereotypic hand movements, abnormal breathing pattern, loss of speech, gait disturbance, growth failure, and epilepsy.

The study resulted in the molecular diagnosis in 23 of 33 consenting patients in many different genes expressed in the brain and mainly of importance to aspects of neuronal signaling and synapse function.

The findings underline that RTT symptoms are highly genetic and therefore, these patients should be molecular investigated, and sometimes the gene analyses should be repeated or supplemented with extensive genetic testing. The clinical investigation of the cohort and comparison to the RTT patients in the Danish RTT cohort gave the possibility to suggest an updated set of clinical criteria with more applicable items and which also include the molecular genetic diagnosis.

The project showed that the major gene in typical RTT is indeed MECP2 and with the proposal of a revised set of diagnostic criteria to diagnose typical RTT and atypical RTT with the aid of molecular diagnostics.

The PhD study was completed in 2019.

For further information, please contact: rett.rigshospitalet@regionh.dk

PhD study conducted by Michelle Stahlhut, PhD and research PT

Rett syndrome (RTT) is a rare neurodevelopmental disorder usually affecting females. It is associated with multiple disabilities including intellectual disability leading to a high level of dependency in all aspects of daily living including participation in physical activities. The overall aim of this thesis was to investigate physical activity behaviors by developing measures of walking, describing patterns of physical behavior and influencing factors, and evaluating the effects of an intervention that focuses on participation in standing and walking activities (i.e. ‘uptime’ activities) in Danish girls and women with RTT. 

The thesis comprises four studies. In study I, measurement properties of a modified two-minute walk test (2MWT) and a modified RTT-specific functional mobility scale (FMS-RS) were determined. Forty-two girls and women with RTT aged 2.4–60.9 years were included. Comparison measures were the Clinical Severity Score (CSS), Rett Syndrome Gross Motor Scale (RSGMS) and the mobility domain in the Pediatric Evaluation of Disability Inventory (PEDI-m). In study II, patterns of sedentary behavior and physical activity were described in a population-based sample including 48 girls and women with RTT aged 5.5–60.5 years. Participants wore the activPAL and StepWatch Activity Monitor (SAM) for at least four days. In study III, facilitators and barriers to participation in ‘up-time’ were explored from the perspectives of parents and professionals using focus groups. Data was analyzed using thematic analysis. In study IV, the feasibility and effectiveness of an individualized 12-wk ‘uptime’ participation intervention (U-PART) were evaluated in 14 girls and women with RTT aged 5.6-48.3 years. Each individual program focused on participation in enjoyable activities to promote ‘uptime’ in home, school/day center and community settings. Feasibility was assessed using a study-specific questionnaire. Primary outcomes were sedentary time (activPAL) and daily steps (SAM). Secondary outcomes were gross motor skills (RSGMS), walking capacity (2MWT), quality of life (Quality of Life Inventory-Disability, QI-Disability) and participation-level goals (Goal Attainment Scaling, GAS). Outcomes were evaluated on four occasions: at baseline and after a 6-week interval, immediately following the 12-week intervention program and 12 weeks after the intervention program. 

Results showed low-moderate and moderate-high correlations between comparison measures and the 2MWT and FMS-RS, respectively. Intraclass correlation coefficients (ICC) were high for both the 2MWT (ICC=0.86-0.98) and FMS-RS (ICC=0.94-0.99) test values. In the 2MWT standard error of measurement (SEM) was 13.8m and minimal detectable difference (MDD) was calculated to be 38m (study I). On average 83.3% (SD 13.9%) of waking hours were spent in sedentary behaviors (n=48) and the median (IQR) daily step count was 5128 (2829–7704) (n=28). Advancing age and poorer walking skills were associated with higher levels of sedentary time (study II). Several facilitators and barriers of ‘uptime’ activities were identified within five subthemes relating to the individual girl/woman and her physical, organizational, social and attitudinal environment. The resources within each of the five areas needed to be balanced to enable optimal participation in ‘uptime’ activities (study III). Stakeholders perceived the U-PART intervention as feasible and significant positive effects were seen after the intervention in sedentary time (-4.1%), daily steps (+708 steps), 2MWT (+18.9m), QI-Disability (+2.8) and for individually determined goals. At follow-up, effects on sedentary time (-3.4%) and 2MWT (+12.4m) were maintained (study IV).

In conclusion both walking measures showed good concurrent validity and test-retest reliability and have the potential to be used in both clinical practice and research (study I). High levels of sedentary time and low daily step counts were demonstrated in RTT (study II). Parents and professionals described how opportunity for participation in ‘uptime’ activities depended on a balance of facilitators and barriers within the individual with RTT and the environment (study III). Knowledge from study I-III enabled the planning and implementing of a health-promoting intervention. The U-PART intervention was considered feasible with regards to acceptability and practicality, and positive effects were seen in the outcomes of sedentary time, daily step count, walking capacity, quality of life and participation-level goals, some maintained after a further 12 weeks (study IV).This thesis contributes important knowledge to disability research in Denmark and internationally by focusing on the availability of valid outcome measures and health-promoting strategies in girls and women with RTT.

The PhD study was completed in 2018.

For further information: 

PubMed
portal.research.lu.se (pdf, opens in new tap)

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PhD study conducted by Gitte Rønde, PhD and MD, Pediatrics

Rett syndrome (RTT) is a severe neurodevelopmental disorder, affecting mainly females due to de novo mutations in the X-linked gene, Methyl-CpG-binding protein 2 (MECP2) located at Xq28. MECP2 undergoes X chromosome inactivation (XCI). The MeCP2 protein is involved in transcriptional silencing of target genes, but the knowledge of relevant target genes is still sparse. RTT has a worldwide distribution with a prevalence of 1:10.000 in Denmark. Classical and atypical forms of RTT have been described giving a very broad spectrum of symptoms, including mental retardation, diminished motor skills and locomotion, epileptic seizures, movement disorders and stereotyped hand movements. In the past decade low bone mass and increased fracture risk have been reported, indicating fragile bones in RTT. Still, fracture occurrence in RTT has not been well characterized. Furthermore, previous reports of low bone mass might be influenced by growth retardation, evident in most patients with RTT. Finally, bone metabolism has not been examined.

The objects of this Ph D study were to characterize bone mass, bone metabolism and fracture occurrence among Danish patients with RTT. Aims were to identify associated risk factors of low bone mass and fracture occurrence in RTT. A total of 61 female RTT patients with a verified MECP2 mutation and 122 healthy controls matched according to age, gender and pubertal/menopausal status were examined by questionnaires, bone biomechanical markers in blood, XCI studies, dual-energy x-ray absorptiometry (DXA), clinical and x-ray evaluations. National register search on fracture diagnosis was done to obtain complete fracture histories.

In the first study we examined the prevalence of fractures, fracture mechanism and associations to risk factors. Our results showed that RTT patients sustained significantly more low-energy fractures from an early age compared to healthy controls, but overall fracture occurrence was not increased. Low-energy fractures were significantly associated with reduced mobility and lack of ambulation. Associations with MECP2 mutation type, epilepsy and anti-epileptic treatment were not demonstrated. Measures of vitamin D status indicated a possible need for vitamin D supplementation in RTT.

In the second study we examined areal bone mineral density (aBMD) and volumetric bone mineral apparent density (vBMAD) of the spine and hip by DXA and calculated vertebral size. We demonstrated that RTT patients were significantly smaller regarding both body height and vertebral size in the order of 10%. Still, patients with RTT had lower values of spine and hip aBMD and VBMAD, adjusted for age, pubertal status and BMI. Low-energy fractures in patients were associated to spine aBMD, VBMAD and hip aBMD. Of investigated risk factors in patients, only reduced ambulation was associated to hip aBMD and VBMAD, but the latter association disappeared in a model adjusted for multiple risk factors including age and BMI. No associations were found between spine and hip aBMD and VBMAD each and MECP2 mutations groups or XCI status.

In the third study we investigated bone metabolism in RTT compared to controls by bone formation markers: N-terminal propeptides of collagen type 1 (P1NP), Osteocalcin (OC), Bone-specific alkaline phosphatase (B-ALP) and bone resorption marker: C-terminal telopeptide cross links (CTX), measured in plasma. In general, the level of all bone markers was highest in the pre-pubertal years, followed by a decrease through puberty and by age. Patients with RTT had lower values of all markers of bone metabolism in childhood compared to controls, whereas patients older than 25 years had bone marker levels equal to controls regarding P1NP, CTX and OC. vBMAD of the spine and hip did not influence bone marker levels. Neither did bone marker levels differ according to MECP2 mutation group.

In conclusion, small bone size and low bone density as well as reduced bone turnover evident in childhood and adolescence indicate an apparent low bone formation phenotype in RTT, associated to the occurrence of low-energy fractures from an early age. This suggests a general influence of MECP2 on growth and bone formation in particular, but the specific relation to the osteoblast function and activity and the interplay with the osteoclast remains to be elucidated. Our findings indicate perspectives for future studies of bone mass and prevention and treatment of bone fragility in RTT.   

The PhD study was completed in 2011.

For further information, please contact: 

rett.rigshospitalet@regionh.dk​