Umeå universitets logga

A 25-year-old MECP2-mutated female with odd developmental and dyspraxic/ataxic features, followed up through two decades, is reported. She does not fit either the classical Rett syndrome or the criteria required for any Rett variant phenotypes so far described. Nevertheless, she belongs clinically to the latter group. This case deserves attention in order, among other things, to provide important clues to better understand the puzzling battery of neuroimpairments and behavioural abnormalities met in classical Rett phenotypes and Rett variants defined thus far.

ObjectivesWe developed clinical guidelines for the management of bone health in Rett syndrome through evidence review and the consensus of an expert panel of clinicians.

MethodsAn 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.

ResultsAgreement 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.

ConclusionA 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.

Rett syndrome (RTT) is a rare, severe neurodevelopmental disorder, which partly develops in a predictable way, and influences many bodily functions. Regression, i.e. loss of earlier achieved abilities, is one of the clinical criteria for RTT. Research on motor function has to some extent focused on this loss, and less on the possibility to keep, regain or develop abilities. RTT is mainly verified in girls/women, and the prevalence of classic RTT in Sweden for girls born between 1965 and 1976 was 1 in 10.000-12.000. Clinical criteria are used for diagnosis, but since 1999 RTT can be confirmed by a genetic test. As there is no cure so far, development of clinical intervention and management is important, and with good treatment it is possible to improve quality of life.

The main aim was to acquire more knowledge about motor development in RTT, both, early development, and development over time. Another aim was to study if there were deviating orthostatic reactions when rising from sitting to standing, and during standing, compared with normally developed, healthy people, matched by sex and age.

Clinical experience as well as reports from parents showed that some people with RTT had lost abilities, some had been able to keep abilities, and some had been able to learn new abilities after regression. For good results, the person with RTT had to be motivated, and the intervention jointly planned; it was also important to realize that dyspraxia causes dependence on other people’s initiatives. Information about one person with RTT, collected over several years, showed the possibility to develop in some areas over time and the tendency to deteriorate in other areas. Studying orthostatic reactions when rising to standing, and standing for three minutes, revealed that those with RTT mainly had the same reactions as the healthy controls. The quicker initial drop in systolic blood pressure in people with RTT, when rising, has not been documented earlier. 

 In conclusion, this thesis shows that it is possible for some people with RTT to keep abilities, regain abilities, and also learn new abilities after regression. Since those with RTT recovered their blood pressure in the same way as the healthy controls, there is no reason to recommend limitations in standing, though the quicker initial drop in systolic blood pressure should be noted. The deterioration in walking found in our previous studies does not seem to be due to deviation in orthostatic reactions. Individual analysis, as well as good knowledge about the development of the disorder and variation in its expression, is essential. Since many people with RTT live to adulthood, planning for lifelong intervention and care is most important.

People with Rett syndrome have deficient central autonomic control, which may interfere with walking. We have limited knowledge regarding the effects of exertion during physical activity in Rett syndrome. The aim was to investigate the autonomic responses during walking on a treadmill in Rett syndrome. Twenty-six females, 12 with Rett syndrome and 14 healthy females were included. All individuals started on the treadmill by standing still, followed by walking slowly with progressive speed until reaching maximum individual speed, which they kept for 6 min. Heart rate (HR), systolic (SBP), diastolic (DBP), mean arterial blood pressures (MAP), cardiac vagal tone (CVT), cardiac sensitivity to baroreflex (CSB), transcutaneous partial pressures of oxygen (pO2), carbon dioxide (pCO2), and breathing movements were recorded simultaneously and continuously. Autonomic responses were assessed by MAP, CSB and CVT during walking at 3 and 6 min. The changes in CSB and CVT in people with Rett syndrome compared to controls indicated more arousal, but only when the treadmill was started; as they continued walking, the arousal dropped to control level. People with Rett syndrome exhibited little changes in pCO2 whereas the controls showed increased values during walking. This suggests poor aerobic respiration in people with Rett syndrome during walking. Five people with Rett syndrome had Valsalva type of breathing at rest, three of those had normal breathing while walking on the treadmill while the remaining two started but soon stopped the Valsalva breathing during the walk. Our results show that individuals with Rett syndrome can walk for up to 6 min at their own maximum sustainable speed on a treadmill. Energy production may be low during walking in Rett syndrome, which could cause early tiredness. A treadmill can be used in people with Rett syndrome, but must be introduced slowly and should be individually tailored. We propose that walking promotes regular breathing in Rett syndrome.

The aim of this study was to investigate orthostatic reactions in females with Rett syndrome (RTT), and also whether the severity of the syndrome had an impact on autonomic reactions. Based on signs of impaired function of the central autonomic system found in RTT, it could be suspected that orthostatic reactions were affected. The orthostatic reactions in 21 females with RTT and 14 normally developed femalesmatched by age were investigated when they rose from a sitting position, and during standing for 3 min. Reactions of the heart, the blood pressure and the time for recovery of systolic blood pressure, were studied in real time, heartbeat by heartbeat, simultaneously. There was no difference between participants with RTT and the normally developed controls regarding general orthostatic reactions (heart rate, systolic and diastolic blood pressure, and mean arterial pressure) when getting up from a sitting position, and when standing erect for 3min. In the specific immediate response by the heart to standing up, the 30:15 ratio, significantly lower values were found for females with RTT. In the RTT group, the maximum fall of systolic blood pressure showed a tendency to a larger decrease, and the initial decrease in systolic blood pressure was significantly faster. The time for recovery of systolic blood pressure from standing erect did not differ between groups. At baseline the females with RTT had significantly lower systolic blood pressure and a tendency to a higher heart rate. The results do not indicate any autonomic limitations for people with RTT in getting up from a sitting position and standing. The participants with RTT had normal orthostatic reactions indicated by the heart and blood pressure responses when standing erect for 3 min. A faster initial drop in systolic blood pressure in people with RTT was notable.

A main task for the physiotherapist at the Swedish Rett Center is to document and report successful treatment. This report shows the possibility to regain function, get variation and avoid contractures for several years. A thorough neurologic, orthopaedic and physiotherapeutic assessment and analysis is essential. We stress the importance of keeping the feet in good position, using surgery and well fitting orthoses when needed, making standing possible and for some persons, walking. For the effect of treatment the following factors were of vital importance: the expectations of the persons treating the girl/woman – what they believed she could do, the motivation of the girl/woman herself, a joint plan for intervention including everyone involved, and well educated personnel, well informed about Rett syndrome – its problems and possibilities.