An Intensive Anti-Scoliosis Postural Intervention Supported by an Application for Individuals With Rett Syndrome
Phase: NA
Conditions: Rett Syndrome
Sponsor: Ariel University

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An intensive Anti-Scoliosis Postural Intervention Supported by an Application for 
Individuals with Rett syndrome 
 
Document date: 22/07/2022 
 
 

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Abstract 
Background: Scoliosis is the most common orthopedic comorbidity in Rett syndrome (RTT), 
with a prevalence of 94% and a mean curve progression of 14-21° Cobb annually. A scoliosis 
prevention intervention based on daily activity programs was proposed for people with RTT 
within uncontrolled study designs.  
Aim: The current study aims to evaluate the effectiveness of a home-based activity program 
carried out during daily life to slow the progression of scoliosis in girls with RTT.  
Ethics: The proposal was approved by Ariel university IRB. All participants’ parents will sign 
informed consent forms.    
Participants: Twenty Italian girls aged between six and 16 years with a genetically confirmed 
classic RTT and scoliosis at a severity level between 10° and 40° Cobb will be recruited and 
randomly divided into two groups (immediate intervention – Group 1; wait-list-intervention – 
Group 2). Both groups will follow the same 10-month intervention program, 10 months apart.  
Outcome measures: Participants’ scoliosis Cobb’s angle, motor functioning, and behavioral 
characteristics will be assessed three times.  
Procedure: The interventions will comprise daily home-based activity programs carried out 
by participants’ caregivers within everyday living environments. An expert therapist will 
remotely supervise each program through an ad hoc developed smartphone application.  
 
 
 
 

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Table of contents 
Introduction ................................................................................................................................ 4 
Background ................................................................................................................................ 5 
Study Aim .................................................................................................................................. 7 
Research Questions .................................................................................................................... 7 
Materials and Methods ............................................................................................................... 7 
Preliminary steps ...................................................................................................................... 13 
Importance of the Research ..................................................................................................... 14 
References ................................................................................................................................ 15 
Appendix 1 – Ariel University Institutional Review Board approval 
Appendix 2 - Informed consent form 
Appendix 3 – Research timetable 
Appendix 4 – Anamnestic information data collection sheet 
Appendix 5 – Rett Assessment Rating Scale (RARS)  
Appendix 6 – Rett Syndrome Motor Evaluation Scale (RESMES)  
Appendix 7 - Rett Syndrome Behavior Questionnaire (RSBQ)  
 
 
 

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Introduction 
Rett syndrome (RTT) is a severe neurodevelopmental disease caused by a mutation in 
the MECP2 gene located on the X chromosome,[1] affecting about 1/10,000 females 
worldwide.[2–4] Scoliosis is the most common orthopedic comorbidity in RTT,[5–7] 
showing a prevalence of up to 94%.[7–11] Reported median age of scoliosis onset in RTT is 
at 9.8 years, with 25% of subjects affected by the age of 6 years, about 79% by the age of 13 
years, and 85% by the age of 16 years or older.[7,9,12,13] Scoliosis in RTT is neurogenic in 
origin and can result in pain, loss of sitting balance, deterioration of motor skills, and 
progressive restrictive lung disease development.[14] Diminished early development, 
inability to sit and walk without support, the onset of puberty, and enhanced clinical severity 
are also associated with developing scoliosis at an early age.[11,13,15]  
The case literature suggests a fast mean curve progression in this population ranging 
from 14° to 21° Cobb per year, accompanied by an acceleration in the progression at puberty 
with an average age of 13 years.[11,14,16] Moreover, in a large cohort study analyzing 
radiographs of 128 girls and women with RTT followed for two years (three radiographs for 
each subject), the magnitude of scoliosis was found to generally increase with age with a 
yearly 0.438-unit increase in the square root of the baseline Cobb’s angle (95% Confidence 
Interval 0.374 – 0.503).[17] 
A corset is usually suggested for individuals with RTT with Cobb’s angle greater than 
20-25°, and spinal fusion is considered if Cobb’s angle progresses over 40-50°.[12,15,18]  
Spinal surgery is considered the definitive management of neuromuscular 
scoliosis.[19] In most cases, posterior-only spinal fusion is performed.[20] However, if an 
anteroposterior surgery is required, a single-stage approach is preferable to reduce anesthetic 
and surgical complications.[12] Fixation to the pelvis is indicated in non-ambulant children 
with pelvic obliquity[12] and in the presence of a preceding rapid decline in neurological 
function with a lethargic presentation and uncontrolled, treatment-resistant daily seizures.[21] 
Surgery should not be delayed until skeletal maturity has been achieved. Barney and 
colleagues suggested the need for RTT-specific postoperative pain management.[22] The 
authors reported that, after spinal fusion, patients with RTT received fewer total doses of 
opioids compared to girls with cerebral palsy and idiopathic scoliosis. With modern 
technology, severe curves can be safely treated,[21] and positive outcomes following spinal 
surgery were reported.[23–26] Even so, the decision to perform the operation is challenging 
for the family due to anxiety about their daughter undergoing such a complex medical 
procedure.[8,24] Moreover, a large cohort study reported that 18.5% of subjects with RTT 

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and scoliosis had spinal instrumentation,[15] showing that the vast majority of this group of 
clients will not undergo surgery and therefore will rely on non-surgical, conservative 
treatment. Thus, the development and evaluation of such programs are critical for individuals 
with RTT.  
Background 
Available conservative interventions for scoliosis include observation and monitoring, 
bracing, orthotics, and physical therapy.[27–29] As specific guidelines for the management of 
scoliosis for people with RTT were published,[12] the available treatments for scoliosis were 
here described in the light of such guidelines. The scoliosis monitoring for these patients 
should start before the diagnosis of scoliosis. Before-diagnosis monitoring strategies for 
people with RTT include genetic testing, parental teaching on the characteristic aspects of 
scoliosis, and physical assessment upon the diagnosis of RTT and at least every six months 
thereafter.[12] After diagnosing scoliosis, yearly spine radiographs are suggested to monitor 
the curve progression. The collection of radiographs every six months is recommended if 
Cobb’s angle progresses over 25° before the skeletal maturity. The maintenance of physical 
examinations every six months is advised after the scoliosis diagnosis.[12] Bracing strategies 
were suggested in the literature for neuromuscular scoliosis management among its 
conservative treatments. A recent literature review identified 23 typologies of braces 
proposed to care for scoliosis curves of different types (“C” or “S” shaped), levels (thoracic, 
lumbar, and thoracolumbar), and entities, using different approaches (passive and active 
correction).[30] Indications for bracing are stronger in younger children and more 
controversial in adolescents. Bracing aims to contain the curve until skeletal maturity[31] and 
regain the sitting position.[32] However, the role of bracing in patients with neuromuscular 
scoliosis is contentious, and there is no compelling evidence supporting the use and success 
of braces in preventing the deformity progression in neuromuscular scoliosis.[19,32] There is 
no consensus among experts on RTT that bracing is beneficial in reducing the scoliosis 
progression in this population.[12] Nevertheless, bracing may be valuable if support is 
needed in a sitting position (usually for extremely hypotonic children who find it difficult to 
maintain an erect posture for long periods) or delay the necessity of surgery.[12,33,34]  
 When considering conventional interventions regarding scoliosis, there is a consensus 
among experts that efforts should be made to maintain the ability to walk and increase the 
duration and distance walked to counteract the curve progression.[19,27,35] However, the 
capacity of physical therapy treatments to reduce scoliosis or prevent mild scoliosis from 

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rapidly progressing has received scarce consideration in the literature.[35] Although so far, 
physical therapy interventions have not been found to improve etiological factors for 
neuromuscular scoliosis or prevent progression of established scoliosis, they were reported as 
helpful in avoiding any adverse effects, such as: prolonged brace use, prevention or 
prolonging onset of joint contractures, and maintenance of both chest mobility and 
respiratory excursion.[27,32] The implementation of physical therapy for scoliosis must be 
based on the particular spinal deformity characteristics and requires specifically trained 
therapists and clinicians.[28]  
To our knowledge, only one anti-scoliotic physical therapy intervention explicitly 
directed to patients with RTT was proposed in the literature.[35] This is a specific physical 
therapy regimen comprised of an intensive program of postural positioning and enhanced 
activity level carried out in cooperation with the participant’s family members and caregivers 
(within the educational facility). The intervention was conducted with a 5-year-old girl with 
RTT whose Cobb’s angle reduced from 30° to 20° over an 18-month treatment period through 
the use of positioning equipment, postural strategies (activating automatic equilibrium 
reactions, which oppose the natural scoliotic curve), and a motor activity program (walking 
or standing) during waking hours. This result was maintained for three years until the routine 
mentioned above ceased, when the child’s scoliosis rapidly regressed. A recently published 
article from Romano et al. [36] replicated this intervention method with 20 participants with 
RTT in Italy and reported no change in scoliosis severity for this group of clients during a 
one-year follow-up. Thereby strengthening the validity of the approach proposed by Lotan, 
Merrick, and Carmeli.[35] Moreover, previous programs were found helpful in increasing the 
motor function of five girls with RTT in Ireland,[37]  17 girls and women with RTT in 
Italy,[38] and 40 individuals with RTT in northern Italy.[39] This accumulation of evidence 
provides initial evidence of the feasibility and acceptability of this type of treatment in a 
broad age range and a wide functional range of participants.  
The intervention proposed in the current protocol is ecological and intensive in nature, 
will be carried out by primary caregivers within the participants’ daily living environment 
(home and educational facility), and will be planned and supervised by therapists experienced 
in treating individuals with RTT. Moreover, the authors will remotely supervise the 
intervention by using an ad hoc developed smartphone application. 
 
 

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Study Aim 
The current study aims to evaluate the effectiveness of an anti-scoliotic physiotherapy 
program carried out during daily life and focuses on hypercorrective postures and on 
increasing the level of activity to assess whether or not it is possible to slow the progression 
of scoliosis in girls with Rett syndrome (RTT).  
The current research project has the following research objectives: 
• Primary objectives: 
1. Build, implement and evaluate a physiotherapy program for contrasting scoliosis 
trajectory adapted to individuals with RTT; 
2. Develop a secondary deformity prevention program through early intervention for 
people with RTT.  
• Secondary objectives: 
1. Build and evaluate the efficiency of a support application for carrying out 
rehabilitation exercises; 
2. Explore the factors influencing adherence and implementation of intervention from 
the perspective of both families and therapists in light of the above-mentioned 
application. 
Research Questions 
• Can an individualized, remotely supervised physiotherapy program contrast the scoliosis 
progression of girls with RTT? 
• Can a smartphone application support the adherence and the implementation of an 
individualized activity program carried out at home by caregivers of girls with RTT? 
• Can the use of the application reduce the costs of remote supervision?  
• Which factors influence the adherence and implementation of the intervention from the 
perspective of both families and therapists? 
Materials and Methods 
Study Design 
A randomized controlled study with a waiting list design will be applied. 
 
 

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Study Population 
For this study, 20 girls aged between six and 16 years with genetically confirmed 
classic RTT and scoliosis will be recruited from the San Paolo Hospital (Milan, Italy) or the 
Italian Rett Association (AIRett – Verona, Italy). 
Sample Size and Power Calculation 
The information available in the literature suggests that the Cobb angle in RTT 
typically increases by approximately 14 ± 8° Cobb per year. Based on these data, an alpha of 
0.05 and a beta of 0.8, we estimate that for this study, the researchers will need a sample size 
including two groups of 10 subjects and that statistical significance will be achieved if both 
groups of participants will show an average increase in the scoliotic curve of less than 12° 
Cobb after the implementation of the proposed program. 
Inclusion Criteria 
• Diagnosis of RTT with confirmed MECP2 gene mutation;[40] 
• Diagnosis of unstructured flexible scoliosis (Cobb angle between 10° and 40°) measured 
radiologically with an x-ray performed no more than six months before the recruitment; 
• Age between 6 and 16 years. 
Exclusion Criteria 
• Presence of psychomotor developmental deficit evidenced in the first six months of life or 
diseases of neurometabolic, infectious, or secondary brain damage trauma origin; 
• Previous surgical intervention to the spine or its planning within the study period; 
• Use of a corset during most waking hours; 
• Clinical judgment of the evaluating specialist doctor who certifies unstable health 
conditions that are not compatible with the performance of the rehabilitation program 
(e.g., ongoing or recurrent infections, severe gastrointestinal disorders, drug-resistant 
epilepsy with multi-day seizures).  
• Clinical judgment of the research team suggesting an inability of the home environment 
to perform the intervention program (change in residence, a planned pregnancy, a pre-
planned complex surgical/medical procedure within the period of the planned intervention 
program for the child of family memeber) within the intervention period. 
 
 

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Ethical Issues 
The Ariel University Institutional Review Board (IRB) approved the study (no. AU-
HEA-ML-20201019 – See IRB approval in Appendix 1) that will be conducted according to 
the ethical principles of the Helsinki Declaration and local regulations. All details relating to 
the study procedure will be discussed with participants’ parents or legal representatives, and 
an informed consent form (See Appendix 2) will be signed for all. Enrolment will be 
voluntary, with participants not receiving any incentives, financial or otherwise, for 
participation. 
Study Protocol 
The participants’ parents will receive an information sheet regarding the study and 
informed consent for participation and collection of video materials at the recruitment. A 
reference telephone number and an e-mail address will be provided to be contacted in case 
they would like further information or would like to communicate the exit from the study. 
The eligibility of the candidates will be assessed at the time of recruitment (T1) through an 
initial neurological or physiatrist evaluation. At the same time, each participant will undergo 
a rehabilitation evaluation to collect the outcome measures (see section “Data collection”) 
and create an individualized intervention plan specific to the participant’s scoliosis, functional 
abilities, and parental/educational setting’s availability. During the evaluation, the postural 
needs of the participants will also be identified, and a qualified technician will build or adjust 
the positioning devices, making them suitable for each intervention plan. Using block 
randomization, participating girls will be randomly divided into treatment (Group 1) or 
delayed treatment (Group 2) groups. Participants in Group 1 will begin carrying out the 
rehabilitation program immediately after the first assessment session (T1). Each program will 
require the daily performance of different postures and therapeutic activities at the girls’ 
educational facilities and homes, based on the availability of families, for a duration of 10 
months. Specific strategies that will be implemented will include maintaining asymmetrical 
postures that oppose the scoliosis curve during activities and exercises in sitting, standing, 
and walking positions (according to each participant’s functional abilities). These strategies 
refer to a hypercorrective postural positioning of scoliosis. In addition, activities involving 
weight bearing on the lower limbs, such as walking and standing for at least two hours a day, 
will be encouraged, and passive stretching and spinal mobilization exercises will be 
conducted.  

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Participants’ parents and local reference physiotherapists who will supervise the 
program in the educational or home setting will be involved in training sessions aimed at 
learning the performance of the child’s program activities. In addition, a smartphone 
“ActivRett” activity application will be constructed for this research. The application will be 
downloaded and used by the group that takes care of each participant. It will contain the 
participant’s individualized therapeutic indications and allow the collection of data relating to 
the development and execution of the program. Further support for parents, caregivers, and 
therapists will be provided via Skype by an Italian therapist (AR) experienced in treating 
individuals with RTT at the program’s start and after every two months. These meetings will 
be aimed at discussing the progress of the program, solving problems, reorganizing 
schedules, adjusting the suggested exercises, assessing the achievement of objectives, and, if 
needed, setting additional goals.  
At the end of the intervention of Group 1 (10 months after its start), the outcome 
measures will be collected again for all participants (T2), and those in group 1 will be 
allowed to continue using the application yet without receiving the above-mentioned skype 
calls. Then, those included in Group 2 will be reevaluated and start to actively participate in 
the planned intervention, which will be carried out for the second period of 10 months. At the 
end of the intervention phase of Group 2, the outcome measures will be collected again for all 
participants (T3), and the data obtained will be analyzed by the researchers. At the end of 
each intervention phase, a specific questionnaire will be administered to the parents, 
therapists, teachers, and other caregivers involved in the intervention program mentioned 
above to assess the participants’ satisfaction with different aspects of the intervention 
conducted. The research timetable is outlined in Appendix 3. 
Outcome measures 
Anamnestic Information 
The anamnestic information collected for each participant will include age, age at 
diagnosis of scoliosis, the amount of motor therapy interventions received, and the type of 
genetic mutation (see data collection sheet in Appendix 4). 
Rett syndrome severity level 
The Rett Assessment Rating Scale (see RARS form in Appendix 5) will be used to 
evaluate the severity of RTT clinical manifestation at T1. The RARS is a 31-items RTT-
specific severity scale.[41] Each item concerns a specific phenotypic RTT characteristic. The 

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total score indicates the participant’s RTT severity level ranging from a mild deficit (reflected 
by lower scores) to severe symptoms (reflected by higher scores). A standardization 
procedure for the Italian population with RTT was conducted for the RARS. Skewness and 
kurtosis values, calculated for the total score distribution, were 0.110 and 0.352, respectively. 
The distribution was found to be normal. Internal consistency for the total score (0.912), as 
well as for the subscales, was high (0.811–0.934).[41,42] 
Scoliosis Progression 
The progression of scoliosis will be assessed during the study by measuring Cobb’s 
angle on three anteroposterior X-rays of the spine collected respectively at T1, T2, and T3. 
The girl will be positioned in the most upright position comfortable for her. The angle will be 
measured using standard procedures. If the participant has an X-ray examination of the spine 
carried out in the manner prescribed for this study in the six months prior to the start of the 
intervention, this radiograph will be used as a pre-intervention examination. If the participant 
does not have an x-ray examination with the characteristics described above, it will be carried 
out as part of this project in compliance with the international guidelines for the management 
of scoliosis in RTT, which provide for the carrying out of six-monthly radiographic 
examinations in the presence of evolving scoliosis.[12] Moreover, the radiographic 
examinations carried out periodically by the participants before the recruitment at the 
participants’ reference hospitals will be collected by the researchers to allow the extraction of 
data relating to the evolutionary trajectory of scoliosis up to the time of recruitment. The 
Cobb’s angle will be obtained from the average value of three measurements carried out by 
independent blinded (to the treatment status of each subject) medical specialists with clinical 
experience concerning scoliosis in RTT. Using the results provided by different clinicians 
blinded to the procedure, the date of the x-ray is taken, and the functional state of each 
participant will allow a more reliable final measurement.[43] 
Adherence to the Program 
The compliance with the intervention will be measured through the smartphone 
application. This will allow an assessment of the amount of treatment received, which is 
essential for calculating the correlation between the number of therapeutic activities 
performed and the variation of Cobb’s angle.  
 
 

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Gross Motor Function Level 
The gross motor function level, including the ability to walk, will be measured during 
the rehabilitation assessments using the Rett Syndrome Motor Evaluation Scale (RESMES – 
Appendix 6). This scale includes 25 items that examine motor function divided into six 
sections: standing, sitting, postural transfers, walking, running, and climbing / descending 
stairs. Sixteen items are rated on a discrete scale, ranging from 0 (indicates no or very mild 
impairment) and 4 (severe impairment). Nine items related to walking skills are evaluated on 
a discrete scale with a score from 0 to 2 where 0 indicates that the activity could always be 
completed by the subject and 2 that is assigned if the item cannot be carried out. The items’ 
scores are added together, thus giving a total RESMES score (range: 0 to 82). Moreover, a 
score for each section can be calculated. Additionally, the RESMES was designed to be 
completed by the primary caregivers of the person with RTT. Comparing the total score 
obtained by parents and doctors revealed a high correlation and no statistically significant 
difference.[44] This scale was recently validated on a sample of 60 girls and women with 
RTT (mean age: 12 years 5 months SD: 8 years 9 months; range: 3–40 years), showing 
optimal agreement between the assessors and strong internal consistency (reliability 
coefficient = 0.96 SD = 0.18; Cronbach’s alpha coefficient for the full scale = 0.95 CI 0.93–
0.97).[45]  
Behavioral Characteristics 
The behavioral characteristics of the participants will be evaluated at T1, T2, and T3 
through the administration of the Rett Syndrome Behavior Questionnaire (RSBQ - Appendix 
7).[46] The RSBQ is a questionnaire created by comparing the behavioral characteristics of 
people with RTT with those of individuals with severe intellectual disability. The 
questionnaire is filled in by parents who are asked to provide an evaluation of the behavioral 
characteristics shown by their child at the time of completion. Because people with RTT 
suffer from severe physical and cognitive deficits linked to behavioral and emotional 
disturbances, the RSBQ includes elements describing behavioral characteristics and assessing 
physical capabilities, including hand function and sitting and walking skills. Other items 
evaluated by the questionnaire include sleep disturbances, respiratory difficulties, mood 
disturbances, self-harm, social skills, and stereotyped hand movements. The Chronbach’s 
alpha for the RSBQ was high (>0.90) for the RSBQ total score and moderate (0.60–0.79) to 
high for all the sub-scales. The questionnaire test-retest reliability was assessed by calculating 
intra-class correlations between two completions of the questionnaire. Intra-class correlations 

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were high (>0.80) or moderate (0.60–0.79) for the RSBQ total score and all the sub-
scales.[46] 
Caregivers’ Burden 
The burden related to the implementation of the treatment will be assessed through the 
administration, at the end of the study, of a questionnaire to all parents, therapists, teachers, 
and other caregivers involved in the intervention. The items included in this questionnaire 
will address the burden derived from the treatment implementation, the parental satisfaction, 
and the intervention’s perceived efficacy concerning functional skills and posture of the trunk 
and spine. The same questionnaire was successfully used when evaluating previous results of 
a few remote rehabilitation research with individuals with RTT.[38,47]  
Statistical analysis 
The normality of each variable’s distribution will be assessed using the Shapiro-Wilk 
normality test. The ages, amount of received physical rehabilitation interventions, scoliotic 
curve degrees, behavioral characteristics, and activity and gross motor functional levels 
obtained at T1 will be compared between the two groups to assess their comparability 
through Wilcoxon’s signed-rank test or Student’s T-test (dependent of the variable 
distribution characteristics). Changes that occurred in the variables of each group at T1, T2, 
and T3 will be evaluated with Friedman’s test or with the repeated measure ANOVA 
(dependent on the variable distribution characteristics). Between groups comparison for each 
variable collected at T1, T2, and T3 and for their variations that occurred between T1 and T2 
and between T2 and T3 will be conducted using the Wilcoxon’s signed-rank test or Student’s 
T-test (dependent of the variable distribution characteristics), applying an appropriate 
adjustment for the age and gross motor skills of the participants. Relations will be searched 
between variables collected at T1 and the changes in the scoliosis curve degree and motor 
functioning after the treatment using Spearman’s rank correlation coefficient or Pearson’s 
correlation coefficient (dependent on the variable distribution characteristics). Moreover, a 
relation between the compliance with the proposed program and the changes in the scoliosis 
curve degree and motor functioning after the treatment will be searched using the Spearman’s 
rank correlation coefficient or Pearson’s correlation coefficient (dependent on the variable 
distribution characteristics). The threshold for significance of the above-described analyses 
will be set at α = 0.05. No correction for multiple comparisons will be applied.[48] 
 
 

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Importance of the Research 
The current study is of high importance for the population with RTT as no established 
conservative treatment is available for scoliosis prevention in RTT. Previous findings 
suggested that intense daily-based activity programs hold the potential to reduce the scoliosis 
progression in people with RTT and, in some cases, to reduce the scoliotic curve.[35,36] 
However, the proposed study will be the first attempt to prove the efficacy of such programs 
within a randomized controlled trial where the control group is enrolled as a waiting-list 
group. The results gathered from the current protocol will add to the existing literature 
supporting the implementation of a supervised activity program for all individuals with RTT 
urging clinicians to provide this service to their clients with RTT. Moreover, the information 
obtained from the current research will allow the researcher to identify the fundamental 
elements that can incentivize or limit the effectiveness of these activity programs, allowing 
the creation of guidelines for the construction of such individualized programs. 
Moreover, the application developed within the current project will represent a valid 
and reliable tool to support and monitor the development of the activity programs in a home-
based environment, thereby enabling all the involved professionals to closely follow their 
clients and caregivers to have all the information necessary for the program’s implementation 
available. The developed application will be available in five languages (Italian, English, 
Hebrew, Arabic, and Russian), allowing its use across several countries. Moreover, we trust 
that such an application can be a significant incentive to families and support teams for many 
with disabilities, thereby enabling adherence to remote rehabilitation programs with minimal 
costs. 

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References 
[1] 
Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett 
syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding 
protein 2. Nat Genet 1999;23:185–8. doi:10.1038/13810. 
[2] 
Fombonne E, Simmons H, Ford T, Meltzer H, Goodman R. Prevalence of pervasive 
developmental disorders in the British nationwide survey of child mental health. Int 
Rev Psychiatry 2003;15:158–65. doi:10.1080/0954026021000046119. 
[3] 
Skjeldal OH, von Tetzchner S, Aspelund F, Aas Herder G, Lofterød B. Rett syndrome: 
geographic variation in prevalence in Norway. Brain Dev 1997;19:258–61. 
doi:10.1016/S0387-7604(97)00572-X. 
[4] 
Pini G, Milan M, Zappella M. Rett syndrome in Northern Tuscany (Italy): Family tree 
studies. Clin Genet 1996;50:486–90. doi:10.1111/j.1399-0004.1996.tb02718.x. 
[5] 
Logan SW, Huang HH, Stahlin K, Galloway JC. Modified ride-on car for mobility and 
socialization: Single-case study of an infant with down syndrome. Pediatr Phys Ther 
2014;26:418–4269. doi:10.1097/PEP.0000000000000070. 
[6] 
Hagberg B, Witt-Engerström I, Opitz JM, Reynolds JF. Rett Syndrome: A suggested 
staging system for describing impairment profile with increasing age towards 
adolescence. Am J Med Genet 1986;25:47–59. doi:10.1002/ajmg.1320250506. 
[7] 
Bassett GS, Tolo VT. The Incidence and Natural History of Scoliosis in Rett 
Syndrome. Dev Med Child Neurol 1990;32:963–6. doi:10.1111/j.1469-
8749.1990.tb08118.x. 
[8] 
Ager S, Downs J, Fyfe S, Leonard H. Parental experiences of scoliosis management in 
Rett syndrome. Disabil Rehabil 2009;31:1917–24. doi:10.1080/09638280902846392. 
[9] 
Ager S, Fyfe S, Christodoulou J, Jacoby P, Schmitt L, Leonard H. Predictors of 
scoliosis in Rett syndrome. J Child Neurol 2006;21:809–13. 
doi:10.1177/08830738060210091501. 
[10] Riise R, Brox JI, Sorensen R, Skjeldal OH. Spinal deformity and disability in patients 
with Rett syndrome. Dev Med Child Neurol 2011;53:653–7. doi:10.1111/j.1469-
8749.2011.03935.x. 
[11] Lidström J, Stokland E, Hagberg B. Scoliosis in rett syndrome clinical and biological 
aspects. Spine (Phila Pa 1976) 1994;19:1632–5. doi:10.1097/00007632-199407001-
00013. 
[12] Downs J, Bergman A, Carter P, Anderson A, Palmer GM, Roye D, et al. Guidelines for 
Management of Scoliosis in Rett Syndrome Patients Based on Expert Consensus and 

16 
 
Clinical Evidence. Spine (Phila Pa 1976) 2009;34:E607–17. 
doi:10.1097/BRS.0b013e3181a95ca4. 
[13] Percy AK, Lee HS, Neul JL, Lane JB, Skinner SA, Geerts SP, et al. Profiling scoliosis 
in rett syndrome. Pediatr Res 2010;67:435–9. doi:10.1203/PDR.0b013e3181d0187f. 
[14] Huang TJ, Lubicky JP, Hammerberg KW. Scoliosis in Rett syndrome. Orthop Rev 
1994;23:931–7. doi:10.1097/01241398-198808020-00003. 
[15] Killian JT, Lane JB, Lee HS, Skinner SA, Kaufmann WE, Glaze DG, et al. Scoliosis in 
Rett Syndrome: Progression, Comorbidities, and Predictors. Pediatr Neurol 
2017;70:20–5. doi:10.1016/j.pediatrneurol.2017.01.032. 
[16] Harrison DJ, Webb PJ. Scoliosis in the rett syndrome: Natural history and treatment. 
Brain Dev 1990;12:154–6. doi:10.1016/S0387-7604(12)80200-2. 
[17] Downs J, Torode I, Wong K, Ellaway C, Elliott EJ, Christodoulou J, et al. The natural 
history of scoliosis in females with rett syndrome. Spine (Phila Pa 1976) 2016;41:856–
63. doi:10.1097/BRS.0000000000001399. 
[18] Neul JL, Fang P, Barrish J, Lane J, Caeg EB, Smith EO, et al. Specific mutations in 
methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology 
2008;70:1313–21. 
[19] Mehta J., Gibson M. The treatment of neuromuscular scoliosis. Curr Orthop 
2003;17:313–21. doi:10.1016/S0268-0890(03)00002-1. 
[20] Westerlund LE, Gill SS, Jarosz TS, Abel MF, Blanco JS. Posterior-only unit rod 
instrumentation and fusion for neuromuscular scoliosis. Spine (Phila Pa 1976) 
2001;26:1984–9. 
[21] Rocos B, Zeller R. Correcting Scoliosis in Rett Syndrome. Cureus 2021;13. 
doi:10.7759/CUREUS.15411. 
[22] Barney CC, Merbler AM, Quest K, Byiers BJ, Wilcox GL, Schwantes S, et al. A case-
controlled comparison of postoperative analgesic dosing between girls with Rett 
syndrome and girls with and without developmental disability undergoing spinal 
fusion surgery. Paediatr Anaesth 2017;27:290–9. doi:10.1111/pan.13066. 
[23] Larsson EL, Aaro S, Ahlinder P, Normelli H, Tropp H, Öberg B. Long-term follow-up 
of functioning after spinal surgery in patients with Rett syndrome. Eur Spine J 
2009;18:506–11. doi:10.1007/s00586-008-0876-6. 
[24] Downs J, Young D, de Klerk N, Bebbington A, Baikie G, Leonard H. Impact of 
scoliosis surgery on activities of daily living in females with Rett syndrome. J Pediatr 
Orthop 2009;29:369–74. doi:10.1097/BPO.0b013e3181a53b41. 

17 
 
[25] Downs J, Torode I, Wong K, Ellaway C, Elliott EJ, Izatt MT, et al. Surgical fusion of 
early onset severe scoliosis increases survival in Rett syndrome: a cohort study. Dev 
Med Child Neurol 2016;58:632–8. doi:10.1111/dmcn.12984. 
[26] Kerr AM, Webb P, Prescott RJ, Milne Y. Results of surgery for scoliosis in Rett 
syndrome. J Child Neurol 2003;18:703–8. doi:10.1177/08830738030180101201. 
[27] Roberts SB, Tsirikos AI. Factors influencing the evaluation and management of 
neuromuscular scoliosis: A review of the literature. J Back Musculoskelet Rehabil 
2016;29:613–23. doi:10.3233/BMR-160675. 
[28] SOSORT guideline committee, Weiss H-R, Negrini S, Rigo M, Kotwicki T, Hawes 
MC, et al. Indications for conservative management of scoliosis (guidelines). Scoliosis 
2006;1:5. doi:10.1186/1748-7161-1-5. 
[29] Kotwicki T, Jozwiak M. Conservative management of neuromuscular scoliosis: 
Personal experience and review of literature. Disabil Rehabil 2008;30:792–8. 
doi:10.1080/09638280801889584. 
[30] Karimi M, Rabczuk T. Scoliosis conservative treatment: A review of literature. J 
Craniovertebral Junction Spine 2018;9:3. doi:10.4103/JCVJS.JCVJS_39_17. 
[31] Haleem S, Nnadi C. Scoliosis: a review. Paediatr Child Health (Oxford) 2018;28:209–
17. doi:10.1016/j.paed.2018.03.007. 
[32] Ferrari A, Ferrara C, Balugani M, Sassi S. Severe scoliosis in neurodevelopmental 
disabilities: Clinical signs and therapeutic proposals. Eur J Phys Rehabil Med 
2010;46:563–79. 
[33] Downs J, Torode I, Ellaway C, Jacoby P, Bunting C, Wong K, et al. Family satisfaction 
following spinal fusion in Rett syndrome. Dev Neurorehabil 2016;19:31–7. 
doi:10.3109/17518423.2014.898107. 
[34] Olafsson Y, Saraste H, Al-Dabbagh Z. Brace treatment in neuromuscular spine 
deformity. Stud Health Technol Inform 1999;59:332–5. doi:10.3233/978-1-60750-903-
5-332. 
[35] Lotan M, Merrick J, Carmeli E. Managing Scoliosis in a Young Child with Rett 
Syndrome: A Case Study. Sci World J 2005;5:264–73. doi:10.1100/tsw.2005.33. 
[36] Romano A, Ippolito E, Risoli C, Malerba E, Favetta M, Sancesario A, et al. Intensive 
Postural and Motor Activity Program Reduces Scoliosis Progression in People with 
Rett Syndrome. J Clin Med 2022;11:559. doi:10.3390/jcm11030559. 
[37] Lotan M, Downs J, Elefant C. A Pilot Study Delivering Physiotherapy Support for Rett 
Syndrome Using a Telehealth Framework Suitable for COVID-19 Lockdown. Dev 

18 
 
Neurorehabil 2021;24:429–34. doi:10.1080/17518423.2021.1914762. 
[38] Romano A, Di Rosa G, Tisano A, Fabio RA, Lotan M. Effects of a remotely supervised 
motor rehabilitation program for individuals with Rett syndrome at home. Disabil 
Rehabil 2021:1–11. doi:10.1080/09638288.2021.1949398. 
[39] Romano A, Ippolito E, Favetta M, Lotan M, Moran DS. Individualised Remotely-
Supervised Motor Activity Programs Promote Rehabilitation Goal Achievement, 
Motor Functioning, and physical activity of People with Rett Syndrome. Res Dev 
Disabil n.d. 
[40] Jeffrey L. Neul, Kaufmann WE, Glaze DG, Christodoulou J, Clarke AJ, Bahi-Buisson 
N, et al. Rett syndrome: Revised diagnostic criteria and nomenclature. Ann Neurol 
2010;68:944–50. doi:10.1002/ana.22124. 
[41] Fabio RA, Martinazzoli C, Antonietti A. Development and standardization of the 
“rars”(Rett assessment rating scale). Life Span Disabil 2005;8:257–81. 
[42] Romano A, Caprì T, Semino M, Bizzego I, Di Rosa G, Fabio RA. Gross Motor, 
Physical Activity and Musculoskeletal Disorder Evaluation Tools for Rett Syndrome: 
A Systematic Review. Dev Neurorehabil 2020;23:485–501. 
doi:10.1080/17518423.2019.1680761. 
[43] van Urk P, van den Berg M, Lotan M, Downs J, Royen Van B, Curfs L. Profiling 
scoliosis in Rett syndrome patients; a retrospective study in the Netherlands. 3rd Rett 
Syndr. Eur. Conf., Maastricht: 2013. 
[44] Rodocanachi Roidi ML, Isaias IU, Cozzi F, Grange F, Scotti FM, Gestra VF, et al. 
Motor function in Rett syndrome: comparing clinical and parental assessments. Dev 
Med Child Neurol 2019;61:957–63. doi:10.1111/dmcn.14109. 
[45] Rodocanachi Roidi ML, Isaias IU, Cozzi F, Grange F, Scotti FM, Gestra VF, et al. A 
New Scale to Evaluate Motor Function in Rett Syndrome: Validation and 
Psychometric Properties. Pediatr Neurol 2019;100:80–6. 
doi:10.1016/j.pediatrneurol.2019.03.005. 
[46] Mount RH, Charman T, Hastings RP, Reilly S, Cass H. The Rett Syndrome Behaviour 
Questionnaire (RSBQ): refining the behavioural phenotype of Rett syndrome. J Child 
Psychol Psychiatry 2002;43:1099–110. doi:10.1111/1469-7610.00236. 
[47] Lotan M, Ippolito E, Favetta M, Romano A. Skype Supervised, Individualized, Home-
Based Rehabilitation Programs for Individuals With Rett Syndrome and Their Families 
– Parental Satisfaction and Point of View. Front Psychol 2021;12:3995. 
doi:10.3389/fpsyg.2021.720927. 

19 
 
[48] Armstrong RA. When to use the Bonferroni correction. Ophthalmic Physiol Opt 
2014;34:502–8. doi:10.1111/opo.12131. 
 

1 
 
Appendix 1 – Ariel University Institutional Review Board approval

1 
 
Appendix 2 - Informed consent form 
 
Title of the study: 
An intensive Anti-Scoliosis Postural Intervention Supported by an Application 
for Individuals with Rett syndrome 
 
I, the undersigned  ___________________________________________________________ 
                        Legally recognized family member / representative. 
 
as _________________________________________________________________________ 
Indicate the relationship with the patient (legally recognized family member / representative). 
 
of _________________________________________________________________________ 
                                                    Surname and Name of the patient.  
 
born in, on: _________________________________________________________________ 
                                                  Place and date of birth of the patient. 
 
 
DECLARE THE FOLLOWING: 
1. I have read and understood the Patient Information Sheet; 
2. I 
received 
complete 
explanations 
on 
the 
clinical 
study 
from 
Dr. 
____________________________ (investigator or authorized member of the team) to 
whom I had the possibility to ask questions and explanations and from whom I received 
satisfactory answers to my questions; 
3. I was told the nature, purpose, and duration of the study, the procedures that will be 
adopted for carrying out the research, and the type of collaboration that will be required; 
4. I understand that the participation of the patient I represent is free and voluntary and 
that at any time, I can decide to terminate her participation and withdraw her from the 
research without having to provide justification, without her being deprived in any way of 
care and assistance she needs or access to new diagnostic and / or therapeutic perspectives, 

2 
 
and without compromising her rights and her relationship with the involved doctors, health 
professionals, and technicians;  
5. I understand that the staff of the department (doctors and physiotherapists) and those 
engaged in the research will be able to view - under the direction and with the authorization 
of the doctor in charge of the study - the data collected relating to the patient; 
6. I accept that, as part of this research project, video recordings of myself and my 
daughter can be made and that these can be used anonymously for research purposes, in 
congresses and conferences, and for professional development; 
7. Under the Italian Legislative Decree 196/2003 and subsequent amendments, I agree to 
the collection, analysis, opening and transfer of my data (including the transfer outside the 
European Economic Area) for health care or medical research purposes. 
 
Understood all this, in my full capacity to understand and want, and without any form 
of conditioning or coercion, I confirm that I agree to the patient’s participation, of 
which I am the legally recognized Representative in the study described in this 
document. 
 
Signature of the legally recognized family member / Representative:  
 
___________________________________________ 
 
 
Place and date: _________________________ 
 
 

3 
 
PART RESERVED TO THE INVESTIGATOR OR AUTHORIZED MEMBER OF THE 
TEAM:  
 
I, the undersigned Dr. ____________________________________________  
                                                             (Surname and Name). 
 
declare: 
 
a. to have explained to the legally recognized Representative the nature and purpose of 
the research as well as the procedures that will be adopted and the type of collaboration that 
will be requested; 
b. not to have tried to influence or force in any way the legally recognized Representative 
to induce him / her to give his / her consent to the patient’s participation in the research; 
c. to have issued to the legally recognized Representative a signed and dated copy of this 
form and the information sheet. 
 
 
 
Place and date: ___________________________         
 
Signature: _____________________________ 
 
 
 

1 
 
Appendix 3 – Research timetable 
 
 
A. Organize the research: gather the participants, obtain the IRB approval in Italy, and prepare the forms. 
B. Evaluation of each participant. Construction of the individualized equipment for postural alignment and a workshop for parents / 
caregivers / therapists from Group 1 (one week). 
C. Start of the intervention for Group 1. 
D. Intervention in progress for Group 1 with supervision via Skype calls and Group 2 waiting-list phase. 
E. Evaluation of each participant.  
F. Construction of the individualized equipment for postural alignment and a workshop for parents / caregivers / therapists from Group 2 
(one week). 
G. Start of the intervention for Group 2. 
H. Intervention in progress for Group 2 with supervision via Skype calls and Group 1 follow-up. 
I. Evaluation of each participant.  
J. Summary of results. 
1 month
10 months 
First year 
Second year 
10 months 
2 months 
A           B   C                       D 
E  F                        G                         H     I 

1 
 
Appendix 4 – Anamnestic information data collection sheet 
 
An intensive Anti-Scoliosis Postural Intervention Supported by an Application for 
Individuals with Rett syndrome 
 
Dear family, 
we kindly ask you to fill in this anamnestic questionnaire for participation in the research you 
have joined and send it to Airett (email: centrorett@airett.it). 
AIRett will send the questionnaire to Dr. Marina Rodocanachi, the doctor responsible for the 
clinical aspects of the research, from which you will then be contacted to arrange a remote 
interview for verification of the clinical aspects relating to participation. A possible physiatric 
examination of your daughter can subsequently be scheduled at the San Paolo Hospital in 
Milan. 
 
Compilation date: ___/___/_____    
Name and surname of your daughter ___________________________    
Residence address: ___________________________________________________________ 
___________________________________________________________________________ 
Name, surname and telephone number of parents: __________________________________ 
___________________________________________________________________________ 
Parents' email address: ________________________________________________________ 
Name, surname and contact (telephone or email) of the therapist:_______________________ 
___________________________________________________________________________ 
Name, surname and contact (telephone or email) of the referring general practitioner: ______ 
___________________________________________________________________________ 
 
DEMOGRAPHIC DATA 
Date of birth (dd/mm/yyyy) 
Current head circumference: 
Current weight: 
Current height: 
 
 

2 
 
ANAMNESTIC DATA 
Duration of pregnancy 
Full-term☐ 
Preterm ☐ 
Head circumference at birth (cm): 
 
Deceleration of the head circumference in the first year of 
life 
YES ☐ 
NO ☐ 
 
 
 
Psychomotor development in the first year of life: 
 
 
– delay from the first months of life 
YES ☐ 
NO ☐ 
– regression in the first six months of life 
YES ☐ 
NO ☐ 
– regression within the first year of life 
YES ☐ 
NO ☐ 
– late regression (after the first year of life) 
YES ☐ 
NO ☐ 
– First regressive symptom highlighted by the family: 
 
 
When:  
 
– First symptom of motor regression: 
 
 
When: 
 
Genetic mutation 
 
MECP2 gene mutation code: 
…………………………………………….………………...……… 
 
Exam performed at: 
………………………………….……………….…………......……………..…….. 
Education (current year of school attendance): 
 
Attendance at a day center for people with disability 
YES ☐ 
NO ☐ 
If yes, for how many hours? 
 
 
Rehabilitation activity 
YES ☐ 
NO ☐ 
If there is currently no ongoing rehabilitation project, 
has there been in the past? 
YES ☐ 
NO ☐ 
If yes, indicate the year of start and end of treatment: 
 

3 
 
The patient uses augmentative communication: 
YES ☐ 
NO ☐ 
Frequency of augmentative communication (indicate 
the number of times per week or month): 
 
Duration of the augmentative communication (in 
years): 
 
 
The patient does music therapy: 
YES ☐ 
NO ☐ 
Frequency of music therapy (indicate the number of 
sessions per month): 
 
Duration of music therapy (in years): 
 
 
 
 
If at least one rehabilitation intervention is in progress, circle the number of times a 
week your daughter receives therapy sessions from a rehabilitation professional 
(therapist) 
Intervention 
Weekly sessions 
Duration of each session 
Physiotherapy 
1 
2 
3 
4 
<30 min 
30-45 min 
>45 min 
Hydrotherapy 
1 
2 
3 
4 
<30 min 
30-45 min 
>45 min 
Occupational therapy 
1 
2 
3 
4 
<30 min 
30-45 min 
>45 min 
Psychomotricity 
1 
2 
3 
4 
<30 min 
30-45 min 
>45 min 
Speech therapy 
1 
2 
3 
4 
<30 min 
30-45 min 
>45 min 
Music therapy 
1 
2 
3 
4 
<30 min 
30-45 min 
>45 min 
Hippotherapy 
1 
2 
3 
4 
<30 min 
30-45 min 
>45 min 
Osteopathy 
1 
2 
3 
4 
<30 min 
30-45 min 
>45 min 
If your daughter receives other rehabilitation interventions not mentioned, please 
specify them below 
Intervention: 
1 
2 
3 
4 
<30 min 
30-45 min 
>45 min 
Intervention: 
1 
2 
3 
4 
<30 min 
30-45 min 
>45 min 
 
 
 
 
 
 
 
 

4 
 
CLINICAL SITUATION 
 
1. Epilepsy 
0. Not present 
1. Single or sporadic 
seizures (no drug 
treatment) 
2. Controlled by drugs 
3. Not controlled 
(drug-resistant) 
 
– Current frequency of seizures (if any): 
0. Sporadic 
1. Multi-monthly 
2. Multi-weekly 
3. Multi-daily 
 
– Current antiepileptic therapy: ……………………………………………………………… 
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
 
2. Sleep disorders 
0. Not present 
1. Mild 
2. Moderate 
3. Severe 
 
What type of sleep disorder is present? (indicate even more than 
one): 
 
 
Awakenings at night 
YES ☐ 
NO ☐ 
Difficulty falling asleep 
YES ☐ 
NO ☐ 
Insomnia throughout the night 
YES ☐ 
NO ☐ 
Early awakening in the morning 
YES ☐ 
NO ☐ 
Daytime sleepiness  
YES ☐ 
NO ☐ 
Others 
 
 
 
– Current therapy for sleep disorder: ………………………………………………………… 
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
 

5 
 
3. Behavioral problems 
0. Not present 
1. Mild 
2. Moderate 
3. Severe 
 
What type of behavior disorder? (indicate even more than one): 
 
 
 
Night agitation 
YES ☐ 
NO ☐ 
Daytime agitation 
YES ☐ 
NO ☐ 
Changes in mood (depressive symptoms) 
YES ☐ 
NO ☐ 
Others 
 
 
 
– Current therapy for behavioral problems: …………………………………………………… 
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
 
4. Respiratory problems 
0. Not present 
1. Mild 
2. Moderate 
3. Severe 
 
What type of breathing disorder is present? (indicate even more 
than one): 
 
 
Apneas 
YES ☐ 
NO ☐ 
Hyperventilation 
YES ☐ 
NO ☐ 
Others 
 
 
 
– Current therapy for respiratory problems: …………………………………………………… 
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
 
 
 

6 
 
5. Gastrointestinal problems 
0. Not present 
1. Mild 
2. Moderate 
3. Severe 
 
 
What type of gastrointestinal disorder is present? (indicate even 
more than one): 
 
 
Constipation 
YES ☐ 
NO ☐ 
Gastroesophageal reflux 
YES ☐ 
NO ☐ 
Abdominal distension due to aerophagia 
YES ☐ 
NO ☐ 
Lack of appetite 
YES ☐ 
NO ☐ 
Bruxism  
YES ☐ 
NO ☐ 
Other: (e.g., Tube feeding, PEG, gastrostomy...) 
 
 
 
– Current therapy for gastrointestinal problems: ……………………………………………… 
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
 
6. Nutrition  
WHAT she eats / Preferences / Refusal: …………………………………………………… 
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
 
She is fed with (check one or more boxes):    □ Liquid              □ Semi-solid              □ Solid 
Does she chew? 
YES ☐ 
NO ☐ 
Does she lose food from the mouth? 
YES ☐ 
NO ☐ 
Does she bring food to her mouth? 
YES ☐ 
NO ☐ 
Others 
 
 

7 
 
How she drinks: ………………………………………..……………………………………… 
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
 
Describe the duration of the meal (e.g., very short, prolonged...): …………………………… 
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
 
Do parents think she is well fed: .…………………………………………………………… 
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
 
7. Musculoskeletal problems 
0. Not present 
1. Mild 
2. Moderate 
3. Severe 
 
 
What type of musculoskeletal problem is present: 
Scoliosis 
YES ☐ 
NO ☐ 
Joint deformities 
YES ☐ 
NO ☐ 
Has she ever had a spine x-ray? 
YES ☐ 
NO ☐ 
Date of the last radiograph: * 
 
 
Has she ever had a pelvis x-ray? 
YES ☐ 
NO ☐ 
Date of the last radiograph: * 
 
 
Have you ever had a lower limb x-ray? 
YES ☐ 
NO ☐ 
Date of the last radiograph: * 
 
 
Joint deformities 
YES ☐ 
NO ☐ 
Surgery for scoliosis 
YES ☐ 
NO ☐ 
Joint deformity surgery 
YES ☐ 
NO ☐ 
Botulinum toxin 
YES ☐ 
NO ☐ 
Wear a brace for the scoliosis 
YES ☐ 
NO ☐ 
* it is helpful to bring the most recent radiographs to the clinical evaluation 
 

8 
 
8. Walking:  
0. Normal 
1. Compromised 
2. Acquisition lost 
3. Never acquired 
 
If she walks, she does it: 
 
Independently  ☐ 
With 
support ☐ 
First steps (age): 
Age at which she stopped walking: 
Use the wheelchair: 
YES   ☐ 
NO  ☐ 
Use other aids (describe below): 
YES   ☐ 
NO  ☐ 
If yes, describe which aids she uses: ………………………………………………………… 
……………………………………….………………………………………………………… 
……………………………………….………………………………………………………… 
 
9. Assistive devices 
Orthotics / Shoes 
YES ☐ 
NO ☐ 
AFO 
YES ☐ 
NO ☐ 
Upper limb brace 
YES ☐ 
NO ☐ 
Corset (specify the type and the hours of use) 
YES ☐ 
NO ☐ 
Custom-made chair 
YES ☐ 
NO ☐ 
Positioning system 
YES ☐ 
NO ☐ 
Stroller 
YES ☐ 
NO ☐ 
Outdoor wheelchair 
YES ☐ 
NO ☐ 
Standing frame 
YES ☐ 
NO ☐ 
Walker 
YES ☐ 
NO ☐ 
Lifter 
YES ☐ 
NO ☐ 
Shower wheelchair 
YES ☐ 
NO ☐ 
Bed 
YES ☐ 
NO ☐ 
Other devices (theratogs, functional bandages…) 
 
 
 
 

9 
 
10. Verbal communication: 
First words (age): …………………………………….……………………………………… 
 
Currently: …………………………………………………………………………………… 
…………………………………………………..………………………….………………… 
………………………………………………………………………………………………… 
 
Does she use phrases? 
YES ☐ 
NO ☐ 
Does she use single words? 
YES ☐ 
NO ☐ 
She does not speak                      
YES ☐ 
NO ☐ 
 
Age at which she stopped talking: ……………………………….…………………………… 
 
11. Other aspects of clinical-health interest and related therapies: 
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
…………………………………………………………………………………………………
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
 
12. Other accesses to medical services not yet mentioned (e.g., hospital or first aid 
admissions, surgeries that took place in the previous year). Indicate the type of 
intervention and the reason for access: 
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
…………………………………………………………………………………………………
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
 

10 
 
13. Other medications in use not listed above: 
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
…………………………………………………………………………………………………
………………………………………………………………………………………………… 
………………………………………………………………………………………………… 
 
Signature of the authorized member of the team 
 
 
 
 
____________________________  
 
 
 
Parent’s signature 
 
____________________________ 
 
We thank you for your attention and time dedicated 
 

1 
 
Appendix 5 – Rett Assessment Rating Scale (RARS) 
 
 
R.A.R.S. is a tool developed to assess the level of seriousness of the illness in girls suffering from 
Rett syndrome. It comprises 31 points concerning the various behavioural areas, each of which will 
be assigned a variable score from 1 to 4. The sum total of the scores will give an overall value 
determining a slight, average or high seriousness of Rett syndrome. 
 
 
COGNITIVE AREA 
 
I. Attention: 
 
 
 
 
 
 
 
 
 
II. Spatial orientation: 
 
 
 
 
 
 
 
 
 
 
 
III. . Temporal orientation: 
 
 
 
 
 
 
 
 
 
 
IV. Memory: 
 
 
 
 
 
  
 
V. Eye contact, replying by smiling, shared attention: 
 
.  
 
 
 
 
 
 
 
 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl has a constant attention span 
over time, in other words there is not 
alternation between a state of 
excitability and a state of calm.  
 
The girl has slight difficulty in 
maintaining attention over time, in 
other words there is no significant 
alternation between a state of 
excitability and a state of calm.  
  
The girl often has difficulty in 
maintaining attention over time, in 
other words there is frequent 
alternation between s state of 
excitability and a state of calm. 
The girl has excessive difficulty in 
maintaining attention over time, in 
other words there is a significant 
alternation between a state of 
excitability and a state of calm, 
leading to selective attention 
deficiency. 
1 
2 
3 
4 
1.5 
2.5 
3.5 
If the girl is asked to look at or go to 
the kitchen or another location 
without assistance, she orients 
herself well. 
If the girl is asked to look at or go to 
the kitchen or another location 
without assistance, she has slight 
difficulty in orienting herself. 
If the girl is asked to look at or go to 
the kitchen or another location 
without assistance, she often has 
difficulty in orienting herself. 
If the girl is asked to look at or go to 
the kitchen or another location 
without assistance, she cannot orient 
herself. 
1 
2 
3 
4 
1.5 
2.5 
3.5 
If the word “later” is said to the girl, 
she understands that she has to wait. 
If the word “later” is said to the girl, 
she sometimes understands that she 
has to wait. 
If the word “later” is said to the girl, 
she hardly ever understands that she 
has to wait. 
If the word “later” is said to the girl, 
she never understands that she has to 
wait. 
1 
2 
3 
4 
1.5 
2.5 
3.5 
 The girl accurately remembers 
places and people she has already 
met, recognising them by smiling. 
The girl does not always accurately 
remember places and the people she 
has already met, recognising them by 
smiling. 
The girl hardly ever accurately 
remembers places and the people she 
has already met, recognising them by 
smiling. 
The girl never remembers places and 
the people she has already met, 
recognising them by smiling. 
1 
The girl has not difficulty in sharing 
attention, spontaneously looks for 
attention from adults and smiles 
when cuddled. 
2 
The girl sometimes has difficulty in 
establishing and maintaining 
spontaneous eye contact, smiling 
when cuddled or in the presence of 
social stimulus and sharing attention. 
2.5 
3 
4 
3.5 
The girl never establishes 
spontaneous eye contact, never 
responds to cuddling or social 
stimulus by smiling and never shares 
attention. 
 
The girl often has difficulty in 
establishing and maintaining 
spontaneous eye contact, smiling 
when cuddled or in the presence of 
social stimulus and sharing attention. 
1.5 

2 
 
 
VI. Verbal communication:        
 
 
 
 
 
 
 
 
 
 
 
 
VII.  Non-verbal communication: 
 
 
 
 
 
 
 
 
 
 
 
 
 
SENSORAL AREA 
 
VIII. Eyesight:    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IX. Hearing: 
      
 
 
 
 
 
 
 
 
 
 
MOTORIAL AREA 
 
X. Body:      
 
 
 
 
 
 
 
1 
2 
3 
4 
1.5 
2.5 
3.5 
Visual response is in the norm with 
respect to age and is used as a means 
of exploring new objects and there is 
a fixed look towards objects. 
 
Visual response is not within the 
norm with respect to age; it is not 
always used as a means of exploring 
new objects and there is not always a 
fixed look towards objects. 
 
The girl uses an intermittent and 
peripheral look (does not look 
directly at objects, but does so from 
out of the corner of the eye), 
recognising the difference between 
known and unknown objects.  
The girl seems not to recognise the 
difference between known and 
unknown objects when looking at 
them. 
1 
2 
3 
4 
1.5 
2.5 
3.5 
Hearing response is in the norm with 
respect to age and is used as a means 
of exploring the surrounds. 
 
Hearing response is not in the norm 
with respect to age and is not always 
used as a means of exploring the 
surrounds. 
Hearing response varies; the girl 
alternates periods of hypersensitive 
hearing with moments of very low 
hearing (she recognises aural 
stimulus as being very strong or not 
at all). 
The girl has an excessive or no 
reaction to sounds, independently of 
their type. 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl is able to maintain an erect 
position and to walk by herself. She 
knows how to look where she is 
going, walk on any surface and go 
up and down stairs. 
The girl is able to maintain an erect 
position but sometimes needs 
support when walking. 
The girl is able to maintain an erect 
position but always needs support 
when walking. 
The girl is unable to maintain an 
erect position or walk by herself. She 
needs a wheelchair or a pram in 
order to move around. 
 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl show intention in verbal 
communications; she manages to 
express her needs using sounds or 
short words. 
The girl only sometimes manages to 
express her needs using sounds or 
short words. 
The girl hardly ever manages to 
express her needs using sounds or 
short words. 
The girl never communicates 
verbally in any way. 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl normally uses non-verbal 
communication; she knows how to 
express herself using gestures and 
facial expressions. 
The girl has difficulty in non-verbal 
communication; she manages to 
point and reach out to what she 
wants with her hand but only 
inaccurately. 
The girl manages to point and reach 
out to what she wants only 
inaccurately and only sometimes.          
The girl generally cannot express her 
needs or wishes in a non-verbal 
manner. 
 

3 
 
 
 
 
XI. Hands:    
 
 
 
 
 
 
 
 
 
 
 
 
 
XII. Scoliosis: 
      
 
 
 
 
 
 
 
 
XIII. Feet: 
      
 
 
 
 
 
 
 
 
 
 
BASIC EMOTIONS 
 
XIV. Basic emotions: 
      
 
 
 
 
 
 
 
 
 
 
 
 
  
XV. Others emotions:      
 
 
 
 
 
 
 
1 
2 
3 
4 
1.5 
2.5 
3.5 
Functional use of the hands is only 
slightly affected; the girl manages to 
grip and hold objects for long 
enough to enable her to make ample 
movements. She has good hand-eye 
coordination. Stereotypes to not 
influence the intentional use of the 
hands. 
 
Functional use of the hands is more 
compromised; the girl manages to 
touch, push or hit objects but not to 
grip them. Hand-eye coordination is 
scarce. The girl is inhibited in 
moving by stereotypes. 
 
 
Functional use of the hands is 
compromised; the girl is not always 
able to use her hands intentionally; 
she does not always manage to touch 
objects, even if strongly motivated to 
do so, especially in the presence of 
marked stereotypes. 
Functional use of the hands is almost 
completely compromised; the girl is 
not able to use her hands 
intentionally; she does not manage to 
touch objects even if strongly 
motivated to do so, especially 
because of insistent stereotypes. 
 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl has no difficulty in 
expressing her basic emotions 
(happiness, anger, fear, sadness) 
through visual expressions, body 
language and emotive expressions. 
The girl has some difficulty in 
expressing her basic emotions 
(happiness, anger, fear, sadness) 
through visual expressions, body 
language and emotive expressions. 
The girl has major difficulty in 
expressing her basic emotions 
(happiness, anger, fear, sadness) 
through visual expressions, body 
language and emotive expressions. 
The girl is unable to express her 
emotions. 
 
1 
2 
3 
4 
The girl shows no signs of scoliosis. 
 
The girl shows signs of minor 
scoliosis. 
The girl shows signs of major 
scoliosis. 
The girl shows signs of very serious 
scoliosis. 
1.5 
2.5 
1 
2 
3 
4 
The girl has no problems with her 
feet. 
 
The girl has slightly small feet, with 
minor circulation problems. 
The girl has small, valgus or 
different sized feet, with circulation 
problems. 
The girl has problems with her feet, 
to the extent that she is unable to 
walk. 
1.5 
2.5 
3.5 
3.5 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl has no difficulty in 
understanding others emotions. 
 
The girl has some difficulty in 
understanding others emotions. 
 
The girl has major difficulty in 
understanding others emotions. 
 
The girl is unable to understand 
others emotions. 
 

4 
 
 
 
AUTONOMY 
 
XVI. Control of the sphincter: 
      
 
 
 
 
 
 
 
 
 
 
XVII. Feeding:      
 
 
 
 
 
 
 
 
 
 
XVIII. Ability to wash and dress: 
 
 
 
 
 
 
 
 
 
 
 
CHARACTERISTICS OF RETT SYNDROME 
 
XIX. Mood changes:      
 
 
 
 
 
 
 
 
 
XX. Convulsions:      
 
 
 
 
 
 
 
 
XXI. Breathing problems: 
 
 
 
 
 
 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl does not have breathing 
difficulties characterised by changes 
in breathing rhythm and frequency. 
The girl sometimes has breathing 
difficulties characterised by changes 
in breathing rhythm and frequency. 
The girl often has breathing 
difficulties characterised by changes 
in breathing rhythm and frequency. 
The girl very often has breathing 
difficulties characterised by changes 
in breathing rhythm and frequency. 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl has full control of her 
excretive functions. 
The girl is not always able to control 
her excretive functions. 
The girl only has part control of 
her excretive functions; she needs 
help. 
The girl has no control of her 
excretive functions. 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl eats and drinks by herself. 
The girl has some difficulty in eating 
and drinking by herself. 
The girl needs a little help in eating 
and drinking. 
The girl is unable to eat and drink by 
herself; she needs to be fed. 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl is able to wash and dress by 
herself. 
The girl has some difficulty in 
washing and dressing. 
The girl needs a little help washing 
and dressing. 
The girl needs to be washed and 
dressed. 
1 
2 
3 
4 
1.5 
2.5 
3.5 
 The girl has no mood changes. 
 
The girl sometimes has mood 
changes. 
The girl often has mood changes. 
The girl always has mood changes. 
 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl does not have convulsions. 
The girl sometimes has convulsions. 
 
The girl often has convulsions. 
The girl very often has convulsions. 
 

5 
 
 
 
XXII. Hyperactivity: 
   
 
 
 
 
 
 
 
 
 
XXIII. Anxiety: 
      
 
 
 
 
 
 
 
 
 
XXIV. Aggressiveness:      
 
 
 
 
 
 
 
 
 
XXV. Bruxism: 
      
 
 
 
 
 
 
 
 
XXVI. Rolling of the eyes:      
 
 
 
 
 
 
 
   
 
 
XXVII. Epilepsy: 
 
 
 
 
 
 
 
 
 
XXVIII. Aerophagia:      
 
 
 
 
 
 
 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl does not behave worryingly 
or impulsively. 
The girl sometimes behaves 
worryingly or impulsively. 
The girl often behaves worryingly or 
impulsively. 
The girl always behaves worryingly 
or impulsively. 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl does not have anxiety 
attacks. 
The girl sometimes has anxiety 
attacks. 
The girl often has anxiety attacks. 
 
The girl always has anxiety attacks. 
 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl does not show any 
aggression. 
The girl is sometimes aggressive. 
The girl is often aggressive. 
The girl is always aggressive. 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl never gnashes her teeth. 
 
The girl sometimes gnashes her 
teeth. 
The girl often gnashes her teeth. 
 
The girl always gnashes her teeth. 
 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl never rolls her eyes towards 
each other. 
The girl sometimes rolls her eyes 
towards each other. 
 
The girl often rolls her eyes towards 
each other. 
 
The girl always rolls her eyes 
towards each other. 
 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl never has epileptic fits. 
 
The girl sometimes has epileptic fits. 
 
The girl often has epileptic fits. 
       
The girl very often has epileptic fits. 
 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl does not suffer from 
aerophagia or intestinal problems. 
The girl sometimes suffers from 
aerophagia or intestinal problems. 
The girl often suffers from 
aerophagia or intestinal problems.  
The girl very often suffers from 
aerophagia or intestinal problems. 

6 
 
 
XXIX. Muscular tension: 
 
      
 
 
 
 
 
 
 
 
XXX. Feeding habits: 
      
 
 
 
 
 
 
 
 
 
XXXI. Overall impression: 
      
 
 
 
 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl always eats willingly. 
The girl does not always eats 
willingly. 
The girl often does not want to eat. 
The girl never wants to eat. 
1 
2 
3 
4 
1.5 
2.5 
3.5 
The girl has no symptoms 
characteristic of Rett syndrome. 
The girl has some symptoms 
characteristic of Rett syndrome. 
The girl has many symptoms 
characteristic of Rett syndrome. 
The girl has all the symptoms 
characteristic of Rett syndrome. 
1 
2 
3 
4 
The girl has no muscular tension. 
 
The girl has some muscular tension.
 
 
The girl has quite high muscular 
tension. 
The girl has very high muscular 
tension. 
1.5 
2.5 
3.5 

1 
 
Appendix 6 – Rett Syndrome Motor Evaluation Scale (RESMES) 
 
Item 
Item definitions 
Score 
Comments 
 
Standing 
The patient should stand on the floor (avoid soft surfaces) without external 
support for as long as possible.  
Score as follow: 
0 = >60s;  
1 = 30-60s;  
2 = 10-29s;  
3 = <10s; 
4 = Impossible. 
Standing position 
Independent The standing position should be maintained 
without any external support. 
  
  
Single 
support 
The standing position should be maintained with 
one single support. Support should be provided 
with one hand to the patient’s hand or wrist (not to 
the elbow or shoulder).    
  
  
Double 
support 
The standing position should be maintained with 
double support. Support should be provided with 
two hands to the patient’s hands or wrists (not the 
elbows or shoulders).    
  
  
 
Sitting 
The patient should sit as long as she can. Do not use chairs with backrests.  
Score as follow: 
0 = >60s;  
1 = 30-60s;  
2 = 10-29s;  
3 = <10s; 
4 = Impossible. 
Sitting position 
On a stool 
without feet 
support 
The patient should sit on a stool without back 
support and feet raised from the floor.  
0 = the patient can maintain the position easily and 
indefinitely.  
4 = The patient needs any kind of support (also 
minimal) to maintain the position.    
  
  
On a stool 
with feet on 
the floor 
The patient should sit on a stool without back 
support and feet on the floor. 0 = the patient can 
maintain the position easily and indefinitely.  
4 = The patient needs any kind of support (also 
minimal) to maintain the position.    
  
  
On the floor 
The patient should sit on the floor. Legs could be 
crossed or extended based on which is easier for 
the patient.  
0 = the patient can maintain the position easily and 
indefinitely.  
4 = The patient needs any kind of support (also 
minimal) to maintain the position.    
  
  

2 
 
 
Postural 
change 
Score as follow: 
0 = Yes, independently, always, without external support; 
1 = Yes, independently but leaning on supports (e.g., furniture); 
2 = Yes, with the help of one person;  
3 = NO, but if passively placed in the position, it can be maintained; 
4 = NO and, if passively placed in the position, it can’t be maintained. 
Postural changes 
Rolling 
supine to 
side 
0 = The rolling is possible independently and 
frequently when the patient is lying on her back 
without help or encouragement.  
1 = The independent rolling is not frequently 
observed, but it is referred that the patient left 
supine was sometimes found on the side.  
2 = help is intended as a person who initiates the 
patient’s rolling movement by rotating a shoulder 
or moving an arm or a leg toward the rolling side. 
  
  
Rolling 
supine to 
prone  
0 = the rolling is possible independently and 
frequently when the child is lying on her back and 
if it happens without help or encouragement.  
1 = the independent rolling is not frequently 
observed, but it is referred that the patient left 
supine was sometimes found on the stomach.  
2 = help is intended as a person who initiates the 
patient’s rolling movement by rotating a shoulder 
or moving an arm or a leg toward the rolling side. 
  
  
From 
supine to 
sitting 
position 
The patient can use the floor as a support base. 
Moreover, a stick can be placed next to the child 
(on the right or left side, indifferently – stick 
diameter: 2,5 cm). The patient can hold the stick 
to perform the task (score = 2). 
0 = Yes, she usually sits from a supine position 
alone without pushing on her upper limbs to 
complete the position change; 
1 = Yes, putting one or two elbows on the ground, 
but without leaning on persons or supports or 
passing through the side or prone position and 
then to a sitting position.  
2 = help is intended as one adult’s hand support or 
leaning on the stick. The adult can exert little 
traction and stabilize the balance but does not have 
to pull the patient to a sitting position or use two 
hands.  
3 = No, but if passively seated from the supine 
position, she can remain seated for at least15 sec; 
4 = NO, and if passively seated from the supine 
position, she can’t maintain the sitting position. 
  
  
From sitting 
on the floor 
to a 
standing 
position 
The patient can use the floor as a support base. 
Moreover, a stick can be placed next to the child 
(on the right or left side, indifferently – stick 
diameter: 2,5 cm). The patient can hold the stick 
to perform the task (score = 1). 
  
  

3 
 
0 = Yes, she usually stands up from sitting on the 
floor alone without any support. 
1 = Yes, with any kind of support (e.g., floor, 
stick, or furniture), but without the help of a 
person.  
2 = help is intended as one adult’s hand support. 
The adult can exert little traction and stabilize the 
balance but does not have to pull the patient to a 
standing position or use two hands.  
From sitting 
on a chair to 
a standing 
position 
The patient can use the armrests as support. 
Moreover, a stick can be placed next to the child 
(on the right or left side, indifferently – stick 
diameter: 2,5 cm). The patient can hold the stick 
to perform the task (score = 1). 
0 = Yes, she usually stands up from sitting on a 
chair, alone, without any kind of support. 
1 = Yes, with any kind of support (e.g., Stick or 
armrests), but without the help from a person.  
2 = help is intended as one adult’s hand support. 
The adult can exert little traction and stabilize the 
balance but does not have to pull the patient to a 
standing position or use two hands.  
  
  
From 
standing to 
sitting on 
the floor 
0 = Yes, she usually sits on the floor from the 
standing position, alone, without any kind of 
support. 
1 = Yes, with any kind of support (e.g., furniture), 
but without the help from a person.  
2 = help is intended as one adult’s hand support. 
The adult can slightly push the patient and 
stabilize the balance but does not have to push the 
patient to a sitting position strongly or use two 
hands. 
  
  
From 
standing to 
sitting on a 
chair 
0 = Yes, she usually sits on a chair from the 
standing position, alone, without any kind of 
support. 
1 = Yes, with any kind of support (e.g., Furniture 
or armrests), but without the help from a person.  
2 = help is intended as one adult’s hand support. 
The adult can slightly push the patient and 
stabilize the balance but does not have to strongly 
push the patient to sit on a chair position or use 
two hands. 
  
  
 
Walking 
The test can be performed with shoes and any lower limbs aid usually used 
by the patient. 
Let the patient walks straight on a long enough pathway with a regular floor 
(avoid soft surface). Report the gait characteristics in the note. 
Score as follow: 
0 = >11 passi;  
1 = <10 passi; 
2 = NON eseguibile. 

4 
 
Walking 
Independent If the patient needs any kind of support to walk, 
score = 2 
  
  
Single 
support 
Support should be provided with one hand to the 
patient’s hand or wrist (not to the elbow or 
shoulder).    
 
 
Double 
support 
Support should be provided with two hands to the 
patient’s hands or wrists (not the elbows or 
shoulders).    
 
 
 
Step over 
obstacles 
The test can be performed with shoes and any lower limbs aid usually used 
by the patient on a regular floor. 
Obstacles should be sticks (3 cm diameter) placed on the floor. The double 
obstacles are two sticks placed with 3 mt distance between each other.  
Score as follow: 
0 = Yes: the obstacle overcoming is not casual; the patient does not touch 
the obstacle for at least three attempts on five; 
1 = Sometimes: the patient goes over the obstacle slightly touching it or 
exploring the obstacle with the foot before overcoming it at least one 
attempt out of five. 
2 = No: the patient never overcame the obstacle in any of the five attempts.  
Step over a single 
Independent The patient should overcome the obstacle without 
any external support.   
 
 
Single 
support 
Support should be provided with one hand to the 
patient’s hand or wrist (not to the elbow or 
shoulder).    
 
 
Double 
support 
Support should be provided with two hands to the 
patient’s hands or wrists (not the elbows or 
shoulders).    
 
 
Step over a double 
Independent The patient should overcome the obstacles 
without any external support.   
 
 
Single 
support 
Support should be provided with one hand to the 
patient’s hand or wrist (not to the elbow or 
shoulder).   
 
 
Double 
support 
Support should be provided with two hands to the 
patient’s hands or wrists (not the elbows or 
shoulders).    
 
 
Runs 
Runs 
Run is intended as a faster walking with a phase in 
which both feet are in the air. 
Support should be provided to the patient’s hands 
or wrists (not to the elbow or shoulder). 
Score as follow: 
0 = Always possible and independent;  
1 = Possible independently at intervals (at least 
three consecutive steps without double support);  
2 = Possible with single support (at least three 
consecutive steps without double support);  
3 = Possible with double support (at least three 
consecutive steps without double support); 
4 = Not possible. 
 
 

5 
 
 
Stairs 
Support should be provided to the patient’s hands or wrists (not to the elbow 
or shoulder). 
Score as follow: 
0 = The patient goes up / down the stairs independently, without holding 
the handrail, and with one foot for each step.  
1 = The patient climbs / descends the stairs with or without one foot for 
each step or holding the handrail, but without the help of a person.  
2 = The patient climbs / descends one or more steps with or without one 
foot for each step and with unilateral support provided by a person;  
3 = The patient climbs / descends one or more steps with both feet for each 
step with bilateral support by a person;  
4 = The patient cannot climb stairs even with support.  
Stairs 
Upstairs 
Observe the patient going up a whole flight of 
stairs. 
 
 
Downstairs Observe the patient going down a whole flight of 
stairs. 
 
 
Total score: 
 
 
 
 

1 
 
Appendix 7 - Rett Syndrome Behavior Questionnaire (RSBQ) 
 
 
 
0 
1 
2 
1. She screams hysterically for long periods of time and cannot be 
consoled. 
0 
1 
2 
2. Although she can stand independently, she tends to lean on 
objects or people. (If your daughter does not stand, please leave 
blank) 
0 
1 
2 
3. Restricted patterns of hand movement. 
0 
1 
2 
4. The abdomen fills with air and sometimes feels hard. 
0 
1 
2 
5. Spells of laughter for no apparent reason during the day. 
0 
1 
2 
6. She has wounds on her hands as a result of repetitive hand 
movements. 
0 
1 
2 
7. She makes mouth grimaces. 
0 
1 
2 
8. There are times when she is irritable for no apparent reason. 
0 
1 
2 
9. Spells of inconsolable crying for no apparent reason during the 
day. 
0 
1 
2 
10. She uses eye gaze to convey feelings, needs, and wishes. 
0 
1 
2 
11. She makes repetitive tongue movements. 
0 
1 
2 
12. She rocks herself when her hands are prevented from moving. 
For each characteristic LISTED BELOW, please think about whether or not it accurately 
describes your daughter at this very point in time. 
• For those VERY TRUE characteristics OR OFTEN TRUE, please tick box 2. 
• For those  SOMEWHAT OR SOMETIMES TRUE characteristics, please tick box 
1. 
• If the behavior DOES NOT describe your daughter, please tick box 0 to indicate 
that the behavior is NOT TRUE AS FAR AS YOU KNOW. 
 
 
Example   
If your daughter uses gesturing very frequently to obtain desired objects, you will tick box 
2 to indicate that it is very true or often true: 
0 
1 
√2 
  

2 
 
0 
1 
2 
13. She makes grimacing expressions on her face. 
0 
1 
2 
14. She has difficulty breaking/stopping repetitive hand 
movements. 
0 
1 
2 
15. She vocalizes for no apparent reason. 
0 
1 
2 
16. Spells of laughter for no apparent reason during the night. 
0 
1 
2 
17. Spells of apparent panic. 
0 
1 
2 
18. She walks with stiff legs. (If your daughter does not walk, 
please leave blank) 
0 
1 
2 
19. She tends to bring her hands together in front of her chin or 
chest. 
0 
1 
2 
20. Rocks body repeatedly. 
0 
1 
2 
21. The amount of time spent looking at objects is longer than the 
time spent holding or manipulating them. (If your daughter 
doesn’t hold/manipulate objects, leave blank) 
0 
1 
2 
22. Spells of inconsolable crying for no apparent reason during the 
night. 
0 
1 
2 
23. She appears isolated. 
0 
1 
2 
24. She makes repetitive hand movements involving fingers around 
the tongue. 
0 
1 
2 
25. Grinds teeth. 
0 
1 
2 
26. Vacant ‘staring’ spells 
0 
1 
2 
27. There are times when breathing is deep and fast 
(hyperventilation). 
0 
1 
2 
28. Spells of screaming for no apparent reason during the day. 
0 
1 
2 
29. She makes repetitive hand movements with her hands apart. 
0 
1 
2 
30. There are times when the breath is held. 
0 
1 
2 
31. Air or saliva is expelled from the mouth with force. 
0 
1 
2 
32. Spells of apparent anxiety/fear in unfamiliar situations. 
0 
1 
2 
33. She seems frightened when there are sudden changes in her 
body position. 
0 
1 
2 
34. There are times when parts of the body are held rigid. 

3 
 
0 
1 
2 
35. She shifts her gaze with a slow horizontal turn of the head. 
0 
1 
2 
36. She has an expressionless face. 
0 
1 
2 
37. Spells of screaming for no apparent reason during the night. 
0 
1 
2 
38. She presents abrupt mood changes. 
0 
1 
2 
39. There are certain days/periods where she performs much worse 
than usual. 
0 
1 
2 
40. There are times when she appears miserable for no apparent 
reason. 
0 
1 
2 
41. She seems to look through people into the distance. 
0 
1 
2 
42. She does not use her hands for purposeful grasping. 
0 
1 
2 
43. She swallows air. 
0 
1 
2 
44. Her hand movements are uniform and monotonous. 
0 
1 
2 
45. She has frequent naps during the day.