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Orthopedic Conditions and Interplay with Functional Abilities and 'MECP2' Variant Subtype in Rett Syndrome Patients

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Title: Orthopedic Conditions and Interplay with Functional Abilities and 'MECP2' Variant Subtype in Rett Syndrome Patients
Language: English
Authors: María Galán-Olleros (ORCID 0000-0001-9074-9215), Elena González-Alguacil, Víctor Soto-Insuga, María Teresa Vara-Arias, Nelmar Valentina Ortiz-Cabrera, J. Ignacio Serrano, Rosa M. Egea-Gámez, Juan José García-Peñas, Ignacio Martínez-Caballero, Salvadora Aleza Esteras, Carlota Aparicio Fernández de Gatta, Elvira Cañedo Villarroya, Daniel Clemente Garulo, Rocío Falcón Roca, Silvia Gutiérrez Priego, Blanca López Monedero, Paula Moreno Gutiérrez, Miriam Martín Mangas, Francisca Romero Andujar, Amalia Tamariz Martel
Source: Journal of Autism and Developmental Disorders. 2025 55(8):2873-2883.
Availability: Springer. Available from: Springer Nature. One New York Plaza, Suite 4600, New York, NY 10004. Tel: 800-777-4643; Tel: 212-460-1500; Fax: 212-460-1700; e-mail: customerservice@springernature.com; Web site: https://link.springer.com/
Peer Reviewed: Y
Page Count: 11
Publication Date: 2025
Document Type: Journal Articles
Reports - Research
Descriptors: Genetic Disorders, Intellectual Disability, Physical Disabilities, Patients, Children, Adolescents, Incidence
DOI: 10.1007/s10803-024-06399-y
ISSN: 0162-3257
1573-3432
Abstract: Purpose: Rett syndrome (RTT) is a rare multi-systemic disorder primarily linked to mutations in "MECP2" gene. This study aims to describe the prevalence of orthopedic conditions in RTT patients, and examine their intricate interplay with functional capabilities, and "MECP2" variant subtypes. Methods: Conducted as a cross-sectional retrospective observational study, the research encompassed 55 patients meeting clinical RTT criteria and holding "MECP2" mutations. A review of clinical records was performed to gather demographic data, mutation subtypes, orthopedic conditions, management strategies, and assessments of function. Results: Mean age of the participants was 10.22 ± 4.64 years (range, 2.9-19.41). Prevalence rates of orthopedic conditions were as follows: kyphoscoliosis 63.6%, hip displacement 14.6%, knee problems 40%, and foot deformities 75.5%. Significant relationship emerged between spinal (p < 0.01) and knee deformities (p < 0.01) with reduced motor function across various domains. Hip displacement significantly affected sitting ability (p = 0.002), and foot deformities impacted standing and walking capabilities (p = 0.049). Mutation clusters analysis revealed significant correlations with spinal (p = 0.022) and knee deformities (p = 0.002). Linear models highlighted the critical importance of mutation clusters, spine deformities, age, and hip management concerning functional variables. Conclusions: In this study, foot deformities were the most frequent orthopedic manifestation, followed by spinal, knee, and hip deformities; and unveiled their relationships with functional status and groups of mutations in RTT patients. Level of Evidence: Level IV, Case series.
Abstractor: As Provided
Entry Date: 2025
Accession Number: EJ1478301
Database: ERIC
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  Value: &lt;anid&gt;AN0186910035;aut01aug.25;2025Jul29.02:32;v2.2.500&lt;/anid&gt; &lt;title id=&quot;AN0186910035-1&quot;&gt;Orthopedic Conditions and Interplay with Functional Abilities and MECP2 Variant Subtype in Rett Syndrome Patients&#160;&lt;/title&gt; &lt;p&gt;Purpose: Rett syndrome (RTT) is a rare multi-systemic disorder primarily linked to mutations in MECP2 gene. This study aims to describe the prevalence of orthopedic conditions in RTT patients, and examine their intricate interplay with functional capabilities, and MECP2 variant subtypes. Methods: Conducted as a cross-sectional retrospective observational study, the research encompassed 55 patients meeting clinical RTT criteria and holding MECP2 mutations. A review of clinical records was performed to gather demographic data, mutation subtypes, orthopedic conditions, management strategies, and assessments of function. Results: Mean age of the participants was 10.22 &#177; 4.64 years (range, 2.9–19.41). Prevalence rates of orthopedic conditions were as follows: kyphoscoliosis 63.6%, hip displacement 14.6%, knee problems 40%, and foot deformities 75.5%. Significant relationship emerged between spinal (p &amp;lt; 0.01) and knee deformities (p &amp;lt; 0.01) with reduced motor function across various domains. Hip displacement significantly affected sitting ability (p = 0.002), and foot deformities impacted standing and walking capabilities (p = 0.049). Mutation clusters analysis revealed significant correlations with spinal (p = 0.022) and knee deformities (p = 0.002). Linear models highlighted the critical importance of mutation clusters, spine deformities, age, and hip management concerning functional variables. Conclusions: In this study, foot deformities were the most frequent orthopedic manifestation, followed by spinal, knee, and hip deformities; and unveiled their relationships with functional status and groups of mutations in RTT patients. Level of Evidence: Level IV, Case series.&lt;/p&gt; &lt;p&gt;Keywords: Rett syndrome; Scoliosis; Orthopedics; Functional assessment; MECP2 mutation; Medical and Health Sciences Clinical Sciences&lt;/p&gt; &lt;p&gt;Members of RTT-HNJ, Rett Syndrome Multidisciplinary Group of Hospital Infantil Universitario Ni&#241;o Jes&#250;s are listed in Acknowledgments section.&lt;/p&gt; &lt;hd id=&quot;AN0186910035-2&quot;&gt;Introduction&lt;/hd&gt; &lt;p&gt;Rett syndrome (RTT) stands as a rare genetic disorder, primarily caused by mutations in the X-linked &lt;emph&gt;MECP2&lt;/emph&gt; gene (Amir et al., [&lt;reflink idref=&quot;bib1&quot; id=&quot;ref1&quot;&gt;1&lt;/reflink&gt;]). It is one of the leading genetic causes of developmental and intellectual impairment among girls (Hagberg, [&lt;reflink idref=&quot;bib14&quot; id=&quot;ref2&quot;&gt;14&lt;/reflink&gt;]; Rett, [&lt;reflink idref=&quot;bib31&quot; id=&quot;ref3&quot;&gt;31&lt;/reflink&gt;]). While RTT predominantly affects females, advancements in genetic testing have shown that males can also exhibit RTT phenotypes, ranging from severe encephalopathy to forms more typical of RTT (Villard et al., [&lt;reflink idref=&quot;bib38&quot; id=&quot;ref4&quot;&gt;38&lt;/reflink&gt;], Wen et al., [&lt;reflink idref=&quot;bib39&quot; id=&quot;ref5&quot;&gt;39&lt;/reflink&gt;]). Despite being rooted in mutations within a single gene, disease severity can vary significantly among individuals. The condition encompasses various &lt;emph&gt;MECP2&lt;/emph&gt; variant subtypes, and substantial evidence supports a correlation between the clinical severity of RTT and specific genotypes (Cuddapah et al., [&lt;reflink idref=&quot;bib6&quot; id=&quot;ref6&quot;&gt;6&lt;/reflink&gt;]; Neul et al., [&lt;reflink idref=&quot;bib25&quot; id=&quot;ref7&quot;&gt;25&lt;/reflink&gt;]). This variability is not only evident in the neurological symptoms but also profoundly impacts musculoskeletal health, functional abilities, and overall quality of life.&lt;/p&gt; &lt;p&gt;The MeCP2 protein, central to this condition, is a pivotal transcriptional regulator in the brain, essential for normal neurodevelopment (Tillotson &amp;amp; Bird, [&lt;reflink idref=&quot;bib37&quot; id=&quot;ref8&quot;&gt;37&lt;/reflink&gt;]). However, RTT extends beyond neurological symptoms; it unfolds as a complex multi-systemic condition with a wide array of clinical manifestations (Fu et al., [&lt;reflink idref=&quot;bib12&quot; id=&quot;ref9&quot;&gt;12&lt;/reflink&gt;]), including significant musculoskeletal issues. These orthopedic conditions, closely linked to the regression of motor function, manifest as gait disturbances, movement disorders such as stereotypies or dystonia and structural deformities like scoliosis, hip displacement, knee deformities, and foot issues (Loder et al., [&lt;reflink idref=&quot;bib23&quot; id=&quot;ref10&quot;&gt;23&lt;/reflink&gt;]). The progression and management of these orthopedic conditions pose considerable challenges, and directly affect patient&#39;s functional abilities, which vary widely across individuals and over time. Additionally, the functional capabilities are influenced by the underlying neurologic disorder (Bernardo et al., [&lt;reflink idref=&quot;bib3&quot; id=&quot;ref11&quot;&gt;3&lt;/reflink&gt;]) and specific variant subtype (Downs et al., [&lt;reflink idref=&quot;bib8&quot; id=&quot;ref12&quot;&gt;8&lt;/reflink&gt;]). The gait is typically apraxic, marked by fluctuating muscle tone and poor coordination (Humphrey et al., [&lt;reflink idref=&quot;bib18&quot; id=&quot;ref13&quot;&gt;18&lt;/reflink&gt;]). While some patients can stand and walk independently or with minimal support, others are limited to sitting or require support to remain seated (Downs et al., [&lt;reflink idref=&quot;bib7&quot; id=&quot;ref14&quot;&gt;7&lt;/reflink&gt;]; Monteiro et al., [&lt;reflink idref=&quot;bib24&quot; id=&quot;ref15&quot;&gt;24&lt;/reflink&gt;]). This variability in functional abilities along with differences in other neurodevelopmental domains, highlights the complexity and heterogeneity of RTT.&lt;/p&gt; &lt;p&gt;The prevalence and management of orthopedic conditions in individuals with RTT exhibit considerable variability in the literature, which has not been thoroughly investigated. Given this broad variability, our study seeks to deepen the understanding of the potential interplay between genetic factors, functional capabilities, and orthopedic conditions. We hypothesize that orthopedic manifestations in RTT are not merely coincidental but are likely influenced by specific &lt;emph&gt;MECP2&lt;/emph&gt; variant subtypes and gross motor function. This could provide insights into the severity and management of these conditions. Building on the established genotype–phenotype correlations in RTT (Neul et al., [&lt;reflink idref=&quot;bib25&quot; id=&quot;ref16&quot;&gt;25&lt;/reflink&gt;]; Cuddapah et al., [&lt;reflink idref=&quot;bib6&quot; id=&quot;ref17&quot;&gt;6&lt;/reflink&gt;]), this research advances with two primary objectives: (&lt;reflink idref=&quot;bib1&quot; id=&quot;ref18&quot;&gt;1&lt;/reflink&gt;) to provide a detailed overview of the type and management of orthopedic conditions in individuals with RTT; and (&lt;reflink idref=&quot;bib2&quot; id=&quot;ref19&quot;&gt;2&lt;/reflink&gt;) to assess the connections between orthopedic conditions, patient&#39;s functional capabilities, and their specific genetic variant subtypes, ultimately paving the way for improved understanding and tailored approaches in addressing this multifaceted condition.&lt;/p&gt; &lt;hd id=&quot;AN0186910035-3&quot;&gt;Materials and Methods&lt;/hd&gt; &lt;p&gt;&lt;/p&gt; &lt;hd id=&quot;AN0186910035-4&quot;&gt;Study Design and Population&lt;/hd&gt; &lt;p&gt;This cross-sectional retrospective observational study was approved by the Institutional Review Board (n&#176;. R-0106/23). We identified 73 patients from the database of a multidisciplinary group specializing in RTT at our national reference center. Eligible patients met the clinical RTT criteria, which include regression followed by recovery or stabilization, and the presence of all four main criteria: loss of acquired purposeful hand skills, loss of acquired spoken language, gait abnormalities, and stereotypic hand movements (Neul et al., [&lt;reflink idref=&quot;bib26&quot; id=&quot;ref20&quot;&gt;26&lt;/reflink&gt;]). Of these, 55 patients with a confirmed pathogenic &lt;emph&gt;MECP2&lt;/emph&gt; mutation were included, as &lt;emph&gt;MECP2&lt;/emph&gt; mutations account for over 95% of RTT cases. Patients with mutations in &lt;emph&gt;CDKL5&lt;/emph&gt; and &lt;emph&gt;FOXG1&lt;/emph&gt;, which are now recognized as distinct neurodevelopmental conditions, were excluded (FOXG1-related epileptic-dyskinetic encephalopathy; ORPHA: 561,854 [https://&lt;ulink href=&quot;http://www.orpha.net/consor/cgi-bin/OC%5fExp.php?lng=EN&amp;amp;Expert=561854]&quot;&gt;www.orpha.net/consor/cgi-bin/OC%5fExp.php?lng=EN&amp;amp;Expert=561854]&lt;/ulink&gt; and CDKL5-deficiency disorder; ORPHA: 505,652 [https://&lt;ulink href=&quot;http://www.orpha.net/consor/cgi-bin/OC%5fExp.php?lng=EN&amp;amp;Expert=505652]&quot;&gt;www.orpha.net/consor/cgi-bin/OC%5fExp.php?lng=EN&amp;amp;Expert=505652]&lt;/ulink&gt;). Cases with incomplete medical records were also excluded. Data collection occurred from October to November 2023, covering evaluations performed from September 2022 to September 2023.&lt;/p&gt; &lt;hd id=&quot;AN0186910035-5&quot;&gt;Multidisciplinary Evaluation&lt;/hd&gt; &lt;p&gt;Patients underwent annual evaluations by a team of three pediatric neurologists and 11 specialists in fields including pneumology, psychiatry, gastroenterology, clinical genetics, orthopedic surgery, rehabilitation, cardiology, oral and dental health, rheumatology, family psychology, and ophthalmology, coordinated by a dedicated liaison nurse. The comprehensive evaluations, scheduled over two consecutive days, concluded with a team meeting to integrate findings and plan individualized follow-up care.&lt;/p&gt; &lt;hd id=&quot;AN0186910035-6&quot;&gt;Data Collection&lt;/hd&gt; &lt;p&gt;We collected demographic data, &lt;emph&gt;MECP2&lt;/emph&gt; gene variants (determined by the mutation&#39;s position within the protein) and orthopedic conditions, which were identified through a review of electronic medical records by the two main authors, an orthopedic surgeon and a neurologist. These findings were further reviewed and interpreted by two additional orthopedic surgeons and a rehabilitation physician. The conditions assessed included:&lt;/p&gt; &lt;p&gt;&lt;/p&gt; &lt;ulist&gt; &lt;item&gt; Spinal conditions were classified by deformity type into normal, mild scoliosis (major coronal curve less than 25&#176;), moderate scoliosis (25–50&#176;), severe scoliosis (more than 50&#176;), mild kyphosis (40–60&#176; thoracic kyphosis), moderate kyphosis (60–80&#176;), or severe kyphosis (more than 90&#176;). For patients with both coronal and sagittal deformities, classification was based on the most severe deformity. The Cobb angle, measured using full-spine radiographs, assessed coronal deformity, while thoracic kyphosis was measured between vertebrae T4 and T12. Treatments included observation, use of wheelchair with supports, bracing, or surgery.&lt;/item&gt; &lt;p&gt;&lt;/p&gt; &lt;item&gt; Hip conditions were assessed using the Reimers Index to measure the migration percentage (MP) (Reimers, [&lt;reflink idref=&quot;bib30&quot; id=&quot;ref21&quot;&gt;30&lt;/reflink&gt;]), originally designed for evaluating hip dislocation in cerebral palsy but widely used to quantifying hip displacement in various neuromuscular conditions. Hips were categorized as at risk (MP 10–33%), subluxation (MP 33–90%) and dislocation (MP over 90%). Treatment options included observation, botulinum toxin injection (if spasticity was detected) or surgery.&lt;/item&gt; &lt;p&gt;&lt;/p&gt; &lt;item&gt; Knee conditions on the sagittal plane were categorized based on physical examination findings as normal, showing hyperextension or recurvatum, or having flexion deformity. Treatments ranged from observation to non-operative interventions such as botulinum toxin injections, orthosis use, serial casting, or surgery.&lt;/item&gt; &lt;p&gt;&lt;/p&gt; &lt;item&gt; Foot deformities included conditions like equinus, plano-valgus, equinovarus, and equino-plano-valgus, classified though physical exams and, when available, weight-bearing radiographs. Management strategies varied, involving footwear modifications, orthotics or insoles, botulinum toxin injections, serial casting, or surgery, depending on the specific deformity and its severity.&lt;/item&gt; &lt;/ulist&gt; &lt;p&gt;Gross motor function was assessed using several functional scales administered during multidisciplinary clinics with parental assistance:&lt;/p&gt; &lt;p&gt;&lt;/p&gt; &lt;ulist&gt; &lt;item&gt; The &lt;emph&gt;Gross Motor Function Classification System &lt;/emph&gt;(&lt;emph&gt;GMFCS&lt;/emph&gt;) sorts gross motor function into five levels, from Level I (less impaired) to Level V (most impaired) (Palisano et al., [&lt;reflink idref=&quot;bib27&quot; id=&quot;ref22&quot;&gt;27&lt;/reflink&gt;]). While not RTT-specific, it is widely recognized, straightforward, and applicable in routine practice for various neuromuscular diseases.&lt;/item&gt; &lt;p&gt;&lt;/p&gt; &lt;item&gt; The &lt;emph&gt;Rett Syndrome Gross Motor Scale &lt;/emph&gt;(&lt;emph&gt;RSGMS&lt;/emph&gt;) is tailored for the precise evaluation of children with RTT, involving observational tests of predefined gross motor skills, like sitting, standing, walking, and challenge activities (Downs et al., [&lt;reflink idref=&quot;bib7&quot; id=&quot;ref23&quot;&gt;7&lt;/reflink&gt;]).&lt;/item&gt; &lt;p&gt;&lt;/p&gt; &lt;item&gt; The &lt;emph&gt;Manual Ability Classification System &lt;/emph&gt;(&lt;emph&gt;MACS&lt;/emph&gt;) ranks individuals into five levels based on their ability to use their hands for daily activities such as playing, self-care, eating, and dressing. It considers their independence and the extent of support or adaptation required (Eliasson et al., [&lt;reflink idref=&quot;bib11&quot; id=&quot;ref24&quot;&gt;11&lt;/reflink&gt;]).&lt;/item&gt; &lt;/ulist&gt; &lt;hd id=&quot;AN0186910035-7&quot;&gt;Statistical Analysis&lt;/hd&gt; &lt;p&gt;Data analysis was performed using IBM SPSS Statistics for Windows, version 29 (IBM Corp, Armonk, NY). Descriptive statistics included means, standard deviations, minimum and maximum values for continuous variables, and counts and percentages for categorical data. A multivariate analysis of variance (MANCOVA) tested the impact of orthopedic conditions and genetic mutations on RSGMS, with age as a covariate. Differences in ordinal scales, such as the GMFCS and the MACS were assessed using Kruskal–Wallis tests, with post hoc analyses applying Tukey&#39;s test for continuous data, Dunn-Sidak adjustment for ranked data, and Bonferroni-corrected post hoc z-tests for categorical data. Given the variety of mutation categories relative to the size of our sample, mutations were clustered in subgroups so that the groups presented the maximum difference in RSGMS between them (Table 1). Optimal linear models were developed for each functional scale, representing the best subset of mutation clusters, orthopedic conditions, and management approaches—those producing the most refined models. Statistical significance was set at P-values &amp;lt; 0.05.&lt;/p&gt; &lt;p&gt;Table 1 MECP2 variants subtypes clustered in subgroups maximizing the inter-cluster difference in Rett Syndrome Gross Motor Scale (RSGMS)&lt;/p&gt; &lt;p&gt; &lt;ephtml&gt; &amp;lt;table frame=&quot;hsides&quot; rules=&quot;groups&quot;&amp;gt;&amp;lt;thead&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;High functional cluster&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Middle functional cluster&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Low functional cluster&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;/thead&amp;gt;&amp;lt;tbody&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;c.-120&amp;amp;#95;-104dup&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;deletion of exons 3 and 4&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;c.414-2A &amp;amp;#62; G&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Arg133Cys&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Arg168Ter&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Large deletion&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Arg306Cys&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Arg255Ter&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Ala263ProfsTer26&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Ile293LysfsTer24&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Arg270Ter&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Arg162fs&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Pro389Ter&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Arg294Ter&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.glu310glyfster7&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Asp156Glu&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Leu386fs&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Asp427GlyfsTer41&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Lys321Ter&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Ser349ArgfsTer44&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Lys364&amp;amp;#95;Ser401del&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Thr158Met&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Pro152Arg&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Pro388Argfs&amp;amp;#42;8&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;p.Prol152Arg&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;/tbody&amp;gt;&amp;lt;/table&amp;gt; &lt;/ephtml&gt; &lt;/p&gt; &lt;hd id=&quot;AN0186910035-8&quot;&gt;Results&lt;/hd&gt; &lt;p&gt;&lt;/p&gt; &lt;hd id=&quot;AN0186910035-9&quot;&gt;Descriptive Analysis&lt;/hd&gt; &lt;p&gt;The study included 55 female patients with an average age of 10.22 &#177; 4.64 years (range, 2.9–19.41). Demographic characteristics, functional scores, and information related to &lt;emph&gt;MECP2&lt;/emph&gt; variants of the study participants are presented in Supplementary Table 1. The prevalence of orthopedic conditions and their management is summarized in Table 2. Among the total patients, 35 individuals (63.63%) had kyphoscoliosis, 8 presented hip displacement (14.55%), 22 (40%) experienced knee problems, and 83 feet (75.45%) showed deformities. Supplementary Fig. 1 shows the proportion of patients with each subtype of orthopedic condition by age range. Supplementary Table 2 displays the descriptive statistics for the functional variables of the study&#39;s participants, and Supplementary Table 3 details the genetic &lt;emph&gt;MECP2&lt;/emph&gt; variant subtypes.&lt;/p&gt; &lt;p&gt;Table 2 Distribution and management of orthopedic conditions in study participants&lt;/p&gt; &lt;p&gt; &lt;ephtml&gt; &amp;lt;table frame=&quot;hsides&quot; rules=&quot;groups&quot;&amp;gt;&amp;lt;thead&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;th align=&quot;left&quot; /&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Condition subtype&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Participants (%)&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot; /&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;None or Observation&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Chair with supports&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Brace&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Surgery&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;/thead&amp;gt;&amp;lt;tbody&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot; rowspan=&quot;6&quot;&amp;gt;&amp;lt;p&amp;gt;Spine&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;None&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;20 (36.3%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot; rowspan=&quot;6&quot;&amp;gt;&amp;lt;p&amp;gt;Management Spine&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;20 (100%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Mild hyperkyphosis&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;4 (7.3%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;3 (75%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;1 (25%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Mod. hyperkyphosis&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;2 (3.6%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;2 (100%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Mild scoliosis&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;14 (25.5%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;6 (42.9%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;8 (57.1%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Moderate scoliosis&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;7 (12.7%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;3 (43%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;4 (57.1%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Severe scoliosis&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;8 (14.6%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;1 (12.5%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;7 (87.5%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;/tbody&amp;gt;&amp;lt;/table&amp;gt; &lt;/ephtml&gt; &lt;/p&gt; &lt;p&gt; &lt;ephtml&gt; &amp;lt;table frame=&quot;hsides&quot; rules=&quot;groups&quot;&amp;gt;&amp;lt;thead&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;th align=&quot;left&quot; /&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Condition subtype&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Participants (%)&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot; /&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;RI Avg. (std.)&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;None or Observation&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Botulinum toxin&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Surgery&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;/thead&amp;gt;&amp;lt;tbody&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot; rowspan=&quot;3&quot;&amp;gt;&amp;lt;p&amp;gt;Hips&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;At risk&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;57 (85.5%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot; rowspan=&quot;3&quot;&amp;gt;&amp;lt;p&amp;gt;Management Hips&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;NA&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;47 (100%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Subluxation&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;6 (10.9%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;28.3 (7.5%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;3 (50%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;1 (16.7%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;2 (33.3%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Dislocation&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;2 (3.6%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;70 (14.1%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;1 (50%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;1 (50%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;/tbody&amp;gt;&amp;lt;/table&amp;gt; &lt;/ephtml&gt; &lt;/p&gt; &lt;p&gt; &lt;ephtml&gt; &amp;lt;table frame=&quot;hsides&quot; rules=&quot;groups&quot;&amp;gt;&amp;lt;thead&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;th align=&quot;left&quot; /&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Condition subtype&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Participants (%)&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot; /&amp;gt;&amp;lt;th align=&quot;left&quot; /&amp;gt;&amp;lt;th align=&quot;left&quot; /&amp;gt;&amp;lt;th align=&quot;left&quot; /&amp;gt;&amp;lt;th align=&quot;left&quot; /&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;/thead&amp;gt;&amp;lt;tbody&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot; rowspan=&quot;4&quot;&amp;gt;&amp;lt;p&amp;gt;Knees&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;None&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;33 (60%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;One with hyperextension&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;1 (1.8%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Both with hyperextension&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;9 (16.4%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Both with flexion deformity&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;12 (21.8%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;/tbody&amp;gt;&amp;lt;/table&amp;gt; &lt;/ephtml&gt; &lt;/p&gt; &lt;p&gt; &lt;ephtml&gt; &amp;lt;table frame=&quot;hsides&quot; rules=&quot;groups&quot;&amp;gt;&amp;lt;thead&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;th align=&quot;left&quot; /&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Condition subtype&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Participants (%)&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot; /&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;None or observation&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Insole, AFO&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Botulinum toxin&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Surgery&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;/thead&amp;gt;&amp;lt;tbody&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot; rowspan=&quot;5&quot;&amp;gt;&amp;lt;p&amp;gt;Feet&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;None&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;27 (24.6%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot; rowspan=&quot;5&quot;&amp;gt;&amp;lt;p&amp;gt;Management Feet&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;19 (70.4%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;8 (29.6%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Equinus&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;21 (19.1%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;7 (33.3%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;8 (38.1%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;4 (19.1%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;2 (9.5%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Equinus-Varus&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;26 (23.6%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;7 (26.9%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;4 (15.4%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;2 (7.7%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;13 (50%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Plano-Valgus&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;26 (23.6%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;5 (19.2%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;16 (61.5%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;5 (19.2%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Equinus-Plano-Valgus&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;10 (9.1%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;2 (20%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;6 (60%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;0 (0%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;5 (19.2%)&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;/tbody&amp;gt;&amp;lt;/table&amp;gt; &lt;/ephtml&gt; &lt;/p&gt; &lt;p&gt;Data expressed as counts (percentages). Management strategies are listed as percentages of participants with each type of condition who received that specific management &lt;emph&gt;Mod.&lt;/emph&gt; Moderate, &lt;emph&gt;Avg.&lt;/emph&gt; Average, &lt;emph&gt;Std.&lt;/emph&gt; Standard deviation, &lt;emph&gt;AFO&lt;/emph&gt; Ankle foot orthosis, &lt;emph&gt;RI&lt;/emph&gt; Reimers Index&lt;/p&gt; &lt;hd id=&quot;AN0186910035-10&quot;&gt;Analysis of the Relationship Between Orthopedic Conditions and Function&lt;/hd&gt; &lt;p&gt;Significant relationships were observed between spinal deformities, hip displacement, and knee problems, with functional variables such as RSGMS and its subscales, and GMCFS (Table 3). Foot deformities significantly impacted the standing and walking subscale of the RSGMS [F(4.49) = 2.575;p = 0.049] and the GMFCS [H(&lt;reflink idref=&quot;bib4&quot; id=&quot;ref25&quot;&gt;4&lt;/reflink&gt;) = 10.761;p = 0.029]. No significant post hoc pairwise differences were found for spinal deformities and the sitting subscale of RSGMS, for hip displacement and overall RSGMS, as well as for the standing and walking and challenge subscales of RSGMS, and for foot deformities and the standing and walking subscale of RSGMS. Figure 1 and Supplementary Fig. 2 visually represent these relationships between orthopedic conditions and functional variables.&lt;/p&gt; &lt;p&gt;Table 3 Statistics and p-values of the significant effects of orthopedic conditions on functional variables for both limbs of each joint considered&lt;/p&gt; &lt;p&gt; &lt;ephtml&gt; &amp;lt;table frame=&quot;hsides&quot; rules=&quot;groups&quot;&amp;gt;&amp;lt;thead&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;N = 55&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Spine deformities&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Hip displacement&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Knee problems&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;th align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;Foot deformities&amp;lt;/p&amp;gt;&amp;lt;/th&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;/thead&amp;gt;&amp;lt;tbody&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;RSGMS total&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;F(5,48) = 5.266, p &amp;amp;#60; 0.0010&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;F(2,51) = 5.131, p = 0.009&amp;lt;sup&amp;gt;&amp;amp;#167;&amp;lt;/sup&amp;gt;&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;F(3,50) = 6.687, p &amp;amp;#60; 0.001&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;RSGMS sitting&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;F(5,48) = 3.216, p = 0.014&amp;lt;sup&amp;gt;&amp;amp;#167;&amp;lt;/sup&amp;gt;&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;F(2,51) = 4.395, p = 0.017&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;F(2,51) = 5.949, p = 0.005&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;RSGMS standing and walking&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;F(5,48) = 4.148, p = 0.003&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;F(2,51) = 4.252, p = 0.020&amp;lt;sup&amp;gt;&amp;amp;#167;&amp;lt;/sup&amp;gt;&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;F(2,51) = 9.760, p &amp;amp;#60; 0.001&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;F(4,49) = 2.575, p = 0.049&amp;lt;sup&amp;gt;&amp;amp;#167;&amp;lt;/sup&amp;gt;&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;RSGMS challenge&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;F(5,48) = 5.163, p &amp;amp;#60; 0.001&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;F(2,51) = 3.621, p = 0.034&amp;lt;sup&amp;gt;&amp;amp;#167;&amp;lt;/sup&amp;gt;&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;F(2,51) = 6.100, p = 0.004&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot; /&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;tr&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;GMFCS&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;H(5) = 22.490, p &amp;amp;#60; 0.001&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;H(2) = 7.422, p = 0.024&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;H(3) = 17.807, p &amp;amp;#60; 0.001&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;td align=&quot;left&quot;&amp;gt;&amp;lt;p&amp;gt;H(4) = 10.761, p = 0.029&amp;lt;/p&amp;gt;&amp;lt;/td&amp;gt;&amp;lt;/tr&amp;gt;&amp;lt;/tbody&amp;gt;&amp;lt;/table&amp;gt; &lt;/ephtml&gt; &lt;/p&gt; &lt;p&gt; &lt;sups&gt;&#167;&lt;/sups&gt;No significant post hoc pairwise differences&lt;/p&gt; &lt;p&gt;Graph: Fig. 1 Box plots of the Rett Syndrome Gross Motor Scale (RSGMS) scale and subscales for the different orthopedic conditions that presented significant differences. Lines denote statistically significant pairwise post hoc differences&lt;/p&gt; &lt;hd id=&quot;AN0186910035-11&quot;&gt;Analysis of the Relationship Between Genetic Variants and Orthopedic Conditions/Function&lt;/hd&gt; &lt;p&gt;Initial analysis suggested significant differences only in sagittal knee problems among genetic variant subtypes [χ&lt;sups&gt;2&lt;/sups&gt;(&lt;reflink idref=&quot;bib33&quot; id=&quot;ref26&quot;&gt;33&lt;/reflink&gt;) = 55.423, p = 0.009]. However, subsequent adjustments with post hoc tests revealed these differences were not statistically significant, indicating a lack of robust evidence to support specific genetic influences on this condition. There were no significant differences in functional scales based on genetic mutations.&lt;/p&gt; &lt;hd id=&quot;AN0186910035-12&quot;&gt;Analysis of the Relationship Between Mutation Clusters and Orthopedic Conditions&lt;/hd&gt; &lt;p&gt;Significant differences were observed for the presence of spine deformities (χ&lt;sups&gt;2&lt;/sups&gt; (&lt;reflink idref=&quot;bib10&quot; id=&quot;ref27&quot;&gt;10&lt;/reflink&gt;) = 20.862, p = 0.022), and knee problems [χ&lt;sups&gt;2&lt;/sups&gt; (&lt;reflink idref=&quot;bib6&quot; id=&quot;ref28&quot;&gt;6&lt;/reflink&gt;) = 17.832; p = 0.007] when grouped by functional capability derived from mutation clusters (high, middle, and low functional) (Supplementary Fig. 3). A notable disparity in knee problems was observed within the low-functioning group, primarily due to a higher prevalence of knee flexion issues. No significant differences were detected for hip and foot conditions.&lt;/p&gt; &lt;hd id=&quot;AN0186910035-13&quot;&gt;Analysis of the Relationship Between Mutation Clusters and Function&lt;/hd&gt; &lt;p&gt;Significant differences were found between the mutation groups and several functional variables: the total RSGMS [F(&lt;reflink idref=&quot;bib2&quot; id=&quot;ref29&quot;&gt;2&lt;/reflink&gt;,&lt;reflink idref=&quot;bib51&quot; id=&quot;ref30&quot;&gt;51&lt;/reflink&gt;) = 20.620; p &amp;lt; 0.001], the Standing &amp;amp; Walking subscale [F(&lt;reflink idref=&quot;bib2&quot; id=&quot;ref31&quot;&gt;2&lt;/reflink&gt;,&lt;reflink idref=&quot;bib51&quot; id=&quot;ref32&quot;&gt;51&lt;/reflink&gt;) = 23.787; p &amp;lt; 0.001], the Challenge subscale [F(&lt;reflink idref=&quot;bib2&quot; id=&quot;ref33&quot;&gt;2&lt;/reflink&gt;,&lt;reflink idref=&quot;bib51&quot; id=&quot;ref34&quot;&gt;51&lt;/reflink&gt;) = 9.801; p &amp;lt; 0.001], the GMFCS [H(&lt;reflink idref=&quot;bib2&quot; id=&quot;ref35&quot;&gt;2&lt;/reflink&gt;) = 23.522; p &amp;lt; 0.001], and MACS [H(&lt;reflink idref=&quot;bib2&quot; id=&quot;ref36&quot;&gt;2&lt;/reflink&gt;) = 10.730; p = 0.005] (Fig. 2). These findings suggest that mutation clusters significantly influence a range of functional abilities in individuals with RTT.&lt;/p&gt; &lt;p&gt;Graph: Fig. 2 Box plots of the Rett Syndrome Gross Motor Scale (RSGMS) and subscales, Gross Motor Function Classification System (GMFCS) and Manual Ability Classification System (MACS) for the different mutation clusters that presented significant differences. Lines denote statistically significant pairwise post hoc differences&lt;/p&gt; &lt;hd id=&quot;AN0186910035-14&quot;&gt;Multivariate Analysis and Linear Models for Functional Scales&lt;/hd&gt; &lt;p&gt;Among the factors analyzed, variant subtype, spinal deformity, and hip treatment emerged as the most influential in predicting RSGMS and GMFCS scores, highlighting the significant impact of these variables on functional outcomes. Our statistical models provide robust support for these findings, with significant results across various subscales: RSGMS [F(&lt;reflink idref=&quot;bib8&quot; id=&quot;ref37&quot;&gt;8&lt;/reflink&gt;,&lt;reflink idref=&quot;bib54&quot; id=&quot;ref38&quot;&gt;54&lt;/reflink&gt;) = 10.858; p &amp;lt; 0.0005], sitting subscale [F(&lt;reflink idref=&quot;bib5&quot; id=&quot;ref39&quot;&gt;5&lt;/reflink&gt;,&lt;reflink idref=&quot;bib54&quot; id=&quot;ref40&quot;&gt;54&lt;/reflink&gt;) = 11.704; p &amp;lt; 0.0005], standing and walking subscale [F(&lt;reflink idref=&quot;bib9&quot; id=&quot;ref41&quot;&gt;9&lt;/reflink&gt;,&lt;reflink idref=&quot;bib54&quot; id=&quot;ref42&quot;&gt;54&lt;/reflink&gt;) = 10.794; p &amp;lt; 0.0005], and the GMFCS [F(&lt;reflink idref=&quot;bib9&quot; id=&quot;ref43&quot;&gt;9&lt;/reflink&gt;,&lt;reflink idref=&quot;bib54&quot; id=&quot;ref44&quot;&gt;54&lt;/reflink&gt;) = 14.979, p &amp;lt; 0.0005]. Figure 3 illustrates the scatter plots of actual versus predicted values from the linear models, along with the linear regression lines, demonstrating that RSGMS and GMFCS can be estimated with reasonable accuracy (&#177; 8 and &#177; 0.6, respectively) based on factors such as genetic variant subtype, orthopedic conditions, their respective treatments, and patient age. Specifically, age significantly influenced only the standing subscale of RSGMS, with minimal impact on other areas. GMFCS scores were particularly affected by knee problems, whereas sitting function was mainly influenced by how hip conditions were managed, independent of the genetic mutation. Notably, foot deformities showed little impact on the functional scale estimations.&lt;/p&gt; &lt;p&gt;Graph: Fig. 3 Left column: scatter plots of the actual values of the functional scales and the values estimated for their corresponding linear models together with the linear regression. Right column: Variables in each model and their relative explained variance. r: Pearson&#39;s correlation coefficient; R2: Coefficient of adjustment; RMSE: Root mean standard error; *p &amp;lt; 0.05; **p &amp;lt; 0.0005&lt;/p&gt; &lt;hd id=&quot;AN0186910035-15&quot;&gt;Discussion&lt;/hd&gt; &lt;p&gt;Our findings demonstrate a high prevalence of orthopedic conditions among 55 patients with RTT and confirmed &lt;emph&gt;MECP2&lt;/emph&gt; pathogenic variant, underscoring a notable correlation with their functional abilities as measured by recognized scales. Mutation clusters within the &lt;emph&gt;MECP2&lt;/emph&gt; variant subtypes exert influence on both the orthopedic conditions and the range of functional capabilities. Through the application of multivariate analysis and linear models, our findings show that RSGMS and GMFCS can be accurately predicted, based on genetic variant subtype, specific orthopedic conditions and their management strategies, as well as patient age.&lt;/p&gt; &lt;p&gt;Our results highlight the significant impact of orthopedic conditions on individuals with RTT, differing from earlier studies (Downs et al., [&lt;reflink idref=&quot;bib9&quot; id=&quot;ref45&quot;&gt;9&lt;/reflink&gt;]; Guidera et al., [&lt;reflink idref=&quot;bib13&quot; id=&quot;ref46&quot;&gt;13&lt;/reflink&gt;]; Hennessy &amp;amp; Haas, [&lt;reflink idref=&quot;bib17&quot; id=&quot;ref47&quot;&gt;17&lt;/reflink&gt;]; Killian et al., [&lt;reflink idref=&quot;bib21&quot; id=&quot;ref48&quot;&gt;21&lt;/reflink&gt;]; Loder et al., [&lt;reflink idref=&quot;bib23&quot; id=&quot;ref49&quot;&gt;23&lt;/reflink&gt;]; Percy et al., [&lt;reflink idref=&quot;bib29&quot; id=&quot;ref50&quot;&gt;29&lt;/reflink&gt;]; Roberts &amp;amp; Conner, [&lt;reflink idref=&quot;bib33&quot; id=&quot;ref51&quot;&gt;33&lt;/reflink&gt;]), where scoliosis was often reported as the most prevalent condition. Previous research rarely mentioned knee issues (Cass et al., [&lt;reflink idref=&quot;bib5&quot; id=&quot;ref52&quot;&gt;5&lt;/reflink&gt;]), and seldom reported on foot deformities (Borst et al., [&lt;reflink idref=&quot;bib4&quot; id=&quot;ref53&quot;&gt;4&lt;/reflink&gt;]; Kanashvili et al., [&lt;reflink idref=&quot;bib20&quot; id=&quot;ref54&quot;&gt;20&lt;/reflink&gt;]), while hip displacement was reported to be more common (Kanashvili et al., [&lt;reflink idref=&quot;bib19&quot; id=&quot;ref55&quot;&gt;19&lt;/reflink&gt;]; Tay et al., [&lt;reflink idref=&quot;bib36&quot; id=&quot;ref56&quot;&gt;36&lt;/reflink&gt;]). This study finds foot deformities to be the most common orthopedic issue in RTT patients, affecting 76% of the sample. These are followed by spinal deformities (64%), knee problems (40%), and hip displacement (15%). This discrepancy in reported conditions could be attributed to the younger average age of our study&#39;s participants (10 years), since significant scoliosis development typically occurs in adolescence (Downs et al., [&lt;reflink idref=&quot;bib9&quot; id=&quot;ref57&quot;&gt;9&lt;/reflink&gt;]; Killian et al., [&lt;reflink idref=&quot;bib21&quot; id=&quot;ref58&quot;&gt;21&lt;/reflink&gt;]), and may become more prevalent as these patients age. Additionally, the underreporting of knee and foot deformities in past literature contribute to the variance in observed prevalence rates.&lt;/p&gt; &lt;p&gt;Our results confirm significant variability in functional abilities among RTT patients, aligning with earlier research (Hagberg et al., [&lt;reflink idref=&quot;bib15&quot; id=&quot;ref59&quot;&gt;15&lt;/reflink&gt;]; Monteiro et al., [&lt;reflink idref=&quot;bib24&quot; id=&quot;ref60&quot;&gt;24&lt;/reflink&gt;]). It highlighted the diverse functional capabilities seen in patients as classified by GMFCS and RSGMS. We observed that specific orthopedic conditions substantially impact the functional status of individuals with RTT, affecting daily activities and motor skills, and thereby emphasizing their importance in the patients&#39; overall well-being. For example, spinal deformities were closely associated with various functional variables, including RSGMS, and its subscales (standing and walking, challenges) and GMFCS. Their presence is linked to reduced motor function, highlighting the need to maintain abilities like walking and sitting to mitigate their development and progression in RTT patients (Downs et al., [&lt;reflink idref=&quot;bib9&quot; id=&quot;ref61&quot;&gt;9&lt;/reflink&gt;]; Percy et al., [&lt;reflink idref=&quot;bib29&quot; id=&quot;ref62&quot;&gt;29&lt;/reflink&gt;]; Riise et al., [&lt;reflink idref=&quot;bib32&quot; id=&quot;ref63&quot;&gt;32&lt;/reflink&gt;]; Tay et al., [&lt;reflink idref=&quot;bib36&quot; id=&quot;ref64&quot;&gt;36&lt;/reflink&gt;]). Likewise, the lack of independent walking has been identified as a risk factor for scoliosis (Anderson et al., [&lt;reflink idref=&quot;bib2&quot; id=&quot;ref65&quot;&gt;2&lt;/reflink&gt;]; Killian et al., [&lt;reflink idref=&quot;bib21&quot; id=&quot;ref66&quot;&gt;21&lt;/reflink&gt;]) and the Rett Syndrome Motor Evaluation Scale (RESMES) also shows a high correlation with scoliosis presence and severity (Rodocanachi et al., [&lt;reflink idref=&quot;bib34&quot; id=&quot;ref67&quot;&gt;34&lt;/reflink&gt;]). This risk pattern is consistent with other neuromuscular and developmental conditions, such as cerebral palsy (H&#228;gglund et al., [&lt;reflink idref=&quot;bib16&quot; id=&quot;ref68&quot;&gt;16&lt;/reflink&gt;]; Saito et al., [&lt;reflink idref=&quot;bib35&quot; id=&quot;ref69&quot;&gt;35&lt;/reflink&gt;]) or Down syndrome (Egea-G&#225;mez et al., [&lt;reflink idref=&quot;bib10&quot; id=&quot;ref70&quot;&gt;10&lt;/reflink&gt;]). Similarly, knee issues also influence functional abilities, particularly affecting the sitting subscale of the RSGMS. This reflects their impact on basic functional abilities, a dynamic similarly observed in various neuromuscular disorders (Pantzar-Castilla et al., [&lt;reflink idref=&quot;bib28&quot; id=&quot;ref71&quot;&gt;28&lt;/reflink&gt;]). Additionally, our findings indicate that hip displacement significantly affects sitting capabilities, often exacerbated by unilateral displacement (Tay et al., [&lt;reflink idref=&quot;bib36&quot; id=&quot;ref72&quot;&gt;36&lt;/reflink&gt;]). In contrast, foot deformities, were notably associated with GMFCS levels but not with specific functional domains. This observation aligns with previous findings that foot deformities occur irrespective of mobility status (Kanashvili et al., [&lt;reflink idref=&quot;bib20&quot; id=&quot;ref73&quot;&gt;20&lt;/reflink&gt;]), and may be more related to the dystonic movement disorder characteristic of RTT (Temudo et al., 2008).&lt;/p&gt; &lt;p&gt;While genetic mutations provide some insights, orthopedic conditions often offer more direct guidance on the impact of motor deficits. Our analysis revealed a lack of robust evidence supporting specific genetic influences on orthopedic conditions. However, further in-depth analysis, considering mutation clusters based on RSGMS function, showed that certain mutation clusters may carry a higher propensity for developing spine deformities and knee issues. Previous research exploring how different genetic variants relate to scoliosis in larger RTT cohorts found that specific mutations influenced the age of onset and risk of scoliosis, with large deletions and p.Arg270* mutations increasing scoliosis risk, while p.Arg306Cys and p.Arg294* mutations offering some protection (Downs et al., [&lt;reflink idref=&quot;bib9&quot; id=&quot;ref74&quot;&gt;9&lt;/reflink&gt;]). Similarly, other studies identified protective effects against scoliosis severity in certain mutations (Cuddapah et al., [&lt;reflink idref=&quot;bib6&quot; id=&quot;ref75&quot;&gt;6&lt;/reflink&gt;]; Killian et al., [&lt;reflink idref=&quot;bib21&quot; id=&quot;ref76&quot;&gt;21&lt;/reflink&gt;]; Percy et al., [&lt;reflink idref=&quot;bib29&quot; id=&quot;ref77&quot;&gt;29&lt;/reflink&gt;]). These findings partially resonate with our results, suggesting a link between lower functional clusters and a higher risk of kyphoscoliosis, supporting the impact of specific mutation clusters on the severity and development of scoliosis. On the other side, previous research did not establish a significant connection between genetic severity and hip displacement (Kanashvili et al., [&lt;reflink idref=&quot;bib19&quot; id=&quot;ref78&quot;&gt;19&lt;/reflink&gt;]) or foot deformities (Kanashvili et al., [&lt;reflink idref=&quot;bib20&quot; id=&quot;ref79&quot;&gt;20&lt;/reflink&gt;]), possibly due to limited sample sizes, genetic diversity and the stratification of genetic severity based on epilepsy and other non-orthopedic manifestations that might not directly relate to orthopedic conditions. In contrast, our approach which involved clustering mutations by functional type using the RSGMS, has a more direct association with orthopedic issues. Yet, our findings remained consistent with prior research, showing no significant differences for hip displacement and foot deformities based on mutation clusters. This absence of clear genotype–phenotype relationship for these orthopedic issues may stem from the similar functional impact across different genetic variants.&lt;/p&gt; &lt;p&gt;Furthermore, our analysis extends beyond replicating existing studies by exploring how &lt;emph&gt;MECP2&lt;/emph&gt; mutation subtypes influence orthopedic outcomes and functional abilities in RTT patients. While we observed no significant direct impact of mutation subtype on functional abilities, clear differences emerged between the mutation clusters concerning several functional variables, such as total RSGMS, Standing &amp;amp; Walking subscale, Challenge, GMFCS, and MACS. We categorized some of the most prevalent mutations into groups based on functional capabilities. For instance, patients with p.Arg133Cys and p.Arg306Cys mutations were grouped within the high functional cluster, indicative of better motor outcomes. In contrast, individuals with large deletions were categorized in the low functional cluster, showing a more significant impact on motor abilities. Previous research supports this genotype–phenotype correlation (Leonard et al., [&lt;reflink idref=&quot;bib22&quot; id=&quot;ref80&quot;&gt;22&lt;/reflink&gt;]). A study of 396 female patients with RTT found that 76% of those with the p.Arg133Cys mutation and 81% with the p.Arg294* mutation were able to walk, a rate significantly higher compared to only 27% of those with large deletions (Anderson et al., [&lt;reflink idref=&quot;bib2&quot; id=&quot;ref81&quot;&gt;2&lt;/reflink&gt;]). Similarly, a video analysis of 99 girls revealed better gross motor skills in patients with p.Arg133Cys and p.Arg294* mutations (Downs et al., [&lt;reflink idref=&quot;bib7&quot; id=&quot;ref82&quot;&gt;7&lt;/reflink&gt;]), while another study highlighted better ambulation skills in those carrying the p.Arg133Cys mutation (Cuddapah et al., [&lt;reflink idref=&quot;bib6&quot; id=&quot;ref83&quot;&gt;6&lt;/reflink&gt;]). These findings suggest that understanding specific &lt;emph&gt;MECP2&lt;/emph&gt; variant subtypes can help forecast the severity of motor deficits and, by extension, the likely progression of orthopedic conditions. This analysis underlines the critical role of genetic factors in anticipating the orthopedic needs of RTT patients, thereby enhancing our capacity for tailored intervention strategies.&lt;/p&gt; &lt;p&gt;Our research found that linear models could accurately predict scores for RSGMS and GMFCS by considering variables such as genetic mutation types, orthopedic conditions, their treatments, and patient age. This study offers valuable insights into the factors that influence the functional abilities of individuals with RTT. Key factors identified include the specific genetic mutation subtype, the presence of spinal deformities, and the treatment of hip conditions, all of which also play pivotal roles in a patient&#39;s capacity to stand and walk. Age was a significant contributor to the RSGMS standing subscale, illustrating the impact of developmental stages on motor abilities. Knee problems specifically impacted GMFCS, and hip management was particularly important for sitting ability, underscoring the importance of targeted treatment in this area. On the other hand, foot deformities had a minimal impact on functional scale estimations, suggesting they may not significantly affect overall gross motor function compared to other orthopedic conditions. Our analysis underlines the complex interplay between genetic mutations, orthopedic conditions, and their management, all contributing to the functional abilities of RTT individuals. These findings open up possibilities for creating tailored interventions that focus on certain orthopedic issues and genetic profiles, to enhance functional outcomes for RTT patients.&lt;/p&gt; &lt;p&gt;This study has several limitations that need to be acknowledged for a balanced interpretation of the results. Firstly, the cross-sectional design, involving data collection at a single time point, may not fully capture the dynamic nature of orthopedic issues and functional abilities in individuals with RTT over time. Longitudinal studies tracking patients over several years would provide a more comprehensive understanding of how these conditions evolve. Additionally, retrospective data collection may introduce recall bias, as the data relied on medical records, which could affect the accuracy of the orthopedic and functional assessments. Secondly, the sample size, consisting exclusively of patients with MECP2 mutations, may not represent the entire RTT population. While this narrows the scope, it allows for an in-depth analysis of this specific subgroup. Although the sample size of 55 patients with a rare disease is not large, it still offers a substantial dataset to yield meaningful conclusion. Nevertheless, the diversity of &lt;emph&gt;MECP2&lt;/emph&gt; variants within this group poses a challenge for analyzing orthopedic conditions. We categorized mutations to highlight the most distinct motor function differences, aiming to identify phenotypic patterns that are most relevant to orthopedic outcomes. Thirdly, the age range of our study participants is indeed another limitation to consider. Orthopedic and functional profiles vary significantly across different ages, and our results mostly apply to a younger subset of RTT patients, not capturing the full range of orthopedic issues and functional challenges they may encounter throughout their entire lifespan. Fourthly, conducting the study at a single center could limit the broader applicability of our findings. However, as a national referral center serving patients from various regions, our sample does offer insight into the southern European population. Still, the management of orthopedic issues could reflect the practices of the orthopedic surgeons at our center, which may differ from other healthcare providers. Finally, although we have established associations between variables, causality cannot be assumed. The interactions among studied variables are likely multifactorial and multidirectional. Despite these limitations, this study offers a thorough exploration of the orthopedic, functional, and genetic factors of RTT and their complex interplay, laying the groundwork for future investigations.&lt;/p&gt; &lt;p&gt;In summary, our research sheds light into the prevalence of orthopedic conditions among RTT patients, noting that foot deformities are the most common concern, closely followed by spine, knee, and hip deformities. Our findings reveal that these orthopedic conditions are closely linked to motor functions, particularly spinal deformities and knee issues. Moving beyond individual genetic mutations, our analysis of mutation clusters reveals how specific groups of genetic mutations correlate with orthopedic conditions and functional abilities. This enhanced understanding could enable healthcare providers to craft more targeted surveillance strategies, set realistic expectations, and design personalized care plans tailored to the distinct needs of RTT patients. Moreover, our study emphasizes the importance of ongoing assessment of orthopedic and functional status in RTT individuals. Given the progressive nature of RTT, it is essential that assessments and interventions are regularly updated to optimize functional outcomes as patients transition from childhood through adolescence and into adulthood.&lt;/p&gt; &lt;hd id=&quot;AN0186910035-16&quot;&gt;Acknowledgments&lt;/hd&gt; &lt;p&gt;We wish to express our appreciation to all patient with RTT and their families under the care of our RTT-HNJ multidisciplinary team. We learn from them each day, and their resilience and strength fuel our work. Furthermore, we extend our sincere gratitude to the dedicated healthcare professionals within our RTTHNJ multidisciplinary group, whose committed dedication and exceptional contributions enhance our efforts (Salvadora Alteza Esteras, Liaison Nurse; Carlota Aparicio Fern&#225;ndez de Gatta, Pediatric Cardiology Specialist; Elvira Ca&#241;edo Villarroya, Pediatric Gastroenterology Specialist; Daniel Clemente Garulo, Pediatric Rheumatology Specialist; Roc&#237;o Falc&#243;n Roca, Pediatric Ophthalmology Specialist; Silvia Guti&#233;rrez Priego, Specialist in Child and Adolescent Psychiatry; Blanca L&#243;pez Monedero and Paula Moreno Guti&#233;rrez, Clinical Psychologists; Miriam Mart&#237;n Mangas, Pediatric Dentist; Francisca Romero Andujar, Pediatric Neumology Specialist; Amalia Tamariz Martel, Pediatric Cardiology Specialist).&lt;/p&gt; &lt;hd id=&quot;AN0186910035-17&quot;&gt;Author Contributions&lt;/hd&gt; &lt;p&gt;All authors: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work. Drafting the work or revising it critically for important intellectual content. Final approval of the version to be published. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.&lt;/p&gt; &lt;hd id=&quot;AN0186910035-18&quot;&gt;Funding&lt;/hd&gt; &lt;p&gt;None of the authors have received financial payments or other benefits from any commercial entity related to the subject of this article.&lt;/p&gt; &lt;hd id=&quot;AN0186910035-19&quot;&gt;Data Availability Statement&lt;/hd&gt; &lt;p&gt;The data that support the findings of this study are available from the corresponding author, upon reasonable request.&lt;/p&gt; &lt;hd id=&quot;AN0186910035-20&quot;&gt;Declarations&lt;/hd&gt; &lt;p&gt;&lt;/p&gt; &lt;hd id=&quot;AN0186910035-21&quot;&gt;Conflict of Interest&lt;/hd&gt; &lt;p&gt;The authors report there are no competing interests to declare.&lt;/p&gt; &lt;hd id=&quot;AN0186910035-22&quot;&gt;Ethical Approval&lt;/hd&gt; &lt;p&gt;The study was approved by the Institutional Review Board (n&#176;. R-0106/23). This study was performed in accordance with the ethical standards in the 1964 Declaration of Helsinki.&lt;/p&gt; &lt;hd id=&quot;AN0186910035-23&quot;&gt;Protocol&lt;/hd&gt; &lt;p&gt;This manuscript adhered to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for reporting observational studies. The study design and reporting have been structured in accordance with the STROBE checklist to ensure transparency and comprehensive reporting of our research findings.&lt;/p&gt; &lt;hd id=&quot;AN0186910035-24&quot;&gt;Quality Assessment&lt;/hd&gt; &lt;p&gt;All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.&lt;/p&gt; &lt;hd id=&quot;AN0186910035-25&quot;&gt;Supplementary Information&lt;/hd&gt; &lt;p&gt;Below is the link to the electronic supplementary material.&lt;/p&gt; &lt;p&gt;Graph: Supplementary file1 Supplementary Fig.&#160;1. Bar charts showing the proportion of patients with each subtype of spine, hip, knee and foot problems by age range. Each color represents a different category of conditions, facilitating visual differentiation of proportions within each age group. (PNG 1854 KB)&lt;/p&gt; &lt;p&gt;Graph: Supplementary file2 Supplementary Fig.&#160;2. Box plots of the Gross Motor Function Classification System (GMFCS) scale for the different orthopedic conditions that presented significant differences. Lines denote statistically significant pairwise post hoc differences. (TIFF 11163 KB)&lt;/p&gt; &lt;p&gt;Graph: Supplementary file3 Supplementary Fig.&#160;3. Distribution of the orthopedic conditions in the joints among different mutation clusters that presented significant differences. Lines denote statistically significant pairwise post hoc differences. (TIFF 7084 KB)&lt;/p&gt; &lt;p&gt;Graph: Supplementary file4 (DOCX 28 KB)&lt;/p&gt; &lt;p&gt;Graph: Supplementary file5 (DOCX 16 KB)&lt;/p&gt; &lt;p&gt;Graph: Supplementary file6 (DOCX 16 KB)&lt;/p&gt; &lt;hd id=&quot;AN0186910035-26&quot;&gt;Publisher&#39;s Note&lt;/hd&gt; &lt;p&gt;Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.&lt;/p&gt; &lt;ref id=&quot;AN0186910035-27&quot;&gt; &lt;title&gt; References &lt;/title&gt; &lt;blist&gt; &lt;bibl id=&quot;bib1&quot; idref=&quot;ref1&quot; type=&quot;bt&quot;&gt;1&lt;/bibl&gt; &lt;bibtext&gt; 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. 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  Data: Orthopedic Conditions and Interplay with Functional Abilities and &#39;MECP2&#39; Variant Subtype in Rett Syndrome Patients
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  Data: 10.1007/s10803-024-06399-y
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  Data: 0162-3257&lt;br /&gt;1573-3432
– Name: Abstract
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  Data: Purpose: Rett syndrome (RTT) is a rare multi-systemic disorder primarily linked to mutations in &quot;MECP2&quot; gene. This study aims to describe the prevalence of orthopedic conditions in RTT patients, and examine their intricate interplay with functional capabilities, and &quot;MECP2&quot; variant subtypes. Methods: Conducted as a cross-sectional retrospective observational study, the research encompassed 55 patients meeting clinical RTT criteria and holding &quot;MECP2&quot; mutations. A review of clinical records was performed to gather demographic data, mutation subtypes, orthopedic conditions, management strategies, and assessments of function. Results: Mean age of the participants was 10.22 &#177; 4.64 years (range, 2.9-19.41). Prevalence rates of orthopedic conditions were as follows: kyphoscoliosis 63.6%, hip displacement 14.6%, knee problems 40%, and foot deformities 75.5%. Significant relationship emerged between spinal (p &lt; 0.01) and knee deformities (p &lt; 0.01) with reduced motor function across various domains. Hip displacement significantly affected sitting ability (p = 0.002), and foot deformities impacted standing and walking capabilities (p = 0.049). Mutation clusters analysis revealed significant correlations with spinal (p = 0.022) and knee deformities (p = 0.002). Linear models highlighted the critical importance of mutation clusters, spine deformities, age, and hip management concerning functional variables. Conclusions: In this study, foot deformities were the most frequent orthopedic manifestation, followed by spinal, knee, and hip deformities; and unveiled their relationships with functional status and groups of mutations in RTT patients. Level of Evidence: Level IV, Case series.
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  Data: 2025
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RecordInfo BibRecord:
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      – Type: doi
        Value: 10.1007/s10803-024-06399-y
    Languages:
      – Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 11
        StartPage: 2873
    Subjects:
      – SubjectFull: Genetic Disorders
        Type: general
      – SubjectFull: Intellectual Disability
        Type: general
      – SubjectFull: Physical Disabilities
        Type: general
      – SubjectFull: Patients
        Type: general
      – SubjectFull: Children
        Type: general
      – SubjectFull: Adolescents
        Type: general
      – SubjectFull: Incidence
        Type: general
    Titles:
      – TitleFull: Orthopedic Conditions and Interplay with Functional Abilities and 'MECP2' Variant Subtype in Rett Syndrome Patients
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            – TitleFull: Journal of Autism and Developmental Disorders
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