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OBJECTIVE: To evaluate retrospectively the effect of robotic rehabilitation in a large group of children with motor impairment; an additional goal was to identify the effects in children with cerebral palsy (CP) and acquired brain injury (ABI) and with different levels of motor impairment according to the Gross Motor Function Classification System. Finally, we examined the effect of time elapsed from injury on children's functions. DESIGN: A cohort, pretest-posttest retrospective study was conducted. SETTING: Hospitalized care. PARTICIPANTS: A total of 182 children, 110 with ABI and 72 with CP and with Gross Motor Function Classification System (GMFCS) levels I-IV, were evaluated retrospectively. INTERVENTIONS: Patients underwent a combined treatment of robot-assisted gait training and physical therapy. MAIN OUTCOME MEASURES: All the patients were evaluated before and after the training using the 6-minute walk test and the Gross Motor Function Measure. A linear mixed model with 3 fixed factors and 1 random factor was used to evaluate improvements. RESULTS: The 6-minute walk test showed improvement in the whole group and in both ABI and CP. The Gross Motor Function Measure showed improvement in the whole group and in the patients with ABI but not in children with CP. The GMFCS analysis showed that all outcomes improved significantly in all classes within the ABI subgroup, whereas improvements were significant only for GMFCS III in children with CP. CONCLUSIONS: Children with motor impairment can benefit from a combination of robotic rehabilitation and physical therapy. Our data suggest positive results for the whole group and substantial differences between ABI and CP subgroups, with better results for children with ABI, that seem to be consistently related to time elapsed from injury.
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Lesões Encefálicas/complicações , Paralisia Cerebral/complicações , Transtornos Neurológicos da Marcha/reabilitação , Modalidades de Fisioterapia , Robótica/métodos , Lesões Encefálicas/fisiopatologia , Paralisia Cerebral/fisiopatologia , Criança , Feminino , Marcha , Transtornos Neurológicos da Marcha/etiologia , Humanos , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
INTRODUCTION: Phelan-McDermid syndrome (PMS) is caused by SHANK3 haploinsufficiency. Its wide phenotypic variation is attributed partly to the type and size of 22q13 genomic lesion (deletion, unbalanced translocation, ring chromosome), partly to additional undefined factors. We investigated a child with severe global neurodevelopmental delay (NDD) compatible with her distal 22q13 deletion, complicated by bilateral perisylvian polymicrogyria (BPP) and urticarial rashes, unreported in PMS. METHODS: Following the cytogenetic and array-comparative genomic hybridization (CGH) detection of a r(22) with SHANK3 deletion and two upstream duplications, whole-genome sequencing (WGS) in blood and whole-exome sequencing (WES) in blood and saliva were performed to highlight potential chromothripsis/chromoanagenesis events and any possible BPP-associated variants, even in low-level mosaicism. RESULTS: WGS confirmed the deletion and highlighted inversion and displaced order of eight fragments, three of them duplicated. The microhomology-mediated insertion of partial Alu-elements at one breakpoint junction disrupted the topological associating domain joining NFAM1 to the transcriptional coregulator TCF20. WES failed to detect BPP-associated variants. CONCLUSIONS: Although we were unable to highlight the molecular basis of BPP, our data suggest that SHANK3 haploinsufficiency and TCF20 misregulation, both associated with intellectual disability, contributed to the patient's NDD, while NFAM1 interruption likely caused her skin rashes, as previously reported. We provide the first example of chromoanasynthesis in a constitutional ring chromosome and reinforce the growing evidence that chromosomal rearrangements may be more complex than estimated by conventional diagnostic approaches and affect the phenotype by global alteration of the topological chromatin organisation rather than simply by deletion or duplication of dosage-sensitive genes.
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Transtornos Cromossômicos/genética , Cromotripsia , Translocação Genética , Cesárea , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/epidemiologia , Transtornos Cromossômicos/patologia , Cromossomos Humanos Par 22/genética , Hibridização Genômica Comparativa , Feminino , Genômica , Haploinsuficiência/genética , Humanos , Lactente , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Gravidez , Cromossomos em Anel , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: In 2020, a multiprofessional panel was set up in collaboration with the Italian FightTheStroke Foundation family association to produce evidence-based recommendations for the management and neuromotor rehabilitation of persons with cerebral palsy aged 2-18 years to implement in clinical practice in Italy. METHODS: The recommendations of these care pathways were developed according to the American Academy for Cerebral Palsy and Developmental Medicine guidelines for Care Pathways Development and the Grading of Recommendations Assessment Development and Evaluation working group for adoption, adaptation, or de novo development of recommendations from high-quality guidelines (GRADE-ADOLOPMENT). RESULTS: Four strong positive recommendations were developed regarding comprehensive management, and twenty-four addressed neuromotor treatment. CONCLUSIONS: A holistic, individualized approach was affirmed in terms of both multidimensional patient profile and interdisciplinary management in a network with the school where children and adolescents are integrated. It was defined that all motor rehabilitation approaches must be individually tailored considering age and developmentally appropriate activities as interventions and goals, in light of the reference curves addressing prognosis for Gross Motor Function and Manual Ability Classification Systems. Intervention must be structured with adaptations of the task and/or of the context (objects and environment) based on the analysis of the child's skills to support motivation and avoid frustration.
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Background: Evidence regarding the management of several aspects of cerebral palsy improved in recent years. Still, discrepancies are reported in clinical practice. Italian professionals and stakeholders expressed the need of setting up updated, evidenced-based, shared statements, to address clinical practice in cerebral palsy rehabilitation. The objective of the present study was to provide an updated overview of the state of knowledge, regarding the management and motor rehabilitation of children and young people with cerebral palsy, as the framework to develop evidence-based recommendations on this topic. Methods: Guidelines and systematic reviews were searched, relative to evidence-based management and motor treatment, aimed at improving gross motor and manual function and activities, in subjects with cerebral palsy, aged 2-18 years. A systematic search according to the Patients Intervention Control Outcome framework was executed on multiple sites. Independent evaluators provided selection and quality assessment of the studies and extraction of data. Results: Four guidelines, 43 systematic reviews, and three primary studies were included. Agreement among guidelines was reported relative to the general requirements of management and motor treatment. Considering the subject's multidimensional profile, age and developmentally appropriate activities were recommended to set individual goals and interventions. Only a few approaches were supported by high-level evidence (i.e., bimanual therapy and constraint-induced movement therapy to enhance manual performance). Several task-specific active approaches, to improve gross motor function and gait, were reported (mobility and gait training, cycling, backward gait, and treadmill), based on low-level evidence. Increasing daily physical activity and countering sedentary behavior were advised. Based on the available evidence, non-invasive brain stimulation, virtual reality, action-observation therapy, hydrotherapy, and hippotherapy might be complementary to task or goal-oriented physical therapy programs. Conclusion: A multiple-disciplinary family-centered evidence-based management is recommended. All motor rehabilitation approaches to minors affected by cerebral palsy must share the following fundamental characteristics: engaging active involvement of the subject, individualized, age and developmentally appropriate, goal-directed, skill-based, and preferably intensive and time-limited, but suitable for the needs and preferences of the child or young person and their family, and feasible considering the implications for themselves and possible contextual limitations.
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Children with cerebral palsy (CP) suffer deficits in their motor, sensory, and cognitive abilities, as well as in their visuospatial competences. In the last years, several authors have tried to correlate the visuospatial abilities with the navigational ones. Given their importance in everyday functions, navigation skills have been deeply studied using increasingly cutting-edge techniques such as virtual reality (VR). However, to our knowledge, there are no studies focused on training using immersive VR (IVR) in children with movement disorders. For this reason, we proposed an IVR training to 35 young participants with CP and conceived to improve their navigation skills in a "simil-real" environment while playing on a dynamic platform. A subgroup performed a part of the training which was specifically dedicated to the use of the allocentric strategy (i.e., looking for landmarks) to navigate the virtual environment. We then compared the children's navigation and spatial skills pre- and post-intervention. All the children improved their visual-spatial abilities; particularly, if the IVR activities specifically trained their ability to look for landmarks and use them to navigate. The results of this work highlight the potential of an IVR training program to increase the navigation abilities of patients with CPs.
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Purpose: Human navigation skills are essential for everyday life and rely on several cognitive abilities, among which visual-spatial competences that are impaired in subjects with cerebral palsy (CP). In this work, we proposed navigation tasks in immersive virtual reality (IVR) to 15 children with CP and 13 typically developing (TD) peers in order to assess the individual navigation strategies and their modifiability in a situation resembling real life. Methods: We developed and adapted to IVR an application based on a 5-way maze in a playground that was to be navigated to find a reward. The learning process, navigation strategies, and adaptation to changes were compared between participants with CP and their TD peers and correlated with visual-spatial abilities and cognitive competences. Results: Most participants with CP needed more attempts than TD participants to become proficient in navigation. Furthermore, the learning phase was correlated to visual-spatial memory but not with cognitive competences. Interestingly, navigation skills were comparable between groups after stabilization. While TD participants mainly relied on allocentric strategies based on environmental cues, egocentric (self-centered) strategies based on body motion prevailed in participants with CP. Furthermore, participants with CP had more difficulties in modifying their navigation strategies, caused by difficulties in executive processes beyond the visual-perceptual impairment, with an inefficient shift between implicit and explicit competences. Conclusions: The navigation abilities in participants with CP seem to be different from their TD peers in terms of learning and adaptation to new conditions; this could deeply affect their everyday life and ultimately participation and inclusion. A regular assessing and focused rehabilitative plans could help to better navigate the environment and affect self-perception.
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OBJECTIVE: The minimum clinically important difference (MCID) is a standard way of measuring clinical relevance. The objective of this work was to establish the MCID for the 6-minute walking test (6minWT) and the Gross Motor Function Measure (GMFM-88) in pediatric gait disorders. METHODS: A cohort, pretest-posttest study was conducted in a hospitalized care setting. A total of 182 patients with acquired brain injury (ABI) or cerebral palsy (CP) performed 20 robot-assisted gait training sessions complemented with 20 sessions of physical therapy over 4 weeks. Separate MCIDs were calculated using 5 distribution-based approaches, complemented with an anonymized survey completed by clinical professionals. RESULTS: The MCID range for the 6minWT was 20-38 m in the ABI cohort, with subgroup ranges of 20-36 m for GMFCS I-II, 23-46 m for GMFCS III, and 24-46 m for GMFCS IV. MCIDs for the CP population were 6-23 m, with subgroup ranges of 4-28 m for GMFCS I-II, 9-19 m for GMFCS III, and 10-27 m for GMFCS IV. For GMFM-88 total score, MCID values were 1.1%-5.3% for the ABI cohort and 0.1%-3.0% for the CP population. For dimension "D" of the GMFM, MCID ranges were 2.3%-6.5% and 0.8%-5.2% for ABI and CP populations, respectively. For dimension "E," MCID ranges were 2.8%-6.5% and 0.3%-4.9% for ABI and CP cohorts, respectively. The survey showed a large interquartile range, but the results well mimicked the distribution-based methods. CONCLUSIONS: This study identified for the first time MCID ranges for 6minWT and GMFM-88 in pediatric patients with neurological impairments, offering useful insights for clinicians to evaluate the impact of treatments. Distribution-based methods should be used with caution: methods based on pre-post correlation may underestimate MCID when applied to patients with small improvements over the treatment period. Our results should be complemented with estimates obtained using consensus- and anchor-based approaches.
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Terapia por Exercício , Marcha/fisiologia , Transtornos Motores/terapia , Resultado do Tratamento , Adolescente , Lesões Encefálicas/fisiopatologia , Lesões Encefálicas/terapia , Paralisia Cerebral/fisiopatologia , Paralisia Cerebral/terapia , Criança , Limiar Diferencial , Terapia por Exercício/métodos , Terapia por Exercício/estatística & dados numéricos , Feminino , Humanos , Masculino , Transtornos Motores/fisiopatologia , Destreza Motora/fisiologia , Estudos Retrospectivos , Robótica/métodos , Teste de CaminhadaRESUMO
Recessive mutations in DDHD2 cause SPG54, a complex hereditary spastic paraplegia (HSP) with less than forty patients reported worldwide. In this retrospective, multicenter study we describe eight additional SPG54 cases harboring homozygous or compound heterozygous DDHD2 variants. Finally, we reviewed literature data on SPG54, with the aim to better define the phenotype and the brain magnetic resonance imaging (MRI) pattern as well as genotype-phenotype correlations. SPG54 is typically characterized by early-onset (i.e., congenital or, more frequently, infantile) delay in motor and cognitive milestones, coupled or followed by appearance of spasticity. Cognitive impairment is absent in adult-onset cases. Spasticity progresses over time. Abnormal eye movement, found in about 50% of cases, is the feature most frequently associated with spasticity and developmental delay. Cerebellar ataxia is a prominent sign in several patients, including one adult of this study, suggesting to include SPG54 in the differential diagnosis of spastic-ataxia syndromes. Brain MRI shows thin corpus callosum and non-specific periventricular white matter lesions in about 90% and 70% of cases, respectively. Brain MR spectroscopy reveals abnormal lipid peak in 90% of investigated patients. Twenty-one pathogenic changes have been reported so far, many of which are nonsense or small deletion/duplication. Most mutations appear to be private, with only two mutations recurring in three (i.e., R287*) or more families (i.e., D660H). The identification of nine novel variants expands the molecular spectrum of DDHD2-related HSP and corroborates the notion of a quite homogeneous clinical and neuroradiological phenotype in spite of different genotypes.
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Fosfolipases/genética , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/patologia , Adolescente , Encéfalo/patologia , Criança , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Paraplegia Espástica Hereditária/fisiopatologia , Adulto JovemRESUMO
The feasibility and effectiveness of a year-long integrated rehabilitation program for young children (less than 6 years old) with cerebral palsy was evaluated, and efficacy of different treatment schedules was compared. A sample of 40 children (20 male; mean age, 3 years +/-1.22) took part: 20 presented with tetraparesis, 12 with diparesis, and 8 with hemiparesis. Participants' motor abilities were classified according to the Gross Motor Function Measure classification system at baseline and after 1 year of treatment. For half of the participants, treatment consisted of continuous integrated intervention twice a week; for the other half, treatment was the 3i intervention (Intermittent, Intensive, Integrated), in which a month of intensive, twice-a-day treatment was followed by a continuous, twice-a-week phase, lasting 5 months. Overall, there was an improvement in gross motor function, with 37% of children improving and no children showing lowered function. Neither baseline general cognitive abilities nor age had a significant effect on the level of improvement, although initial gross motor function did. Children undergoing the intensive intermittent intervention showed the greatest motor function improvement. Results support the effectiveness of the integrated intervention and of periods of higher frequency intervention in young children.
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Paralisia Cerebral/reabilitação , Paralisia Cerebral/terapia , Quadriplegia/reabilitação , Quadriplegia/terapia , Agendamento de Consultas , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Análise por Pareamento , Atividade Motora , Paresia/reabilitação , Paresia/terapia , Projetos Piloto , Resultado do TratamentoRESUMO
Immersive virtual reality (IVR) offers new possibilities to perform treatments in an ecological and interactive environment with multimodal online feedbacks. Sixteen school-aged children (mean age 11 ± 2.4 years) with Bilateral CP-diplegia, attending mainstream schools were recruited for a pilot study in a pre-post treatment experimental design. The intervention was focused on walking competences and endurance and performed by the Gait Real-time Analysis Interactive Lab (GRAIL), an innovative treadmill platform based on IVR. The participants underwent eighteen therapy sessions in 4 weeks. Functional evaluations, instrumental measures including GAIT analysis and parental questionnaire were utilized to assess the treatment effects. Walking pattern (stride length left and right side, respectively p = 0.001 and 0.003; walking speed p = 0.001), endurance (6MWT, p = 0.026), gross motor abilities (GMFM-88, p = 0.041) and most kinematic and kinetic parameters significantly improved after the intervention. The changes were mainly predicted by age and cognitive abilities. The effect could have been due to the possibility of IVR to foster integration of motor/perceptual competences beyond the training of the walking ability, giving a chance of improvement also to older and already treated children.
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Paralisia Cerebral/reabilitação , Terapia por Exercício , Realidade Virtual , Caminhada/fisiologia , Adolescente , Paralisia Cerebral/fisiopatologia , Criança , Feminino , Humanos , Masculino , Projetos PilotoRESUMO
BACKGROUND: Children with cerebral palsy (CP) and acquired brain injury (ABI) often exhibit upper limb impairment, with repercussions in their daily activities. Robotic rehabilitation may promote their functional recovery, but evidence of its effectiveness is often based on qualitative functional scales. The primary aim of the present work was to assess movement precision, velocity, and smoothness using numerical indices from the endpoint trajectory of Armeo®Spring. Secondly, an investigation of the effectiveness of robotic rehabilitation in CP and ABI children was performed. METHODS: Upper limb functional changes were evaluated in children with CP (N=21) or ABI (N=22) treated with Armeo®Spring (20 45-minute sessions over 4 weeks) using clinical scales and numerical indices computed from the exoskeleton trajectory. RESULTS: Functional scales (i.e., QUEST and Melbourne) were sensitive to changes produced by the treatment for the whole study group and for the two etiology-based subgroups (improvements above Minimal Clinically Importance Difference). Significant improvement was also observed in terms of velocity, fluidity, and precision of the movement through the numerical indices of kinematic performance. Differences in the temporal evolution of the motor outcome were highlighted between the ABI and CP subgroups, pointing toward adopting different rehabilitative protocols in these two populations. CONCLUSIONS: Robot-assisted upper limb rehabilitation seems to be a promising tool to promote and assess rehabilitation in children affected by acquired and congenital brain diseases.
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Lesões Encefálicas/fisiopatologia , Paralisia Cerebral/fisiopatologia , Movimento/fisiologia , Recuperação de Função Fisiológica/fisiologia , Adolescente , Fenômenos Biomecânicos/fisiologia , Criança , Feminino , Humanos , Masculino , Robótica/métodos , Reabilitação do Acidente Vascular Cerebral/métodos , Extremidade Superior/fisiopatologiaRESUMO
BACKGROUND: Acquired brain injury (ABI) may result in lifelong impairment of physical, cognitive, and psychosocial functions. Several rehabilitative treatments are often needed to support walking recovery, thus participants' engagement becomes a crucial aspect, especially when patients are children. In the last few years, traditional physiotherapy (PT) has been flanked by innovative technologies for rehabilitation in the fields of robotics and Virtual Reality (VR). Preliminary results have shown interesting perspectives in the use of a VR system, the GRAIL (Gait Real-time Analysis Interactive Lab), in improving walking abilities in a small group of children with ABI, although further insights are needed about its use as rehabilitative tool in the pediatric population. OBJECTIVES: To evaluate the efficacy of a rehabilitation treatment on a GRAIL system for the improvement of walking abilities, in a group of children suffering from ABI. METHODS: 12 children with ABI (study group - SG; mean ageâ=â12.1 ± 3.8 years old) underwent a 10-session treatment with the GRAIL, an instrumented multi-sensor platform based on immersive VR for gait training and rehabilitation in engaging VR environments. Before (T0) and at the end of the treatment (T1), the participants were assessed by means of functional scales (Gross Motor Function Measure (GMFM), Functional Assessment Questionnaire (FAQ), 6-Minute Walk Test (6minWT) and the 3D-Gait Analysis, over ground (OGA) and on GRAIL (GGA). RESULTS: All the participants completed the rehabilitative treatment. The functional evaluations showed an improvement in Gross Motor abilities (GMFM-88, p = 0.008), especially in standing (GMFM-D, p = 0.007) and walking (GMFM-E, p = 0.005), an increase of the endurance (6minWT, p = 0.002), and enhanced autonomy in daily life activities (FAQ, p = 0.025). OGA identified a significant decrease of the Gillette Gait Index for the impaired side and a general increase of symmetry. GGA showed improvements in spatiotemporal parameters and joints range of motion that moved towards normality and symmetry recovery. CONCLUSIONS: A 10-session treatment with GRAIL on children with ABI led to improvements in their walking abilities and enhanced their engagement during the training. This is desirable when long life impairments are faced and children's motor functions have to be regained and it supports the leading role that VR might have in the rehabilitation field.
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Lesões Encefálicas/fisiopatologia , Interface Usuário-Computador , Caminhada/fisiologia , Adolescente , Algoritmos , Criança , Pré-Escolar , Terapia por Exercício , Feminino , Marcha/fisiologia , Humanos , MasculinoRESUMO
BACKGROUND: Robot-Assisted Gait Training (RAGT) is a widespread approach for locomotion rehabilitation but information about intervention frequency and duration is still lacking. OBJECTIVE: To evaluate the effect of frequency and duration of a RAGT on motor outcome of children affected by Cerebral Palsy (CP). METHODS: Forty-four CP children (age 4-17) underwent one among four different intensive trainings with equal dose of intervention, combining Task-Oriented Physiotherapy (TOP) and RAGT: 40 sessions (4 sessions/week) over 10 weeks of sole TOP (group1) or RAGT (group2) or RAGT and TOP (2 + 2 sessions/week; group3); 40 sessions in shorter period (4 weeks) of RAGT and TOP (5 + 5 sessions/week; group4). Each child was assessed before, after the training and after 3 months with: Ashworth, gross motor function measure (GMFM)-88, GMFM-66, six minutes walking test and gait analysis. RESULTS: No differences among the 4 protocols were highlighted although both groups with exclusive physiotherapy and RAGT obtained significant improvements in GMFM-88, GMFM-E and GMFM-66 while the mixed approaches did not show significant changes. CONCLUSION: Single-treatment approaches seem to be more effective than mixed approaches, independently from the duration (4 or 10 weeks). RAGT seems to have similar effect with respect to the traditional TOP, at least over 10 weeks.
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Paralisia Cerebral/reabilitação , Terapia por Exercício/métodos , Robótica/métodos , Caminhada , Adolescente , Criança , Pré-Escolar , Feminino , Marcha , Humanos , Masculino , Modalidades de FisioterapiaRESUMO
BACKGROUND: Few systematic studies describe rehabilitation trainings for upper limb in diplegic children with cerebral palsy (CP), who - especially once grown up - are often not considered as a target for rehabilitation interventions. AIM: In this pilot study, we describe the details and the effectiveness of an intensive, technology assisted intervention for upper limb. SETTING: The treatment combines the utilization of Armeo® Spring with a training focused on hand/finger fluency and dexterity in a pre-post treatment experimental design. POPULATION: Participants were ten school-aged children (mean age 11.2) with bilateral CP and diplegia, attending mainstream schools. METHODS: Participants underwent 40 therapy sessions in four weeks. Armeo® Spring measures, standardized motor and perceptual outcome indexes, as well as everyday life indicators were utilized to assess the effect of the intervention. RESULTS: Upper limb coordination, fluency and quality of movements mainly of hands and fingers significantly improved, with a good transferability to everyday life also in areas not specifically trained, such as self-care abilities and mobility. Probably due to the visual feedback provided by the virtual reality setting (which was all in one the context, the incentive and the product of activities), perceptual abilities significantly improved, too. CONCLUSIONS: Our study suggests the importance of intervention on upper limb even in milder CP diplegic forms and in relatively grown-up children. The possibility of modification at least partially relies on learning processes that are active all along development and benefit from stimulation. CLINICAL REHABILITATION IMPACT: Though further studies with control groups and follow-up perspective are needed to confirm, new technologies offer interesting possibilities to be integrated into new evidence-based rehabilitation models.
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Atividades Cotidianas , Paralisia Cerebral/diagnóstico , Paralisia Cerebral/reabilitação , Terapia por Exercício/tendências , Extremidade Superior/fisiopatologia , Adolescente , Fatores Etários , Criança , Terapia por Exercício/métodos , Feminino , Previsões , Humanos , Itália , Masculino , Força Muscular/fisiologia , Manipulações Musculoesqueléticas/métodos , Manipulações Musculoesqueléticas/tendências , Projetos Piloto , Amplitude de Movimento Articular/fisiologia , Medição de Risco , Autocuidado , Índice de Gravidade de Doença , Fatores Sexuais , Análise e Desempenho de Tarefas , Resultado do TratamentoRESUMO
Complicated hereditary spastic paraplegias (HSP) are a heterogeneous group of HSP characterized by spasticity associated with a variable combination of neurologic and extra-neurologic signs and symptoms. Among them, HSP with thin corpus callosum and intellectual disability is a frequent subtype, often inherited as a recessive trait (ARHSP-TCC). Within this heterogeneous subgroup, SPG11 and SPG15 represent the most frequent subtypes. We analyzed the mutation frequency of three genes associated with early-onset forms of ARHSP with and without TCC, CYP2U1/SPG56, DDHD2/SPG54 and GBA2/SPG46, in a large population of selected complicated HSP patients by using a combined approach of traditional-based and amplicon-based high-throughput pooled-sequencing. Three families with mutations were identified, one for each of the genes analyzed. Novel homozygous mutations were identified in CYP2U1 (c.1A>C/p.Met1?) and in GBA2 (c.2048G>C/p.Gly683Arg), while the homozygous mutation found in DDHD2 (c.1978G>C/p.Asp660His) had been previously reported in a compound heterozygous state. The phenotypes associated with the CYP2U1 and DDHD2 mutations overlap the SPG56 and the SPG54 subtypes, respectively, with few differences. By contrast, the GBA2 mutated patients show phenotypes combining typical features of both the SPG46 subtype and the recessive ataxia form, with marked intrafamilial variability thereby expanding the spectrum of clinical entities associated with GBA2 mutations. Overall, each of three genes analyzed shows a low mutation frequency in a general population of complicated HSP (<1 % for either CYP2U1 or DDHD2 and approximately 2 % for GBA2). These findings underline once again the genetic heterogeneity of ARHSP-TCC and the clinical overlap between complicated HSP and the recessive ataxia syndromes.