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Background: Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes., Methods and Results: We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (-0.80%) and SF (-0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (-11.01 mL/m2, p = 0.03) while for dp116 were correlated with decreased EF (-4.14%, p = <0.001). The rs10880 genotype in the LTBP4 gene, previously shown to prolong ambulation, was also associated with increased EF and decreased EDV (+3.29%, p = 0.002, and -10.62 mL/m2, p = 0.008) with a recessive model., Conclusions: We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4 genotype of DCM in DMD.

The aim of the study was to retrospectively evaluate the consistency of longitudinal findings on intellectual functioning in DMD boys and their relationship to behavioral and neuropsychiatric difficulties. The cohort included 70 patients of age 3 to 17 years with at least two assessments using the Wechsler scales. CBCL and clinical observation of behavior were also performed. Changes in total intelligence quotient were interpreted as stable or not stable using the reliable-change method. On the first assessment 43/70 had normal quotients, 18 borderline, 5 mild, and 4 moderate intellectual disability, while 27/70 had no behavioral disorders, 17 had abnormal CBCL, and 26 patients had clear signs of attention deficits despite normal CBCL. The remaining seven were untestable. The mean total intelligence quotient change in the cohort was -2.99 points (SD: 12.29). Stable results on TIQ were found in 63% of the paired assessments. A third of the consecutive cognitive assessments showed a difference of more than 11 points with changes up to 42 points. Boys with no behavioral/attention disorder had smaller changes than those with attention ( p = 0.007) and behavioral disorders ( p = 0.002). Changes in IQ may occur in Duchenne and are likely to be associated with behavioral or attention deficits.

Background: the present study aims to assess language in preschool-aged Duchenne muscular dystrophy (DMD) boys with normal cognitive quotients, and to establish whether language difficulties are related to attentional aspects or to the involvement of brain dystrophin isoforms., Methods: 20 children aged between 48 and 72 months were assessed with language and attention assessments for preschool children. Nine had a mutation upstream of exon 44, five between 44 and 51, four between 51 and 63, and two after exon 63. A control group comprising 20 age-matched boys with a speech language disorder and normal IQ were also used., Results: lexical and syntactic comprehension and denomination were normal in 90% of the boys with Duchenne, while the articulation and repetition of long words, and sentence repetition frequently showed abnormal results (80%). Abnormal results were also found in tests assessing selective and sustained auditory attention. Language difficulties were less frequent in patients with mutations not involving isoforms Dp140 and Dp71. The profile in Duchenne boys was different form the one observed in SLI with no cognitive impairment., Conclusion: The results of our observational cross-sectional study suggest that early language abilities are frequently abnormal in preschool Duchenne boys and should be assessed regardless of their global neurodevelopmental quotient.

The aim of this study was to establish the possible effect of age, corticosteroid treatment and brain dystrophin involvement on motor function in young boys affected by Duchenne Muscular Dystrophy who were assessed using the North Star Ambulatory Assessment between the age of 4 and 7 years. The study includes 951 North Star assessments from 226 patients. Patients were subdivided according to age, to the site of mutation and therefore to the involvement of different brain dystrophin isoforms and to corticosteroids duration. There was a difference in the maximum North Star score achieved among patients with different brain dystrophin isoforms (p = 0.007). Patients with the involvement of Dp427, Dp140 and Dp71, had lower maximum NSAA scores when compared to those with involvement of Dp427 and Dp140 or of Dp427 only. The difference in the age when the maximum score was achieved in the different subgroups did not reach statistical significance. Using a linear regression model on all assessments we found that each of the three variables, age, site of mutation and corticosteroid treatment had an influence on the NSAA values and their progression over time. A second analysis, looking at 12-month changes showed that within this time interval the magnitude of changes was related to corticosteroid treatment but not to site of mutation. Our findings suggest that each of the considered variables appear to play a role in the progression of North Star scores in patients between the age of 4 and 7 years and that these should be carefully considered in the trial design of boys in this age range., Competing Interests: The authors have declared that no competing interests exist.

The aim of this retrospective study was to review body mass index (BMI) in a large cohort of Italian pediatric type 2 spinal muscular atrophy (SMA) patients, aged between 0 and 20 years and to establish possible differences in relation to a number of variables such as ventilation, motor function, and survival motor neuron 2 gene copies. Cross-sectional data were collected from 102 patients for a total of 344 visits. Standard growth charts for height and weight were used as reference, with age adjusted BMI calculated using the Center for Disease and Prevention Children's BMI Tool. In the 344 visits, weight ranged between 3.90 and 83 kg, and the BMI between 8.4 and 31.6 with a BMI/age z-scores <  - 2SD present in 28% and BMI/age z-scores >  + 2SD in 9% of the measurements. The BMI/age z-scores were relatively stable < 5 years of age with an increasing number of patients <  - 2SD after the age of 5, and a wider range of BMI/age z-scores after the age of 13. A difference on the BMI/age z-scores was found among the different age subgroups (< 5, 5-12, ≥ 13 years). A multivariate analysis in 58 patients with longitudinal assessments showed that baseline BMI/age z-scores and gender were significantly contributing to the changes while other variables were not., Conclusion: Our results confirm that careful surveillance of weight and BMI/age z-scores is needed in type 2 SMA. Further studies, including assessments of chewing and swallowing and of lean/fat body mass, will help to better understand the possible mechanisms underlying weight issues., What Is Known: • Feeding difficulties have been reported in a few studies and were invariably found in patients with type 1 SMA. • Type 2 SMA patients often have low BMI with a relevant number of patients requiring tube feeding., What Is New: • Reduction in BMI/age z-score overtime appeared to depend on baseline BMI/age z-score and gender. • Patients with a low BMI/age z-score were at higher risk of developing further reduction., (© 2022. The Author(s).)

The term autism spectrum disorder (ASD) includes a wide variability of clinical presentation, and this clinical heterogeneity seems to reflect a still unclear multifactorial etiopathogenesis, encompassing different genetic risk factors and susceptibility to environmental factors. Several studies and many theories recognize as mechanisms of autism a disruption of brain development and maturation time course, suggesting the existence of common neurobiological substrates, such as defective synaptic structure and aberrant brain connectivity. Magnetic resonance imaging (MRI) plays an important role in both assessment of region-specific structural changes and quantification of specific alterations in gray or white matter, which could lead to the identification of an MRI biomarker. In this study, we performed measurement of cortical thickness in a selected well-known group of preschool ASD subjects with the aim of finding correlation between cortical metrics and clinical scores to understand the underlying mechanism of symptoms and to support early clinical diagnosis. Our results confirm that recent brain MRI techniques combined with clinical data can provide some useful information in defining the cerebral regions involved in ASD although large sample studies with homogeneous analytical and multisite approaches are needed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lucibello, Bertè, Verdolotti, Lucignani, Napolitano, D’Abronzo, Cicala, Pede, Chieffo, Mariotti, Colosimo, Mercuri and Battini.)

Previous natural history studies suggest that type II SMA patients remain stable over one year but show some progression over two years. Since nusinersen approval, there has been increasing attention to identify more specific age-related changes. The aim of the study was to establish 12-month changes in a cohort of pediatric type II SMA treated with nusinersen and to establish possible patterns of treatment effect in relation to different variables such as age, baseline value and SMN2 copy number. The Hammersmith Functional Motor Scale Expanded and the Revised Upper Limb Module were performed at T0 and 12 months after treatment (T12). Data in treated patients were compared to available data in untreated patients collected by the same evaluators.Seventy-seven patients of age between 2.64 and 17.88 years (mean:7.47, SD:3.79) were included. On t-test there was an improvement, with increased mean scores between T0 and T12 on both scales (p < 0.001). Using multivariate linear regression analysis, age and baseline scores were predictive of changes on both scales (p < 0.05) while SMN2 copy number was not. Differences were also found between study cohort and untreated data on both scales (p < 0.001). At 12 months, an increase in scores was observed in all the age subgroups at variance with natural history data. Our real-world data confirm the treatment effect of nusinersen in pediatric type II SMA patients and that the data interpretation should take into account different variables. These data confirm and expand the ones already reported in the Cherish study., Competing Interests: Declaration of Competing Interest GC, RDS, JM, AMG, SDY, MP, SM, ADA, BTD, EB, VAS, JD, FM, DCDV, RF, CB, EM reports personal fees BIOGEN S.R.L. outside the submitted work; GC, MCP, RDS, JM, AMG, SDY, MS, BTD, EB, JD, FM, DCDV, RF, CB, EM reports personal fees ROCHE outside the submitted work; GC reports personal fees GENESIS PHARMA and Biologix outside the submitted work; GC, RDS, AMG, MP, SM, BTD, EB, VAS, JD, FM, DCDV, RF, CB, EM reports personal fees AVEXIS outside the submitted work; AP, SDY, reports personal fees SMA FOUNDATION outside the submitted work; SDY reports personal fees SCHOLAR ROCK outside the submitted work; ADA, JD, RF reports personal fees NOVARTIS outside the submitted work; SL, SC, LA, AF, FS, PT, MC, TD, have nothing to disclose., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The aim was to assess 3-year longitudinal data using 6MWT in 26 ambulant boys affected by DMD carrying nonsense mutations and to compare their results to other small mutations. We also wished to establish, within the nonsense mutations group, patterns of change according to several variables. Patients with nonsense mutations were categorized according to the stop codon type newly created by the mutation and also including the adjacent 5' (upstream) and 3' (downstream) nucleotides. No significant difference was found between nonsense mutations and other small mutations (p > 0.05) on the 6MWT. Within the nonsense mutations group, there was no difference in 6MWT when the patients were subdivided according to: Type of stop codon, frame status of exons involved, protein domain affected. In contrast, there was a difference when the stop codon together with the 3' adjacent nucleotide ("stop+4 model") was considered (p < 0.05) with patients with stop codon TGA and 3' adjacent nucleotide G (TGAG) having a more rapid decline. Our finding suggest that the stop+4 model may help in predicting functional changes. This data will be useful at the time of interpreting the long term follow up of patients treated with Ataluren that are becoming increasingly available., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021. Published by Elsevier B.V.)

Objective: The aim of this paper was to report the 2-year follow-up in type I patients treated with Nusinersen and to assess whether possible changes in motor function are related to the subtype, age, or SMN2 copy number., Methods: Sixty-eight patients, with ages ranging from 0.20 to 15.92 years (mean: 3.96; standard deviation: +3.90) were enrolled in the study. All patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the developmental section of the Hammersmith Infant Neurological Examination (HINE-2) at the time they started treatment and 12 and 24 months after that., Results: For both CHOP and HINE-2 repeated measures analysis of variance showed a significant difference (P < 0.001) between baseline and 12 months, 12 months and 24 months, and baseline and 24-month scores for the whole group. When age subgroups (<210 days, <2 years, 2-4 years, 5-11 years, 12-18 years) were considered, on the CHOP INTEND the difference was significant between baseline and 24 months in all age subgroups. On the HINE-2, the difference between baseline and 24 months was significant in all the subgroups before the age of 4 years. Age was predictive of changes on both scales (P < 0.05), whereas SMN2 copy number and decimal classification were not., Interpretation: Our results suggest that some improvement of motor function can be observed even after the first year of treatment. This is more obvious in the infants treated in the first 2 years but some improvement can also be found in older children., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The objective of this study was to identify developmental trajectories of developmental/behavioral phenotypes and possibly their relationship to epilepsy and genotype by analyzing developmental and behavioral features collected prospectively and longitudinally in a cohort of patients with Dravet syndrome (DS). Thirty-four patients from seven Italian tertiary pediatric neurology centers were enrolled in the study. All patients were examined for the SCN1A gene mutation and prospectively assessed from the first years of life with repeated full clinical observations including neurological and developmental examinations. Subjects were found to follow three neurodevelopmental trajectories. In the first group (16 patients), an initial and usually mild decline was observed between the second and the third year of life, specifically concerning visuomotor abilities, later progressing towards global involvement of all abilities. The second group (12 patients) showed an earlier onset of global developmental impairment, progressing towards a generally worse outcome. The third group of only two patients ended up with a normal neurodevelopmental quotient, but with behavioral and linguistic problems. The remaining four patients were not classifiable due to a lack of critical assessments just before developmental decline. The neurodevelopmental trajectories described in this study suggest a differential contribution of neurobiological and genetic factors. The profile of the first group, which included the largest fraction of patients, suggests that in the initial phase of the disease, visuomotor defects might play a major role in determining developmental decline. Early diagnosis of milder cases with initial visuomotor impairment may therefore provide new tools for a more accurate habilitation strategy., (Copyright © 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Background and Objectives: Sleep disorders are common in children with Autism Spectrum Disorder (ASD). The aims of this study were to describe the incidence and characteristics of sleep disorders using a questionnaire completed by the caregiver in a sample of preschool-aged children with ASD and to identify possible differences in a control group of peers. Materials and Methods: Sleep disorders were investigated with the Sleep Disturbance Scale for Children (SDSC) in a population of pre-school-aged (3-5 years) ASD children and in a control group. The Autism Diagnostic Observation Schedule-second ed. (ADOS-2) was further used to assess autism symptom severity. A total of 84 children (69 males; mean age 3.9 ± 0.8 years) with a diagnosis of ASD and 84 healthy controls (65 males; mean age of 3.7 ± 0.8 years) that were matched for age and sex were enrolled. Results: ASD children reported significantly higher (pathological) scores than the control group on the SDSC total scores and in some of the factor scores, such as Difficulty in Initiating and Maintaining Sleep (DIMS), disorders of excessive somnolence (DOES), and sleep hyperhidrosis. A total of 18% of ASD children had a pathological SDSC total T-score, and 46% had an abnormal score on at least one sleep factor; DIMS, parasomnias, and DOES showed the highest rates among the sleep factors. Younger children (3 years) reported higher scores in DIMS and sleep hyperhidrosis than older ones (4 and 5 years). No specific correlation was found between ADOS-2 and SDSC scores. Conclusions: Pre-school children with ASD showed a high incidence of sleep disorders with different distributions of specific sleep factors according to their age. We suggest a screening assessment of sleep disorders using the SDSC in these children with a more in-depth evaluation for those reporting pathological scores on the questionnaire.

Background: Over the last few years there has been increasing attention to detect early signs of impairment in young Duchenne muscular dystrophy boys but less has been reported on whether the delay may also affect the very early aspects of motor development, such as gross motor milestones., Objective: The aim of this study was to retrospectively assess the age when early motor milestones were achieved in Duchenne muscular dystrophy., Methods: The study is a retrospective analysis of data collected as part of a larger natural history project. Information on past medical history, collected at the time the boys were seen for the first time, were recorded and re available on clinical notes and on electronic CRF., Results: Data were collected in 134 DMD boys. Sitting was achieved at 7.04 months. The % of DMD boys not achieving sitting by 9.4 months was 10%, ranging from 2% in the boys with mutations before exon 44 to 33% in those beyond exon 63. Walking was achieved at a mean age of 16.35 months. The % of DMD boys not achieving independent walking by 18 months was 17%, ranging from 9% in the boys with mutations between 44 and 51 to 42% in those beyond exon 63., Conclusions: Our results showed that the risk of a delay in sitting and walking was increasingly high in patients with mutations predictive of the involvement of different brain dystrophin isoforms.

We describe the development of a new tool specifically designed to record oral abilities, swallowing and, more generally, feeding in young type 1 SMA patients, to be used during the first 24 months of life.The tool is composed by a checklist and a separate section summarizing the functional abilities into levels of feeding/swallowing impairment. The checklist includes 12 questions assessing aspects thought to be clinically meaningful for a type 1 SMA population and developmentally appropriate for infants during the first months of life. Each item is graded with a score of 0 or 1, depending on the child's ability to perform the activity. As some items are age-dependent, the number of items to be used, and therefore the maximum score, changes with increasing age. The levels of feeding/swallowing impairment include four levels that can be identified using easily identifiable clinical criteria.In an attempt to validate the tool in an untreated population we applied it to 24 type 1 SMA patients (age range: 2.3-24.1 months, mean: 10.8) in whom the same information collected by the new tool had been previously recorded using a less-structured format.When patients were classified in three groups according to the Dubowitz decimal classification, there was a significant difference both at baseline and at follow-up (p < 0.001). The items assessing fatigue during the nursing sessions were the most frequently impaired even in infants who did not have any other obvious clinical sign of swallowing difficulties.

Objective: We report natural history data in a large cohort of 199 patients with spinal muscular atrophy (SMA) type III assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE). The aim of the study was to establish the annual rate and possible patterns of progression according to a number of variables, such as age of onset, age at assessment, SMN2 copy number, and functional status., Methods: HFMSE longitudinal changes were assessed using piecewise linear mixed-effects models. The dependency in the data due to repeated measures was accounted for by a random intercept per individual and an unstructured covariance R matrix was used as correlation structure. An additional descriptive analysis was performed for 123 patients, for a total of 375 12-month assessments., Results: A break point at age 7 years was set for the whole cohort and for SMA IIIA and IIIB. Age, SMA type, and ambulatory status were significantly associated with changes in mean HFMSE score, whereas gender and SMN2 copy number were not. The increase in response before the break point of age 7 years is significant only for SMA IIIA (β = 1.79, p < 0.0001). After the break point, the change in the rate of HFMSE score significantly decrease for both SMA IIIA (β = -1.15, p < 0.0001) and IIIB (β = -0.69, p = 0.002)., Interpretation: Our findings contribute to the understanding of the natural history of SMA type III and will be helpful in the interpretation of the real-world data of patients treated with commercially available drugs. ANN NEUROL 2020;88:1109-1117., (© 2020 American Neurological Association.)

Background: Retinopathy of prematurity (ROP) is often associated with visual impairment and multiple developmental disabilities., Aims: As most of the previous studies include infants with brain lesions, that can determine visual impairment per se, a cohort of low neurological risk preterm infants without ROP and with various degree of severity of ROP was assessed in order to establish visual and neurodevelopmental outcome., Study Design: Preterm infants born at <31 weeks gestation, without major brain lesions, underwent visual function assessment at 1 year corrected age and neurodevelopmental assessment at 2 years corrected age., Subjects: One hundred and five infants were included in the study: 42 infants did not develop ROP, 7 reached stage 1 in zone 2 ROP, 37 reached prethreshold (untreated) type 2 ROP. The remaining 19 infants were classified as type 1 ROP., Outcome Measures: Visual function (including fixing, tracking, visual acuity, visual field, attention at distance and nystagmus) were assessed at 12 months corrected age and Griffiths Scales at 2 years corrected age., Results: The severity of ROP was strongly correlated (p < 0.001) with both visual function at 1 year and neurodevelopment at 2 years. Similarly, the presence of nystagmus was also strongly correlated with visual and neurodevelopmental sequelae., Conclusions: Infants with no or milder retinopathy showed normal visual function at 1 year and neurodevelopment at 2 years. Infants who underwent treatment more frequently showed abnormal results on several aspects of visual function. Presence of nystagmus appeared to increase the risk for abnormal visual function and neurodevelopmental outcome., Competing Interests: Declaration of competing interest None., (Copyright © 2020. Published by Elsevier B.V.)

Objective: The aim of this study was to use a structured questionnaire in a large cohort of Duchenne Muscular Dystrophy (DMD) patients to assess caregivers and patients views on respiratory function and to establish if their responses were related to the patients' age or level of functional impairment., Methods: Questionnaires were administered to caregivers in 205 DMD patients of age between 3 and 36 years (115 ambulant, 90 non-ambulant), and to 64 DMD patients (3 ambulant, 61 non-ambulant) older than 18 years, subdivided into groups according to age, FVC, ambulatory and ventilatory status., Results: Some differences were found in relation to FVC % values ( p = 0.014), ambulatory ( p = 0.043) and ventilatory status ( p = 0.014). Nearly half of the caregivers expected deterioration over the next years, with the perspective of deterioration more often reported by caregivers of non-ambulant ( p = 0.018) and ventilated patients ( p = 0.004). Caregivers appeared to be aware of the relevance of respiratory function on quality of life (84%) showing willingness to enter possible clinical trials if these were aiming to stabilize the progression of respiratory function with a very high number of positive responses across the spectrum of age, FVC, ambulatory and ventilatory status. The boys older than 18 years showed similar results., Conclusions: Our study showed that the concern for respiratory function increases with age and with the reduction of FVC or the need for ventilation, but the need for intervention was acknowledged across the whole spectrum of age and functional status., (©2020 Gaetano Conte Academy - Mediterranean Society of Myology, Naples, Italy.)

Objective: To investigate ultrasound features of diaphragm motion and function in type 1 spinal muscular atrophy (SMA-1) patients., Design: Prospective study., Patients: The study cohort included SMA-1 children younger than 18-year-old. Control subjects included type 2 and type 3 SMA and other neuromuscular disorders younger than 18-year-old., Methodology: Diaphragm ultrasound evaluating diaphragmatic excursion, speed of diaphragmatic contraction, duration of the respiratory cycle, inspiratory/expiratory relationship, end-inspiratory and -expiratory thickness, thickening fraction, and pattern of contractility. The interrater reliability for each variable was established by calculation of Cohen's k coefficient., Results: Twenty-three SMA-1 patients and 12 controls were evaluated. Diaphragm ultrasound values were within normal ranges in all study cohort patients and no difference was found with controls. There was a gradient of diaphragm function with SMA 1.9 subgroup having the best and SMA 1.1 having the worst parameters, particularly in end-inspiratory thickness and diaphragmatic excursion (P = .031 and P = .041, respectively). Seventy-four percent of SMA-1 patients had a dysmotility pattern of diaphragm contraction, mostly represented in SMA 1.9 subgroup (P = .001). This pattern was observed in 92.8% of children on noninvasive ventilation (NIV) for less than 16 hours/d of and in 20% patients with invasive ventilation or NIV for more than 16 hours/d (P = .027). The dysmotility pattern was never observed in the control group. The levels of interobserver agreement were high for "diaphragm irregularities," "inspiratory/expiratory relationship," and "diaphragm thickness," and good for the other variables., Conclusions: Ultrasound can be used to evaluate diaphragm function and contractility in SMA-1 children, providing additional information to the clinical examination and functional respiratory tests, describing a characteristic contractility pattern in these patients. Longitudinal studies are needed to understand the impact of diaphragm dysmotility and other parameters on long-term outcome in SMA-1 patients., (© 2020 Wiley Periodicals LLC.)

Background: Movement Disorders - Childhood Rating Scale for age 4-18 (MD-CRS 4-18) is a tool aimed to evaluate movement disorders in developmental age, validated since 2008 and applied in the literature. Psychometric properties, including inter- and intra-reliability and construct validity have been evaluated over time on children and adolescents with different types of movement disorders., Aim: The aim of the study is to revise the Movement Disorders - Childhood Rating Scale 4-18 (MD-CRS 4-18 R) and evaluate its psychometric properties, compared to previous version of the scale, in dyskinetic cerebral palsy., Design: This is a measurement-focused study of video recorder sessions., Setting: Video session carried out inpatient and outpatient., Population: This measurement-focused study was carried out on a cohort of 57 participants with DCP (37 males; mean age 9 years and 6 months ±3 years and 8 months) evaluated through video-recorded sessions by experienced scorers using MD-CRS 4-18 and MR-CRS 4-18 R., Methods: Inter-rater reliability, intra-rater reliability of MD-CRS 4-18 and MD-CRS 4-18 R were performed., Results: This study supports the relevant contribution of MD-CRS 4-18 R to identify the severity of movement disorders in dyskinetic cerebral palsy, as indicated by the higher ICC values on Index II compared to previous MD-CRS 4-18 results. Standard Error Measurement (SEM) and Minimally Detectable Difference (MDD) of MD-CRS 4-18 R in DCP were all very low, with SEMs ranging from 0.01 to 0.02 and MDD from 0.03 to 0.06., Conclusions: Data obtained with MD-CRS 4-18 R are in accordance with previous scale on individuals with movement disorders due to different etiologies, tested with MD-CRS 4-18., Clinical Rehabilitation Impact: MD-CRS 4-18 R is able to verify natural history of the disease and represents a standardized clinical outcome measure in the evaluation and follow-up of children with DCP. Also MD-CRS 4-18 Revised form is a feasible tool, now easier to understand than the previous one, more available for incoming clinical trials.

Background: The Early Childhood Attention Battery (ECAB) has been used to assess three different components of attention in preschool children, namely, selective, sustained and attentional control., Aim: The aim of the study was: I) to adapt the ECAB to the Italian language; II) to collect Italian reference data using the translated version and III) to expand the available reference data using 6-month age intervals., Study Design: The adaptation of the ECAB to Italian language and the collection of Italian reference data was performed in four phases: translation and identification of the manual and subtests that needed adaptation; interobserver reliability and feasibility of the Italian version; application of the Italian ECAB; statistical analysis., Subjects: The ECAB was performed on a low risk population between 3 and 5 years, 11 months., Results: Statistical analysis was conducted subdividing the cohort in 6-month age groups. The final cohort included 300 low-risk typically developing children. The assessment was well accepted and enjoyed by most of the children except for some in the youngest group who refused to complete all of the tests. Our data showed a progressive improvement in attention across age in seven of the eight subtests of the ECAB., Conclusion: The ECAB is a feasible battery in Italian as in the English version, for the assessment of early attention in preschool children, allowing the assessment of the different components of attention and a specific maturation follow up with increasing age., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The advent of new therapies in spinal muscular atrophy (SMA) has highlighted the need to have natural history data for comparison. Natural history studies using structured assessments in type I however are very limited. We identified and reviewed all the existing longitudinal history data in infants with type I SMA first assessed before the age of 7 months with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND)., Main Text: Three longitudinal natural history studies, two performed in the United States and one in Italy, were identified. The different study design of these three studies made it possible for the cumulative dataset to include the full spectrum of severity; from infants with neonatal onset to those with a milder phenotype that were not always included in the individual natural history studies. The cumulative analysis confirmed that, even in a larger cohort, there was never an improvement on the CHOP INTEND over time. This was true for all the infants, irrespective of their age or baseline CHOP INTEND scores. Infants with neonatal onset had low CHOP INTEND scores and a fast decline. The relatively large number of patients allowed us to calculate the rate of progression in subgroups identified according to SMN2 copy number and baseline CHOP INTEND scores., Conclusion: A detailed understanding of the existing data is important, as it will be difficult to acquire new systematic longitudinal history data because of the availability of disease modifying therapies. The cumulative findings in this review help to better understand the variability of natural history data in untreated patients and will be of use for comparison to the real world patients treated with the recently approved therapies that have shown encouraging results in clinical trials.

Background: The advent of new therapies has increased the need to achieve early diagnosis in Spinal Muscular Atrophy (SMA). The aim of the present study was to define the age of diagnosis in the three main types of SMA with pediatric-onset and the timing between the recognition of clinical signs and confirmed genetic diagnosis., Methods: All patients with a confirmed diagnosis of type I, II, III SMA followed in 5 Italian centers were included in this study, assessing age at symptoms onset, presenting sign or symptom, age at diagnosis, interval between clinical onset and diagnosis and type of medical investigations conducted in order to obtain the diagnosis., Results: The cohort included 480 patients, 191 affected by SMA type I, 210 by type II and 79 by type III. The mean age at diagnosis was 4.70 months (SD ±2.82) in type I, 15.6 months (SD±5.88) in type II, and 4.34 years (SD±4.01) in type III. The mean time between symptom onset and diagnosis was 1.94 months (SD±1.84) in type I, 5.28 months (SD±4.68) in type II and 16.8 months (SD±18.72) in type III., Conclusions: Our results suggest that despite improved care recommendations there is still a marked diagnostic delay, especially in type III. At the time new therapies are becoming available more attention should be devoted to reducing such delay as there is consistent evidence of the benefit of early treatment., Competing Interests: The authors have declared that no competing interests exist.

Cobalamin C (cblC) defect is the most common inherited disorder of cobalamin metabolism. Developmental delay, behavioral problems, and maculopathy are common, but they have not been systematically investigated. The aim of this study was to define early neurodevelopment in cblC patients and the possible contribution of different factors, such as mode of diagnosis, age at diagnosis, presence of brain lesions and epilepsy. Children up to the age of 4 years with a visual acuity ≥1/10 were evaluated using the Griffiths' Mental Development Scales. Eighteen children were enrolled (age range 12-48 months). Four were diagnosed by newborn screening (NBS); in the others mean age at diagnosis was 3.5 months (range 0.3-18 months). Eight had seizures: three in the first year, and five after the second year of life. Fourteen had brain lesions on magnetic resonance imaging (MRI). Neurovisual assessment evidenced low visual acuity (<3/10) in 4/18. NBS diagnosed patients had higher general and subquotients neurodevelopmental scores, normal brain MRI, and no epilepsy. The others showed a progressive reduction of the developmental quotient with age and language impairment, which was evident after 24 months of age. Our findings showed a progressive neurodevelopmental deterioration and a specific fall in language development after 24 months in cblC defect. The presence of brain lesions and epilepsy was associated with a worst neurodevelopmental outcome. NBS, avoiding major disease-related events and allowing an earlier treatment initiation, appeared to have a protective effect on the development of brain lesions and to promote a more favorable neurodevelopment., (© 2019 SSIEM.)

The aim of this prospective multicentric study was to document disease progression in young boys affected by Duchenne muscular dystrophy (DMD) between age 3 and 6 years (±3 months) using the North Star Ambulatory Assessment scale. One hundred fifty-three DMD boys (573 assessments) younger than 6 years (mean: 4.68, SD: 0.84) with a genetically proven DMD diagnoses were included. Our results showed North Star Ambulatory Assessment scores progressively increased with age. The largest increase was observed between age 3 and 4 years but further increase was steadily observed until age of 6 years. Using a multiple linear regression analysis, we found that both the use of corticosteroids and the site of mutation significantly contributed to the North Star Ambulatory Assessment changes (p < 0.001). At each age point, boys on corticosteroid treatment had higher scores than corticosteroid naïve ones (p < 0.001). Similarly, patients with mutations downstream exon 44, had lower baseline scores and lower magnitude of changes compared to those with mutations located at the 5' end of the gene (p < 0,001). Very few boys achieved the age appropriate maximum score. These results provide useful information for the assessment and counselling of young DMD boys and for the design of clinical trials in this age group., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To report the long-term progression in a cohort of patients with type II spinal muscular atrophy (SMA) assessed with the Hammersmith Functional Motor Scale-Expanded., Methods: Seventy-three patients (age 2.6-25 years) were included in the study. Twenty-eight of the 73 were first assessed before the age of 5 years and had been followed up for ≈5 years or longer. We observed an overall progression that was not linear. A piecewise regression analysis showed an improvement of scores in the younger patients with a point of slope change at ≈5 years of age, a decline between 5 and 13 years of age, and stability/slower decline after that., Results: Patients with the lowest scores at baseline had the earliest onset of scoliosis and a higher need for noninvasive ventilation compared to those with higher scores. Our results confirm that on the long-term follow-up all patients with type II SMA show a clear and progressive decline., Conclusion: The severity of functional impairment at baseline can help to predict the magnitude of changes over time and the overall progression, including onset of scoliosis and need for noninvasive ventilation., (© 2019 American Academy of Neurology.)

Objective: The aim of the study was to report 12-month changes after treatment with nusinersen in a cohort of 85 type I spinal muscular atrophy patients of ages ranging from 2 months to 15 years and 11 months., Methods: All patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination-Section 2 (HINE-2)., Results: Two of the 85 patients had 1 SMN2 copy, 61 had 2 copies, and 18 had 3 copies. In 4 patients the SMN2 copy number was not available. At baseline, the mean CHOP INTEND scores ranged between 0 and 52 (mean = 15.66, standard deviation [SD] = ±13.48), and the mean HINE-2 score was between 0 and 5 (mean = 0.69, SD = ±1.23). There was a difference between baseline and the 12-month scores on both the CHOP INTEND and the HINE-2 for the whole group (p < 0.001), the subgroups with 2 SMN2 copies (p < 0.001), and those with 3 SMN2 copies (p < 0.001). The difference was found not only in patients younger than 210 days at baseline (p < 0.001) but also in those younger than 5 years on the CHOP INTEND and younger than 2 years on the HINE-2., Interpretation: Our results, expanding the age range and the severity of type I patients treated with nusinersen over 1 year, provide additional data on the range of efficacy of the drug that will be helpful in making an informed decision on whether to start treatment in patients of different ages and severity. ANN NEUROL 2019;86:443-451., (© 2019 American Neurological Association.)

Objective: To report cross-sectional clinical findings in a large cohort of patients affected by type 1 spinal muscular atrophy., Methods: We included 122 patients, of age ranging between 3 months and 22 years, 1 month. More than 70% (85/122) were older than 2 years and 25% (31/122) older than 10 years. Patients were classified according to the severity of phenotype and to the number of SMN2 copies., Results: Patients with the more common and the most severe phenotype older than 2 years were, with few exceptions, on noninvasive ventilation and, with increasing age, more often had tracheostomy or >16-hour ventilation and a gastrostomy inserted. In contrast, 25 of the 28 patients with the mildest phenotype older than 2 years had no need for tracheostomy or other ventilatory or nutritional support. In patients older than 2 years, the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores were generally lower compared to those found in younger patients and showed distinct levels of functional abilities according to the severity of the phenotype. Similar findings were also observed on the Hammersmith Infant Neurological Examination., Conclusions: Our findings confirm that, after the age of 2 years, patients with type 1 spinal muscular atrophy generally survive only if they have gastrostomy and tracheostomy or noninvasive ventilation >16 hours and have low scores on the functional scales. More variability, however, can be expected in those with the mildest phenotype, who achieve head control. These data provide important baseline information at the time treatments are becoming available., (© 2018 American Academy of Neurology.)

We report preliminary data on the six month use of Nusinersen in 104 type 1 patients of age ranging from three months to 19 years, 9 months. Ten of the 104 were classified as 1.1, 58 as 1.5 and 36 as 1.9. Three patients had one SMN2 copy, 65 had two and 24 had three copies. In 12 the SMN2 copy number was not available. After six months an improvement of more than two points was found in 58 of the 104 (55.7%) on the CHOP INTEND and in 21 of the 104 (20.19%) on the Hammersmith Infant Neurological Examination (HINE). Changes more than two points were found in 26/71 patients older than two years, and in seven of the 20 older than 10 years. Changes ≥ four points were found in 20/71 older than two years, and in six of the 20 patients older than 10 years. The difference between baseline and six months on both CHOP INTEND and HINE was significant for the whole group (p < 0.001) as well as for the subgroups with two (p < 0.001), and three SMN2 copies (p < 0.001). Our preliminary results suggest that functional improvement can be observed in type 1 patients outside the range of the inclusion criteria used in the Endear study., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To evaluate the prevalence of joint laxity in children born preterm assessed in the first 2 years, the relationship between joint laxity and motor performance at preschool age, and possible changes over time in a subgroup of children followed longitudinally., Study Design: The revised scale of Beighton Score was used to evaluate joint laxity in a population of 132 preschool children born preterm between 24 and 32 weeks of gestational age. All were assessed for joint laxity between 12 and 24 months of age. Children also performed the Movement Assessment Battery for Children-Second Edition between the age of 3 years and 6 months and 4 years; the age at onset of independent walking also was recorded., Results: The total Beighton Score ranged between 0 and 8. Twenty percent of the cohort showed joint laxity. No differences related to sex or gestational age were observed. Children born preterm with joint laxity achieved later independent walking and achieved lower scores on Movement Assessment Battery for Children-Second Edition than those without joint laxity. In 76 children born preterm, an assessment for joint laxity was repeated once between 25 and 36 months and again after >36 months. No statistically significant difference was observed between the 3 assessments., Conclusions: The Beighton Score can be used to assess generalized joint laxity in children born preterm. As the presence of joint laxity influenced motor competences, the possibility to early identify these infants in the first 2 years is of interest to benefit from early intervention and potentially improve gross motor skills and coordination., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Movement Disorder-Childhood Rating Scales (MD-CRS) have been designed in two forms (0-3 and 4-18 years) to accurately evaluate various movement disorders in children., Aim: The aim of this study is to evaluate the MD-CRS reliability when used by clinicians and professionals of rehabilitation after a one-day training on scoring it., Design: This is a measurement-focused study of video-recorded sessions., Setting: Video session carried out inpatient and outpatient., Population: Children with different types of movement disorders., Methods: After brief training in scoring MD-CRS, five health professionals (a resident doctor, a child neurologist and three physical therapists) independently scored 40 patient videotapes, of children with movement disorders for inter-rater reliability. In addition, the resident doctor scored 80 videos of 40 patients evaluated twice for intra-rater reliability. Reliability was assessed by Intraclass Correlation Coefficient (ICC) and was calculated separately for the two forms of the scale and for each score (Index I, Index II and Global Index). Standard Error of Measurement (SEM) and Minimal Detectable Difference (MDD) were also calculated., Results: For both forms, inter-rater reliability of Global Index and Index I were good with an ICC ranged between 0.83 and 0.95. Instead, results of Index II were substantially moderate for both forms, with an ICC of 0.53 and 0.57, respectively. Intra-rater reliability for all Indexes in both forms was substantial or almost perfect, with values of ICCs ranging from 0.74 to 0.99. MDD values were between 0.05 and 0.17., Conclusions: MD-CRS 0-3 and MD-CRS 4-18 remain reliable clinical measurement tools for evaluation of movement disorders in developmental age when used by clinicians and professionals of rehabilitation after a specific short training., Clinical Rehabilitation Impact: MD-CRS 0-3 and MD-CRS 4-18 appear to be a promising outcome measurement tool in large scale studies with children and adolescents affected by various movement disorders either to verify natural history of the disorder or to plan pharmacological and/or surgical intervention programs.

This study aimed at comparing implicit sequence learning in individuals affected by Duchenne Muscular Dystrophy without intellectual disability and age-matched typically developing children. A modified version of the Serial Reaction Time task was administered to 32 Duchenne children and 37 controls of comparable chronological age. The Duchenne group showed a reduced rate of implicit learning even if in the absence of global intellectual disability. This finding provides further evidence of the involvement of specific aspects of cognitive function in Duchenne muscular dystrophy and on its possible neurobiological substrate.

The advent of clinical trials has highlighted the need for natural history studies reporting disease progression in type 1 spinal muscular atrophy. The aim of this study was to assess functional changes using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale in a cohort of type 1 infants. Nutritional and respiratory longitudinal data were also recorded. Patients were classified according to the severity of the phenotype and age of onset. SMN2 copies were also assessed. Twenty patients were included, eight with early onset most severe phenotype, eight with the more typical type 1 phenotype and 4, who achieved some head control, with a milder phenotype. Both baseline values and trajectories of progression were different in the three subgroups (p = 0.0001). Infants with the most severe phenotype had the lowest scores (below 20) on their first assessment and had the most rapid decline. Those with the typical phenotype had scores generally between 20 and 40 and also had a fast decline. The infants with the milder phenotype had the highest scores, generally above 35, and a much slower deterioration. Infants with three SMN2 copies had an overall milder phenotype and milder progression while two SMN2 copies were found in all three subgroups., (Copyright © 2017. Published by Elsevier B.V.)

Background: Reports on the clinical meaningfulness of outcome measures in spinal muscular atrophy (SMA) are rare. In this two-part study, our aim was to explore patients' and caregivers' views on the clinical relevance of the Hammersmith Functional Motor Scale Expanded- (HFMSE)., Methods: First, we used focus groups including SMA patients and caregivers to explore their views on the clinical relevance of the individual activities included in the HFMSE. Then we asked caregivers to comment on the clinical relevance of possible changes of HFMSE scores over time. As functional data of individual patients were available, some of the questions were tailored according to their functional level on the HFMSE., Results: Part 1: Sixty-three individuals participated in the focus groups. This included 30 caregivers, 25 patients and 8 professionals who facilitated the discussion. The caregivers provided a comparison to activities of daily living for each of the HFMSE items. Part 2: One hundred and forty-nine caregivers agreed to complete the questionnaire: in response to a general question, 72% of the caregivers would consider taking part in a clinical trial if the treatment was expected to slow down deterioration, 88% if it would stop deterioration and 97% if the treatment was expected to produce an improvement. Caregivers were informed of the first three items that their child could not achieve on the HFMSE. In response 75% indicated a willingness to take part in a clinical trial if they could achieve at least one of these abilities, 89% if they could achieve two, and 100% if they could achieve more than 2., Conclusions: Our findings support the use of the HFMSE as a key outcome measure in SMA clinical trials because the individual items and the detected changes have clear content validity and clinical meaningfulness for patients and their caregivers.

Objective: To provide a revision of the Beighton score adapted for children younger than the age of 5 years, to apply the revised version in a cohort of preschool age children, and to verify the reliability of the revised version in a cohort of preschool children with genetic syndromes associated with hypermobility., Study Design: The revised Beighton score was applied in a population of preschool children to evaluate joint hypermobility in 5 parts of the body, bilaterally (passive dorsiflexion of the fifth finger; passive hyperextension of the elbow; passive hyperextension of the knee; passive apposition of the thumb to the flexor side of the forearm; passive dorsiflexion of the ankle joint). The frequency distribution of the total scores was calculated with a range between 0 and 10., Results: A total of 284 healthy preschool children (146 boys and 138 girls) and 26 preschool children with genetic disorders (15 boys and 11 girls) were assessed. Mean age was 33.6 ± 12.7 months. A score ≤4 was found in more than 90% of the whole cohort; therefore, a cut-off score >4 was used to identify hypermobility. Twenty-two of the 284 (7%) healthy children and 23 of the 26 children (89%) with genetic syndromes associated with hypermobility had a score >4. The joints reporting a greater incidence of hypermobility were "apposition of the thumb to the forearm" and "passive dorsiflexion of the ankle," in 34% and 22% respectively. No differences related to sex or age were observed., Conclusions: The revised version of the Beighton score can be used to define generalized hypermobility for children up to 5 years of age and to assess and follow-up longitudinally patients with isolated hypermobility or those in whom the laxity is associated with other clinical features., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The aim of this study was to investigate language disorders prospectively in patients with Dravet syndrome (DS) during the first years of life in order to identify their features and possibly the underlying mechanisms of the disease. At the Child Neurology Unit of Catholic University in Rome (Italy), thirteen patients with typical findings of DS were enrolled in the study. Full clinical observations, including neurological examination and long-term EEG monitoring, were prospectively and serially performed until a mean of 6years of age (range: 4years to 7years and 8months). The epileptic history was also collected in each case. In particular, developmental, cognitive, and detailed language assessments were performed with different tests according to the age of the patient. In addition to cognitive decline, characteristic language impairment was also found with a relative preservation of receptive abilities (comprehension) and a strong impairment of productive skills. This defect in sensorimotor verbal processing integration is discussed to highlight the possible mechanisms underlying cognitive decline., (Copyright © 2015 Elsevier Inc. All rights reserved.)