Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.

Although the best-known spinocerebellar ataxias (SCAs) are triplet repeat diseases, many SCAs are not caused by repeat expansions. The rarity of individual non-expansion SCAs, however, has made it difficult to discern genotype-phenotype correlations. We therefore screened individuals who had been found to bear variants in a non-expansion SCA-associated gene through genetic testing, and after we eliminated genetic groups that had fewer than 30 subjects, there were 756 subjects bearing single-nucleotide variants or deletions in one of seven genes: CACNA1A (239 subjects), PRKCG (175), AFG3L2 (101), ITPR1 (91), STUB1 (77), SPTBN2 (39), or KCNC3 (34). We compared age at onset, disease features, and progression by gene and variant. There were no features that reliably distinguished one of these SCAs from another, and several genes-CACNA1A, ITPR1, SPTBN2, and KCNC3-were associated with both adult-onset and infantile-onset forms of disease, which also differed in presentation. Nevertheless, progression was overall very slow, and STUB1-associated disease was the fastest. Several variants in CACNA1A showed particularly wide ranges in age at onset: one variant produced anything from infantile developmental delay to ataxia onset at 64 years of age within the same family. For CACNA1A, ITPR1, and SPTBN2, the type of variant and charge change on the protein greatly affected the phenotype, defying pathogenicity prediction algorithms. Even with next-generation sequencing, accurate diagnosis requires dialogue between the clinician and the geneticist.

Exploring variability in cognitive functioning in patients with spinal muscular atrophy: a scoping review.

The cognitive functioning of individuals with spinal muscular atrophy (SMA) is not well understood, prompting a call for more research to better grasp cognitive involvement in SMA. This study aims to explore recent findings regarding cognitive outcomes in SMA patients, including correlations between clinical features and cognitive abilities. The investigation seeks to identify commonly used measures for assessing cognitive function in this patient population. A scoping review following the Joanna Briggs Institute methodology examined literature until December 2023. Two databases were searched along with relevant article references using specific terms such as "spinal muscular atrophy," "SMA," "cognitive," "abilities," "functions," "intellective," or "intellectual." Screening focused on titles and abstracts from English language peer-reviewed journals. After the initial research, 1452 articles were identified. Subsequent screening and selection led to the inclusion of 13 articles in the review. Among these studies, four indicated a cognitive trend within the normal range for SMA patients. In four other studies, the majority of patients fell within the normal range. However, smaller proportions were observed to be either above or below the norm compared to the controls. Three studies reported noted cognitive performance below the average, while two showed above-average scores. The scoping review suggests that most SMA patients have cognitive abilities similar to the general population, with types II and III showing even lesser impact. However, certain cognitive domains may be affected in type I patients, highlighting the need for further research to fully understand cognitive involvement in SMA.

Social cognition in two brothers with Becker muscular dystrophy: an exploratory study revealing divergent behavioral phenotypes.

BACKGROUND AND OBJECTIVE: Only few studies investigated social cognition in Becker muscular dystrophy (BMD). However, brain dystrophin deficiency could be a neural substrate for cognitive, emotional, and neuropsychological features in BMD. METHODS: We compared interoceptive accuracy and interpersonal comfort distance in two brothers with BMD presenting with the same genetic deletion and a healthy control. When possible, we collected neuropsychological and psychopathological assessments. RESULTS: Our BMD patients were significantly different in interoceptive accuracy, with patient 1 being extremely accurate and patient 2 being significantly less accurate than his brother but more accurate than the control. Interestingly, they presented opposite patterns of interpersonal distance. Patient 1 was comfortable with very short interpersonal distance (≤50 cm from the confederate/object) vs the control and patient 2. By contrast, patient 2 preferred larger distance vs the control and patient 1. Patient 1 also presented difficulties in social and emotional skills on the psychopathological assessment. CONCLUSIONS: We are aware this is a small sample; nonetheless, this is also the first description of such aspects in BMD and the first report ever of such divergent behavioral pattern. As impaired social cognition affects the quality of life and social relationship, further studies are needed for a closer understanding of involved mechanisms.

Pain assessment in autism: updating the ethical and methodological challenges through a state-of-the-art review.

Sensory features of autism include hypo- or hyper-reactivity to pain; however, previous studies on pain in autism lead to conflicting results. Here, we present the state of the art and the methodological challenges concerning pain perception in autism, focusing on studies that used standardized protocol as Quantitative Sensory Testing (QST) to measure perception. Despite there are still scant evidences found with the use of QST, they have challenged the presumed hyposensitivity to pain in autisms, which emerged from parents' reports. Both, peripheral and central mechanisms, have been found involved in typical features of perception in autism. Nonetheless, evidences with controlled protocols are still scarce, and even scarcer are studies focused on children. Overall, complex ethical challenges have to be overcome in order to collect subjective and objective measures from autistic children. With heterogeneous neurodevelopmental features, or intellectual disability, novel or modified protocols are needed.

Exploring Visual Perspective Taking and body awareness in children with Autism Spectrum Disorder.

INTRODUCTION: Recent evidence suggests that impairments in social cognition are associated to the cognitive abilities needed to take several viewpoints in perceptual situations and body awareness. The aim of the current study was to investigate Visual Perspective Taking (VPT) and Body awareness performance in a group of children with Autism Spectrum Disorders (ASD) compared with a group of children with Intellectual Disability (ID) and typically developing (TD) children. METHODS: Our groups were administered an IQ test and a VPT task, and body awareness tests. RESULTS: Children with ASD or ID were more impaired in body awareness development compared to TD (p < .001) children. The ASD group differentiates largely from the other two groups in the mean VPT (p < .001) scores. CONCLUSIONS: The current study provides a framework for considering social impairments in autism on a broader scale, including visuoperceptual and body awareness difficulties as a core contributor to social interaction difficulties.

Treatment with ataluren in four symptomatic Duchenne carriers. A pilot study.

Duchenne muscular dystrophy (DMD) is a devastating X-linked neuromuscular disorder caused by dystrophin gene deletions (75%), duplications (15-20%) and point mutations (5-10%), a small portion of which are nonsense mutations. Women carrying dystrophin gene mutations are commonly unaffected because the wild X allele may produce a sufficient amount of the dystrophin protein. However, approximately 8-10% of them may experience muscle symptoms and 50% of those over 40 years develop cardiomyopathy. The presence of symptoms defines the individual as an affected "symptomatic or manifesting carrier". Though there is no effective cure for DMD, therapies are available to slow the decline of muscle strength and delay the onset and progression of cardiac and respiratory impairment. These include ataluren for patients with nonsense mutations, and antisense oligonucleotides therapies, for patients with specific deletions. Symptomatic DMD female carriers are not included in these indications and little data documenting their management, often entrusted to the discretion of individual doctors, is present in the literature. In this article, we report the clinical and instrumental outcomes of four symptomatic DMD carriers, aged between 26 and 45 years, who were treated with ataluren for 21 to 73 months (average 47.3), and annually evaluated for muscle strength, respiratory and cardiological function. Two patients retain independent ambulation at ages 33 and 45, respectively. None of them developed respiratory involvement or cardiomyopathy. No clinical adverse effects or relevant abnormalities in routine laboratory values, were observed.

De Novo Pathogenic Variant in FBRSL1, Non OMIM Gene Paralogue AUTS2, Causes a Novel Recognizable Syndromic Manifestation with Intellectual Disability; An Additional Patient and Review of the Literature.

FBRSL1, together with FBRS and AUTS2 (Activator of Transcription and Developmental Regulator; OMIM 607270), constitutes a tripartite AUTS2 gene family. AUTS2 and FBRSL1 are evolutionarily more closely related to each other than to FBRS (Fibrosin 1; OMIM 608601). Despite its paralogous relation to AUTS2, FBRSL1's precise role remains unclear, though it likely shares functions in neurogenesis and transcriptional regulation. Herein, we report the clinical presentation with therapeutic approaches and the molecular etiology of a patient harboring a de novo truncating variant (c.371dupC) in FBRSL1, leading to a premature stop codon (p.Cys125Leufs*7). Our study extends previous knowledge by highlighting potential interactions and implications of this variant, alongside maternal and paternal duplications, for the patient's phenotype. Using sequence conservation data and in silico analysis of the truncated protein, we generated a predicted domain structure. Furthermore, our in silico analysis was extended by taking into account SNP array results. The extension of in silico analysis was performed due to the possibility that the coexistence of FBRSL1 truncating variant contemporary with maternal and paternal duplication could be a modifier of proband's phenotype and/or influence the novel syndrome clinical characteristics. FBRSL1 protein may be involved in neurodevelopment due to its homology with AUTS2, together with distinctive neuronal expression profiles, and thus should be considered as a potential modulation of clinical characteristics in a novel syndrome. Finally, considering that FBRSL1 is apparently involved in neurogenesis and in transcriptional regulatory networks that orchestrate gene expression, together with the observation that different genetic syndromes are associated with distinct genomic DNA methylation patterns, the specific episignature has been explored.

Sitting Postural Management to Prevent Migration Percentage Progression in Non-Ambulatory Children with Cerebral Palsy: Randomized Controlled Trial Preliminary Data.

Background/Objectives: To determine whether a sitting position with the femoral heads centered into the acetabulum is more effective than the usual sitting position in preventing migration percentage progression in non-ambulatory children with bilateral cerebral palsy. Methods: This was a multicenter, randomized controlled trial. INCLUSION CRITERIA: spastic or dyskinetic cerebral palsy, Gross Motor Function Classification System level IV-V, age 1-6 years, migration percentage <41%, and informed consent. EXCLUSION CRITERIA: contractures affecting the hip, anterior luxation, previous hip surgery, and lumbar scoliosis. The treatment group sat with their hips significantly abducted to reduce the head into the acetabulum in a customized system for at least five hours/day for two years. Controls sat with the pelvis and lower limbs aligned but the hips less abducted in an adaptive seating system. The primary outcome was migration percentage (MP) progression. Health-related quality of life and family satisfaction were among the secondary outcomes. The study was approved by the local ethics board and conducted in accordance with CONSORT reporting guidelines. CLINICALTRIALS: gov ID: NCT04603625. RESULTS: Overall median MP progression was 1.6 after the first year and 2.5 after the second year. No significant differences were observed between the groups. MP exceeded 40% and 50% in 1.8% and 0% of the experimental group and 5.4% and 3.6% of controls in years 1 and 2, respectively. Both groups expressed satisfaction with the postural system and stable health-related quality of life. Conclusions: MP remained stable over the two-year period in both groups. Considering outliers which progressed over 50%, a more protective trend of the hip-centering sitting approach emerged, but this needs to be confirmed in a final, larger dataset.

Factors associated with pharmacological treatment in children with attention-deficit/hyperactivity disorders: a retrospective study of a series of 77 cases in a single third-level reference Centre in Apulia region.

BACKGROUND: The present study analysed data on children and adolescents with a diagnosis of attention-deficit/hyperactivity disorder (ADHD) who were referred to the ADHD reference centre of Scientific Institute IRCCS E. Medea (Brindisi, Italy) for ADHD pharmacotherapy initiation and monitoring overtime. The main aim of the study was to examine differences in pharmacological treatment status (i.e., treatment continuation vs discontinuation) between patients. METHODS: Seventy-seven children and adolescents (mean age at pharmacotherapy initiation = 9.5, standard deviation = 2.6) with ADHD received drugs treatment for ADHD at the reference center between January, 2013 and May, 2022. Demographic and clinical data were obtained from the Italian Registry for ADHD and medical records. Child Behavior Checklist (CBCL) available data were used. RESULTS: Pharmacological treatment status was examined for patients (n = 63) with at least 12 months of follow-up after the first pharmacological treatment for ADHD. After starting pharmacotherapy treatment, 77.8% (n = 49) patients were still on treatment whereas 22.2% (n = 14) discontinued it. No between group difference were observed in demographic and clinical data except for the intelligence quotient/intellectual disability and rule-breaking behavior (n = 40). CONCLUSIONS: This study stressed the need of periodical assessments, monitoring difficulties with treatment and/or reasons for poor treatment compliance to provide individualized care.

Association between feeding/mealtime behavior problems and internalizing/externalizing problems in autism spectrum disorder, other neurodevelopmental disorders and typically developing children.

BACKGROUND: The aim of current study was to examine the nature and prevalence of feeding problems and mealtime behavior problems in children with autism spectrum disorder (ASD) comparing to children with other neurodevelopmental disorders (NNDs) and TD children. We also investigated the impact of intelligence quotient (IQ) and/or emotional and behavioral problems on feeding and mealtime behavior problems. METHODS: Participants completed the following tests: Social Communication Questionnaire (SCQ), Child Behavior Checklist (CBCL), Brief Autism Mealtime Behavior Inventory (BAMBI) and Behavioral Pediatric Feeding Assessment Scale (BPFAS). RESULTS: Children with ASD showed more feeding and mealtime behavior problems including food refusal (P<0.001, P<0.001) and limited variety of foods (P=0.014; P=0.018) compared with NDDs and TD children. ASD group showed more problems in mealtime behavior (P=0.034) and parent behaviors (P=0.028) compared to TD group. Internalizing (P=0.003) and externalizing (P=0.008) problems were positively related to parent frustration during mealtime in ASD group. CONCLUSIONS: These results suggest that routine screening for feeding and mealtime behavior problems among children with ASD is necessary to prevent dietary inadequacies that may be associated with eating habits.

A narrative review of the use of a cutting-edge virtual reality rehabilitation technology in neurological and neuropsychological rehabilitation.

BACKGROUND: Virtual reality (VR) interventions have been increasingly used in the rehabilitation of a wide range of neurological and neuropsychological dysfunctions. Findings of previous reviews showed positive and promising effects of VR-based interventions. However, they summarized findings on VR-based intervention carried out through different VR systems and tasks. OBJECTIVE: We carried out a narrative review with the aim of qualitatively synthesising the results of previous studies that used specific VR systems, i.e. the Khymeia -Virtual Reality Rehabilitation System, for treatment purposes. METHODS: We searched the literature in various databases (i.e. EMBASE, Web of Science, SCOPUS, PubMed and PubMed Central) for studies published until November 23, 2023. RESULTS: 30 studies were selected. The VRRS was used for neuromotor rehabilitation only in 13 studies, for cognitive rehabilitation in 11 studies, and for both neuromotor and cognitive rehabilitation in six studies. The study design was heterogeneous including 15 randomised controlled trials. CONCLUSION: After discussing each study according to the type of rehabilitation we concluded that the use and efficacy of VRRS rehabilitative intervention for increasing the neurological and neuropsychological functioning of patients are promising but more evidence is needed to make a comparison with conventional treatment. Future studies should also include long-term follow-up as well as cost-effectiveness analysis.

Prevalence of Spinal Muscular Atrophy in the Era of Disease-Modifying Therapies: An Italian Nationwide Survey.

OBJECTIVE: Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in the SMN1 gene. The aim of this study was to assess the prevalence of SMA and treatment prescription in Italy. METHODS: An online survey was distributed to 36 centers identified by the Italian government as referral centers for SMA. Data on the number of patients with SMA subdivided according to age, type, SMN2 copy number, and treatment were collected. RESULTS: One thousand two hundred fifty-five patients with SMA are currently followed in the Italian centers with an estimated prevalence of 2.12/100,000. Of the 1,255, 284 were type I, 470 type II, 467 type III, and 15 type IV with estimated prevalence of 0.48, 0.79, 0.79 and 0.02/100,000, respectively. Three patients with SMA 0 and 16 presymptomatic patients were also included. Approximately 85% were receiving one of the available treatments. The percentage of treated patients decreased with decreasing severity (SMA I: 95.77%, SMA II: 85.11%, SMA III: 79.01%). DISCUSSION: The results provide for the first time an estimate of the prevalence of SMA at the national level and the current distribution of patients treated with the available therapeutical options. These data provide a baseline to assess future changes in relation to the evolving therapeutical scenario.

Septo-optic dysplasia-plus and dyskinetic cerebral palsy in a child.

Septo-optic dysplasia (SOD), also called De Morsier's syndrome, is a highly heterogeneous condition comprising a spectrum of central nervous system malformations that involves in various degrees the optic nerves, the hypothalamic-pituitary axis, and other midline structures such as the septum pellucidum and the corpus callosum. In a discrete number of cases, schizencephaly, agenesis of the corpus callosum or other cortical malformations are associated (SOD-plus). The authors present a 6-year-old boy with dyskinetic cerebral palsy (athetoid-dystonic subtype) associated with SOD-plus. Cranial magnetic resonance imaging (cMRI) revealed the total absence of septum pellucidum, optic nerve hypoplasia, hypoplasia of the corpus callosum and right occipital cortical dysplasia. The patient was diagnosed with septo-optic dysplasia-plus syndrome based on the cMRI findings. To the best of our knowledge, this is the first reported case in which defects of midline brain structures, like in SOD-plus, are associated with a significant hyperkinetic movement disorder such as dyskinesia.

Neuromuscular disorders and transition from pediatric to adult care in a multidisciplinary perspective: a narrative review of the scientific evidence and current debate.

Objective: Standards of care and new genetic and molecular therapies have contributed to increasing life expectancy of patients with neuromuscular diseases (NMDs). This review presents the clinical evidence for an adequate transition from pediatric to adult care in patients with NMDs considering both physical and psychosocial aspects and attempts at identifying a general pattern of transition in the literature that can be used for all patients with NMDs. Method: A search was performed on PubMed, Embase and Scopus using generic terms that could be referred to the transition construct specifically related to NMDs. A narrative approach was used to summarise the available literature. Results: Our review shows that few or no studies explored the transition process from pediatric to adult care in neuromuscular diseases and tried to identify a general pattern of transition applicable to all NMDs. Conclusions: A transition process taking into consideration physical, psychological, social needs of patient and caregiver could produce positive outcomes. However, there is still no unanimous agreement in the literature on what it consists of and how to achieve an optimal and effective transition.