Far Transfer Effects of Trainings on Executive Functions in Neurodevelopmental Disorders: A Systematic Review and Metanalysis.

Executive Functions are a set of interrelated, top-down processes essential for adaptive goal-directed behaviour, frequently impaired across different neurodevelopmental disorders with variable degrees of severity. Many executive-function-training studies in children with neurodevelopmental disorders have focused on near effects, investigating post-treatment improvements on directly trained processes, while enhancements of skills not directly trained, defined as far effects, are less considered, albeit these could be extremely relevant for reducing the negative impact of a disorder's core symptomatology. This systematic review and metanalysis aims to investigate the far effect outcomes after EF training in children with different types of neurodevelopmental disorders. 17 studies met the inclusion criteria for the systematic review, while 15 studies were selected in the metanalysis. An overall statistically significant effect size was found in the majority of far effect outcome measures considered in the studies. In particular, trainings on executive functions determine significant far effects on daily life functioning (0.46, 95% CI: [0.05-0.87]) and clinical symptoms (0.33, 95% CI: [0.15-0.51]). Despite a high variability of the results, intensity, frequency and the laboratory/life contexts dimension seem to be the most influential variables in determining far effects. This systematic review and metanalysis highlights the need to measure far effects of executive function training in neurodevelopmental disorders, selecting treatments not only on directly targeted processes, but also according to far impacts on the functional weakness of the disorder.

A case of febrile infection-related epilepsy syndrome (FIRES) in young adult: still a diagnostic and therapeutic challenge.

A new onset of status epilepticus in a previously healthy adult preceded by a recent minor febrile infection represents a diagnostic and therapeutic challenge in clinical practice. Considering the broad spectrum of epileptic encephalopathies caused by autoimmune mechanisms, differential diagnosis for new-onset refractory status epilepticus (NORSE) should include febrile infection-related epilepsy syndrome (FIRES), in order to not underestimate the underlying etiological condition triggering epilepsy in non-epileptic patients (Hon et al. in Recent Pat Inflamm Allergy Drug Discov 12:128-135, 2018). We report a case of acute encephalopathy with refractory seizures after a febrile illness (FIRES) in a young adult with complete remission of symptoms as well as dramatic improvement of EEG abnormalities following intravenous immunoglobulin and proper antiepileptic medications. We conducted an extensive workup including lumbar puncture, blood tests, EEG serial monitoring, MRI brain, total body CT scan, and PET brain with FDG to shed light on the etiology of the disease.

Recurrent convulsive syncope misdiagnosed as seizures due to a diaphragmatic hernia.

Differential diagnosis of seizures and convulsive syncope may be challenging in clinical practice. Furthermore, a misleading diagnosis of epilepsy may be detrimental for the patient as it often implies an over-prescription and an over-use of antiepileptic drugs which can cause adverse reactions. Moreover, a wrong diagnosis also causes distress to the patient with the risk of performing plenty of investigations without any benefits on the symptoms. In this case, we present a 57-year-old patient suffering from recurrent convulsive syncope over the last 7 years for which he underwent several cardiological and neurological tests and took plenty of antiepileptic drugs without any benefits on his convulsive episodes with loss of consciousness. During hospitalization, a chest X-ray was performed revealing an unknown diaphragmatic hernia with eventration of the transverse colon in the right hemitorax and mild cardiac compression. The patient underwent laparotomic surgery and diaphragmatic reconstruction with complete recovery. After 6-month follow-up, the patient no longer had episodes of convulsive syncope.

NGS in Hereditary Ataxia: When Rare Becomes Frequent.

The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1, PRKCG, and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.

Bi-allelic mutations in HARS1 severely impair histidyl-tRNA synthetase expression and enzymatic activity causing a novel multisystem ataxic syndrome.

Mutations in histidyl-tRNA synthetase (HARS1), an enzyme that charges transfer RNA with the amino acid histidine in the cytoplasm, have only been associated to date with autosomal recessive Usher syndrome type III and autosomal dominant Charcot-Marie-Tooth disease type 2W. Using massive parallel sequencing, we identified bi-allelic HARS1 variants in a child (c.616G>T, p.Asp206Tyr and c.730delG, p.Val244Cysfs*6) and in two sisters (c.1393A>C, p.Ile465Leu and c.910_912dupTTG, p.Leu305dup), all characterized by a multisystem ataxic syndrome. All mutations are rare, segregate with the disease, and are predicted to have a significant effect on protein function. Functional studies helped to substantiate their disease-related roles. Indeed, yeast complementation assays showing that one out of two mutations in each patient is loss-of-function, and the reduction of messenger RNA and protein levels and enzymatic activity in patient's skin-derived fibroblasts, together support the pathogenicity of the identified HARS1 variants in the patient phenotypes. Thus, our efforts expand the allelic and clinical spectrum of HARS1-related disease.

Application of the p9NORM correction method to timed neuropsychological tests in Parkinson's disease and multiple system atrophy.

OBJECTIVE: Timed neuropsychological tests do not take into account physical impairment during scoring procedures. Dysarthria and upper limb impairment can be easily measured with the PATA rate test (PRT) and the nine-hole pegboard test (9HPT). We recently validated a normalization method for timed neuropsychological tests using the PRT and 9HPT (p9NORM). We now validate the p9NORM in Parkinson's disease (Yarnall et al. Neurology 82(4):308-316; 2014) and multiple system atrophy (MSA). METHODS: We enrolled twenty-six patients with PD, eighteen patients with MSA, and fifteen healthy controls (HC). p9NORM was applied to patients with abnormal PRT and/or 9HPT. All subjects were tested with a comprehensive neuropsychological battery. RESULTS: No differences emerged in demographics across groups: (PD: mean age ± SD 66 ± 8; education 9 ± 4 years; MSA: age 60 ± 8; education 10 ± 4 years; HC: age 61 ± 12; education 9 ± 4 years). In MSA patients, the scores on the trail making test (TMT-A p = 0.003; TMT-B p = 0.018), attentional matrices (AM; p = 0.042), and symbol digit modalities test (SDMT p = 0.027) significantly differed following application of p9NORM. In PD patients, the TMT-A (p < 0.001), TMT-B (p = 0.001), and AM (p = 0.001) differed after correction. PD and MSA showed cognitive impairment relative to HC performance. When comparing MSA with PD, the SDMT, AM, and fluencies were similar. TMT-A and -B raw scores were different between groups (p = 0.006; p = 0.034), but these differences lost significance after p9NORM corrections (p = 0.100; p = 0.186). CONCLUSIONS: We confirm that the p9NORM can be successfully used in both PD and MSA patients, as it mitigates the impact of disability on timed tests, resulting in a more accurate analysis of cognitive domains.

Primary familial brain calcification caused by a novel homozygous MYORG mutation in a consanguineous Italian family.

Primary familial brain calcification (PFBC) is a rare disorder mostly characterized by calcium deposits in the basal ganglia and a wide spectrum of neurologic and psychiatric symptoms, typically inherited as an autosomal dominant trait. Recently, MYORG was reported as the first autosomal recessive causal gene in PFBC patients of Chinese and Middle Eastern origin. Herein, we describe the first PFBC patient of European descent found to carry a novel homozygous MYORG mutation (p.N511Tfs*243). Interestingly, the patient's father, a heterozygous carrier of the same mutation, showed diffuse bilateral cerebral calcifications with no symptoms other than very mild postural tremor.

Degenerative and acquired sporadic adult onset ataxia.

The diagnosis of sporadic adult onset ataxia is a challenging task since a large collection of hereditary and non-hereditary disorders should be taken into consideration. Sporadic adult onset ataxias include degenerative non-hereditary, hereditary, and acquired ataxias. Multiple system atrophy and idiopathic late cerebellar ataxia are degenerative non-hereditary ataxias. Late-onset Friedreich's ataxia, spinocerebellar ataxia type 6 and 2, and fragile X-associated tremor/ataxia syndrome account for most sporadic hereditary ataxias. Alcoholic cerebellar degeneration, paraneoplastic and other autoimmune cerebellar degeneration, vitamin deficiencies, and toxic-induced and infectious cerebellar syndrome are the main causes of acquired cerebellar degeneration. The diagnostic approach should include a history taking, disease progression, general and neurological examination, brain MRI, and laboratory and genetic tests. Novel opportunities in massive gene sequencing will increase the likelihood to define true etiologies.

Longitudinal study of a cohort of MSA-C patients in South Italy: survival and clinical features.

Sixty-six patients with possible or probable MSA (multiple system atrophy) cerebellar type, personally observed between 2006 and 2018 were retrospectively reviewed. The time point of data collection was January 1, 2019. Forty-nine patients lost independent walking after a median time of 5 years (95% C. I. 4-6). Thirty-two patients were confined to wheelchair after a median time of 7 years (95% C. I. 7-8). Twenty-seven patients were deceased after a median time of 9 years (95% C. I. 8-10). A later onset predicted an earlier loss of independent walking (HR 1.07; 95% C.I. 1.03-1.11; p = 0.001). Higher UMSARS score predicted shorter time to loss of independent walking (HR 1.04; 95% C.I. 1.02-1.06; p = 0.001) and to wheelchair (HR 1.03; 95% C.I. 1.01-1.06; p = 0.021). No predictor of time to death was found.

Training RAN or reading? A telerehabilitation study on developmental dyslexia.

Rehabilitation procedures recommended for developmental dyslexia (DD) are still not fully defined, and only few studies directly compare different types of training. This study compared a training (Reading Trainer) working on the reading impairment with one (Run the RAN) working on the rapid automatized naming (RAN) impairment, one of the main cognitive deficits associated with DD. Two groups of DD children (N = 45) equivalent for age, sex, full IQ, and reading speed were trained either by Reading Trainer (n = 21) or by Run the RAN (n = 24); both trainings required an intensive home exercise, lasting 3 months. Both trainings showed significant improvements in reading speed and accuracy of passages and words. Bypassing the use of alphanumeric stimuli, but empowering the cognitive processes underlying reading, training RAN may be a valid tool in children with reading difficulties opening new perspectives for children with severe impairments or, even, at risk of reading difficulties.

Predictors of survival in spinocerebellar ataxia type 2 population from Southern Italy.

One hundred-eighteen spinocerebellar ataxia type 2 patients from 35 distinct families personally observed between 1973 and 2016 were retrospectively reviewed. The time point of data collection was 1 January 2017. Thirty-one patients were confined to wheelchair. The median time to wheelchair was 21 years (95% CI, 17.5-24.6). Thirty-seven patients were deceased. The median time to death was 25 years (95% CI, 22.9-27.1). CAG repeat number and ataxia score at first visit influenced the time to wheelchair and death.

Telerehabilitation in developmental dyslexia: methods of implementation and expected results.

BACKGROUND: Developmental Dyslexia is a disorder, highly frequent in the school population, for which the recommended rehabilitation procedures are not well defined. This study aimed to automatize reading decoding skills by using an innovative system for rehabilitation, based on a telerehabilitation method. It requires an intensive home-exercise with the supervision, by web, of the clinician. The study had three main aims: to diffuse knowledge on new methods for rehabilitation of reading difficulties; to verify whether an intensive and simplified exercise, targeted to the automation of reading, is suitable for different subgroups of dyslexic children; to define the treatment effects on basic cognitive functions underlying reading. METHODS: Twenty-five children, grouped according to the neuropsychological and anamnestic profiles, took part to the treatment by the software Reading Trainer®. RESULTS: Both speed and accuracy of reading decoding increased significantly after treatment, independently from the functional neuropsychological profile or the history of oral language delay. These changes were specific to decoding and not associated with improvements in reading comprehension or spelling skills. However, there was a "cascade effect" of the treatment efficacy on those basic cognitive functions considered precursors of the ability to read, with significant improvements in rapid lexical access, phonological processing and visual attention. CONCLUSIONS: This study provides information on the efficacy of new tools for telerehabilitation of specific reading disorders.

SCAR32: Functional characterization and expansion of the clinical-genetic spectrum.

OBJECTIVE: Biallelic mutations in PRDX3 have been linked to autosomal recessive spinocerebellar ataxia type 32. In this study, which aims to contribute to the growing body of knowledge on this rare disease, we identified two unrelated patients with mutations in PRDX3. We explored the impact of PRDX3 mutation in patient skin fibroblasts and the role of the gene in neurodevelopment. METHODS: We performed trio exome sequencing that identified mutations in PRDX3 in two unrelated patients. We also performed functional studies in patient skin fibroblasts and generated a "crispant" zebrafish (Danio rerio) model to investigate the role of the gene during nervous system development. RESULTS: Our study reports two additional patients. Patient 1 is a 19-year-old male who showed a novel homozygous c.525_535delGTTAGAAGGTT (p. Leu176TrpfsTer11) mutation as the genetic cause of cerebellar ataxia. Patient 2 is a 20-year-old male who was found to present the known c.425C>G/p. Ala142Gly variant in compound heterozygosity with the p. Leu176TrpfsTer11 one. While the fibroblast model failed to recapitulate the pathological features associated with PRDX3 loss of function, our functional characterization of the prdx3 zebrafish model revealed motor defects, increased susceptibility to reactive oxygen species-triggered apoptosis, and an impaired oxygen consumption rate. CONCLUSIONS: We identified a new variant, thereby expanding the genetic spectrum of PRDX3-related disease. We developed a novel zebrafish model to investigate the consequences of prdx3 depletion on neurodevelopment and thus offered a potential new tool for identifying new treatment opportunities.

The wide world of technological telerehabilitation for pediatric neurologic and neurodevelopmental disorders - a systematic review.

Introduction: The use of Information and Communication Technology (ICT) for assessing and treating cognitive and motor disorders is promoting home-based telerehabilitation. This approach involves ongoing monitoring within a motivating context to help patients generalize their skills. It can also reduce healthcare costs and geographic barriers by minimizing hospitalization. This systematic review focuses on investigating key aspects of telerehabilitation protocols for children with neurodevelopmental or neurological disorders, including technology used, outcomes, caregiver involvement, and dosage, to guide clinical practice and future research. Method: This systematic review adhered to PRISMA guidelines and was registered in PROSPERO. The PICO framework was followed to define the search strategy for technology-based telerehabilitation interventions targeting the pediatric population (aged 0-18) with neurological or neurodevelopmental disorders. The search encompassed Medline/PubMed, EMBASE, and Web of Science databases. Independent reviewers were responsible for selecting relevant papers and extracting data, while data harmonization and analysis were conducted centrally. Results: A heterogeneous and evolving situation emerged from our data. Our findings reported that most of the technologies adopted for telerehabilitation are commercial devices; however, research prototypes and clinical software were also employed with a high potential for personalization and treatment efficacy. The efficacy of these protocols on health or health-related domains was also explored by categorizing the outcome measures according to the International Classification of Functioning, Disability, and Health (ICF). Most studies targeted motor and neuropsychological functions, while only a minority of papers explored language or multi-domain protocols. Finally, although caregivers were rarely the direct target of intervention, their role was diffusely highlighted as a critical element of the home-based rehabilitation setting. Discussion: This systematic review offers insights into the integration of technological devices into telerehabilitation programs for pediatric neurologic and neurodevelopmental disorders. It highlights factors contributing to the effectiveness of these interventions and suggests the need for further development, particularly in creating dynamic and multi-domain rehabilitation protocols. Additionally, it emphasizes the importance of promoting home-based and family-centered care, which could involve caregivers more actively in the treatment, potentially leading to improved clinical outcomes for children with neurological or neurodevelopmental conditions. Systematic review registration: PROSPERO (CRD42020210663).

Specific Learning Disabilities and Emotional-Behavioral Difficulties: Phenotypes and Role of the Cognitive Profile.

Specific Learning Disabilities (SLD) are often associated with emotional-behavioral problems. Many studies highlighted a greater psychopathological risk in SLD, describing both internalizing and externalizing problems. The aims of this study were to investigate the emotional-behavioral phenotype through the Child Behavior Checklist (CBCL), and evaluate the mediating role of background and cognitive characteristics on the relationship between CBCL profile and learning impairment in children and adolescents with SLD. One hundred and twenty-one SLD subjects (7-18 years) were recruited. Cognitive and academic skills were assessed, and parents completed the questionnaire CBCL 6-18. The results showed that about half of the subjects manifested emotional-behavioral problems with a prevalence of internalizing symptoms, such as anxiety and depression, over externalizing ones. Older children showed greater internalizing problems than younger ones. Males have greater externalizing problems compared to females. A mediation model analysis revealed that learning impairment is directly predicted by age and familiarity for neurodevelopmental disorders and indirectly via the mediation of the WISC-IV/WAIS-IV Working Memory Index (WMI) by the CBCL Rule-Breaking Behavior scale. This study stresses the need to combine the learning and neuropsychological assessment with a psychopathological evaluation of children and adolescents with SLD and provides new interpretative insights on the complex interaction between cognitive, learning, and emotional-behavioral phenotypes.

Executive Functions and Rapid Automatized Naming: A New Tele-Rehabilitation Approach in Children with Language and Learning Disorders.

Executive function deficits are documented in many neurodevelopmental disorders and may contribute to clinical complexity or rehabilitation resilience. The present research was primarily aimed at presenting and evaluating the feasibility and effectiveness of a telerehabilitation program used during the pandemic period. MemoRAN (Anastasis), a computerised cognitive training to improve executive control during visual-verbal integration tasks was used in a sample of 42 children (5-11 years old) with specific learning or language disorders. The MemoRAN training was based on exercises of inhibition, cognitive flexibility and updating in working memory for three months, with a frequency of approximately three sessions per week. Afterwards, a comparison between a subgroup of children using Memo-RAN and an active control group, using a tele-rehabilitation program directed on reading was conducted. Effect size analysis in pre-post measurements suggests an average effect of MemoRAN in measurements that require control processes, such as accuracy in dictation, reading, inhibition and working memory testing. Comparison with the active control group and the clinical utility implications of these types of treatment will be discussed.

Complex neurodevelopmental disorder in a preterm child with unilateral cerebellar hemorrhage.

BACKGROUND: Cerebellar hemorrhage (CBH) represents the main form of direct cerebellar injury in preterm infants. Most CBHs occur bilaterally, while isolated unilateral hemorrhages are less frequent and often associated with focal atrophy. Limited and heterogeneous data exist on preterm birth, unilateral CBH and consequent long-term neurodevelopmental and non-motor outcomes. CASE REPORT: This is the case of a six-year-old child, born preterm, diagnosed with a complete atrophy of the right cerebellar hemisphere through brain MRI and presenting mild social atypies, visuo-perceptive and pragmatic language impairment, but only minor neurological signs. DISCUSSION: Despite the large extension of the patient's CBH neurological sequelae were mild, likely due to cerebellar plasticity, and only specific deficits in non-motor, behavioral and social skills were shown. Evidence exists on cerebellar contribution to dynamic visual information processing and to perceptual signals detection and prediction, that might explain the presence of non-motor signs.

How many functional brains in developmental dyslexia? When the history of language delay makes the difference.

BACKGROUND: Clinical manifestations of developmental dyslexia (DD) are greatly variable, suggesting complex underlying mechanisms. It was recently advanced that the characteristics of DD in Italian, a language with shallow orthography, are influenced by a positive history for language delay. OBJECTIVE: We explored this hypothesis by studying in Italian individuals with DD (i) the brain representation of phonological processing with functional magnetic resonance imaging and (ii) the correlation between the patterns of activation and the presence/absence of previous language delay. METHOD: Thirteen individuals with DD and 13 controls participated in the functional magnetic resonance imaging experiment consisting of a rhyme-generation task. RESULTS: Individuals with DD showed a reduced activation of phonological processing areas of the left hemisphere, such as the middle frontal gyrus, the precuneus, and the inferior parietal lobule, and in particular the superior temporal gyrus. Furthermore, patients with a history of language delay had reduced activation in the left inferior and medial frontal gyrus, that was associated with worse reading and phonological accuracy than patients with normal language development. CONCLUSIONS: Neurofunctional profiles of Italian individuals with DD are correlated to the history of language delay, suggesting that the relatively better behavioral profiles observed in individuals without a history of language delay are associated with a major activation of frontal networks normally involved in phonological working memory.

Dialogic Reading to Empower Executive Functions in Preschoolers.

Among the interventions recently developed to enhance Executive Functions (EFs) in preschoolers, Quincey Quokka's Quest (QQQ) is an illustrated book proposing EF activities embedded within a shared reading framework (Howard et al., 2017). In the present study, the Italian version of QQQ (QQQIT) was tested in 20 typical developing 4-5 year old children. Standardized tests were used to assess EFs pre- and post- intervention. QQQIT was conducted once a week for 8 weeks in small groups. A positive trend was registered in QQQIT performances from the first to the last sessions and a significant improvement, in comparison to the control condition, was obtained in the Color and Form Game test. These results, supporting the feasibility of the QQQIT intervention and its efficacy in increasing shifting abilities, confirm the usefulness of ecological interventions to empower specific EF components in preschool contexts.

Gene therapy with AR isoform 2 rescues spinal and bulbar muscular atrophy phenotype by modulating AR transcriptional activity.

Spinal and bulbar muscular atrophy (SBMA) is an X-linked, adult-onset neuromuscular condition caused by an abnormal polyglutamine (polyQ) tract expansion in androgen receptor (AR) protein. SBMA is a disease with high unmet clinical need. Recent studies have shown that mutant AR-altered transcriptional activity is key to disease pathogenesis. Restoring the transcriptional dysregulation without affecting other AR critical functions holds great promise for the treatment of SBMA and other AR-related conditions; however, how this targeted approach can be achieved and translated into a clinical application remains to be understood. Here, we characterized the role of AR isoform 2, a naturally occurring variant encoding a truncated AR lacking the polyQ-harboring domain, as a regulatory switch of AR genomic functions in androgen-responsive tissues. Delivery of this isoform using a recombinant adeno-associated virus vector type 9 resulted in amelioration of the disease phenotype in SBMA mice by restoring polyQ AR-dysregulated transcriptional activity.