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BackgroundDominant and recessive variants in the KIF1A gene on chromosome 2q37.3 are associated with several phenotypes, although only three syndromes are currently listed in the OMIM classification: hereditary sensory and autonomic neuropathy type 2 and spastic paraplegia type 30, both recessively inherited, and mental retardation type 9 with dominant inheritance.MethodsIn this retrospective multicentre study, we describe the clinical, neuroradiological and genetic features of 19 Caucasian patients (aged 3–65 years) harbouring heterozygous KIF1A variants, and extensively review the available literature to improve current classification of KIF1A-related disorders.ResultsPatients were divided into two groups. Group 1 comprised patients with a complex phenotype with prominent pyramidal signs, variably associated in all but one case with additional features (ie, epilepsy, ataxia, peripheral neuropathy, optic nerve atrophy); conversely, patients in group 2 presented an early onset or congenital ataxic phenotype. Fourteen different heterozygous missense variants were detected by next-generation sequencing screening, including three novel variants, most falling within the kinesin motor domain.ConclusionThe present study further enlarges the clinical and mutational spectrum of KIF1A-related disorders by describing a large series of patients with dominantly inherited KIF1A pathogenic variants ranging from pure to complex forms of hereditary spastic paraparesis/paraplegias (HSP) and ataxic phenotypes in a lower proportion of cases. A comprehensive review of the literature indicates that KIF1A screening should be implemented in HSP regardless of its mode of inheritance or presentations as well as in other complex neurodegenerative or neurodevelopmental disorders showing congenital or early onset ataxia.

Background The early identification of infants with a risk for neurodevelopmental disorders in the first few years of life is essential for better developmental outcomes. Screenings should be carried out by combining the family pediatricians’ and parents’ perspectives, the two fundamental sources of information on children’s health. The present study has three aims: (a) to test the feasibility of parent-report instruments to detect warning signs in their children’s development; (b) to ascertain whether there is an agreement between the family pediatricians’ (FP) clinical judgments of warning signs and the parental perceptions; (c) to determine whether there is a link between parents’ distress and child development. Methods Within the NASCITA birth cohort, in addition to the family pediatrician’s clinical evaluation with routine tools, the Modified Checklist for Autism in Toddlers, Revised (M-CHAT-R) was completed by parents to assess the child’s language, social skills, behavior, and sensory areas. Parents were also asked to complete the Parenting Stress Index, Short Form (PSI-SF) to verify the magnitude of stress in the parent-child system. Univariate and multivariate analyses were performed to evaluate the association between child and parental characteristics and the presence of warning signs. Results The follow-up assessment was completed for 435 infants: 69 (15.8%) presented warning signs: 43 in the pediatrician’s assessment and 36 in the M-CHAT-R (10 in both). A total of 16 children (14 with warning signs) received a diagnosis after a specialist evaluation. Being male (OR 2.46, 95%CI: 1.23–4.91) and having sleep disorders (OR 2.43, 95% CI 1.17–5.04) was associated with a greater likelihood of warning signs in the multivariate analysis, while reading aloud was a protective factor (not exposed versus exposed (OR = 3.14; 95% CI 1.60–6.17). For 73 children (18.4%), at least one parent tested positive for PSI-SF. An increased prevalence of parental distress was observed in children with warning signs (OR 2.36, 95% CI 1.27–4.37). Conclusions Integrating physician and parental perspectives during well-child visits and in clinical practice appears feasible and can improve the identification of children at risk of developmental disorders.

Ensuring a successful transition to Adult Mental Health Services (AMHS) is fundamental for attention deficit/hyperactivity disorder (ADHD) patients to prevent adverse scenarios in adults (e.g., psychiatric disorders, substance or alcohol abuse). Yet, most European nations do not have appropriate transition guidelines and still fail to adequately support transition processes. This study aims to enquire about the current transition paths in Italy and the perceived experiences of the patients and their clinicians. The present observational study collected 36 interviews with young adults with ADHD who turned 18 between 2017 and 2021. Simultaneously, two questionnaires were filled in by the clinicians (both from paediatric and AMHS) who were involved in their transition paths. These tools collected information about the transition process, the services that cared for the young adults and well-being indicators such as impairment in daily life, employment status and the presence of sentinel events (e.g., critical stage accesses to the emergency room or hospitalizations). Successful and failed referrals were analysed. A referral to an AMHS was attempted for 16 young adults (8 before age 18 and 8 when turning 18), and 8 patients (22.2% overall) were successfully taken into the care of the AMHS. Twenty patients were not referred since it was deemed unnecessary ( = 6) or because of the lack of specialized services or compliance ( = 14). At the time of the interview, only nine participants were still under AMHS care. Of eleven individuals with a high need for care (identified by the level of impairment, support needs or sentinel events), five were not followed by a mental health professional at the time of the interview. For the majority of ADHD young adults, a transition path was never started or completed. While this is partly due to mild levels of impairment, in many cases it was difficult to find a service that could care for the adult patient. Only one out of four young adults are successfully transferred to AMHS care. Creating or improving evidence-based transition guidelines should be a priority of the public health system to ensure healthcare for as many patients as possible. The results of this study will converge towards the need for recommendations for the transition of services from adolescence to adulthood for young people with ADHD for Italian clinical practice.

Cerebral palsy (CP) is still the most common cause of disability developing in infancy. How such a complex disorder affects adult life raises important questions on the critical issues to consider and the most appropriate care pathway right from early childhood. We conducted a multicenter study on a sample of 109 individuals with CP followed up from infancy and recalled for an assessment at ages ranging between 18 and 50 years (mean age 26 years). Semi-structured interviews and specific questionnaires (SF36, LIFE-H and Hollingshead Index) were conducted to assess general psychological state, quality of life, and socio-economic conditions. Our findings showed a globally positive perception of quality of life, albeit with lower scores for physical than for mental health. Our cases generally showed good scores on participation scales, though those with more severe forms scored lower on parameters such as mobility, autonomy, and self-care. These findings were investigated in more depth in interviews, in which our participants painted a picture showing that gradual improvements have been made in several aspects over the years, in the academic attainment and employment, for instance. On the downside, our sample reported persistent limitations on autonomy in daily life. As for the more profound psychological domain, there was evidence of suffering due to isolation and relational difficulties in most cases that had not emerged from the questionnaires. Our data have possible implications for the management of CP during childhood, suggesting the need to avoid an exclusive focus on motor function goals, and to promote strategies to facilitate communication, participation, autonomy, and social relations.

Many studies based on chromosomal microarray and next-generation sequencing (NGS) have identified hundreds of genes associated with autism spectrum disorder (ASD) risk, demonstrating that there are several complex genetic factors that contribute to ASD risk. We performed targeted NGS gene panels for 120 selected genes, in a clinical population of 40 children with well-characterized ASD. The variants identified were annotated and filtered, focusing on rare variants with a minimum allele frequency <1% in GnomAD. We found 147 variants in 39 of the 40 patients. It was possible to perform family segregation analysis in 28 of the 40 patients. We found 4 de novo and 101 inherited variants. For the inherited variants, we observed that all the variants identified in the patients came equally from the paternal and maternal genetic makeup. We identified 9 genes that are more frequently mutated than the others, and upon comparing the mutational frequency of these 9 genes in our cohort and the mutational frequency in the GnomAD population, we found significantly increased frequencies of rare variants in our study population. This study supports the hypothesis that ASD is the result of a combination of rare deleterious variants (low contribution) and many low-risk alleles (genetic background), highlighting the importance of MET and SLIT3 and the potentially stronger involvement of FAT1 and VPS13B in ASD. Taken together, our findings reinforce the importance of using gene panels to understand the contribution of the different genes already associated with ASD in the pathogenesis of the disease.

Background Supporting young ADHD patients in transition to adult services is essential. Yet, the low percentages of successful referrals and the issues reported by patients and clinicians stress the need for further attention to transitioning practices. The present study assessed the transitioning process of Attention-Deficit/Hyperactivity Disorder (ADHD) patients in Child and Adolescent Mental Health Services (CAMHS) and Adult Mental Health Services (AMHS) in the Italian territory. We asked child and adult psychiatrists to report the current state of services and their observations on limitations and possible future matters that must be addressed. Method Seventy-seven centers (42 CAMHS, 35 AMHS) filled in a web-based survey in which they reported the number of ADHD patients, how many transitioning patients they had within the past year, and how they structured transition. Results A fragmented picture emerged from the survey. Lack of resources, training, and communication between services hinder the transition process, and many adult patients remain under CAMHS’ care. While some services have a protocol, there is no structured guidance that can help improve integration and continuity of treatment. Conclusion The observed situation reflects a need for improvement and standard guidelines to enable a successful transition process, considering clinicians' and patients’ necessities.

►Aim. To investigate the current management of transition from CAMHS (Child and Adolescent Mental Health Services) to AMHS (Adult Mental Health Services) in Italy for patients with ADHD (Attention Deficit and Hyperactivity Disorder).►Methods. Observational study placed within phase 2 of the TransiDEA (Transitioning in Diabetes, Epilepsy and ADHD patients) project, sponsored by the Mario Negri Institute for Pharmacological Research. Analysis of the direct experience of a group of 36 young patients with ADHD who turned 18 between 2017 and 2021 and clinicians (Child Neuropsychiatrists and Psychiatrists) involved in their care pathways before, during and after the transition process. Patients were offered a structured interview via video call while clinicians filled out a questionnaire. The questions covered diagnosis, symptomatology, different therapeutic interventions, service management of transition, success rate of referral from CAMHS to AMHS and outcome from clinical and socio-occupational point of view.►Results. In our sample, the rate of diversion from services during transition process is about 50% if we consider attempted referrals from CAMHS to AMHS, and it reaches 75% of the total if we consider successful referrals. For 7 patients, referral was not deemed necessary due to mild symptomatology. For 9 patients, referral was not made due to the absence of sufficiently specialized services for adults with ADHD and for the remaining 5 due to poor compliance by the family. According to the patients’ reports, in 50% of the cases no specific interventions aimed at managing the transition were put in place, in 19% informational meetings between child neuropsychiatry and family were carried out, in 25% a clinical report was sent, and in 6% a case discussion was carried out between professionals. These data are roughly in line with those reported by professionals. With regard to clinical outcome, particular attention was paid to the occurrence of “sentinel events”, indicative of likely severe clinical picture (e.g., ER admissions for substance use, drunken driving accidents and fights), occurred in the period between discharge from CAMHS and the time of the interview. At least one of these episodes was observed in 36% of the young adults not in treatment at the time of the interview and in 14% of those under AMHS’ care.►Conclusions. The results reported in this paper confirm the urgency of putting in place interventions to facilitate the transition process from pediatric to adult services for patients with ADHD. The third phase of the TransiDEA project, currently nearing completion, gathered the information obtained in phases 1 and 2 to draft a document containing organizational and practical directions addressed to treatment services in order to enable better structuring of the transition process in Italy.

When a child develops a psychological disorder, even a mild one, early diagnosis is essential to provide a timely and appropriate intervention that can improve, both, the child’s symptoms and development. Early identification can prevent consequences of differing levels, in the short and long term, and in the individual, in his or her family, and in society as a whole. Hence the importance of paediatrician’s point of view and clinical know-how in identifying potential disorders early, but also the parents’ views. It is therefore important to actively involve parents upon initial diagnosis.In this regard, within the NASCITA Project, a study branch aimed at building a shared, active approach between parents, paediatricians and neuropsychiatrists/psychologists was activated for the age 2-year health assessments (well-child visits) phase. Three tests were used: the M-CHAT-R (Modified Checklist for Autism in Toddlers, Revised) to evaluate language, social skills, behaviour, sensory areas; the PSI-SF (Parenting Stress Index – Short Form) to verify the degree of discrepancy perceived by the parent between the child’s requests and his or her ability to deal with them adequately; the DERS (Difficulties in Emotion Regulation Scale) to highlight the difficulties of each parent in recognising, interpreting, and managing their emotions. The tests were given to 380 parents (142 couples, 215 mothers and 23 fathers) by 45 family paediatricians during the well-child visit held at two years of age. In all, 33 children (9%) resulted at risk, with a score of ≥3, 1 of whom was found to be at high risk. For 64 children (16.8%) at least one of the parents tested positive for PSI-SF and for 19 (5%) children at least one parent tested positive with the DERS. After combining the results obtained from the three tests and the clinical evaluation, and assessing the child’s condition with respect to those results, the pediatrician can provide the parents with a concise description of what emerged and provide a summarised report for the specialist. Such an effort leads to timely, shared communication within the parent-paediatrician-neuropsychiatrist triad that includes specificity of intervention and that can contribute to the effectiveness of the response.

Recent studies in Saccharomyces cerevisiae suggest that the delivery of copper to Cu/Zn superoxide dismutase (SOD1) is mediated by a cytosolic protein termed the copper chaperone for superoxide dismutase (CCS). To determine the role of CCS in mammalian copper homeostasis, we generated mice with targeted disruption of CCS alleles (CCS-/-mice). Although CCS-/-mice are viable and possess normal levels of SOD1 protein, they reveal marked reductions in SOD1 activity when compared with control littermates. Metabolic labeling with64Cu demonstrated that the reduction of SOD1 activity in CCS-/-mice is the direct result of impaired Cu incorporation into SOD1 and that this effect was specific because no abnormalities were observed in Cu uptake, distribution, or incorporation into other cuproenzymes. Consistent with this loss of SOD1 activity, CCS-/-mice showed increased sensitivity to paraquat and reduced female fertility, phenotypes that are characteristic of SOD1-deficient mice. These results demonstrate the essential role of any mammalian copper chaperone and have important implications for the development of novel therapeutic strategies in familial amyotrophic lateral sclerosis.

Neurogenesis is a tightly regulated process whose success depends on the ability to balance the expansion/maintenance of an undifferentiated neural progenitor pool with the precisely timed birth of sequential generations of neurons. The Zfp423 gene encodes a 30-Zn-finger transcription factor (TF) that acts as a scaffold in the assembly of complex transcriptional and cellular machineries regulating neural development. While null mutants for Zfp423 feature a severe cerebellar hypoplasia, the underlying mechanism is only partially characterized. Mutations of the human ortholog ZNF423 have been identified in patients carrying cerebellar vermis hypoplasia (CVH) or Joubert Syndrome (JS), associated with other signs of classical ciliopathy outside the central nervous system (CNS). ZNF423 also plays a role in the DNA damage response (DDR). To further characterize the role of ZFP423 in cerebellar neurogenesis, with a focus on Purkinje cells (PC) development, we analyzed two previously undescribed mutant mouse lines carrying allelic in-frame deletions of the corresponding gene, selectively affecting two functionally characterized protein-protein interaction domains, affecting zinc (Zn) fingers 9-20 or 28-30. Some phenotypic defects are allele specific: Zfp423 9-20/ 9-20 mutants exhibit a depletion of the OLIG2+ PC progenitor pool in the cerebellar ventricular zone (VZ). In these mutants, M-phase progenitors display changes in spindle orientation indicative of a precocious switch from symmetric to asymmetric cell division. Conversely, the Zfp423 28-30/ 28-30 primordium displays a sharp decrease in the expression of PC differentiation markers, including CORL2, despite an abundance of cycling PC progenitors. Moreover, and importantly, in both mutants VZ progenitor cell cycle progression is remarkably affected, and factors involved in the DDR are substantially upregulated in the VZ and in postmitotic precursors alike. Our in vivo evidence sheds light on the domain-specific roles played by ZFP423 in different aspects of PC progenitor development, and at the same time supports the emerging notion that an impaired DNA damage response may be a key factor in the pathogenesis of JS and other ciliopathies.