Autistic traits, sensory sensitivity and eating disturbances in a sample of young adults referring to a generalized mental health clinic.

PURPOSE: The relationship between autistic traits and eating disturbances has been given considerable attention over the last decades. The rise of a dimensional approach to psychopathology has expanded the way we think about autism, acknowledging that subthreshold autistic manifestations span across the general population and are more pronounced in psychiatric patients. Here we investigated the prevalence of eating disorders and its potential relationship with autistic traits and sensory sensitivity in a group of patients who were referred for the first time to a mental health outpatient clinic, without a formal diagnosis yet. METHODS: 259 young adults (between 18 and 24 years old) completed: the Eating Attitude Test (EAT-26), the Swedish Eating Assessment for Autism Spectrum Disorders (SWEAA), the Autism Quotient (AQ), the Ritvo Autism Asperger Diagnostic Scale-Revised (RAADS-R), and the Sensory Perception Quotient-Short Form 35 item (SPQ-SF35). RESULTS: 23.55% of participants scored above the cut-off at the EAT-26, suggesting that they presented a risk for eating disorders and should be assessed by a specialized clinician; associations emerged between hypersensitivity in the touch and vision domain and both the EAT-26 and the SWEAA; the presence of autistic traits was largely associated with eating disturbances. CONCLUSIONS: This study underlines the significance of the eating domain as a central psychopathological feature in the distress experienced by young adults with general psychiatric symptoms and psychological suffering; it adds evidence to the association between autistic traits and eating disorders and opens to new research questions about the role of subthreshold autistic traits in general psychopathology. LEVEL OF EVIDENCE: Level I: Evidence obtained from experimental studies.

Operational diagnosis of epilepsy in children at undetermined risk: A meta-analysis of prognostic factors for seizure recurrence.

PURPOSE: According to the operational epilepsy definition adopted by the International League Against Epilepsy (ILAE) in 2014, in patients with one unprovoked seizure, clinicians must stratify the recurrence risk to determine if the criteria for diagnosis of epilepsy have been met and if antiseizure medications (ASM) are required. A remote symptomatic etiology was considered to be one of the best predictors for seizure recurrence, also according to the available prediction tools, but in children with a previously negative history and a normal neurological examination, estimating the probability of seizure relapse remains less obvious. This meta-analysis aimed to fill this gap of knowledge. METHODS: The PubMed, Embase, and Scopus databases were searched from January 2000 to December 2020. We selected studies reporting children (1 month-18 years old) presenting a first unprovoked seizure. The absence of a known remote neurological pathology had to be clearly stated in the paper or the idiopathic/cryptogenic group data were used; the finding of epileptogenic structural brain MRI abnormalities during the diagnostic workup at the moment of the first unprovoked seizure was not an exclusion criterion. Factors analyzed, as possible predictors of recurrence, included: age at onset, sex, family history of epilepsy, type of seizure (focal or generalized), epileptiform abnormalities on EEG, and epileptogenic structural brain MRI abnormalities. RESULTS: Four studies met the inclusion criteria and the sample size consisted of 741 children. The estimated recurrence rate within 3 years was 50% (95%CI:33.9%-66.0%). Among the predictors of recurrence, focal seizure (OR = 1.52; 95%CI = 1.05-2.19), epileptiform abnormalities on EEG (OR = 1.97; 95%CI = 1.31-2.96), and positive family history for epilepsy (OR = 2.37; 95%CI = 1.56-3.59) were associated with a statistically significant increased risk. CONCLUSION: The analysis of data available until now cannot adequately assess the risk of recurrence after a first unprovoked seizure in neurotypical children. Prospective and multicenter cohort studies are expected.

Clinical overlap between functional neurological disorders and autism spectrum disorders: a preliminary study.

Functional neurological disorders (FNDs) and autism spectrum disorders (ASDs) share common features in terms of deficits in emotion regulation and recognition, sensory sensitivity, proprioception and interoception. Nevertheless, few studies have assessed their overlap. We recruited 21 patients with FNDs, 30 individuals with ASDs without intellectual disabilities and 45 neurotypical adults (NA). Participants completed: the Autism Quotient (AQ); the Ritvo Autism Asperger Diagnostic Scale-Revised (RAADS-R); and a questionnaire assessing functional neurological symptoms (FNS). ASDs participants also completed the Sensory Perception Quotient-Short Form (SPQ-SF35), assessing sensory sensitivity. In the FNDs sample, no patient scored above the clinical cut-off at the AQ and the 19% scored above the cut-off at the RAADS-R, a prevalence similar to the one we found in NA (15.6%; both p > 0.05). The 86.7% of participants with ASDs reported at least one FNS, a prevalence significantly higher than the NA one (35.6%, p < 0.001). In the ASDs sample, tactile hypersensitivity was found to be a risk factor for functional weakness (OR = 0.74, p = 0.033) and paraesthesia (OR = 0.753, p = 0.019). In conclusions, FNDs individuals did not present autistic traits more than NA, but ASDs individuals presented a higher number of FNSs than NA; this rate was associated with higher sensory sensitivity, especially in the touch domain.

Eating disturbances in eating disorders and in high-functioning autism spectrum disorders: a preliminary study.

PURPOSE: The relationship between autism spectrum disorders (ASDs) and eating disorders (EDs) has been widely studied in the last decades. We aimed to directly compare patients with EDs, individuals with high-functioning ASDs (HF-ASDs) and healthy controls (HC) at measures detecting: (1) symptoms of eating disorders, (2) eating disturbances known to be characteristic of autism. METHODS: Thirty-four patients with EDs, 34 individuals with HF-ASDs and 35 HC, all females, completed the eating attitude test (EAT-26) and the Swedish eating assessment for autism spectrum disorders (SWEAA), two self-report questionnaires assessing, respectively, symptoms and concerns characteristic of eating disorders and ASD-related eating disturbances. RESULTS: At the EAT-26, patients with EDs scored significantly higher than individuals with HF-ASDs, and both of them scored higher than HC (p < 0.05, ηp2 = 0.283). Conversely, at the SWEAA, no differences between individuals with HF-ASDs and patients with EDs emerged (p = 901), but they both scored higher than HC (p < 0.05, ηp2 = 0.247). CONCLUSION: Individuals with HF-ASDs did not seem to reach the same level of EDs symptomatology as patients with EDs. Patients with EDs did not seem to present a different amount of autistic-eating behaviours than subjects with HF-ASDs. Patients with EDs and individuals with HF-ASDs scored higher than HC at both scales. Our results give further preliminary evidence of the overlap between autistic traits and EDs symptomatology, and should be taken into account in the definition of a shared model between EDs and ASDs. LEVEL OF EVIDENCE: Level II; Evidence obtained from controlled trial without randomization.

Epilepsy in isolated parenchymal neurocutaneous melanosis: A systematic review.

PURPOSE: Neurocutaneous melanosis (NCM) is a rare congenital syndrome characterized by giant melanocytic cutaneous nevi and melanosis within the central nervous system (CNS), often sparing leptomeninges and concentrated in the brain parenchyma. Epilepsy and neurodevelopmental abnormalities are the only complications reported in children with isolated parenchymal melanosis. A minority of patients experience drug-resistant epilepsy, and up to now, no predictors of epilepsy prognosis have been identified. METHODS: In this systematic review, according to preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines, we aggregated clinical cases of patients with isolated parenchymal melanosis affected by epilepsy, in order to recognize predictors of clinical outcome and to clarify indications of available therapeutic approaches. RESULTS: Sixteen articles (19 patients) were included in the final analysis from initial database research; 4 articles (4 patients) were selected from reference lists and 1 from conference abstracts (1 patient). In our series, distribution of parenchymal melanosis was the best predictor of epilepsy outcome: frequencies of seizure-free patients were different between cases of isolated/bilateral amygdale melanosis and those of multiple localizations (p = 0.037). Failure of antiepileptic drugs (AEDs) and/or surgical epilepsy therapy were associated with poor cognitive outcome (p = 0.03). CONCLUSION: Antiepileptic drugs were effective in the majority of patients with epilepsy with parenchymal melanosis. In case of multifocal distribution, more than one-third of patients presented a drug-resistant epilepsy. Epilepsy surgery is the best choice in patients with isolated amygdala localization. We propose the recognition of a multifactorial nature of cognitive impairment in neuromelanosis, emphasizing the role of drug-resistant epilepsy.

Prognostic factors in epileptic encephalopathies at onset in the first 2 years of life: The experience of a tertiary healthcare center in Italy.

INTRODUCTION: The aim of this retrospective cohort study was to identify some prognostic factors in anamnestic/clinical/instrumental data at the onset of epileptic encephalopathy (EE), for multiple outcome measures. METHODS: We recruited patients diagnosed as affected by EE at Sant'Anna University Hospital, with onset in the first 24 months of life, with follow-up lasting longer than 3 years. RESULTS: At the end of the follow-up, 6 patients (14%) died within 2 years of age; 20 patient (49%) had a drug-resistant epilepsy (DRE); 9 patients (22%) had a language development delay (LDD); 12 patients (30%) had an autism spectrum disorder (ASD); 20 patients (49%) had a global psychomotor impairment (GPI); 9 patients (22%) needed palliative care; and nobody had a normal psychomotor development. Preexisting developmental delay predicts death (p = 0.009), and in survivors, it is associated with a GPI (p < 0.001); patients with normal neurological examination at the onset of EE only develop a LDD (p = 0.020). Neuroimaging structural alterations are associated with DRE (p = 0.012) and with a GPI (p = 0.013). The history of perinatal risk factors predicts the worst prognosis (death: p = 0.035, GPI: p = 0.015, and access to palliative care: p = 0.007). The absence of early response to treatment is correlated to a poor long-term prognosis (GPI, p = 0.019; DRE, p = 0.001). The multivariate analysis confirms that a normal development at onset predicts the most favorable prognosis, both in terms of survival and cognitive outcome (OR [odds ratio] = 0.1). An early response to treatment is a protective factor for DRE (OR = 0.1). A perinatal pathology is confirmed as an independent prognostic factor of severe comorbidities (access to palliative care: OR = 10.4). SIGNIFICANCE: This study was conducted to recognize possible prognostic factors among onset data of patients with EE, considering multiple outcome measures. This study design represents an innovative element compared to available papers, which were centered on isolated endpoints of prognosis, such as the prediction of neurocognitive development impairment or drug resistance. The data obtained from the study confirm that EEs prognosis is generally, but not universally, poor. Structural etiology and/or lack of response to antiepileptic drug (AED) within three months are main risk factors for DRE. Normal development at the onset of EEs and early response to treatment are the main positive prognostic factors.

Dental care protocol based on visual supports for children with autism spectrum disorders.

BACKGROUND: Subjects with Autism Spectrum Disorders (ASDs) have often difficulties to accept dental treatments. The aim of this study is to propose a dental care protocol based on visual supports to facilitate children with ASDs to undergo to oral examination and treatments. MATERIAL AND METHODS: 83 children (age range 6-12 years) with a signed consent form were enrolled; intellectual level, verbal fluency and cooperation grade were evaluated. Children were introduced into a four stages path in order to undergo: an oral examination (stage 1), a professional oral hygiene session (stage 2), sealants (stage 3), and, if necessary, a restorative treatment (stage 4). Each stage came after a visual training, performed by a psychologist (stage 1) and by parents at home (stages 2, 3 and 4). Association between acceptance rates at each stage and gender, intellectual level, verbal fluency and cooperation grade was tested with chi-square test if appropriate. RESULTS: Seventy-seven (92.8%) subjects overcame both stage 1 and 2. Six (7.2%) refused stage 3 and among the 44 subjects who need restorative treatments, only three refused it. The acceptance rate at each stage was statistically significant associated to the verbal fluency (p=0.02; p=0.04; p=0.01, respectively for stage 1, 3 and 4). In stage 2 all subjects accepted to move to the next stage. The verbal/intellectual/cooperation dummy variable was statistically associated to the acceptance rate (p<0.01). CONCLUSIONS: The use of visual supports has shown to be able to facilitate children with ASDs to undergo dental treatments even in non-verbal children with a low intellectual level, underlining that behavioural approach should be used as the first strategy to treat patients with ASDs in dental setting.

Toward an Increased Attention on ADHD Symptoms and Traits in Young Adults: Prevalence Data From Screening Tools in a Psychiatric Outpatient Clinic.

OBJECTIVE: to analyze the prevalence of ADHD symptoms and traits in a heterogeneous clinical psychiatric sample of young adults (aged 18-24 years old), who referred to a specialized outpatient clinic for various psychiatric and psychological disturbances. METHOD: 259 participants completed three validated self-report screening questionnaires for ADHD: the Wender Utah Rating Scale (WURS), the Adult Attention-Deficit/Hyperactivity Disorder Self-Report Screening Scale for DSM-5 (ASRS-5), and the Conners' adult ADHD rating scale (CAARS). RESULTS: 12.4% of our sample scored above the cut-off at both the WURS and the ASRS-5 and was considered at risk of ADHD. CONCLUSION: the prevalence rate in our sample is higher than the one found in the adult general population (6.76%), and in the lower range of the one found in the adult clinical population (6.9%-38.8%). The potential role of sociodemographic (age, sex, gender identity, and employment) and comorbidity factors is discussed.

Traits of narcissistic vulnerability in adults with autism spectrum disorders without intellectual disabilities.

The relationship between Autism Spectrum Disorders (ASD) and Narcissistic Personality Disorder (NPD), considering the dimensions of narcissistic grandiosity and vulnerability, represents an important differential diagnosis and potential ground of comorbidity, since both conditions show high grades of pervasiveness, a life-long course, ego-syntonic traits, and difficulties in building up and sustaining interpersonal relationships Although the co-diagnosis rates, according to the categorical criteria in use, are limited (0%-6.4%), it is common to encounter diagnostic doubts in clinical practice. Here we investigated the dimensions of narcissistic vulnerability and grandiosity in a sample of 87 adults diagnosed with ASD without intellectual disabilities through the administration of the Pathological Narcissism Inventory-52 Items (PNI-52). The mean scores of our sample were compared with the normative distribution available in the literature, and we found that individuals with ASD scored significantly higher than neurotypical controls at the Total Score and at the Vulnerable Narcissism subscale, but not at the Grandiose Narcissism subscales. Demographic features did not influence these results. Vulnerable narcissism was significantly associated with the "Ritvo Autism and Asperger Diagnostic Scale - Revised" subscale Social Relatedness. These findings could potentially be indicative of a greater comorbidity rate between the two disorders with respect to the one reported to date, possibly because DSM-5 criteria are mainly focused on the grandiose dimension. Potential explanatory links between ASD phenomenology and vulnerable narcissism, such as the personality dimension of neuroticism, are discussed, together with the possible role of narcissistic vulnerability in mediating internalizing symptoms (e.g., anxiety, depression) in individuals with ASD.

Incidence of epilepsy in Ferrara, Italy.

Few studies have been carried out in the same area at different times, allowing an assessment of the incidence of epilepsy (E.), including all ages, over time. The available data on temporal trend show a decrease in E. incidence in childhood and an increase in the elderly. We sought to update the incidence of E. in the province of Ferrara, where a previous study estimated an incidence rate of 33.1 per 100,000, 35.8, if standardized to the European population. Newly diagnosed patients aged up to 14 years were drawn from a community-based prospective multi-source registry, and adult onset E. cases were collected through multiple overlapping sources of case collection. Cases were included and classified according to ILAE recommendations. During the study period (2007-2008), 141 newly diagnosed cases (66 men and 75 women) living in the study area were identified. The crude incidence rate was 46.1 per 100,000 person-years (95 % CI 39.0-54.5), 35.5 (95 % CI 28.0-43.0) if adjusted to the European population. The incidence of childhood and adolescence epilepsy was 57.0 per 100,000 person-years (95 % CI 33.8-90.0), lower than that reported in our previous study, and it was 44.8 (95 % CI 37.4-53.6) for adult onset E., which is significantly higher as compared to our previous study. The overall incidence of E. in northern Italy is stable over time. We detected a significant decrease in incidence of childhood and adolescence E. and an increase in adult-onset E. The burden of epilepsy will increase as the population continues to age.

[Management of children with headache in a Pediatric Emergency Department before and after the introduction of the Second International Classification of Headache Disorders (ICHD-II)]. / Il percorso dei pazienti con cefalea in Pronto Soccorso pediatrico prima e dopo la seconda classificazione internazionale delle cefalee.

The aim of this study was to evaluate how the management of children admitted with headache to a Pediatric Emergency Department, was modified by the introduction of the Second International Classification of Headache Disorders ( ICHD-II) published in 2004. The complexity and average costs of the services provided to patients in 2002 and 2011 were compared. The results revealed a decrease in the number of tests performed and in-hospital admissions. However, tests were more complex, and an increase in requests of specialist advice was observed. We hypothesized that this change may be related to the introduction of ICHD-II, which suggests a more rational approach to the child with headache and a better use of hospital resources.

Brief Report: Sensory Sensitivity is Associated with Disturbed Eating in Adults with Autism Spectrum Disorders Without Intellectual Disabilities.

Aim of the present study was to evaluate the relationship between sensory sensitivity and autistic eating behaviours or Eating Disorders (EDs) symptomatology, in a group of 75 adults with Autism Spectrum Disorders (ASDs) without intellectual disabilities, through a series of self-report questionnaires. We found that, controlling for demographic and clinical features: (i) hypersensitivity in the vision domain predicted higher levels of both EDs symptoms and autistic eating behaviours; (ii) hyposensitivity in the taste domain predicted higher levels of EDs symptoms. This gives preliminary evidence that not only in children diagnosed with ASDs, but even in adult individuals, the threshold of sensory sensitivity is associated with dysfunctional eating behaviours.

Long-term Memory of Sensory Experiences from the First Pregnancy, its Peri-partum and Post-partum in Women with Autism Spectrum Disorders without Intellectual Disabilities: A Retrospective Study.

PURPOSE: To explore the recalled experience of pregnancy and motherhood in women diagnosed with Autism Spectrum Disorders (ASD) without intellectual disabilities, focusing on sensory perceptions and mood. METHODS: We retrospectively evaluated, through an ad-hoc structured interview, the sensory sensitivity during the pre-partum, the peri-partum, and the post-partum of thirty-three mothers with ASD and thirty-two neurotypical mothers. Participants also underwent a psychometric assessment about autistic traits, general sensory sensitivity, and post-partum depressive symptomatology. RESULTS: Mothers with ASD recalled a higher sensitivity than the comparison group across the three time-points; however, during the peri-partum their recalled hypersensitivity decreases, and in the post-partum it returned as high as before childbirth. The difference in the length of recall between groups did not statistically influence our results. Higher levels of autistic traits correlated with higher depressive post-partum symptomatology. CONCLUSIONS: Mothers with ASD seem to recall their experience of pregnancy, childbirth, and post-partum period differently from neurotypical mothers, particularly in terms of hypersensitivity. The correlation with depressive symptoms and the potential role of oxytocin and of long-term memory (encoding and recollection) are discussed. Further exploring these aspects might give fundamental hints to provide tailored support to mothers with ASD during pregnancy and motherhood.

Neonatal hemifacial spasm and fourth ventricle mass.

Congential hemifacial spasm is a rare condition that is characterized by the occurrence of paroxysmal hemifacial contractions in neonates. We review the clinical, neurophysiological, neuroimaging, and histopathological findings, as well as the differential diagnosis, therapeutic approach, and outcome of all the described cases. Moreover, we report two new cases including the ictal video-electroencephalography recordings. Hemifacial spasm starts early in life, and is characterized by unilateral, involuntary, irregular tonic or clonic contractions of muscles innervated by the seventh cranial nerve. Hemifacial spasm is associated with eyelid blinking, and sometimes with breathing irregularities, hyperventilation, and/or other neurological manifestations (dystonic movements, nystagmus). Interictal and ictal video-electroencephalography did not reveal epileptiform abnormalities. In all cases, brain magnetic resonance imaging showed a mass involving the cerebellar peduncle, the cerebellar hemisphere, or the floor of the fourth ventricle. The semiology of the paroxysmal attacks is probably due to the activation of cranial nerve nuclei through intralesional hypersynchronous discharges, as shown by the intraoperative recordings and functional brain imaging described in the literature. We point out the importance of identifying such seizures in order to make an early diagnosis of the underlying cerebral lesion.

The Psychological Impact of COVID-19 among a Sample of Italian Adults with High-Functioning Autism Spectrum Disorder: A Follow-Up Study.

The strict lockdowns imposed to contain the COVID-19 pandemic brought an increase in levels of stress, anxiety, and depression in the general population. However, in a previous study, our group found that individuals with High-Functioning Autism Spectrum Disorders (HF-ASD) reported an increase in their psychological wellbeing and a decrease in their daily tiredness, in relation to the social distancing measures imposed during the first Italian lockdown (between March and May 2020). In this follow-up study, conducted during the "second wave" of COVID-19, we included the same group of individuals with HF-ASD and evaluated their levels of stress, anxiety, depression, PTSD-related symptoms, tiredness, and perceived wellbeing; moreover, we compared our results to the ones we obtained during the first lockdown on the same population. We found that individuals with HF-ASD experienced higher levels of the aforementioned psychiatric symptoms during the second lockdown, with respect to the first one. These levels positively correlated with their scores at the Autism Quotient subscale Attention Switching: hence, we speculated that these symptoms might be due not only to the prolonging of the social distancing measures, but also to the uncertainty that HF-ASD participants started experiencing at the end of the first lockdown.

A paradoxical psychological impact of COVID-19 among a sample of Italian adults with High Functioning Autism Spectrum Disorder.

BACKGROUND: Since February 2020, many governments of the world ordered strict social distancing rules to try to contain the COVID-19 pandemic, with a reported consequent increase in levels of stress, anxiety and depression in the general population. Aim of this study was to assess the prevalence of the aforementioned psychiatric symptoms across a sample of individuals with High Functioning Autism Spectrum Disorders (HF-ASDs) with respect to a group of neurotypical adults (NA), during the first two months of COVID-19 pandemic in Italy. METHOD: 45 adults with HF-ASDs and 45NA completed a structured online questionnaire, including; the Depression, Anxiety and Stress Scale - 21 items (DASS-21); the Impact of Event Scale-Revised (IES-R); the Perceived Stress Scale (PSS). We also explored some specific aspects of participants' psychological well-being through an ad-hoc questionnaire. RESULTS: Subjects with HF-ASDs scored significantly higher than NA at the DASS-21, the IES-R Total Score and the PSS; NA reported a higher perceived change of their lifestyle during the lockdown than individuals with HF-ASDs, and subjects with HF-ASDs reported to feel more comfortable and less tired during the lockdown period, in relation to the social distancing measures adopted by Italian authorities. CONCLUSIONS: Adults with HF-ASDs presented higher rates of depression, anxiety, stress and PTSD-related symptoms than NA during the first two months of COVID-19 pandemic. However, they also reported to feel subjectively more comfortable and less tired during the lockdown than before, in relation to the social distancing measures.

Hypermobile spectrum disorders symptoms in patients with functional neurological disorders and autism spectrum disorders: A preliminary study.

Autism spectrum disorders (ASDs) and functional neurological disorders (FNDs) share some clinical characteristics such as alexithymia, sensory sensitivity and interoceptive issues. Recent evidence shows that both the disorders present symptoms compatible with a diagnosis of hypermobile Ehlers-Danlos Syndrome and hypermobile spectrum disorders (hEDS/HSD), a heterogeneous group of heritable connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Here we compared the prevalence of hEDS/HSD-related symptoms in a group of patients with FNDs, of people with ASDs without intellectual disabilities, and a non-clinical comparison group (NC). Twenty patients with FNDs, 27 individuals with ASDs without intellectual disabilities and 26 NC were recruited and completed the Self-reported screening questionnaire for the assessment of hEDS/HSD-related symptoms (SQ-CH). We found that 55% of the patients with FNDs, 44.4% of the individuals with ASDs and 30.8% of NC scored above the cut-off at the SQ-CH; SQ-CH scores of both FNDs and ASDs group were significantly higher than the NC group's ones. In conclusion, both ASDs and FNDs individuals present hEDS/HSD-related symptoms in a higher number than the general population. Imputable mechanisms include (i) overwhelming of executive functions with consequent motor competence impairment for ASDs individuals, and (ii) exacerbation of FNDs symptoms by physical injury and chronic pain due to abnormal range of joint mobility. Moreover, we speculated that the amygdala and the anterior cingulate cortex circuitry might be responsible for the imbalances at the proprioceptive, interoceptive, and emotional levels.

Epilepsy Course and Developmental Trajectories in STXBP1-DEE.

Background and Objectives: Clinical manifestations in STXBP1 developmental and epileptic encephalopathy (DEE) vary in severity and outcome, and the genotypic spectrum is diverse. We aim to trace the neurodevelopmental trajectories in individuals with STXBP1-DEE and dissect the relationship between neurodevelopment and epilepsy. Methods: Retrospective standardized clinical data were collected through international collaboration. A composite neurodevelopmental score system compared the developmental trajectories in STXBP1-DEE. Results: Forty-eight patients with de novo STXBP1 variants and a history of epilepsy were included (age range at the time of the study: 10 months to 35 years, mean 8.5 years). At the time of inclusion, 65% of individuals (31/48) had active epilepsy, whereas 35% (17/48) were seizure free, and 76% of those (13/17) achieved remission within the first year of life. Twenty-two individuals (46%) showed signs of developmental impairment and/or neurologic abnormalities before epilepsy onset. Age at seizure onset correlated with severity of developmental outcome and the developmental milestones achieved, with a later seizure onset associated with better developmental outcome. In contrast, age at seizure remission and epilepsy duration did not affect neurodevelopmental outcomes. Overall, we did not observe a clear genotype-phenotype correlation, but monozygotic twins with de novo STXBP1 variant showed similar phenotype and parallel disease course. Discussion: The disease course in STXBP1-DEE presents with 2 main trajectories, with either early seizure remission or drug-resistant epilepsy, and a range of neurodevelopmental outcomes from mild to profound intellectual disability. Age at seizure onset is the only epilepsy-related feature associated with neurodevelopment outcome. These findings can inform future dedicated natural history studies and trial design.

Mitofusin 2: The missing link between mtDNA maintenance defects and neurotransmitter disorders.

Mitofusin (MFN) 2 belongs to the large family of mitochondrial transmembrane GTPases and has a role in dynamic mitochondrial remodeling process governed by fusion and fission. MFN2 pathogenic variants classically cause Charcot-Marie-Tooth disease type 2A (CMT2A), the most common axonal form of CMT, but patients with complex and unusual phenotypes involving the central and peripheral nervous system have been described, with mitochondrial dysfunction proposed as the underlying pathogenic mechanism. Here, we report the first description of a neurochemical pattern of secondary alterations in the metabolism of biogenic amines linked to the de novo presence of the hotspot MFN2 pathogenic variant p.Arg104Trp. The infant presented a very early onset choreic movement disorder associated with severe axial hypotonia and fluctuating dystonia of limbs. The relationship between mitochondrial DNA (mtDNA) maintenance defects and dopaminergic neurotransmitter disorders, governed by MFN2, is discussed.