[Autistic spectrum disorder in women : how does gender operate?] / Trouble du spectre de l'autisme au féminin : comment le genre opère-t-il ?

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder, that affects both pediatric and adult populations and presents heterogeneously. The understanding of the clinical characteristics of ASD has expanded, in parallel with societal developments, including the integration of the notion of gender in medicine. It appears that individuals affected by this disorder, regardless of their age, are neither detected, diagnosed, nor followed or treated in the same manner depending on their gender. This article proposes to review current knowledge on ASD, its expression based on gender, factors influencing care, and the consequences for patients of exposure to gender bias.

Le trouble du spectre de l'autisme (TSA) est un trouble neurodéveloppemental fréquent. Il touche la population pédiatrique et adulte et se présente de manière hétérogène. La compréhension des caractéristiques clinique du TSA s'est étendue, en parallèle des évolutions sociétales, dont l'intégration de la notion de genre en médecine. Il apparaît que les personnes touchées par ce trouble, quel que soit leur âge, ne sont ni détectées, diagnostiquées, suivies ou traitées de manière identique selon leur genre. Cet article reprend les connaissances actuelles de l'expression du TSA en fonction du genre, et les conséquences pour les patient-e-s de l'exposition aux biais de genre.

Measuring upper limb function in children with hemiparesis with 3D inertial sensors.

PURPOSE: Upper limb assessments in children with hemiparesis rely on clinical measurements, which despite standardization are prone to error. Recently, 3D movement analysis using optoelectronic setups has been used to measure upper limb movement, but generalization is hindered by time and cost. Body worn inertial sensors may provide a simple, cost-effective alternative. METHODS: We instrumented a subset of 30 participants in a mirror therapy clinical trial at baseline, post-treatment, and follow-up clinical assessments, with wireless inertial sensors positioned on the arms and trunk to monitor motion during reaching tasks. RESULTS: Inertial sensor measurements distinguished paretic and non-paretic limbs with significant differences (P < 0.01) in movement duration, power, range of angular velocity, elevation, and smoothness (normalized jerk index and spectral arc length). Inertial sensor measurements correlated with functional clinical tests (Melbourne Assessment 2); movement duration and complexity (Higuchi fractal dimension) showed moderate to strong negative correlations with clinical measures of amplitude, accuracy, and fluency. CONCLUSION: Inertial sensor measurements reliably identify paresis and correlate with clinical measurements; they can therefore provide a complementary dimension of assessment in clinical practice and during clinical trials aimed at improving upper limb function.

Mirror therapy in children with hemiparesis: a randomized observer-blinded trial.

AIM: To determine the efficacy of mirror therapy in children with hemiparesis. METHOD: The design was an observer-blinded parallel-group randomized controlled trial (International Standard Randomised Controlled Trial Number 48748291). Randomization was computer-generated, 1:1 allocation to mirror therapy or comparison groups. The settings were home-based intervention and tertiary centre assessments. Participants were 90 children with hemiparesis aged 7 to 17 years. Intervention was 15 minutes per day of simultaneous arm training, 5 days a week, for 5 weeks. The mirror therapy group used a mirror; those in the comparison group looked at their paretic limb. Assessments comprised measures of upper limb strength, function (Melbourne Assessment 2), daily performance (ABILHAND-Kids), and sensory function at weeks 0 (T0 ), 5 (T1 ), and 10 (T2 ). RESULTS: There were no significant differences in outcomes and their progression over time between the mirror therapy and comparison groups. Post-hoc intention-to-treat analyses showed significant improvements in both groups for grasp strength (T0 -T1 +12.6%), pinch strength (T0 -T2 +9.1%), upper limb function in terms of accuracy (T0 -T2 +2.7%) and fluency (T0 -T2 +5.0%), as well as daily performance (T0 -T2 +16.6%). Per protocol analyses showed additional improvements in dexterity (T0 -T2 +4.0%). INTERPRETATION: The use of the mirror illusion during therapy had no significant effect on treatment outcomes. However, 5 weeks of daily simultaneous arm training significantly improved paretic upper limb strength, function, and daily use.

Could Gait Biomechanics Become a Marker of Atypical Neuronal Circuitry in Human Development?-The Example of Autism Spectrum Disorder.

This perspective paper presents converging recent knowledge in neurosciences (motor neurophysiology, neuroimaging and neuro cognition) and biomechanics to outline the relationships between maturing neuronal network, behavior, and gait in human development. Autism Spectrum Disorder (ASD) represents a particularly relevant neurodevelopmental disorder (NDD) to study these convergences, as an early life condition presenting with sensorimotor and social behavioral alterations. ASD diagnosis relies solely on behavioral criteria. The absence of biological marker in ASD is a main challenge, and hampers correlations between behavioral development and standardized data such as brain structure alterations, brain connectivity, or genetic profile. Gait, as a way to study motor system development, represents a well-studied, early life ability that can be characterized through standardized biomechanical analysis. Therefore, developmental gait biomechanics might appear as a possible motor phenotype and biomarker, solid enough to be correlated to neuronal network maturation, in normal and atypical developmental trajectories-like in ASD.

Sex differences in sensory processing in children with autism spectrum disorder.

Despite the high prevalence of sensory processing difficulties in children with autism spectrum disorder (ASD), little research has focused on the sex differences in sensory processing. Furthermore, there is a lack of knowledge on the female-specific symptoms of ASD, contributing to later referral, diagnosis and intervention. In this study, we examined the sex differences in sensory processing symptoms in large cohorts of ASD children (N = 168; 26 females, 142 males) and typically developing (TD) children (N = 439; 209 females, 230 males). For this, we translated the sensory processing measure (SPM) and SPM - Preschool (SPM-P) Home Forms to French. The SPM/SPM-P are parent/caregiver questionnaires that assess typical behavioral responses to sensory stimuli. Overall, our results showed that the magnitude of the differences in sensory processing between males and females is larger in ASD children relative to TD children, with females showing more severe symptoms in Hearing, as well as Balance and Motion subscales. Additionally, linear discriminant analysis showed that the SPM/SPM-P are good at discriminating TD children from ASD, children with higher accuracy rates for females than for males. These findings are discussed in light of the heterogeneity of sensory processing difficulties present in ASD. Overall, our results suggest that there seem to be female-specific profiles in sensory processing difficulties in ASD. Implications of findings concerning sex differences in sensory processing and their potential for improving identification and diagnosis of ASD females are discussed. LAY SUMMARY: The present study examined sex differences in behavioral responses to sensory stimuli in children with autism spectrum disorder (ASD), and typically developing (TD) children. While there is a small trend for TD males to show more sensory processing atypicalities, female ASD children show significantly more atypical responses compared to their male counterparts. This has important implications for characterizing female autism profiles, and ultimately improving the chance for earlier detection, diagnosis and treatment.

Touch and olfaction/taste differentiate children carrying a 16p11.2 deletion from children with ASD.

BACKGROUND: Sensory processing atypicalities are frequent in Autism Spectrum Disorder (ASD) and neurodevelopmental disorders (NDD). Different domains of sensory processing appear to be differentially altered in these disorders. In this study, we explored the sensory profile of two clinical cohorts, in comparison with a sample of typically developing children. METHODS: Behavioral responses to sensory stimuli were assessed using the Sensory Processing Measure (parent-report questionnaire). We included 121 ASD children, 17 carriers of the 16p11.2 deletion (Del 16p11.2) and 45 typically developing (TD) children. All participants were aged between 2 and 12 years. Additional measures included the Tactile Defensiveness and Discrimination Test-Revised, Wechsler Intelligence Scales and Autism Diagnostic Observation Schedule (ADOS-2). Statistical analyses included MANCOVA and regression analyses. RESULTS: ASD children score significantly higher on all SPM subscales compared to TD. Del16p11.2 also scored higher than TD on all subscales except for tactile and olfactory/taste processing, in which they score similarly to TD. When assessing sensory modulation patterns (hyper-, hypo-responsiveness and seeking), ASD did not significantly differ from del16p11.2. Both groups had significantly higher scores across all patterns than the TD group. There was no significant association between the SPM Touch subscale and the TDDT-R. LIMITATIONS: Sensory processing was assessed using a parent-report questionnaire. Even though it captures observable behavior, a questionnaire does not assess sensory processing in all its complexity. The sample size of the genetic cohort and the small subset of ASD children with TDDT-R data render some of our results exploratory. Divergence between SPM Touch and TDDT-R raises important questions about the nature of the process that is assessed. CONCLUSIONS: Touch and olfaction/taste seem to be particularly affected in ASD children compared to del16p11.2. These results indicate that parent report measures can provide a useful perspective on behavioral expression. Sensory phenotyping, when combined with neurobiological and psychophysical methods, might have the potential to provide a better understanding of the sensory processing in ASD and in other NDD.

De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures.

BACKGROUND: De novo variants in the voltage-gated calcium channel subunit α1 E gene (CACNA1E) have been described as causative of epileptic encephalopathy with contractures, macrocephaly and dyskinesias. METHODS: Following the observation of an index patient with developmental delay and autism spectrum disorder (ASD) without seizures who had a de novo deleterious CACNA1E variant, we screened GeneMatcher for other individuals with CACNA1E variants and neurodevelopmental phenotypes without epilepsy. The spectrum of pathogenic CACNA1E variants was compared to the mutational landscape of variants in the gnomAD control population database. RESULTS: We identified seven unrelated individuals with intellectual disability, developmental regression and ASD-like behavioral profile, and notably without epilepsy, who had de novo heterozygous putatively pathogenic variants in CACNA1E. Age of onset of clinical manifestation, presence or absence of regression and degree of severity were variable, and no clear-cut genotype-phenotype association could be recognized. The analysis of disease-associated variants and their comparison to benign variants from the control population allowed for the identification of regions in the CACNA1E protein that seem to be intolerant to substitutions and thus more likely to harbor pathogenic variants. As in a few reported cases with CACNA1E variants and epilepsy, one patient showed a positive clinical behavioral response to topiramate, a specific calcium channel modulator. LIMITATIONS: The significance of our study is limited by the absence of functional experiments of the effect of identified variants, the small sample size and the lack of systematic ASD assessment in all participants. Moreover, topiramate was given to one patient only and for a short period of time. CONCLUSIONS: Our results indicate that CACNA1E variants may result in neurodevelopmental disorders without epilepsy and expand the mutational and phenotypic spectrum of this gene. CACNA1E deserves to be included in gene panels for non-specific developmental disorders, including ASD, and not limited to patients with seizures, to improve diagnostic recognition and explore the possible efficacy of topiramate.

Cancer Care of Children, Adolescents and Adults With Autism Spectrum Disorders: Key Information and Strategies for Oncology Teams.

Delivering optimal cancer care to children, adolescents and adults with ASD has recently become a healthcare priority and represents a major challenge for all providers involved. In this review, and after consideration of the available evidence, we concisely deliver key information on this heterogenous group of neurodevelopmental disorders, as well as recommendations and concrete tools for the enhanced oncological care of this vulnerable population of patients.

Sudden unexpected death in an infant with L-2-hydroxyglutaric aciduria.

Inherited metabolic disorders are the cause of a small but significant number of sudden unexpected deaths in infancy. We report a girl who suddenly died at 11 months of age, during an intercurrent illness. Autopsy showed spongiform lesions in the subcortical white matter, in the basal ganglia, and in the dentate nuclei. Investigations in an older sister with developmental delay, ataxia, and tremor revealed L-2-hydroxyglutaric aciduria and subcortical white matter changes with hyperintensity of the basal ganglia and dentate nuclei at brain magnetic resonance imaging. Both children were homozygous for a splice site mutation in the L2HGDH gene. Sudden death has not been reported in association with L-2-hydroxyglutaric aciduria so far, but since this inborn error of metabolism is potentially treatable, early diagnosis may be important.

Yield of Outpatient Sleep EEG for Epileptiform Alterations' Detection in Children.

PURPOSE: Ambulatory EEGs in children are frequently ordered as sleep studies. However, the yield according to different clinical situations has received little attention to date. The authors aimed to quantify the added value in terms of detection of epileptiform features of an EEG containing sleep, as compared with only wakefulness, according to the referral diagnoses. METHODS: The authors retrospectively selected consecutive outpatients' EEG recordings of patients between 6 months to 16 years old, performed between January 2014 and February 2015. The authors excluded those lacking at least 10 minutes of waking and/or at least 5 minutes of behavioral sleep. Interictal epileptiform activity (IEA) in wakefulness and sleep was compared among referral suspected diagnoses. Additional yield of sleep was considered if at least one of the following was observed: appearance of interictal epileptiform activity or increase by >50%; interictal epileptiform activity change in localization or morphology, seizure occurrence. RESULTS: A total of 425 recordings (mean age 6.9 ± 4.7 years) were analyzed. Of them, 194 (45.6%) presented an additional yield during sleep, which was dependent on the occurrence of IEA during wakefulness: 77/251 (30.7%) in those without versus 117/174 (67.2%) in those with wakefulness IEA (P < 0.001, χ). The yield was markedly lower in studies performed for nonepileptic referral diagnoses (7% vs. 43% to 100%; P < 0.001, Fisher). CONCLUSIONS: When wakefulness EEG lacks epileptiform features, the yield of sleep EEG in our pediatric population appeared modest, especially in patients without a suspected epileptic syndrome. This information may be used to optimize the request of sleep EEG in children.

Efficacy and tolerability of the galanin analog NAX 5055 in the multiple-hit rat model of symptomatic infantile spasms.

Infantile spasms are seizures manifesting in infantile epileptic encephalopathies that are associated with poor epilepsy and cognitive outcomes. The current therapies are not always effective or are associated with serious side effects. Early cessation of spasms has been proposed to improve long-term outcomes. To identify new therapies for infantile spasms with rapid suppression of spasms, we are using the multiple-hit rat model of infantile spasms, which is a model of refractory infantile spasms. Here, we are testing the efficacy and tolerability of a single dose of the galanin receptor 1 preferring analog, NAX 5055, in the multiple-hit model of spasms. To induce the model, postnatal day 3 (PN3) male Sprague-Dawley rats underwent right intracerebral infusions of doxorubicin and lipopolysaccharide; p-chlorophenylalanine was then injected intraperitoneally (i.p.) at PN5. After the onset of spasms at PN4, 11-14 rats/group were injected i.p. with either NAX 5055 (0.5, 1, 2, or 4mg/kg) or vehicle. Video monitoring for spasms included a 1h pre-injection period, followed by 5h of recording post-injection, and two 2h sessions on PN5. The study was conducted in a randomized, blinded manner. Neurodevelopmental reflexes were assessed daily as well as at 2h after injection. Respiratory function, heart rate, pulse distension, oximetry and blood glucose were measured 4h after injection. The relative expression of GalR1 and GalR2 mRNA over ß-actin in the cerebral cortex and hippocampus was determined with real time reverse transcription polymerase chain reaction. There was no acute effect of NAX 5055 on spasm frequency after the single dose of NAX 5055 (n=11-13 rats/group, following exclusions). Neurodevelopmental reflexes, vital signs, blood glucose measured 4h post-injection, and survival were not affected. A reduction in pulse and breath distention of unclear clinical significance was observed with the 7mg/kg NAX 5055 dose. GalR1 mRNA was present in the cerebral cortex and hippocampus of PN4 and adult rats. The hippocampal - but not the cortical - GalR1 mRNA expression was significantly lower in PN4 pups than in adults. GalR1 mRNA was also at least 20 times less abundant in the PN4 cortex than GalR2 mRNA. In conclusion, a single dose of NAX 5055 has no acute efficacy on spasms or toxicity in the multiple hit rat model of medically refractory infantile spasms. Our findings cannot exclude the possibility that repetitive NAX 5055 administration may show efficacy on spasms. The higher expression of GalR2 in the PN4 cortex suggests that GalR2-preferring analogs may be of interest to test for efficacy on spasms.