1. Álvarez-Mora MI, Sánchez A, Rodríguez-Revenga L, Corominas J, Rabionet R, Puig S, Madrigal I. Diagnostic yield of next-generation sequencing in 87 families with neurodevelopmental disorders. Orphanet journal of rare diseases. 2022; 17(1): 60.

BACKGROUND: Neurodevelopmental disorders (NDDs) are a group of heterogeneous conditions, which include mainly intellectual disability, developmental delay (DD) and autism spectrum disorder (ASD), among others. These diseases are highly heterogeneous and both genetic and environmental factors play an important role in many of them. The introduction of next generation sequencing (NGS) has lead to the detection of genetic variants in several genetic diseases. The main aim of this report is to discuss the impact and advantages of the implementation of NGS in the diagnosis of NDDs. Herein, we report diagnostic yields of applying whole exome sequencing in 87 families affected by NDDs and additional data of whole genome sequencing (WGS) from 12 of these families. RESULTS: The use of NGS technologies allowed identifying the causative gene alteration in approximately 36% (31/87) of the families. Among them, de novo mutation represented the most common cause of genetic alteration found in 48% (15/31) of the patients with diagnostic mutations. The majority of variants were located in known neurodevelopmental disorders genes. Nevertheless, some of the diagnoses were made after the use of GeneMatcher tools which allow the identification of additional patients carrying mutations in THOC2, SETD1B and CHD9 genes. Finally the use of WGS only allowed the identification of disease causing variants in 8% (1/12) of the patients in which previous WES failed to identify a genetic aetiology. CONCLUSION: NGS is more powerful in identifying causative pathogenic variant than conventional algorithms based on chromosomal microarray as first-tier test. Our results reinforce the implementation of NGS as a first-test in genetic diagnosis of NDDs.

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2. Cleffi C, Su WC, Srinivasan S, Bhat A. Using Telehealth to Conduct Family-Centered, Movement Intervention Research in Children With Autism Spectrum Disorder During the COVID-19 Pandemic. Pediatric physical therapy : the official publication of the Section on Pediatrics of the American Physical Therapy Association. 2022; 34(2): 246-51.

PURPOSE: After the COVID-19 pandemic, several randomized controlled trials came to a halt; however, we chose to reinvent our study and shifted to a home-based, telehealth intervention delivery format to support children with autism spectrum disorder and their families. Children with autism spectrum disorder have social communication impairments as well as perceptuomotor and cognitive comorbidities. Continued access to care is crucial for their long-term development. METHODS: We created a general movement intervention to target strength, endurance, executive functioning, and social skills through goal-directed games and activities delivered using a telehealth intervention model. FINDINGS: Our family-centered approach allowed for collaboration between trainers and caregivers and made it easy for families to replicate training activities at home. CONCLUSIONS: While more studies comparing telehealth and face-to-face interventions are needed, we encourage researchers and clinicians to consider family-centered telehealth as a valid and feasible intervention delivery method, to increase the likelihood of carryover of skills into the daily lives of children and ultimately enhance their long-term development.

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3. Isaksson J, Ruchkin V, Aho N, Lundin Remnélius K, Marschik PB, Bölte S. Nonshared environmental factors in the aetiology of autism and other neurodevelopmental conditions: a monozygotic co-twin control study. Molecular autism. 2022; 13(1): 8.

BACKGROUND: A significant proportion of variation in likelihood of neurodevelopmental conditions (NDCs) has been attributed to nonshared environmental (NSE) factors, although it remains unclear which NSE factors pose specific risks for certain NDCs. METHODS: A monozygotic co-twin design was applied in a sample of 224 twins (mean age = 17.70 years, SD = 6.28) controlling for confounders such as genes and shared environment. Generalized estimating equation models were fitted, using perinatal and postnatal indications of NSEs as exposure, operationalized both as separate risk factors and as cumulative risk loads. Categorical and dimensional operationalizations of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), intellectual disability and other NDCs were used as outcomes. RESULTS: Birth weight discordance was associated with dimensional autism and ADHD for the smaller twin, and medication during infancy was associated with dimensional autism. Among postnatal factors scarlet fever during early childhood was associated with lower IQ. Especially autism was associated with a greater cumulative perinatal or postnatal risk load. LIMITATIONS: When exploring the associations between each condition and specific NSEs the risk of being statistically underpowered increases. Hence, we limit the reported findings on specific indicators of NSEs to trait levels and present descriptive data for categorical NDCs. CONCLUSIONS: The findings support previous research by indicating an association between exposure to perinatal and postnatal risks and subsequent NDCs within twin pairs and suggest that autism may be especially linked to accumulative early environmental risks. The findings are potentially important for developmental outcomes prognoses and may inform targeted prevention and early interventions.

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4. O’Connor RJ, Plant JL, Riggs KJ. Autistic Adults Show Similar Performance and Sensitivity to Social Cues on a Visual Perspective Taking Task as Non-autistic Adults. Journal of autism and developmental disorders. 2022.

Autistic and non-autistic adults completed a visual perspective taking (VPT) task, reporting an object’s location from an actor’s perspective, or their own. On half the trials the actor looked at and reached for the object, and on half did not. Accuracy and reaction time were measured. In Experiment 1, both groups (N = 34, mean age = 24 years) responded slower when reporting the actor’s perspective, with no group differences in this effect. Experiment 2 included « other » VPT trials only. Both groups (N = 30, mean age = 25 years) showed sensitivity to the actor’s behaviour, more accurately reporting his perspective when he acted upon the object. No group differences were observed. In contrast to developmental studies, these experiments suggest similar VPT abilities in autistic and non-autistic adults.

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5. Park G, Jeon SJ, Ko IO, Park JH, Lee KC, Kim MS, Shin CY, Kim H, Lee YS. Decreased in vivo glutamate/GABA ratio correlates with the social behavior deficit in a mouse model of autism spectrum disorder. Molecular brain. 2022; 15(1): 19.

To diagnose autism spectrum disorder (ASD), researchers have sought biomarkers whose alterations correlate with the susceptibility to ASD. However, biomarkers closely related to the pathophysiology of ASD are lacking. Even though excitation/inhibition (E/I) imbalance has been suggested as an underlying mechanism of ASD, few studies have investigated the actual ratio of glutamate (Glu) to γ-aminobutyric acid (GABA) concentration in vivo. Moreover, there are controversies in the directions of E/I ratio alterations even in extensively studied ASD animal models. Here, using proton magnetic resonance spectroscopy ((1)H-MRS) at 9.4T, we found significant differences in the levels of different metabolites or their ratios in the prefrontal cortex and hippocampus of Cntnap2(-/-) mice compared to their wild-type littermates. The Glu/GABA ratio, N-acetylaspartate (NAA)/total creatine (tCr) ratio, and tCr level in the prefrontal cortex were significantly different in Cntnap2(-/-) mice compared to those in wild-type mice, and they significantly correlated with the sociability of mice. Moreover, receiver operating characteristic (ROC) analyses indicated high specificity and selectivity of these metabolites in discriminating genotypes. These results suggest that the lowered Glu/GABA ratio in the prefrontal cortex along with the changes in the other metabolites might contribute to the social behavior deficit in Cntnap2(-/-) mice. Our results also demonstrate the utility of (1)H-MRS in investigating the underlying mechanisms or the diagnosis of ASD.

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6. Talukder NT, Feezel A, Lankford JE. Mild encephalitis/encephalopathy with a reversible splenial lesion associated with systemic Mycoplasma pneumoniae infection in North America: a case report. Journal of medical case reports. 2022; 16(1): 74.

BACKGROUND: Mild encephalitis/encephalopathy with reversible splenial lesion is a clinical-radiological entity found to occur in the setting of an acute systemic inflammatory state with isolated lesions of the splenium of the corpus callosum and mild encephalopathy. Mild encephalitis/encephalopathy with reversible splenial lesion is commonly found to occur in children in the setting of viral infections. It has rarely been associated with Mycoplasma pneumoniae in the United States, unlike in Eastern and Southern Asia where this is much more prominent. CASE PRESENTATIONS: A 5-year-old African-American boy with autism spectrum disorder presented to our emergency department with acute onset intractable vomiting, diarrhea, and abnormal tensing movements for 2 days, following a 6-day period of fatigue, fever, and spastic abdominal pain. Emergent work-up in our department ruled out acute gastrointestinal pathologies. Given the high fevers and encephalopathy, there was concern for meningitis or encephalitis. His cerebrospinal fluid profile was concerning for viral meningitis, however extensive infectious workup was negative. Magnetic resonance imaging of his brain demonstrated a T2 fluid-attenuated inversion recovery sequence hyperintensity in the splenium of the corpus callosum, read as postictal changes by radiology. Continuous video electroencephalography demonstrated mild diffuse encephalopathy without electrographic correlate of his tensing episodes. He was determined to have mild encephalitis/encephalopathy with a reversible splenial lesion in the setting of a postinfectious etiology. He was treated with a single pulse-dose of intravenous methylprednisolone, following which he gradually returned to his baseline the next day. Repeat magnetic resonance imaging and cerebrospinal fluid evaluation demonstrated resolution of previous findings. He was ultimately diagnosed with an acute M. pneumoniae infection, which was determined to be the etiology of his mild encephalitis/encephalopathy with a reversible splenial lesion. CONCLUSIONS: The presentation of mild encephalitis/encephalopathy with a reversible splenial lesion is often nonspecific, with behavioral symptoms ranging from irritability to disturbances in consciousness. Its prevalence is higher in the pediatric population, and is thought to be more of an infection-associated encephalopathy syndrome in this group. The infections are typically viral, more so than bacterial. M. pneumoniae, a small, atypical bacterium lacking a peptidoglycan cell wall, is a common respiratory tract pathogen found in children. Despite infection being so rampant in the pediatric community, very few cases of M. pneumoniae-associated mild encephalitis/encephalopathy with a reversible splenial lesion in the United States have been reported. In Eastern and Southern Asian countries, however, M. pneumoniae-associated mild encephalitis/encephalopathy with a reversible splenial lesion is much more commonly reported. This difference may potentially lie in the prevalence of macrolide-resistant M. pneumoniae, which is significantly higher in Asian countries given more liberal antibiotic use in M. pneumoniae infections. Infections with macrolide-resistant M. pneumoniae are reportedly greater in severity and duration. This amplified state may suggest a correlation between intensity of inflammatory response and the development of mild encephalitis/encephalopathy with a reversible splenial lesion. Given the rarity of M. pneumoniae-associated mild encephalitis/encephalopathy with a reversible splenial lesion in the United States, much remains unknown regarding predilection and optimum treatment strategy. As rates of macrolide-resistant M. pneumoniae begin to rise in the United States, maintaining a high level of suspicion remains key in better understanding this unique phenomenon.

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