Autism with Epilepsy: A Neuropsychopharmacology Update.

The association between autism spectrum disorders (ASD) and epilepsy has been extensively documented, and the estimated prevalence varies depending upon the selected population and the clinical characteristics. Currently, there are a lack of studies assessing the patient care pathways in ASD, particularly for comorbidity with epilepsy, despite its personal, familial, and economic impacts. Genetic abnormalities are likely implicated in the association of ASD and epilepsy, although they are currently detectable in only a small percentage of patients, and some known genetic and medical conditions are associated with ASD and epilepsy. There is no specificity of seizure type to be expected in children and adolescents with ASD compared with other neurodevelopmental disorders or epileptic syndromes. Treatment options include antiepileptic drugs (AED) and developmentally-based early interventions for ASD. Carbamazepine and lamotrigine are the most used AED, but further studies are needed to more precisely define the most suitable medications for this specific group of children with ASD.

Natural history of KBG syndrome in a large European cohort.

KBG syndrome (KBGS) is characterized by distinctive facial gestalt, short stature and variable clinical findings. With ageing, some features become more recognizable, allowing a differential diagnosis. We aimed to better characterize natural history of KBGS. In the context of a European collaborative study, we collected the largest cohort of KBGS patients (49). A combined array- based Comparative Genomic Hybridization and next generation sequencing (NGS) approach investigated both genomic Copy Number Variants and SNVs. Intellectual disability (ID) (82%) ranged from mild to moderate with severe ID identified in two patients. Epilepsy was present in 26.5%. Short stature was consistent over time, while occipitofrontal circumference (median value: -0.88 SD at birth) normalized over years. Cerebral anomalies, were identified in 56% of patients and thus represented the second most relevant clinical feature reinforcing clinical suspicion in the paediatric age when short stature and vertebral/dental anomalies are vague. Macrodontia, oligodontia and dental agenesis (53%) were almost as frequent as skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age. In 28.5% of individuals, prenatal ultrasound anomalies were reported. Except for three splicing variants, leading to a premature termination, variants were almost all frameshift. Our results, broadening the spectrum of KBGS phenotype progression, provide useful tools to facilitate differential diagnosis and improve clinical management. We suggest to consider a wider range of dental anomalies before excluding diagnosis and to perform a careful odontoiatric/ear-nose-throat (ENT) evaluation in order to look for even submucosal palate cleft given the high percentage of palate abnormalities. NGS approaches, following evidence of antenatal ultrasound anomalies, should include ANKRD11.

Breathing Abnormalities During Sleep and Wakefulness in Rett Syndrome: Clinical Relevance and Paradoxical Relationship With Circulating Pro-oxidant Markers.

Background: Breathing abnormalities are common in Rett syndrome (RTT), a pervasive neurodevelopmental disorder almost exclusively affecting females. RTT is linked to mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. Our aim was to assess the clinical relevance of apneas during sleep-wakefulness cycle in a population with RTT and the possible impact of apneas on circulating oxidative stress markers. Methods: Female patients with a clinical diagnosis of typical RTT (n = 66), MECP2 gene mutation, and apneas were enrolled (mean age: 12.5 years). Baseline clinical severity, arterial blood gas analysis, and red blood cell count were assessed. Breathing was monitored during the wakefulness and sleep states (average recording time: 13 ± 0.5 h) with a portable polygraphic screening device. According to prevalence of breath holdings, the population was categorized into the wakefulness apnea (WA) and sleep apnea (SA) groups, and apnea-hypopnea index (AHI) was calculated. The impact of respiratory events on oxidative stress was assessed by plasma and intra-erythrocyte non-protein-bound iron (P-NPBI and IE-NPBI, respectively), and plasma F2-isoprostane (F2-IsoP) assays. Results: Significant prevalence of obstructive apneas with values of AHI > 15 was present in 69.7% of the population with RTT. The group with SA showed significantly increased AHI values > 15 (p = 0.0032), total breath holding episodes (p = 0.007), and average SpO2 (p = 0.0001) as well as lower nadir SpO2 (p = 0.0004) compared with the patients with WAs. The subgroups of patients with WA and SA showed no significant differences in arterial blood gas analysis variables (p > 0.089). Decreased mean cell hemoglobin (MCH) (p = 0.038) was observed in the group with WAs. P-NPBI levels were significantly higher in the group with WA than in that with SAs (p = 0.0001). Stepwise multiple linear regression models showed WA being related to nadir SpO2, average SpO2, and P-NPBI (adjusted R 2 = 0.613, multiple correlation coefficient = 0.795 p < 0.0001), and P-NPBI being related to average SpO2, blood PaCO2, red blood cell mean corpuscular volume (MCV), age, and topiramate treatment (adjusted R 2 = 0.551, multiple correlation coefficient = 0.765, p < 0.0001). Conclusion: Our findings indicate that the impact of apneas in RTT is uneven according to the sleep-wakefulness cycle, and that plasma redox active iron represents a potential novel therapeutic target.

Identification of a Novel SHANK2 Pathogenic Variant in a Patient with a Neurodevelopmental Disorder.

Genetic defects in the SHANK2 gene, encoding for synaptic scaffolding protein, are associated with a variety of neurodevelopmental conditions, including autism spectrum disorders and mild to moderate intellectual disability. Until now, limited patient clinical descriptions have been published. Only 13 unrelated patients with SHANK2 pathogenic variations or microdeletions have been reported worldwide. By Exome Sequencing, we identified a de novo stop-gain variant, c.334C>T, p.(Gln112*), in an Italian patient with a neurodevelopmental disorder. The patient (9 years old) presented the following facial features: a flat profile, thick eyebrows, long eyelashes, a bulbous nasal tip and a prominent columella, retracted ears, dental anomalies. The patient showed speech delay and mild neuromotor delay but not autism spectrum disorder. In conclusion, this patient with a novel pathogenic variant in SHANK2 enlarges the phenotypic spectrum of SHANK2-mutated patients and demonstrates that the severity of SHANK2-associated disorders is highly variable.

Neurodevelopmental Disorders and Adaptive Functions: A Study of Children With Autism Spectrum Disorders (ASD) and/or Attention Deficit and Hyperactivity Disorder (ADHD).

Introduction: Autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder (ADHD) are the two most common neurodevelopmental disorders observed in childhood. The DSM-5 accepts a combined diagnosis of ADHD and ASD, while the DSM-IV did not. The aim of this study was to identify and evaluate the adaptive profile of children and adolescents with a diagnosis of comorbid ADHD and ASD, in comparison with adaptive functioning in subjects with a diagnosis of only ASD or ADHD. Materials and Methods: Ninety-one children (77 boys, 14 girls), aging from 3.1 to 13.4 years (mean age: 8.3 ± 7.2), who met the criteria for a diagnosis of ASD and/or ADHD were enrolled. A neuropsychological evaluation involving cognitive and adaptive assessment was conducted using the Autism Diagnostic Observation Schedule - Second Edition (ADOS-2), the Conners' Parent Rating Scale - Revised: Long Version (CPRS-R), the Wechsler Intelligence Scale - Fourth Edition or the Griffiths Mental Developmental Scales - Extended Revised, the Vineland Adaptive Behaviour Scale - Second Edition (VABS-II). Conclusion: As to the adaptive skills in the three groups evaluated, a worse general profile was ascertained in the ASD and in ASD plus ADHD groups in comparison with respect to the ADHD-only group. With VABS-II evaluation, we found significant differences among the three groups across all domains and combined scores: Communication (F = 18.960; p < 0.001), Socialization (F = 25.410; p < 0.001), Daily Living Skills (F = 19.760; p < 0.001), Motor (F = 9.615; p < 0.001), and Adaptive behavior composite [ABC] (F = 29.370; p < 0.001). Implications of neurodevelopmental double diagnosis such as ASD plus ADHD are discussed.

Exploring Self-Consciousness From Self- and Other-Image Recognition in the Mirror: Concepts and Evaluation.

A historical review of the concepts of self-consciousness is presented, highlighting the important role of the body (particularly, body perception but also body action), and the social other in the construction of self-consciousness. More precisely, body perception, especially intermodal sensory perception including kinesthetic perception, is involved in the construction of a sense of self allowing self-other differentiation. Furthermore, the social other, through very early social and emotional interactions, provides meaning to the infant's perception and contributes to the development of his/her symbolization capacities. This is a necessary condition for body image representation and awareness of a permanent self in a time-space continuum (invariant over time and space). Self-image recognition impairments in the mirror are also discussed regarding a comprehensive developmental theory of self-consciousness. Then, a neuropsychological and neurophysiological approach to self-consciousness reviews the role of complex brain activation/integration pathways and the mirror neuron system in self-consciousness. Finally, this article offers new perspectives on self-consciousness evaluation using a double mirror paradigm to study self- and other- image and body recognition.

22q11 deletion syndrome and multiple complex developmental disorder: a case report.

22q11.2 Deletion Syndrome (22q11 DS) is a multisystemic condition that may also include neuropsychiatric disorders. We present a case of a 15-year-old boy that was evaluated for social difficulties, and anxiety with the above genetic abnormality. Clinical features were rather complex as different neuropsychiatric symptoms emerged from assessment and clinical evaluation. As a result we propose that Multiple Complex Developmental Disorder (MCDD) would be the best fitting comprehensive diagnosis to be added to the DSM-IV category of Pervasive Developmental Disorder-Not Otherwise Specified.

372 kb microdeletion in 18q12.3 causing SETBP1 haploinsufficiency associated with mild mental retardation and expressive speech impairment.

Several cases of interstitial deletion encompassing band 18q12.3 are described in patients with mild dysmorphic features, mental retardation and impairment of expressive language. The critical deleted region contains SETBP1 gene (SET binding protein 1). Missense heterozygous mutations in this gene cause Schinzel-Giedion syndrome (SGS, MIM#269150), characterized by profound mental retardation and multiple congenital malformations. Recently, a 18q12.3 microdeletion causing SETBP1 haploinsufficiency has been described in two patients that show expressive speech impairment, moderate developmental delay and peculiar facial features. The phenotype of individual with partial chromosome 18q deletions does not resemble SGS. The deletion defines a critical region in which SETBP1 is the major candidate gene for expressive speech defect. We describe an additional patient with the smallest 18q12.3 microdeletion never reported that causes the disruption of SETBP1. The patient shows mild mental retardation and expressive speech impairment with striking discrepancy between expressive and receptive language skills. He is able to communicate using gestures and mimic expression of face and body with surprising efficacy. The significant phenotypic overlap between this patient and the cases previously reported enforce the hypothesis that SETBP1 haploinsufficiency may have a role in expressive language development.

Nicolaides-Baraitser syndrome: two new cases with autism spectrum disorder.

Nicolaides-Baraitser syndrome is a rare clinical condition characterized by mental retardation with impairment of expressive language, short stature, microcephaly, sparse hair, typical facial dysmorphisms, and interphalangeal joint swellings. To date 24 cases have been reported, most of them being sporadic. The genetic background of Nicolaides-Baraitser syndrome is unclear in terms of cause and mode of inheritance, one of the more probable explanations is de novo mutation of a dominant gene. Some reported patients presented autistic features, although in none of these patients was the diagnosis of autism spectrum disorder formally made. We describe two unrelated patients with clinical features suggesting Nicolaides-Baraitser syndrome and, in addition, autism spectrum disorder is defined by the presence of the three cardinal core features: qualitative impairments in social, communicative, and behavioral development.

Psychopharmacology in autism: an update.

Autism spectrum disorders are characterized by impairment in social reciprocity, disturbances in language and communication, restricted interests and repetitive behaviors of various types, as defined by the DSM-IV. The neurobiological bases of these disorders are poorly understood, although several abnormalities have been found. Pharmacotherapy in autism spectrum disorders lacks a solid, reliable neurobiological basis and at present it is mainly directed at the so-called associated behavioral symptoms, with limited relevance to core symptoms. Atypical neuroleptics, especially risperidone, have been shown to be useful in the treatment of behavioral symptoms in autism. Recent trials with SSRIs did not show remarkable results, in spite of their promising potential role. Attention deficit and hyperactivity disorder medications may be useful for counteracting the additional features of hyperactivity and short attention span. Antiepileptics have shown promising results but there are no specific indications for them as of yet. Research is now directed at evaluating novel treatments and combined behavioral and pharmacologic treatments, since behavioral interventions are the mainstay of the early treatment of autism. An update of currently available pharmacological treatments is provided.

Risperidone in the treatment of behavioral disorders associated with autism in children and adolescents.

This is a review of the clinical trials investigating the efficacy and safety of risperidone in the treatment of children with autistic spectrum disorders (ASD). The main clinical characteristics are impairment in social skills, communication difficulties, repetitive movements and behaviors, including stereotypies. Pharmacotherapy is mainly directed at the so-called target symptoms, ie, behavioral disorders and the various kinds of repetitions associated with ASD. According to the available data, risperidone seems to be moderately efficacious and safe for treating behavioral disorders. 4 double blind controlled trial. 3 reanalysis studies, and 12 open studies have documented the role of risperidone in children with ASD. Controlled studies have been thoroughly considered in this review.