Early Motor Signs in Autism Spectrum Disorder.

A growing number of literature data suggest the presence of early impairments in the motor development of children with autism spectrum disorder, which could be often recognized even before the appearance of the classical social communication deficits of autism. In this narrative review, we aimed at performing an update about the available data on the early motor function in children with autism spectrum disorder. Early motor impairment in these children can manifest itself both as a mere delay of motor development and as the presence of atypicalities of motor function, such as a higher rate and a larger inventory, of stereotyped movements both with and without objects. In the perspective of a timely diagnosis, the presence of early motor signs can be an important clue, especially in an individual considered at high risk for autism. Motor and communication (both verbal and non-verbal) skills are connected and a pathogenetic role of early motor dysfunctions in the development of autism can be hypothesized. From this, derives the importance of an early enabling intervention aimed at improving motor skills, which could also have favorable effects on other aspects of development

Advanced glycation endproducts, dityrosine and arginine transporter dysfunction in autism - a source of biomarkers for clinical diagnosis.

Background: Clinical chemistry tests for autism spectrum disorder (ASD) are currently unavailable. The aim of this study was to explore the diagnostic utility of proteotoxic biomarkers in plasma and urine, plasma protein glycation, oxidation, and nitration adducts, and related glycated, oxidized, and nitrated amino acids (free adducts), for the clinical diagnosis of ASD. Methods: Thirty-eight children with ASD (29 male, 9 female; age 7.6 \ub1 2.0 years) and 31 age-matched healthy controls (23 males, 8 females; 8.6 \ub1 2.0 years) were recruited for this study. Plasma protein glycation, oxidation, and nitration adducts and amino acid metabolome in plasma and urine were determined by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. Machine learning methods were then employed to explore and optimize combinations of analyte data for ASD diagnosis. Results: We found that children with ASD had increased advanced glycation endproducts (AGEs), N\u3b5-carboxymethyllysine (CML) and N\u3c9-carboxymethylarginine (CMA), and increased oxidation damage marker, dityrosine (DT), in plasma protein, with respect to healthy controls. We also found that children with ASD had increased CMA free adduct in plasma ultrafiltrate and increased urinary excretion of oxidation free adducts, alpha-aminoadipic semialdehyde and glutamic semialdehyde. From study of renal handling of amino acids, we found that children with ASD had decreased renal clearance of arginine and CMA with respect to healthy controls. Algorithms to discriminate between ASD and healthy controls gave strong diagnostic performance with features: plasma protein AGEs\u2014CML, CMA\u2014and 3-deoxyglucosonederived hydroimidazolone, and oxidative damage marker, DT. The sensitivity, specificity, and receiver operating characteristic area-under-the-curve were 92%, 84%, and 0.94, respectively. Conclusions: Changes in plasma AGEs were likely indicative of dysfunctional metabolism of dicarbonyl metabolite precursors of AGEs, glyoxal and 3-deoxyglucosone. DT is formed enzymatically by dual oxidase (DUOX); selective increase of DT as an oxidative damage marker implicates increased DUOX activity in ASD possibly linked to impaired gutmucosal immunity. Decreased renal clearance of arginine and CMA in ASD is indicative of increased arginine transporter activity which may be a surrogate marker of disturbance of neuronal availability of amino acids. Data driven combination of these biomarkers perturbed by proteotoxic stress, plasma protein AGEs and DT, gave diagnostic algorithms of high sensitivity and specificity for ASD

Brain magnetic resonance findings in 117 children with autism spectrum disorder under 5 years old.

We examined the potential benefits of neuroimaging measurements across the first 5 years of life in detecting early comorbid or etiological signs of autism spectrum disorder (ASD). In particular, we analyzed the prevalence of neuroradiologic findings in routine magnetic resonance imaging (MRI) scans of a group of 117 ASD children younger than 5 years old. These data were compared to those reported in typically developing (TD) children. MRI findings in children with ASD were analyzed in relation to their cognitive level, severity of autistic symptoms, and the presence of electroencephalogram (EEG) abnormalities. The MRI was rated abnormal in 55% of children with ASD with a significant prevalence in the high-functioning subgroup compared to TD children. We report significant incidental findings of mega cisterna magna, ventricular anomalies and abnormal white matter signal intensity in ASD without significant associations between these MRI findings and EEG features. Based on these results we discuss the role that brain MRI may play in the diagnostic procedure of ASD

Contribution of CACNA1H Variants in Autism Spectrum Disorder Susceptibility

Autism Spectrum Disorder (ASD) is a highly heterogeneous neuropsychiatric disorder with a strong genetic component. The genetic architecture is complex, consisting of a combination of common low-risk and more penetrant rare variants. Voltage-gated calcium channels (VGCCs or Cav) genes have been implicated as high-confidence susceptibility genes for ASD, in accordance with the relevant role of calcium signaling in neuronal function. In order to further investigate the involvement of VGCCs rare variants in ASD susceptibility, we performed whole genome sequencing analysis in a cohort of 105 families, composed of 124 ASD individuals, 210 parents and 58 unaffected siblings. We identified 53 rare inherited damaging variants in Cav genes, including genes coding for the principal subunit and genes coding for the auxiliary subunits, in 40 ASD families. Interestingly, biallelic rare damaging missense variants were detected in the CACNA1H gene, coding for the T-type Cav3.2 channel, in ASD probands from two different families. Thus, to clarify the role of these CACNA1H variants on calcium channel activity we performed electrophysiological analysis using whole-cell patch clamp technology. Three out of four tested variants were shown to mildly affect Cav3.2 channel current density and activation properties, possibly leading to a dysregulation of intracellular Ca2+ ions homeostasis, thus altering calcium-dependent neuronal processes and contributing to ASD etiology in these families. Our results provide further support for the role of CACNA1H in neurodevelopmental disorders and suggest that rare CACNA1H variants may be involved in ASD development, providing a high-risk genetic background

Neuro-Behavioral Phenotype in 16p11.2 Duplication: A Case Series

Duplications of chromosome 16p11.2, even though rare in the general population, are one of the most frequent known genetic causes of autism spectrum disorder and of other neurodevelopmental disorders. However, data about the neuro-behavioral phenotype of these patients are few. We described a sample of children with duplication of chromosome 16p11.2 focusing on the neuro-behavioral phenotype. The five patients reported presented with very heterogeneous conditions as for characteristics and severity, ranging from a learning disorder in a child with normal intelligence quotient to an autism spectrum disorder associated with an intellectual disability. Our case report underlines the wide heterogeneity of the neuropsychiatric phenotypes associated with a duplication of chromosome 16p11.2. Similarly to other copy number variations that are considered pathogenic, the wide variability of phenotype of chromosome 16p11.2 duplication is probably related to additional risk factors, both genetic and not genetic, often difficult to identify and most likely different from case to case

Relationships between continuous spike-waves during sleep (CSWS) are related to antiepileptic drug resistance

Background and aims: The spectrum of neuropsychiatric disorders associated with continuous spike-waves during slow wave sleep (CSWS) syndromes is widely debated. Although seizures and CSWS disappear within puberty, heterogeneous neuropsychological and behavioural disorders can persist. This feature has increased the interest in etiopathogenesis and negative prognostic factors of these conditions. Delayed diagnosis and appropriate therapy, the high frequency, generalization, early onset, prolonged duration and drug resistance of EEG paroxysmal abnormalities are all unfavourable prognostic factors for neuropsychological and behavioural evolution. Pre-existing cerebral lesions, in some cases, may aggravate the prognosis. Case reports: We describe five patients with drug resistant CSWS presenting different clinical-EEG features. One of them had a typical picture of CSWS with paroxysmal abnormalities occupying more than 85% of N-REM sleep EEG recording (case 4); another had a classical Landau Kleffner Syndrome (LKS) (case 5). All cases presented CSWS resistant to several antiepileptic drugs; the localization of prevailing EEG paroxysmal abnormalities showed a good relation with neuropsychological findings, irrespective of IQ. All patients except case 1 presented IQ regression, with a significant gap between VIQ and PIQ to the detriment of the PIQ for cases 2, 3 and 4 and of VIQ for case 5 with LKS. IQ improved in cases 2 and 4 even if a gap remained to the detriment of PIQ in case 2. Cases 3 and 5 improved after CSWS disappearance even though both had a borderline FIQ at the last observation. Behavioural problems were present in all cases except the first, improving after CSWS fragmentation. Seizures occurred in all patients except case 3 representing the first symptom, but they generally disappeared before CSWS fragmentation. Cerebral lesions were present in cases 2 and 4 but did not seem to be responsible for CSWS evolution. Conclusion: It is necessary to be aware that CSWS can develop and that early diagnosis is very important to start an antiepileptic treatment. Further studies with a large sample and homogeneous EEG criteria are required to better characterize the enigma of CSWS

Unusual phenotype of glucose transport protein type 1 deficiency syndrome: A case report and literature review.

The glucose transport protein type 1 (GLUT1) deficit causes a chronic brain energy failure. The classic phenotype of GLUT1 deficiency syndrome is characterized by: Mild to severe motor delay and mental retardation; infantile-onset epilepsy; head growth deceleration; movement disorders (ataxia, dystonia, spasticity); and non-epileptic paroxysmal events (intermittent ataxia, periodic confusion, recurrent headaches). During last years the classic phenotype of this syndrome, as originally reported, has expanded. We report the atypical phenotype of a boy with GLUT1 deficiency syndrome, characterized by mild mental retardation and drug-resistant absence seizures with onset at the age of 6 years, without movement disorders nor decrease of head circumference. A prompt diagnosis of this disorder is mandatory since the ketogenic diet might represent an effective treatment