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Congenital disorders of glycosylation (CDG) are a group of rare genetic diseases caused by the deficiency of enzymes involved in the biosynthesis or remodeling of the glycan moieties of glycoconjugates. Most of CDG are autosomal recessive; however, few of them show autosomal dominant or X-linked inheritance. ALG12-CDG is an autosomal recessive inherited defect caused by a deficiency in the α-mannosyltransferase, dolichyl-P-mannose: Man7-GlcNAc-2-PP-dolichyl-alpha-6-mannosyltransferase (mannosyltransferase 8), which determines Man7GlcNAc2-PP-dolichol accumulation in tissues including fibroblasts. The clinical features of ALG12-CDG include dysmorphic features, developmental delay, hypotonia, progressive microcephaly, hypogammaglobulinemia, coagulopathies, and failure to thrive. Herein, we describe the case of a Sicilian patient with a milder phenotype bearing an ALG12 homozygous mutation. To date, including this patient, only 16 cases have been described with this form of CDG. Furthermore, our study contributes to understanding the milder ALG12-CDG cases and to further expanding the genotype-phenotype spectrum.

To date, the phenotypic significance of EEG abnormalities in patients with ASD is unclear. In a population affected by ASD we aimed to evaluate: the phenotypic characteristics; the prevalence of EEG abnormalities; the potential correlations between EEG abnormalities and behavioral and cognitive variables. Sixty-nine patients with ASD underwent cognitive or developmental testing, language assessment, and adaptive behavior skills evaluation as well as sleep/wake EEG recording. EEG abnormalities were found in 39.13% of patients. EEG abnormalities correlated with autism severity, hyperactivity, anger outbursts, aggression, negative or destructive behavior, motor stereotypies, intellectual disability, language impairment and self-harm. Our findings confirmed that EEG abnormalities are present in the ASD population and correlate with several associated phenotypic features.

Hereditary spastic paraplegias are clinically and genetically heterogeneous degenerative disorders, and pathological variants in the autosomal recessive ZFYVE26 gene are considered as very rare causes. We describe a novel mutation in ZFYVE26 gene found in a patient with autosomal recessive spastic paraplegias. The use of a 'target-gene' approach allowed us to expand the clinical spectrum associated with hereditary spastic paraplegias.

Fragile X syndrome (FXS) is a common form of intellectual disability and autism caused by the lack of Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein involved in RNA transport and protein synthesis. Upon cellular stress, global protein synthesis is blocked and mRNAs are recruited into stress granules (SGs), together with RNA-binding proteins including FMRP. Activation of group-I metabotropic glutamate (mGlu) receptors stimulates FMRP-mediated mRNA transport and protein synthesis, but their role in SGs formation is unexplored. To this aim, we pre-treated wild type (WT) and Fmr1 knockout (KO) cultured astrocytes with the group-I-mGlu receptor agonist (S)-3,5-Dihydroxyphenylglycine (DHPG) and exposed them to sodium arsenite (NaAsO2), a widely used inducer of SGs formation. In WT cultures the activation of group-I mGlu receptors reduced SGs formation and recruitment of FMRP into SGs, and also attenuated phosphorylation of eIF2α, a key event crucially involved in SGs formation and inhibition of protein synthesis. In contrast, Fmr1 KO astrocytes, which exhibited a lower number of SGs than WT astrocytes, did not respond to agonist stimulation. Interestingly, the mGlu5 receptor negative allosteric modulator (NAM) 2-methyl-6-(phenylethynyl)pyridine (MPEP) antagonized DHPG-mediated SGs reduction in WT and reversed SGs formation in Fmr1 KO cultures. Our findings reveal a novel function of mGlu5 receptor as modulator of SGs formation and open new perspectives for understanding cellular response to stress in FXS pathophysiology.

Niemann-Pick disease type C (NPC) is a progressive lysosomal storage disorder caused by mutations in the

Niemann-Pick disease type C (NPC) is a progressive lysosomal storage disorder caused by mutations in the NPC1 (in 95% of cases) or NPC2 (in ~5% of cases) genes, inherited in an autosomal recessive manner. We report the case of a 38-year-old woman with learning disorder from her first year of schooling, and could notice slow progressed cognitive impairment, social withdrawal, apathy, handwriting alterations, deterioration of language skills and dysphagia. Brain magnetic resonance imaging showed severe cerebellar atrophy, hypoplasia of the corpus callosum, asymmetric lateral ventricular enlargement, and severe enlargement of frontal and parietal subarachnoid spaces. Next generation sequencing for NPC genes (NPC1 and NPC2) detected compound heterozygous mutations in NPC1 gene, including c.1553G[A (p.Arg518Gln), paternally inherited, and c.1270C[T (p.Pro424Ser) maternally inherited. The first mutation has been already described in literature and correlated to NPC, while the second mutation is still unknown. Moreover, filipin test and quantification of plasma oxysterols confirmed NPC diagnosis. We can suggest the missense mutation c.1270C[T (p.Pro424Ser) as a new causative mutation of NPC.

Antipsychotics (APDs) represent the main pharmacological strategy in the treatment of schizophrenia, however, their administration often may result in severe adverse effects, such as extrapyramidal symptoms. Typically, dystonic movements are considered the result of impaired function and/or abnormalities of dopaminergic neurotransmission/signaling in the basal ganglia. The catechol O-methyltransferase (COMT) gene is located within the 22q11.2 region, and its product is an enzyme involved in transferring a methyl group from S-adenosylmethionine to catecholamines, including dopamine. Studies showed that COMT Val158Met polymorphism modifies enzymatic activity and, consequently, synaptic dopamine concentration in specific brain areas. We identified a patient with 22q11.2 deletion syndrome presenting with cervical and trunk dystonia after paliperidone administration, which persisted even after drug discontinuation. Given the patient’s genetic condition, we hypothesized that the dopaminergic dysfunction had been aggravated by COMT involvement, thus causing dystonia. In line with this hypothesis, we carried out a study on psychiatric patients in chronic treatment with APD to evaluate the distribution of the COMT Val158Met polymorphism and its role in the onset of adverse extrapyramidal symptoms. The study included four patients with dystonia after administration of APDs compared to 17 patients who never presented adverse drug reactions. Our data suggest that the Val/Val and Met/Met polymorphisms of the COMT gene are associated with a protective effect for the development of collateral extrapyramidal symptoms in patients treated with APDs, while the Val/Met genotype could be considered a risk factor for the development of dystonia after APDs administration.

Periventricular nodular heterotopia (PNH) is a brain malformation in which nodules of neurons are ectopically retained along the lateral ventricles. Genetic causes include FLNA abnormalities (classical X-linked PNH), rare variants in ARFGEF2, DCHS1, ERMARD, FAT4, INTS8, MAP1B, MCPH1, and NEDD4L, as well as several chromosomal abnormalities. We performed array-CGH in 106 patients with different malformations of cortical development (MCD) and looked for common pathways possibly involved in PNH. Forty-two patients, including two parent/proband couples, exhibited PNH associated or not with other brain abnormalities, 44 had polymicrogyria and 20 had rarer MCDs. We found an enrichment of either large rearrangements or cryptic copy number variants (CNVs) in PNH (15/42, 35.7%) vs polymicrogyria (4/44, 9.1%) (i.e., 5.6 times increased risk for PNH of carrying a pathogenic CNV). CNVs in seven genomic regions (2p11.2q12.1, 4p15, 14q11.2q12, 16p13.3, 19q13.33, 20q13.33, 22q11) represented novel, potentially causative, associations with PNH. Through in silico analysis of genes included in imbalances whose breakpoints were clearly detailed, we detected in 9/12 unrelated patients in our series and in 15/24 previously published patients, a significant (P

Hereditary spastic paraplegias are clinically and genetically heterogeneous degenerative disorders, and pathological variants in the autosomal recessive

Activation of group-I metabotropic glutamate receptors, mGlu1 and mGlu5, triggers a variety of signalling pathways in neurons and glial cells, which are differently implicated in synaptic plasticity. The earliest and much of key studies discovered abnormal mGlu5 receptor function in Fragile X syndrome (FXS) mouse models which then motivated more recent work that finds mGlu5 receptor dysfunction in related disorders such as intellectual disability (ID), obsessive-compulsive disorder (OCD) and autism. Therefore, mGlu1/5 receptor dysfunction may represent a common aetiology of these complex diseases. Furthermore, many studies have focused on dysregulation of mGlu5 signalling to synaptic protein synthesis. However, emerging evidence finds abnormal mGlu5 receptor interactions with its scaffolding proteins in FXS which results in mGlu5 receptor dysfunction and phenotypes independent of signalling to protein synthesis. Finally, both an increased and reduced mGlu5 functioning seem to be associated with ID and autism spectrum disorders, with important consequences for potential treatment of these developmental disorders.

Typical Xq25 duplications are large and associated with heterogeneous phenotypes. Recently, small duplications involving this genomic region and encompassing the GRIA3 and STAG2 genes have been reported. These Xq25 microduplications are associated with a recognizable syndrome including intellectual disability and distinctive facial appearance. We report on Xq25 microduplications in two unrelated families identified by array comparative genomic hybridization. In both families, the genomic imbalances segregated with the disease in male individuals, while the phenotypes of the heterozygous females appeared to be modulated by their X-inactivation pattern. These rearrangements of about 600 kb involved only three genes: THOC2, XIAP, and STAG2. Further characterization by FISH analyses showed tandem duplication in the Xq25 locus of these genes. These data refine the Xq25 candidate region, identifying a minimal duplicated region of about 270 kb encompassing the XIAP and STAG2 genes. We discuss the function of the genes in the rearrangements and their involvement in the pathogenesis of this disorder.

Spinal muscular atrophy (SMA) is an autosomal-recessive neuromuscular disorder characterized by motor neuron degeneration in the anterior horn of the spinal cord and brain stem, resulting in progressive muscle weakness and atrophy. The responsible survival motor neuron gene (SMN1; HGNC: 11117) is localized in 5q11.2-13.3. Screening for carriers of SMA is necessary for effective clinical/prenatal diagnosis and genetic counselling. In this study, the copy number of SMN1 gene was determined from a southern Italian population to estimate carrier frequency. This is the first report addressing the estimation of SMA carrier frequency in an Italian population. Our results show that the SMA carrier frequency in Sicily is higher than in the European populations and lower than in Mediterranean/Middle Eastern countries. The carrier testing could be a helpful tool for genetic counselling, to individuals with a positive family history. SMA is the second most common severe autosomalrecessive disorder after cystic fibrosis and the most frequent genetic cause of infant mortality, with an incidence of one per 6000–10,000 live births (Pearn 1980). Mutations in the survival motor neuron gene (SMN1; HGNC: 11117), localized in 5q11.2-13.3 within a large inverted duplicated element, cause SMA types I, II, III and IV (Lefebvre et al. 1995). Further, between 95% and 98% of individuals with recessive SMA have two deletion mutations (deletion of exons 7–8) and the remaining 2–5% have one deletion mutation (exons 7–8) and a second, different type of mutation (Ogino and Wilson 2002). People generally have between one and three copies of the SMN1 gene. Usually, people with two copies

The Fmr1 knockout (KO) mouse is characterized by an increased audiogenic seizure (AGS) susceptibility and is considered a good animal model for epilepsy and seizures in the human fragile-X (FRAX) syndrome. Here, we tested the hypothesis that the reintroduction of the FMR1 gene is able to revert the AGS susceptibility characterizing Fmr1 KO mice. To this aim, two groups of Fmr1 KO transgenic mice, which have additional copies of the human FMR1 gene (YAC) or FMR1 cDNA (G6) were used. AGS susceptibility of these mice was examined and compared to that of Fmr1 KO, wild type, and wild-type animals in whom the FMR1gene was also introduced (over-expressed). Mice were tested at different ages because AGS susceptibility is age dependent. The intensity of response was scored and the results were analyzed by means of 2-way analysis of variance to evaluate the effects of age and genetic condition. We found that AGS susceptibility rescue is complete in the G6 mice and partial in YAC mice. Our data indicate that the introduction of the human FMR1 gene in Fmr1 KO mice is able to revert the Fmr1 KO epileptic phenotype.

Summary: Purpose: Mental retardation, facial dysmorphisms, and neurologic and brain abnormalities are features of 6q terminal deletions. Epilepsy is frequently associated with this chromosome abnormality, but electroclinical findings are not well delineated. We report five unrelated patients with 6q terminal deletions and a peculiar clinical, EEG, and neuroradiologic picture of epilepsy, mental retardation, and colpocephaly. Methods: These three male and two female patients underwent general and neurologic examinations, repeated awake and sleep EEGs, and brain magnetic resonance imaging (MRI). A cytogenetic study and fluorescent in situ hybridization (FISH) with chromosome-specific subtelomeric probes were carried out in all cases. Results: All subjects had seizures characterized by vomiting, cyanosis, and head and eye version, with and without loss of consciousness. In four cases, EEGs showed posterior spike-andwave complexes, which were activated by sleep. No patient had status epilepticus or prolonged seizures. Brain MRI revealed colpocephaly and dysgenesis of the corpus callosum and brainstem in four patients; three of them also had hypertrophic massa intermedia. FISH analysis revealed a 6q terminal deletion in all patients, which ranged between 9 Mb (cases 2 and 3) and 16 Mb (case 4). Conclusions: We suggest that epilepsy associated with 6q terminal deletions is a new entity. Patients with dysmorphic features associated with focal occipital epilepsy, colpocephaly, and dysgenesis of the corpus callosum, thalami, and brainstem should be considered candidates for testing for 6q subtelomere deletions. Key Words: 6q Deletion—Epilepsy—EEG— Colpocephaly—Chromosome abnormalities.

Fragile X syndrome is caused by the lack of expression of fragile X mental retardation protein (FMRP), an RNA-binding protein involved in mRNA transport and translation. FMRP is a component of mRNA ribonucleoprotein complexes and it can interact with a range of proteins either directly or indirectly, as demonstrated by two-hybrid selection and co-immunoprecipitation, respectively. Most of FMRP-interacting proteins are RNA-binding proteins such as FXR1P, FXR2P and 82-FIP. Interestingly, FMRP can also interact directly with the cytoplasmic proteins CYFIP1 and CYFIP2, which do not bind RNA and link FMRP to the RhoGTPase pathway. The interaction with these different proteins may modulate the functions of FMRP by influencing its affinity to RNA and by affecting the FMRP ability of cytoskeleton remodeling through Rho/Rac GTPases. To better define the relationship of FMRP with its interacting proteins during brain development, we have analyzed the expression pattern of FMRP and its interacting proteins in the cortex, striatum, hippocampus and cerebellum at different ages in wild type (WT) mice. FMRP and FXR2P were strongly expressed during the first week and gradually decreased thereafter, more rapidly in the cerebellum than in the cortex. FXR1P was also expressed early and showed a reduction at later stages of development with a similar developmental pattern in these two regions. CYFIP1 was expressed at all ages and peaked in the third post-natal week. In contrast, CYFIP2 and 82-FIP (only in forebrain regions) were moderately expressed at P3 and gradually increased after P7. In general, the expression pattern of each protein was similar in the regions examined, except for 82-FIP, which exhibited a strong expression at P3 and low levels at later developmental stages in the cerebellum. Our data indicate that FMRP and its interacting proteins have distinct developmental patterns of expression and suggest that FMRP may be preferentially associated to certain proteins in early and late developmental periods. In particular, the RNA-binding and cytoskeleton remodeling functions of FMRP may be differently modulated during development. (C) 2015 Elsevier Ltd. All rights reserved.

The most common form of autosomal dominant hereditary spastic paraplegia is caused by mutations in the gene encoding spastin (SPG4), a member of the AAA family of ATPases. In the current study, we designed a denaturing high-performance liquid chromatography based protocol for the analysis of the SPG4 gene. Using this method, we detected two novel missense mutations, 1375A>G (R459G) and 1378C>T (R460C), one previously described five bases deletion (1215_1219del) and three polymorphic changes. This study suggests that denaturing high-performance liquid chromatography would be a fast and reliable tool in the investigation of the molecular defects in the SPG4 gene.

OBJECTIVE: In this article we describe the course of synchronization between different EEG channels during nocturnal seizures in one patient with nocturnal frontal lobe epilepsy (NFLE).METHODS: The functional interactions between the different EEG channels during the nocturnal seizures were analyzed by means of the so-called synchronization likelihood (SL). SL is a measure of the dynamical interdependencies between a time series (EEG channel) and one or more other time series. In contrast to coherence, SL measures linear as well as non-linear interdependencies and it can do so as a function of time, making it suitable for non-stationary time series.RESULTS: The main result of our single-patient study is the demonstration of a significant hyper-synchronization during NFLE seizures in the 8-12 Hz band which seems to be stopped by an increase in synchronization in the 0.5-4 Hz band, towards the end of each ictal episode.CONCLUSIONS: We suggest that a self-inhibiting complex mechanism might be responsible for the termination of ictal episodes which might take place at the level of the cortical layers and might involve mainly pyramidal neurons.SIGNIFICANCE: This study shows that advanced EEG analysis methods can help the current understanding of ictal manifestations of NFLE.

Alterations in autonomic control of cardiac activity in epileptic patients have been reported by several studies in the past, and both ictal and interictal modifications of heart rate regulation have been described. Alterations of autonomic control of cardiac activity can play an important role in sudden unexplained death in patients with epilepsy (SUDEP). However, the presence of specific changes in heart rate variability (HRV) during sleep, not correlated with seizures, has not been assessed in children with epilepsy; for this reason, we evaluated features of cardiac autonomic function during sleep without ictal epileptiform electroencephalogram (EEG) activity in a group of children with partial epilepsy. Eleven patients (five males and six females; mean age 11.5 years, SD: 3.65 years) affected by partial epilepsy were admitted to this study; 11 normal subjects (five males and six females; mean age 12.9 years, SD: 2.72 years) served as a control group. All subjects slept in the laboratory for two consecutive nights. The data were analyzed during the second night. Sleep was polygraphically recorded [including one electrocardiography (ECG) channel] and signals were digitally stored. A series of 5-min ECG epochs were chosen from each sleep stage, during periods without evident ictal epileptiform activity in the EEG. Electrocardiography signals were analyzed for automatic detection of R-waves and, subsequently, a series of time- and frequency-domain measures were calculated. Epileptic subjects tended to show an overall lower HRV in both time- and frequency-domain parameters, principally during rapid eye movement (REM) sleep and, to a lesser extent, during sleep stage 2. Among the different bands, this decrease was most evident for the high-frequency band (HF) absolute power. For this reason, the ratio between the low-frequency band (LF) and HF was always higher in epileptic patients than in normal controls and the difference was statistically significant during sleep stages 3 and/or 4 and REM sleep. Our results indicate that during sleep, a particular condition of basal modification in autonomic characteristics occurs (mostly during REM sleep) in partial epilepsy patients. This finding might represent an important factor contributing to the complex mechanism of SUDEP which takes place most often during sleep and supports the need of studying HRV specifically during this state in subjects with seizures.

Abstract The present study analyzes the topographic distribution of two newly introduced measures related to the beta and gamma EEG bands during REM sleep. For this purpose, power spectra of three EEG channels (F4, C4, and O2, all referred to A1) were obtained by means of the fast Fourier transform, and the power of the bands ranging from 0.75-4.50 Hz (delta) and 12.50-15.00 (sigma) was calculated for the whole period of analysis (7 h) in 10 healthy subjects. Also, two additional time series - the ratio between beta and gamma2 and between gamma1 and gamma2 - were calculated (beta and gamma ratios). The difference between the mean group values of the delta and sigma bands power, and of the beta and gamma ratios, during the different sleep stages, over the three different scalp locations recorded was evaluated by means of the nonparametric Friedman ANOVA. During non-REM slow-wave sleep, the delta band showed the highest values over the central and frontal regions, followed by those observed over the occipital lead. During sleep stage 2, the sigma band showed the highest values over the central regions, followed by those observed over the occipital areas and, lastly, those from the frontal lead. During REM sleep, the beta ratio showed its highest values over the central field, which were significantly higher that those obtained from both the frontal and the occipital regions. The gamma ratio showed a statistically nonsignificant tendency to show a similar topographic distribution pattern. Sleep can be considered a complex phenomenon with a differential involvement of multiple cortical and subcortical structures. The analysis of high-frequency EEG bands and of our beta and gamma ratios represent an additional important element to include in the study of sleep.

Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.

Objective : The aim of the present study was to analyze in detail the relationship of two newly introduced measures, related to the Beta and Gamma EEG bands during REM sleep, with Delta and Sigma activity at REM sleep onset and REM sleep end, in order to understand their eventual role in the sleep modulation mechanism. Methods : For this purpose, power spectra of 1 EEG channel (C4, referred to A1) were obtained by means of the fast Fourier transform and the power of the bands ranging 0.75–4.50 Hz (Delta), 4.75–7.75 (Theta), 8.00–12.25 (Alpha), 12.50–15.00 (Sigma), 15.25–24.75 (Beta), 25.00–34.75 (Gamma 1), and 35.00–44.75 (Gamma 2) was calculated for the whole period of analysis (7 h), in 10 healthy subjects. Additionally, two other time series were calculated: the ratio between Beta and Gamma2, and between Gamma1 and Gamma2 (Beta and Gamma ratios). For each subject, we extracted 3 epochs of 30 min corresponding to the 15 min preceding and the 15 min following the onset of the first 3 REM episodes. Data were then averaged in order to obtain group mean values and standard deviation. The same process was applied to the 30-min epochs around REM sleep end. Results : The course of the Delta band around REM sleep onset was found to be characterized by a first phase of slow decline lasting from the beginning of our window up to a few seconds before REM onset; this phase was followed by a sudden, short decrease centered around REM onset, lasting for approximately 1.5–2 min. At the end of this phase, the Delta band reached its lowest values and remained stable up to the end of the time window. The Sigma band showed a similar course with stable values before and after REM sleep onset. The Beta and Gamma ratios also showed a 3-phase course; the first phase, in this case, was characterized by stable low values, from the beginning of our window up to approximately 5 min before REM onset. The following second phase was characterized by an increase which reached its maximum shortly after REM sleep onset (approximately 1 min). In the last phase, both Beta and Gamma ratios showed stable high values, up to the end of our time window. At REM sleep end, the Delta band only showed a very small gradual increase, the Sigma band presented a more evident gradual increase; on the contrary, both Beta and Gamma ratios showed a small gradual decrease. Conclusions : The results of the present study show a different time synchronization of the changes in the Delta band and in Beta and Gamma ratios, at around REM sleep onset, and seem to suggest that the oscillations of these parameters might be modulated by mechanisms more complex than a simple reciprocity. All these considerations point to the fact that REM sleep can be considered as a complex phenomenon and the analysis of high-frequency EEG bands and of our Beta and Gamma ratios represent an additional important element to include in the study of this sleep stage.

Chromosome abnormalities are often associated with central nervous system (CNS) malformations and with other neurologic dysfunctions. In particular, patients with chromosomal abnormalities can have mental retardation (MR) and have a higher risk for seizures than that found in the general population (1). Genetic tools such as karyotyping, high-resolution chromosome banding, fluorescent in situ hybridization (FISH), and other molecular genetics techniques have increased the number of chromosome abnormalities detected in subjects with MR or seizures. However, the majority of studies and reports published have usually considered sporadic cases or very small groups of patients with chromosome abnormalities. Furthermore, the characteristics of seizures and EEGs have been described in detail on very few occasions, to define the electroclinical phenotype, and eventually to classify the epilepsy. In recent years, a few identified chromosome abnormality syndromes seem to show a particular clinical and EEG picture; some of them are relatively common, such as Angelman’s syndrome, the fragile-X (fra-X) syndrome, the Miller‐Dieker syndrome; and others are more rare, such as trisomy 12p syndrome, the Wolf‐ Hirschhorn syndrome, and ring 20 syndrome. We review some clinical and neurophysiologic aspects of these syndromes that can support the neurologist in choosing the genetic analysis to be carried out, and help to identify specific genes influencing epileptogenesis. ANGELMAN’S SYNDROME

Objective : FRAXE mental retardation, a recently identified rare genetic condition, is due to a mutation of the FMR2 gene, located at Xq28 region. The phenotype is non-specific and characterized by developmental delay, speech, reading and writing problems, poor adaptive skills, anxiety, aggressiveness, obsessive-compulsive disturbance, and hyperactivity. The objective of this study was to describe the characteristic EEG pattern found in one patient with FRAXE mental retardation. Methods : EEG (with photic stimulation and hand/foot tapping) and median nerve somatosensory evoked potentials were recorded in a 8-year-old male patient with FRAXE mental retardation (diagnosis confirmed by molecular genetic analysis) and speech disturbances. Results : The patient never presented seizures; however, sleep enhanced multifocal spikes were found in the EEG. Moreover, tactile stimulation of hands and feet, as well as intermittent photic stimulation, provoked the appearance of spikes. Somatosensory evoked potentials from the median nerves showed a ‘giant' component at around 60 ms. Conclusions : Considering the rarity of both FRAXE mental retardation and tactile evoked spikes, their association in the same subject might be considered as not casual. If confirmed by future studies, these neurophysiological findings might be considered as a marker for FRAXE mental retardation.

Objective : The EEG spectral content of all-night sleep recordings obtained in 7 healthy young subjects, aged 18–20 years, including frequencies up to 45 Hz, was studied in order to detect eventual changes in the high-frequency range similar to those reported by magnetic field recording during REM sleep at 40 Hz. Methods : For this purpose, power spectra were calculated with a fast Fourier transform and the power of the bands ranging 0.75–4.50 Hz (Delta), 4.75–7.75 (Theta), 8.00–12.25 (Alpha), 12.50–15.00 (Sigma), 15.25–24.75 (Beta), 25.00–34.75 (Gamma1), and 35.00–44.75 (Gamma 2) was calculated for-the whole period of analysis (7 h). Also two additional time series: the ratio between Beta and Gamma2, and between Gamma1 and Gamma2 were calculated (Beta and Gamma ratios). Results : Beta and Gamma1 showed small changes with a tendency to increase during REM sleep; Gamma2, on the contrary, showed small changes with a tendency to decrease during REM sleep. Beta and Gamma ratio peaks were clearly correlated with the occurrence of REM sleep. The small changes shown by Beta, Gamma1 and Gamma2 were not statistically significant; on the contrary, Beta ratio and Gamma ratio showed the most important statistical significance values being highest during REM sleep and lowest during slow-wave sleep. Finally, the calculation of the linear correlation coefficient and of the cross-correlation between the different bands showed a clear reciprocity between Delta and Beta and Gamma ratios. Conclusions : Our study shows a new method for the analysis of high frequencies (up to 45 Hz) in the scalp-recorded sleep EEG which allowed us to better define, as compared to previous studies on the same topic, the changes in power characteristically associated with REM sleep and correlated with the REM/non-REM ultradian rhythm, and to propose it as a tool for future studies.

Polysomnography (EOG, EEG, EMG) was carried out in 17 male children and adolescents with autistic disorder, in seven patients with mental retardation and fragile X syndrome, and in five age- and sex-matched normal male subjects. Density of rapid eye movements was not significantly different in the three groups of subjects; however, some sleep parameters such as time in bed, sleep period time, and total sleep time were significantly lower in subjects with autistic disorder than in normal controls; moreover, patients with autistic disorder showed values of sleep period time, first REM latency and percent (%) sleep stage 1 lower than those of patients with fragile X syndrome with mental retardation. Density of muscle twitches was significantly higher in patients with autistic disorder than in normal controls. In contrast only minor differences were observed between patients with autistic disorder and those with fragile X syndrome with mental retardation. Furthermore, some psychoeducational profile-revised items such as perception and eye-hand coordination, showed significant correlation with some sleep parameters (time in bed, sleep latency, stage shifts, first REM latency and wakefulness after sleep onset). Childhood Autism Rating Scale (CARS) scores to visual response and non-verbal communication showed significant correlation with some tonic sleep parameters, such as sleep period time, wakefulness after sleep onset, and total sleep time. Relating to people and activity level items were found to be significantly correlated with rapid eye movement density. Our results suggest the existence of a sleep pattern in autistic patients different from that observed in subjects with mental retardation and from that of normal controls. In addition, these findings indicate that sleep parameters in these patients are correlated with some psychological indices generally used for the diagnosis of autistic disorder; for this reason, polysomnographies might be useful in the comprehension of the neurophysiological mechanisms underlying this condition.

Summary: Purpose and Methods: One hundred and ninety-two fragile X male patients were investigated for seizures and EEG findings, 168 in a retrospective and 24 in another prospective study, to characterize the natural history of seizures, epilepsy, and EEG abnormalities in males with this syndrome. Results: Seizures were documented in 35 (18.2%) of 192 patients; they never started before the age of 2 years or after the age of 9 years. Seizures were frequently of the complex partial type and less frequently of the partial motor and generalized type. Seizures involving frontal and temporal lobes were commonly seen and were usually well controlled by anticonvulsants. In the majority of young fragile X patients studied, an age-related paroxysmal EEG pattern was found, which showed neurophysiologic characteristics very similar to those of the centrotemporal spikes. Conclusions: These findings confirm that fragile X syndrome can be considered a genetic model of epilepsy.

Autonomic system dysfunction has been reported to occur frequently in patients with Down's syndrome (DS) and is constituted mainly by an imbalance between the sympathetic and vagal systems. The analysis of heart rate variability (HRV) during sleep is a quantitative reliable method for studying such a mechanism, but it has not yet been extensively and adequately applied in DS. In this study, HRV during sleep was evaluated in seven DS patients and in six normal controls, by also controlling for the presence of sleep apnea or arousal. The main results were an increased sympathetic function (low-frequency component of HRV) and a decreased vagal activity (high-frequency component of HRV) in DS with respect to normal controls, during apnea-free periods. Moreover, the presence of apnea, in DS, induced a further significant increase in low-frequency and very low-frequency components of HRV during sleep Stage 2. This study provides additional evidence of a brainstem dysfunctioning in DS, responsible for the abnormal imbalance between the sympathetic and vagal systems and confirms the brainstem involvement already suggested in the literature in order to explain brainstem-auditory evoked potential abnormalities and central sleep apnea in these patients.

In questo studio sono stati esaminati retrospettivamente gli esami di risonanza magnetica (RM), i dati anamnestico-clinici ed EEG di 266 pazienti con ritardo mentale, al fine di valutare la prevalenza di anomalie della migrazione neuronale e della organizzazione corticale (AMNOC) in questa popolazione e di analizzare l'eventuale correlazione tra alterazione neuroanatomica e quadro elettroclinico. Sono stati riscontrati complessivamente 22 casi di AMNOC (8,3%). Di questi 22 pazienti, 17 (77,3%) appartenevano alla popolazione con ritardo mentale ed epilessia, gli altri 5 presentavano solo ritardo mentale senza manifestazioni epilettiche e anomalie EEG. È stata trovata una correlazione spaziale tra anomalie EEG e alterazioni neuroradiologiche in 7/17 casi (41,2 %). Viene discussa l'importanza di una corretta correlazione RM-EEG nei soggetti con AMNOC ed epilessia farmacoresistente, anche in un'eventuale prospettiva chirurgica.

Summary: Purpose: We explored the relationship between myoclonic absence seizures (MAS) and underlying chromosome disorders. Methods: Among 14 patients with MAS observed in three centers, 5 had typical cryptogenic myoclonic absence epilepsy (MAE), 2 had MAS associated with other seizure types (1 with signs of a neuronal migration abnormality and 1 with signs of a metabolic disorder), and 7 had MAS, with or without other seizure types, complicating a chromosome abnormality syndrome-2 with trisomy 12p, 4 with Angelman syndrome, and 1 with inv dup (15). Results: In the 7 patients with chromosomopathy, MAS appeared at a mean age of 2.9 years (range 4 months to 6 years 6 months), had a duration of 4-20 s, and were accompanied by reduced awareness and rhythmic myoclonic jerks involving proximal limb muscles. Ictal EEG showed 2- to 3-Hz generalized spike-and-wave discharges. Conclusions: In these patients, MAS differed slightly from those of typical MAE: age of onset was earlier, absences were of shorter duration, and no clear increase in muscular tone was noted. Abnormal expression of genes codifying for the subfamily of K' channels and for y-aminobutyric acid-3 subunit receptors (GABRBS), both located in the chromosome segments involved in the chromosomopathies presented by our patients, could be responsible for the same generalized seizure type. Chromosome analysis should be performed in patients with mental retardation and MAS, especially when the ictal pattern does not completely overlap that observed in MAE. Key Words: Myoclonic absences-Chromosome disordersTrisomy 12p-inv dup (15)-Angelman syndrome. Myoclonic absence seizures (MAS) are characterized by rhythmic bilateral diffuse myoclonic jerks accompanied by 3-Hz generalized EEG spike-and-wave discharges (SWD) (1,2). In myoclonic absence epilepsy (MAE), which is classified as a cryptogenic or symptomatic generalized epilepsy (3), the MAS tend to last 10-60 s; are accompanied by a mild tonic contraction underlying the jerking; cause only mild, if any, clouding of consciousness; and are very frequent, occurring many times each day. Association with other seizure types is rare (4). However, MAS may also appear with slightly different characteristics, in patients who do not have MAE and can be associated with other types of seizures

In this paper, research on sleep characteristics of subjects with Down syndrome is briefly reviewed and some new data on autonomic function during sleep are reported. Subjects with Down syndrome show a significant reduction in percentage of REM sleep (probably more evident in the most severely retarded subjects), a marked delay in first REM latency and a statistically significant decrease in high-frequency rapid eye movements during REM sleep. The percentage of REM sleep in humans can be considered as an index of brain "plasticity" and the high-frequency REMs can represent an index of the brain ability to organize information; thus, these studies have provided a neurophysiological basis to a psychopedagogical approach for the treatment of learning and memory disabilities in Down syndrome. Moreover, children with Down syndrome show a clearly decreased peak amplitude of growth hormone during sleep; this causes the poor physical development in these subjects and might be related to the occurrence of sleep apnea. Obstructive sleep apnea has also been repeatedly reported in these children; however, if obvious risk factors are absent, children with Down syndrome tend to show the presence of central sleep apnea which is caused by a probable dysfunction of autonomic control at a brainstem level.

In the last two decades neurological research has significantly increased knowledge on the neuroanatomic bases of autism. Several autopsy and quantitative magnetic resonance imaging (MRI) studies have reported central nervous system (CNS) abnormalities which may underlie the social, language and cognitive dysfunction typical of the autistic disorder.Despite the wealth of evidence that the “autistic brain” is different from normal in a number of structures, the relationship between the severity of the developmental impairment in autism and the degree of the brain abnormality remains unknown.The aim of the present study is to correlate the areas of some brain regions, as calculated on the basis of MRI morphometry, with the Childhood Autism Rating Scale (CARS) and with the Psychoeducational Profile Revised (PEP-R) scores in a group of 22 autistic mentally retarded male subjects.

Ocular coloboma is a sight-threatening malformation caused by failure of the choroid fissure to close during morphogenesis of the eye, and is frequently associated with additional anomalies, including microphthalmia and cataracts. Although Hedgehog signaling is known to play a critical role in choroid fissure closure, genetic regulation of this pathway remains poorly understood. Here, we show that the transcription factor Sox11 is required to maintain specific levels of Hedgehog signaling during ocular development. Sox11-deficient zebrafish embryos displayed delayed and abnormal lens formation, coloboma, and a specific reduction in rod photoreceptors, all of which could be rescued by treatment with the Hedgehog pathway inhibitor cyclopamine. We further demonstrate that the elevated Hedgehog signaling in Sox11-deficient zebrafish was caused by a large increase in shha transcription; indeed, suppressing Shha expression rescued the ocular phenotypes of sox11 morphants. Conversely, over-expression of sox11 induced cyclopia, a phenotype consistent with reduced levels of Sonic hedgehog. We screened DNA samples from 79 patients with microphthalmia, anophthalmia, or coloboma (MAC) and identified two novel heterozygous SOX11 variants in individuals with coloboma. In contrast to wild type human SOX11 mRNA, mRNA containing either variant failed to rescue the lens and coloboma phenotypes of Sox11-deficient zebrafish, and both exhibited significantly reduced transactivation ability in a luciferase reporter assay. Moreover, decreased gene dosage from a segmental deletion encompassing the SOX11 locus resulted in microphthalmia and related ocular phenotypes. Therefore, our study reveals a novel role for Sox11 in controlling Hedgehog signaling, and suggests that SOX11 variants contribute to pediatric eye disorders., Author Summary Ocular coloboma is a condition in which tissue is missing from a portion of the eye due to its abnormal development. Coloboma is also frequently associated with additional anomalies, including microphthalmia (abnormally small eye) and cataracts. Although some of the genes that cause coloboma have been identified, in the majority of cases the underlying genetic cause has not been determined. One pathway that has been implicated in coloboma is the Hedgehog (Hh) signaling pathway. In this study, we have taken advantage of the ability to titrate levels of gene expression in zebrafish to demonstrate for the first time that the transcription factor Sox11 is required to limit levels of Hedgehog (Hh) signaling during ocular development. We show that in the absence of Sox11, levels of the Sonic Hedgehog (Shh) ligand are greatly elevated, which disrupts the proper patterning of the optic stalk and optic vesicle, resulting in coloboma. We also provide evidence that SOX11 dosage changes or mutations contribute to human coloboma, microphthalmia, and rod photoreceptor dysfunction. Thus, our work establishes a novel link between Sox11 and Hh signaling, and suggests that mutations in SOX11 contribute to pediatric eye disorders such as coloboma.

The study of the dynamics of non-linear systems allows the evaluation of the correlation dimension which, in turn, provides an estimate of the number of variables needed to model the process. In such a view, the correlation dimension was calculated for the profiles of the EEG slow-wave activity during sleep obtained from 7 young normal controls and in their corresponding artificial stochastic signals. It was possible to evaluate the complexity of all the real profiles which exhibited an average dimension of 3.76 (SD 0.331), but not that of the artificial control ones. This allows us to conclude that sleep regulation might be considered as a deterministic non-linear process and that the already proposed two-process model of sleep regulation needs to include additional variables with non-linear interactions.

Saethre-Chotzen syndrome is a form of acrocephalosyndactyly with autosomal dominant inheritance, characterized by craniosynostosis, facial asymmetry, palpebral ptosis, deviated nasal septum, partial cutaneous syndactyly, and various skeletal abnormalities. We studied in detail the neurological, EEG, and neuroradiological features of a group of 11 (6 male, 5 female) patients with Saethre-Chotzen syndrome. Four subjects were affected by seizures; they had paroxysmal EEG abnormalities, and gross neuroimaging revealed destructive brain lesions or malformations. Our findings suggest that CNS involvement in Saethre-Chotzen syndrome might be more severe than previously reported and support the wider use of neurophysiological and neuroimaging techniques in the study of children with this syndrome.

Epilepsia partialis continua (EPC) has previously been reported in only two patients with Leigh syndrome (LS). We report here a subject in whom LS and partial deficit of cytochrome c oxidase (COX) were associated with EPC. Epilepsy in this subject appeared when neurologic impairment was clearly evident and MRI showed cortical lesions typically associated with congenital lactic acidosis.

In this study, we report the cases of five unrelated patients with Klinefelter's syndrome and seizures or EEG epileptiform abnormalities; the karyotype was 47,XXY in four, and 47,XXY/46,XX in one. They were aged 13-25 years and followed up both clinically and by means of EEG. Two of the patients had epilepsy, one had only one isolated generalized tonic-clonic seizure, one had febrile convulsions and one presented focal epileptiform EEG abnormalities without seizures. In two of the patients, it was possible to classify the epilepsy (childhood epilepsy with occipital paroxysms and cryptogenic or symptomatic generalized epilepsy). Although the electroclinical patterns appeared to be rather heterogeneous in our patients, it is possible to infer the relative good evolution of seizures in Klinefelter's syndrome.

The Kohlschütter syndrome is a very uncommon inherited disorder characterized by epilepsy, dementia, and yellow teeth. We present two new patients who contribute to an increase in our knowledge of the clinical phenotype of this syndrome. They are two siblings born from consanguineous parents. Dysmorphological signs, such as broad thumbs, are reported for the first time in association with this syndrome, together with neurophysiological peculiarities (occipital evoked spikes) and hypoplasia of the cerebellar vermis. The authors suggest that ethnic factors might be important and conclude that the clinical phenotype of the Kohlschütter syndrome is still in need of further characterization.

A deletion of one of the two copies of the 9-bp tandem repeat sequence (CCCCCTCTA), in the small non-coding/untranslated segment located between the cytochrome oxidase II and lysine tRNA genes of mitochondrial DNA (mtDNA), has previously been used as a polymorphic anthropological marker (MIC9D) for people of Africa and Asia, but it has been rarely reported in Europe. 32 Sicilian patients with syndromic hearing loss, negative for mutations in GJB2 and GJB6 genes, were tested for mtDNA known point mutations associated with syndromic or non-syndromic hearing loss by RFLP and/or direct sequencing. We identified the presence of the MIC9D in homoplasmy in lymphocytes and muscle of three subjects with sensorineural hearing loss and encephalomyopathy, two of these also presented moderate mental retardation. This deletion was absent in 300 Caucasian controls. Although further studies are warranted, our results suggest that the MIC9D polymorphism could have a susceptibility role in Caucasus, such as Sicily population.

We have studied the effects of 5-HT1A and 5-HT7 serotonin receptor activation in hippocampal CA3-CA1 synaptic transmission using patch clamp on mouse brain slices. Application of either 5-HT or 8-OH DPAT, a mixed 5-HT1A/5-HT7 receptor agonist, inhibited AMPA receptor-mediated excitatory post synaptic currents (EPSCs); this effect was mimicked by the 5-HT1A receptor agonist 8-OH PIPAT and blocked by the 5-HT1A antagonist NAN-190. 8-OH DPAT increased paired-pulse facilitation and reduced the frequency of mEPSCs, indicating a presynaptic reduction of glutamate release probability. In another group of neurons, 8-OH DPAT enhanced EPSC amplitude but did not alter paired-pulse facilitation, suggesting a postsynaptic action; this effect persisted in the presence of NAN-190 and was blocked by the 5-HT7 receptor antagonist SB-269970. To confirm that EPSC enhancement was mediated by 5-HT7 receptors, we used the compound LP-44, which is considered a selective 5-HT7 agonist. However, LP-44 reduced EPSC amplitude in most cells and instead increased EPSC amplitude in a subset of neurons, similarly to 8-OH DPAT. These effects were respectively antagonized by NAN-190 and by SB-269970, indicating that under our experimental condition LP-44 behaved as a mixed agonist. 8-OH DPAT also modulated the current evoked by exogenously applied AMPA, inducing either a reduction or an increase of amplitude in distinct neurons; these effects were respectively blocked by 5-HT1A and 5-HT7 receptor antagonists, indicating that both receptors exert a postsynaptic action. Our results show that 5-HT1A receptors inhibit CA3-CA1 synaptic transmission acting both pre- and postsynaptically, whereas 5-HT7 receptors enhance CA3-CA1 synaptic transmission acting exclusively at a postsynaptic site. We suggest that a selective pharmacological targeting of either subtype may be envisaged in pathological loss of hippocampal-dependent cognitive functions. In this respect, we underline the need for new selective agonists of 5-HT7 receptors. (c) 2011 Wiley Periodicals, Inc.

Middle-latency somatosensory evoked potentials (MLSEPs) were recorded from 19 scalp electrodes in ten male patients with the fragile X (fraX) syndrome and nine normal controls. One fraX patient was found presenting the so-called "giant" MLSEPs with an amplitude of N60 of about 60 microV and of 40 microV after stimulation of the right and left median nerves, respectively. Tapping of the right hand, in the same patient, induced the appearance of left parietal evoked EEG spikes. These findings further support the already suggested similarity between the epileptic picture of several fraX patients with that of the benign childhood epilepsy with centrotemporal spikes. Color mapping of the MLSEPs recorded in the remaining nine patients, when compared with the control group, showed an abnormally large N30 over the frontal regions, together with an increase in amplitude of P27, over the parietal areas, and of N60 and P100 which also presented abnormal field distributions, being represented preferentially over the frontal regions. These data could suggest the existence of a cortical dysfunction mostly involving the frontal lobes (supplementary motor area, in particular) in the fraX syndrome which could support many behavioral changes usually observed in these patients.

Summary Middle-latency somatosensory evoked potentials (MLSEPs) were recorded from 19 scalp electrodes in 19 patients with Down's syndrome (DS), in 13 age-matched normal controls and in 11 aged normal individuals. DS patients showed an increase in amplitude of P22, N30, P45, and N60. P100 latency was significantly shortened. After this potential, DS subjects showed the occurrence of a high voltage negative potential at around 100–110 msec followed by another high-voltage positive deflection; both these components showed a frontal-central distribution and were not observed in the two control groups. MLSEPs of DS subjects show peculiar alterations which could be supported by particular neurometabolic and/or neuropathologic changes.

EEG during wakefulness and sleep and somatosensory evoked potentials from the median nerve were recorded in a 3 year-old boy with hyperekplexia and his close relatives (parents and two sisters). Centro-temporal spikes during sleep were found in the patient and in the older sister, while somatosensory evoked potentials, in the patient, showed abnormally high amplitude over the centroparietal regions. Pathophysiological mechanisms of hyperekplexia are discussed and the existence of symptomatic forms is suggested.

Background: Fragile X syndrome (FXS) is a genetic cause of intellectual disability and autism. Fmr1 knockout (Fmr1 KO) mice, an animal model of FXS, exhibit spatial memory impairment and synapse malfunctioning in the hippocampus, with abnormal enhancement of long-term depression mediated by metabotropic glutamate receptors (mGluR-LTD). The neurotransmitter serotonin (5-HT) modulates hippocampal-dependent learning through serotonin 1A (5-HT1A) and serotonin 7 (5-HT7) receptors; the underlying mechanisms are unknown. Methods: We used electrophysiology to test the effects of 5-HT on mGluR-LTD in wild-type and Fmr1 KO mice and immunocytochemistry and biotinylation assay to study related changes of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) glutamate receptor surface expression. Results: Application of 5-HT or 8-OH-DPAT (a mixed 5-HT1A/5-HT7 agonist) reversed mGluR-LTD in hippocampal slices. Reversal of mGluR-LTD by 8-OH-DPAT persisted in the presence of the 5-HT1A receptor antagonist WAY-100635, was abolished by SB-269970 (5-HT7 receptor antagonist), and was mimicked by LP-211, a novel selective 5-HT7 receptor agonist. Consistently, 8-OH-DPAT decreased mGluR-mediated reduction of AMPA glutamate receptor 2 (GluR2) subunit surface expression in hippocampal slices and cultured hippocampal neurons, an effect mimicked by LP-211 and blocked by SB-269970. In Fmr1 KO mice, mGluR-LTD was abnormally enhanced; similarly to wild-type, 8-OH-DPAT reversed mGluR-LTD and decreased mGluR-induced reduction of surface AMPA receptors, an effect antagonized by SB-269970. Conclusions: Serotonin 7 receptor activation reverses metabotropic glutamate receptor-induced AMPA receptor internalization and LTD both in wild-type and in Fmr1 KO mice, correcting excessive mGluR-LTD. Therefore, selective activation of 5-HT7 receptors may represent a novel strategy in the therapy of FXS. © 2012 Society of Biological Psychiatry.