1. Anagnostou E, Soorya L, Brian J, Dupuis A, Mankad D, Smile S, Jacob S. {{Intranasal oxytocin in the treatment of autism spectrum disorders: A review of literature and early safety and efficacy data in youth}}. {Brain Res};2014 (Feb 5)
BACKGROUND: There is a paucity of treatments targeting core symptom domains in autism spectrum disorder (ASD). Several animal models and research in typically developing volunteers suggests that manipulation of the oxytocin system may have therapeutic potential for the treatment of social deficits. We review the literature for oxytocin and ASD and report on early dosing, safety and efficacy data of multi-dose oxytocin on aspects of social cognition/function, as well as repetitive behaviors and co-occurring anxiety within ASD. METHODS: Fifteen children and adolescents with verbal IQs >/=70 were diagnosed with ASD using the ADOS and the ADI-R. They participated in a modified maximum tolerated dose study of intranasal oxytocin (Syntocinon). Data were modeled using repeated measures regression analysis controlling for week, dose, age, and sex. RESULTS: Among 4 doses tested, the highest dose evaluated, 0.4IU/kg/dose, was found to be well tolerated. No serious or severe adverse events were reported and adverse events reported/observed were mild to moderate. Over 12 weeks of treatment, several measures of social cognition/function, repetitive behaviors and anxiety showed sensitivity to change with some measures suggesting maintenance of effect 3 months past discontinuation of intranasal oxytocin. CONCLUSIONS: This pilot study suggests that daily administration of intranasal oxytocin at 0.4IU/kg/dose in children and adolescents with ASD is safe and has therapeutic potential. Larger studies are warranted.
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2. Basehore MJ, Friez MJ. {{Molecular analysis of fragile x syndrome}}. {Curr Protoc Hum Genet};2014;80:9 5 1-9 5 19.
The gene responsible for Fragile X syndrome, fragile X mental retardation-1 (FMR1), contains an unstable sequence of CGG trinucleotide repeats in its promoter region. Expansions of >200 trinucleotide repeats are considered full mutations and typically lead to abnormal methylation of the region, resulting in loss of FMR1 expression. Males with loss of FMR1 protein are expected to be affected by Fragile X syndrome, while females may or may not clinically manifest features of the condition. The protocols in this unit outline the complementary use of polymerase chain reaction (PCR) and methylation-sensitive Southern blot hybridization to accurately measure trinucleotide repeat size and methylation status. These protocols are also used to evaluate CGG repeat size in two adult-onset conditions known for their association with FMR1 premutation alleles, Fragile X Tremor/Ataxia (FXTAS) syndrome and Premature Ovarian Failure (POF). Curr. Protoc. Hum. Genet. 80:9.5.1-9.5.19. (c) 2014 by John Wiley & Sons, Inc.
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3. Braat S, Kooy RF. {{Fragile X syndrome neurobiology translates into rational therapy}}. {Drug Discov Today};2014 (Feb 6)
Causal genetic defects have been identified for various neurodevelopmental disorders. A key example in this respect is fragile X syndrome, one of the most frequent genetic causes of intellectual disability and autism. Since the discovery of the causal gene, insights into the underlying pathophysiological mechanisms have increased exponentially. Over the past years, defects were discovered in pathways that are potentially amendable by pharmacological treatment. These findings have inspired the initiation of clinical trials in patients. The targeted pathways converge in part with those of related neurodevelopmental disorders raising hopes that the treatments developed for this specific disorder might be more broadly applicable.
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4. Bruining H, Eijkemans MJ, Kas MJ, Curran SR, Vorstman JA, Bolton PF. {{Behavioral signatures related to genetic disorders in autism}}. {Mol Autism};2014 (Feb 11);5(1):11.
BACKGROUND: Autism spectrum disorder (ASD) is well recognized to be genetically heterogeneous. It is assumed that the genetic risk factors give rise to a broad spectrum of indistinguishable behavioral presentations. METHODS: We tested this assumption by analyzing the Autism Diagnostic Interview-Revised (ADI-R) symptom profiles in samples comprising six genetic disorders that carry an increased risk for ASD (22q11.2 deletion, Down’s syndrome, Prader-Willi, supernumerary marker chromosome 15, tuberous sclerosis complex and Klinefelter syndrome; total n = 322 cases, groups ranging in sample sizes from 21 to 90 cases). We mined the data to test the existence and specificity of ADI-R profiles using a multiclass extension of support vector machine (SVM) learning. We subsequently applied the SVM genetic disorder algorithm on idiopathic ASD profiles from the Autism Genetics Resource Exchange (AGRE). RESULTS: Genetic disorders were associated with behavioral specificity, indicated by the accuracy and certainty of SVM predictions; one-by-one genetic disorder stratifications were highly accurate leading to 63% accuracy of correct genotype prediction when all six genetic disorder groups were analyzed simultaneously. Application of the SVM algorithm to AGRE cases indicated that the algorithm could detect similarity of genetic behavioral signatures in idiopathic ASD subjects. Also, affected sib pairs in the AGRE were behaviorally more similar when they had been allocated to the same genetic disorder group. CONCLUSIONS: Our findings provide evidence for genotype-phenotype correlations in relation to autistic symptomatology. SVM algorithms may be used to stratify idiopathic cases of ASD according to behavioral signature patterns associated with genetic disorders. Together, the results suggest a new approach for disentangling the heterogeneity of ASD.
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5. Cannell JJ. {{Paracetamol, oxidative stress, vitamin D and autism spectrum disorders}}. {Int J Epidemiol};2014 (Feb 11)
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6. Chase A. {{Brain imaging: White matter disruption in autism spectrum disorder is exaggerated by head movements during neuroimaging}}. {Nat Rev Neurol};2014 (Feb 11)
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7. Corbett BA, Schupp CW. {{The Cortisol Awakening Response (CAR) in Male Children with Autism Spectrum Disorder}}. {Horm Behav};2014 (Feb 5)
Our ability to adapt to change is fundamental. The cortisol awakening response (CAR) is a sharp rise in cortisol 30-minutes after waking to help prepare an individual for ensuing stress. Children with autism spectrum disorder (ASD) often have difficulty adapting to change. Exploration of the CAR is warranted; yet, the few studies investigating it are inconclusive. The CAR was investigated in 94 pre-pubertal male children 8-to-12years of age with ASD (46) and typical development (TD, 48). Salivary samples were collected over three diurnal cycles involving two morning samples: M1: Immediately upon Waking and M2: 30-min Post Waking (M2 – M1=CAR). The magnitude of the CAR was measured by independent two sample t-tests, variability was measured using Levene’s Test, the sequence of the CAR was analyzed by a linear mixed-effects model and proportion of children exhibiting a CAR by chi-square test of independence. There were no significant differences on the CAR between the groups based on magnitude (t(92)=-0.14, p=0.89, d=0.04), variability (F(45,47)=1.11, p=0.72, eta2=0.11) or the sequence over three days (F(2,88)=0.26, p=0.77, eta2=0.01). No significant differences were shown in the proportion of children exhibiting a CAR across the groups based on child (chi2(1)=0.02, p=0.89) or adult criterion (chi2(1)=1.82, p=0.18). Despite group differences in the regulation and responsivity of cortisol, the CAR is indistinguishable between children with and without ASD. Inconsistencies across studies may be due to age, criterion used, and diagnostic distinctions.
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8. Cortelazzo A, De Felice C, Guerranti R, Signorini C, Leoncini S, Pecorelli A, Zollo G, Landi C, Valacchi G, Ciccoli L, Bini L, Hayek J. {{Subclinical inflammatory status in rett syndrome}}. {Mediators Inflamm};2014;2014:480980.
Inflammation has been advocated as a possible common central mechanism for developmental cognitive impairment. Rett syndrome (RTT) is a devastating neurodevelopmental disorder, mainly caused by de novo loss-of-function mutations in the gene encoding MeCP2. Here, we investigated plasma acute phase response (APR) in stage II (i.e., « pseudo-autistic ») RTT patients by routine haematology/clinical chemistry and proteomic 2-DE/MALDI-TOF analyses as a function of four major MECP2 gene mutation types (R306C, T158M, R168X, and large deletions). Elevated erythrocyte sedimentation rate values (median 33.0 mm/h versus 8.0 mm/h, P < 0.0001) were detectable in RTT, whereas C-reactive protein levels were unchanged (P = 0.63). The 2-DE analysis identified significant changes for a total of 17 proteins, the majority of which were categorized as APR proteins, either positive (n = 6 spots) or negative (n = 9 spots), and to a lesser extent as proteins involved in the immune system (n = 2 spots), with some proteins having overlapping functions on metabolism (n = 7 spots). The number of protein changes was proportional to the severity of the mutation. Our findings reveal for the first time the presence of a subclinical chronic inflammatory status related to the « pseudo-autistic » phase of RTT, which is related to the severity carried by the MECP2 gene mutation.
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9. Herlihy LE, Brooks B, Dumont-Mathieu T, Barton ML, Fein D, Chen CM, Robins DL. {{Standardized screening facilitates timely diagnosis of autism spectrum disorders in a diverse sample of low-risk toddlers}}. {J Dev Behav Pediatr};2014 (Feb-Mar);35(2):85-92.
OBJECTIVE: Routine, standardized screening for autism spectrum disorder (ASD) has been hypothesized to reduce known racial/ethnic and socioeconomic status (SES) disparities in age of first diagnosis. This study explored demographic differences in toddlers’ age and performance on developmental measures at the time of ASD assessment. METHOD: Toddlers (16-39 months at evaluation) who screened at-risk for developmental delay on the Modified Checklist for Autism in Toddlers (M-CHAT) or M-CHAT-Revised (M-CHAT-R) and follow-up interview participated in a diagnostic assessment. Of these, 44.7% were racial/ethnic minorities and 53.5% were non-minorities. Child race/ethnicity, years of maternal education (MEd), and household yearly income (YI) were parent-reported. RESULTS: Small but significant correlations were observed between MEd or YI and evaluation age and adaptive communication, socialization, and motor scores. Controlling for MEd and YI, minority racial/ethnic group did not predict child’s performance on most measures and did not predict likelihood of ASD diagnosis. Differences in age at evaluation and receptive language skills were small effects. CONCLUSION: Significant but small effects emerged for SES and minority status on toddlers’ age at evaluation and parent-reported adaptive skills, but these did not predict ASD diagnosis. The small magnitude of these effects suggests that routine, standardized screening for ASD in toddlers and timely access to diagnostic evaluation can reduce disparities in age at diagnosis and possibly reduce racial/ethnic disparities in access to services for ASD and other developmental delays.
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10. Iao LS, Leekam SR. {{Nonspecificity and theory of mind: New evidence from a nonverbal false-sign task and children with autism spectrum disorders}}. {J Exp Child Psychol};2014 (Feb 6);122C:1-20.
Understanding of false belief has long been considered to be a crucial aspect of « theory of mind » that can be explained by a domain-specific mechanism. We argue against this claim using new evidence from a nonverbal false representation task (false-sign task) with typically developing children and children with autism spectrum disorders (ASD). Experiments 1 and 2 showed that typically developing children (mean age=62.67months) were equivalent in their performance across nonverbal and verbal forms of both the false-belief and false-sign tasks. Results for these two misrepresentation tasks differed from the results of an outdated representation task (« false »-photograph task). Experiment 3 showed that children with ASD had difficulties with the false representation tasks, and this could not be explained by executive functioning or language impairments. These findings support the view that children with ASD might not have a specific theory-of-mind deficit.
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11. Kalman LV, Tarleton JC, Percy AK, Aradhya S, Bale S, Barker SD, Bayrak-Toydemir P, Bridges C, Buller-Burckle AM, Das S, Iyer RK, Vo TD, Zvereff VV, Toji LH. {{Development of a Genomic DNA Reference Material Panel for Rett Syndrome (MECP2-Related Disorders) Genetic Testing}}. {J Mol Diagn};2014 (Feb 1)
Rett syndrome is a dominant X-linked disorder caused by point mutations (approximately 80%) or by deletions or insertions (approximately 15% to 18%) in the MECP2 gene. It is most common in females but lethal in males, with a distinctly different phenotype. Rett syndrome patients have severe neurological and behavioral problems. Clinical genetic testing laboratories commonly use characterized genomic DNA reference materials to assure the quality of the testing process; however, none are commercially available for MECP2 genetic testing. The Centers for Disease Control and Prevention’s Genetic Testing Reference Material Coordination Program, in collaboration with the genetic testing community and the Coriell Cell Repositories, established 27 new cell lines and characterized the MECP2 mutations in these and in 8 previously available cell lines. DNA samples from the 35 cell lines were tested by eight clinical genetic testing laboratories using DNA sequence analysis and methods to assess copy number (multiplex ligation-dependent probe amplification, semiquantitative PCR, or array-based comparative genomic hybridization). The eight common point mutations known to cause approximately 60% of Rett syndrome cases were identified, as were other MECP2 variants, including deletions, duplications, and frame shift and splice-site mutations. Two of the 35 samples were from males with MECP2 duplications. These MECP2 and other characterized genomic DNA samples are publicly available from the NIGMS Repository at the Coriell Cell Repositories.
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12. Kirby AV, Dickie VA, Baranek GT. {{Sensory experiences of children with autism spectrum disorder: In their own words}}. {Autism};2014 (Feb 11)
First-person perspectives of children with autism spectrum disorder are rarely included in research, yet their voices may help more clearly illuminate their needs. This study involved phenomenological interviews with children with autism spectrum disorder (n = 12, ages 4-13) used to gain insights about their sensory experiences. This article addresses two study aims: determining the feasibility of interviewing children with autism spectrum disorder and exploring how they share information about their sensory experiences during the qualitative interview process. With the described methods, children as young as 4 years old and across a broad range of autism severity scores successfully participated in the interviews. The manner with which children shared information about their sensory experiences included themes of normalizing, storytelling, and describing responses. The interviews also revealed the importance of context and the multisensory nature of children’s experiences. These findings contribute strategies for understanding the sensory experiences of children with autism spectrum disorder with implications for practice and future research.
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13. Ludwig AL, Espinal GM, Pretto DI, Jamal AL, Arque G, Tassone F, Berman RF, Hagerman PJ. {{CNS expression of murine fragile X protein (FMRP) as a function of CGG-repeat size}}. {Hum Mol Genet};2014 (Feb 11)
Large expansions of a CGG-repeat element (>200 repeats; full mutation) in the fragile X mental retardation 1 (FMR1) gene cause fragile X syndrome (FXS), the leading single-gene form of intellectual disability and of autism spectrum disorder. Smaller expansions (55-200 CGG repeats; premutation) result in the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Whereas FXS is caused by gene silencing and insufficient FMR1 protein (FMRP), FXTAS is thought to be caused by ‘toxicity’ of expanded-CGG-repeat mRNA. However, as FMRP expression levels decrease with increasing CGG-repeat length, lowered protein may contribute to premutation-associated clinical involvement. To address this issue, we measured brain Fmr1 mRNA and FMRP levels as a function of CGG-repeat length in a congenic (CGG-repeat knock-in) mouse model using 57 wild-type and 97 expanded-CGG-repeat mice carrying up to approximately 250 CGG repeats. While Fmr1 message levels increased with repeat length, FMRP levels trended downward over the same range, subject to significant inter-subject variation. Human comparisons of protein levels in the frontal cortex of 7 normal and 17 FXTAS individuals revealed that the mild FMRP decrease in mice mirrored the more limited data for FMRP expression in the human samples. In addition, FMRP expression levels varied in a subset of mice across the cerebellum, frontal cortex, and hippocampus, as well as at different ages. These results provide a foundation for understanding both the CGG-repeat-dependence of FMRP expression and for interpreting clinical phenotypes in premutation carriers in terms of the balance between elevated mRNA and lowered FMRP expression levels.
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14. Lyall K, Schmidt RJ, Hertz-Picciotto I. {{Maternal lifestyle and environmental risk factors for autism spectrum disorders}}. {Int J Epidemiol};2014 (Feb 11)
BACKGROUND:: Over the past 10 years, research into environmental risk factors for autism has grown dramatically, bringing evidence that an array of non-genetic factors acting during the prenatal period may influence neurodevelopment. METHODS:: This paper reviews the evidence on modifiable preconception and/or prenatal factors that have been associated, in some studies, with autism spectrum disorder (ASD), including nutrition, substance use and exposure to environmental agents. This review is restricted to human studies with at least 50 cases of ASD, having a valid comparison group, conducted within the past decade and focusing on maternal lifestyle or environmental chemicals. RESULTS:: Higher maternal intake of certain nutrients and supplements has been associated with reduction in ASD risk, with the strongest evidence for periconceptional folic acid supplements. Although many investigations have suggested no impact of maternal smoking and alcohol use on ASD, more rigorous exposure assessment is needed. A number of studies have demonstrated significant increases in ASD risk with estimated exposure to air pollution during the prenatal period, particularly for heavy metals and particulate matter. Little research has assessed other persistent and non-persistent organic pollutants in association with ASD specifically. CONCLUSIONS:: More work is needed to examine fats, vitamins and other maternal nutrients, as well as endocrine-disrupting chemicals and pesticides, in association with ASD, given sound biological plausibility and evidence regarding other neurodevelopmental deficits. The field can be advanced by large-scale epidemiological studies, attention to critical aetiological windows and how these vary by exposure, and use of biomarkers and other means to understand underlying mechanisms.
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15. Rossignol DA, Genuis SJ, Frye RE. {{Environmental toxicants and autism spectrum disorders: a systematic review}}. {Transl Psychiatry};2014;4:e360.
Although the involvement of genetic abnormalities in autism spectrum disorders (ASD) is well-accepted, recent studies point to an equal contribution by environmental factors, particularly environmental toxicants. However, these toxicant-related studies in ASD have not been systematically reviewed to date. Therefore, we compiled publications investigating potential associations between environmental toxicants and ASD and arranged these publications into the following three categories: (a) studies examining estimated toxicant exposures in the environment during the preconceptional, gestational and early childhood periods; (b) studies investigating biomarkers of toxicants; and (c) studies examining potential genetic susceptibilities to toxicants. A literature search of nine electronic scientific databases through November 2013 was performed. In the first category examining ASD risk and estimated toxicant exposures in the environment, the majority of studies (34/37; 92%) reported an association. Most of these studies were retrospective case-control, ecological or prospective cohort studies, although a few had weaker study designs (for example, case reports or series). Toxicants implicated in ASD included pesticides, phthalates, polychlorinated biphenyls (PCBs), solvents, toxic waste sites, air pollutants and heavy metals, with the strongest evidence found for air pollutants and pesticides. Gestational exposure to methylmercury (through fish exposure, one study) and childhood exposure to pollutants in water supplies (two studies) were not found to be associated with ASD risk. In the second category of studies investigating biomarkers of toxicants and ASD, a large number was dedicated to examining heavy metals. Such studies demonstrated mixed findings, with only 19 of 40 (47%) case-control studies reporting higher concentrations of heavy metals in blood, urine, hair, brain or teeth of children with ASD compared with controls. Other biomarker studies reported that solvent, phthalate and pesticide levels were associated with ASD, whereas PCB studies were mixed. Seven studies reported a relationship between autism severity and heavy metal biomarkers, suggesting evidence of a dose-effect relationship. Overall, the evidence linking biomarkers of toxicants with ASD (the second category) was weaker compared with the evidence associating estimated exposures to toxicants in the environment and ASD risk (the first category) because many of the biomarker studies contained small sample sizes and the relationships between biomarkers and ASD were inconsistent across studies. Regarding the third category of studies investigating potential genetic susceptibilities to toxicants, 10 unique studies examined polymorphisms in genes associated with increased susceptibilities to toxicants, with 8 studies reporting that such polymorphisms were more common in ASD individuals (or their mothers, 1 study) compared with controls (one study examined multiple polymorphisms). Genes implicated in these studies included paraoxonase (PON1, three of five studies), glutathione S-transferase (GSTM1 and GSTP1, three of four studies), delta-aminolevulinic acid dehydratase (one study), SLC11A3 (one study) and the metal regulatory transcription factor 1 (one of two studies). Notably, many of the reviewed studies had significant limitations, including lack of replication, limited sample sizes, retrospective design, recall and publication biases, inadequate matching of cases and controls, and the use of nonstandard tools to diagnose ASD. The findings of this review suggest that the etiology of ASD may involve, at least in a subset of children, complex interactions between genetic factors and certain environmental toxicants that may act synergistically or in parallel during critical periods of neurodevelopment, in a manner that increases the likelihood of developing ASD. Because of the limitations of many of the reviewed studies, additional high-quality epidemiological studies concerning environmental toxicants and ASD are warranted to confirm and clarify many of these findings.
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16. Shafai T, Mustafa M, Hild T, Mulari J, Curtis A. {{The Association of Early Weaning and Formula Feeding with Autism Spectrum Disorders}}. {Breastfeed Med};2014 (Feb 7)
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17. van der Molen MJ, Stam CJ, van der Molen MW. {{Resting-state EEG oscillatory dynamics in fragile x syndrome: abnormal functional connectivity and brain network organization}}. {PLoS One};2014;9(2):e88451.
Disruptions in functional connectivity and dysfunctional brain networks are considered to be a neurological hallmark of neurodevelopmental disorders. Despite the vast literature on functional brain connectivity in typical brain development, surprisingly few attempts have been made to characterize brain network integrity in neurodevelopmental disorders. Here we used resting-state EEG to characterize functional brain connectivity and brain network organization in eight males with fragile X syndrome (FXS) and 12 healthy male controls. Functional connectivity was calculated based on the phase lag index (PLI), a non-linear synchronization index that is less sensitive to the effects of volume conduction. Brain network organization was assessed with graph theoretical analysis. A decrease in global functional connectivity was observed in FXS males for upper alpha and beta frequency bands. For theta oscillations, we found increased connectivity in long-range (fronto-posterior) and short-range (frontal-frontal and posterior-posterior) clusters. Graph theoretical analysis yielded evidence of increased path length in the theta band, suggesting that information transfer between brain regions is particularly impaired for theta oscillations in FXS. These findings are discussed in terms of aberrant maturation of neuronal oscillatory dynamics, resulting in an imbalance in excitatory and inhibitory neuronal circuit activity.
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18. Zhang X, Zhao Y, Bao X, Zhang J, Cao G, Wu X. {{[Genetic features and mechanism of Rett syndrome in Chinese population]}}. {Zhonghua Yi Xue Yi Chuan Xue Za Zhi};2014 (Feb);31(1):1-5.
OBJECTIVE: To analyze the genetic characteristics and molecular mechanism of Chinese patients with Rett syndrome (RTT) and assess the recurrent risk in order to provide genetic counseling for the family with RTT patient. METHODS: Methyl-CpG-binding protein 2 (MECP2) gene mutation analysis were performed on 405 Chinese RTT cases and 292 mothers of the patients with MECP2 mutations with polymerase chain reaction (PCR), direct sequencing and multiplex ligation-dependent probe amplification (MLPA). Then cyclin-dependent kinase-like 5 (CDKL5) and forkhead box protein G1 (FOXG1) genes mutation analysis were performed on the patients without MECP2 mutation. Parental origin of mutated MECP2 gene was detected with allele specific PCR analysis. Based on the difference methylation in CpG island of the first exon of human androgen-receptor gene on active and inactive X-chromosomes, methylation sensitive restriction endonuclease digestion was used to analyze the X-chromosome inactive (XCI) patterns. RESULTS: MECP2 gene mutation was found in 86.9% RTT cases. CDKL5 gene mutation was found in only 3 cases with early-onset seizures variant. No FOXG1 mutation was found. There were 94.4% MECP2 mutations of paternal origin,and point mutations were common. However, microdeletions were common in maternal origin mutation. MECP2 gene mutation was found in only 1 (0.34%,1/292) mother with normal phenotype and non-random XCI pattern. Her daughter was a RTT patient with preserved speech variant, and her XCI pattern was random. CONCLUSION: MECP2 is the main pathogenic gene in RTT. CDKL5 gene should be screened in patients with early-onset seizures variant without MECP2 gene mutation. The majority of RTT patients had paternally derived de novo MECP2 gene mutation, which may explain the high female to male ratio in RTT. Only 0.34% mothers carried the pathogenic mutation, indicating a lower recurrent risk for RTT families. The XCI may modulate the phenotype of RTT, so MECP2 gene mutation screening in the mothers is important for genetic counseling.
