Genetics contribution to the understanding of autism]

Autism is a pervasive developmental disorder characterised by an impairment in social interaction and in communication, with unusual behaviour. Genetic factors are predominent in autism pathogenesis, in contrast with the environmental factors that would modulate the phenotype. The genetic polymorphism and the phenotypic heterogeneity make the autism a complex disorder to study. Genetic research on families with multiple affected children and biochemical mechanisms studies represent the sources for identifying the susceptibility genes in autism.     

Autism Spectrum Disorders at 20 and 42 Months of Age: Stability of Clinical and ADI-R Diagnosis

The association between, and stability of, clinical diagnosis and diagnosis derived from the Autism Diagnostic Interview-Revised (ADI-R; Lord, Rutter, & Le Couteur, 1994) was examined in a sample of prospectively identified children with childhood autism and other pervasive developmental disorders assessed at the age of 20 months and 42 months. Clinical diagnosis of autism was stable, with all children diagnosed with childhood autism at age 20 months receiving a diagnosis of childhood autism or a related pervasive developmental disorder (PDD) at age 42 months. Clinical diagnosis of childhood autism was also reasonably sensitive, with all children who went on to receive a clinical diagnosis of childhood autism at 42 months being identified as having autism or PDD at 20 months. However, clinical diagnosis for PDD and Asperger's syndrome lacked sensitivity at 20 months, with several children who subsequently received these diagnoses at 42 months receiving diagnoses of language disorder or general developmental delay, as well as in two cases being considered clinically normal, at the earlier timepoint. The ADI-R was found to have good specificity but poor sensitivity at detecting childhood autism at 20 months; however, the stability of diagnosis from 20 to 42 months was good. In addition, the ADI-R at age 20 months was not sensitive to the detection of related PDDs or Asperger's syndrome. The continuity and discontinuity between behavioural abnormalities identified at both timepoints in the three domains of impairment in autism was examined, both in children who met final clinical criteria for an autistic spectrum disorder, and for children with language disorder who did not, as well as for a small sample of typically developing children.     

Brief report: validity of Finnish registry‐based diagnoses of autism with the ADI‐R

Aims: The aim of the study was to explore the validity of registry‐based diagnoses of autism in Finland using the Autism Diagnostic Interview – Revised (ADI‐R). This study was designed for the Finnish Prenatal Study of Autism and Autism Spectrum Disorders (FIPS‐A), an ongoing research project where registry‐based diagnoses will be used for epidemiological studies. Methods: In this small pilot study, a clinical sample of 95 subjects diagnosed with childhood autism or pervasive developmental disorder/pervasive developmental disorder – not otherwise specified (PDD/PDD‐NOS) or Asperger′s syndrome according to the Finnish Hospital Discharge Register (FHDR) was gathered nationwide. A small control group consisting of siblings without any registered diagnoses of those being examined was also included in the study. Diagnoses were further re‐evaluated by interviewing parents with the ADI‐R. Results: The mean scores of autistic subjects clearly exceeded cut‐off limits for autism on all three ADI‐R domains and 96% of the subjects with registered diagnosis of childhood autism fulfilled the criteria based on the instrument as well. Conclusion: These results suggest that the validity of Finnish registry‐based diagnoses of childhood autism can be considered good. Our findings lay important groundwork for further population‐ based studies of the aetiology of autism.     

The genetics of autism.

Autism is a significant childhood disorder. Studies are underway to define more clearly the disorder and its various manifestations and to correlate this information with an etiology. Genes are known to play an important role in autism, and a vigorous search is underway to define those genes.The Human Genome Project provides the basis that allows us to move beyond single gene disorders and to contemplate progress for complex disorders, such as autism. Genome screens of affected siblings and detailed molecular analyses of chromosome abnormalities identified in autistic subjects has led in the past year to the identification of several candidate genes. However, the problem of determining which are the real genes remains. This is complicated because the presentation of the disorder is so variable, and milder manifestations in relatives are not yet understood. But the fact that we can now name possible genes for this disorder reflects how quickly our understanding is progressing.     

Imprinting, the X-chromosome, and the male brain: explaining sex differences in the liability to autism

Males are at least four times more likely to develop autism than females. Among relatives with a broader autistic phenotype, males predominate too. Autism is a highly heritable disorder, yet genome scans have not revealed any predisposing loci on the sex chromosomes. A nongenetic explanation for male vulnerability, such as exposure to prenatal androgens, is unlikely for a variety of reasons. A novel genetic mechanism that resolves many of the outstanding difficulties is outlined here. The imprinted-X liability threshold model hypothesizes that the threshold for phenotypic expression of many autistic characteristics is influenced by an imprinted X-linked gene(s) that is protective in nature. Imprinted genes are known to play an important role in normal fetal and behavioral development. The gene is expressed only on the X-chromosome that is inherited from the father and raises the threshold for phenotypic expression. It is normally silenced when transmitted maternally. Because only females have a paternal X-chromosome, the threshold for phenotypic expression is higher in them than in males. Evidence for the existence of the genetic locus was found in a study of females with X-monosomy (Turner's syndrome) in which females had either a single paternal or maternal X-chromosome. Identifying the sites of action of this X-linked gene could lead to the discovery of autosomal loci that confer more directly a predisposition to autism.     

Prader-Willi syndrome: intellectual abilities and behavioural features by genetic subtype

BACKGROUND: Studies of chromosome 15 abnormality have implicated over-expression of paternally imprinted genes in the 15q11-13 region in the aetiology of autism. To test this hypothesis we compared individuals with Prader-Willi syndrome (PWS) due to uniparental disomy (UPD--where paternally imprinted genes are over-expressed) to individuals with the 15q11-13 deletion form of the syndrome (where paternally imprinted genes are not over-expressed). We also tested reports that PWS cases due to the larger type I (TI) form of deletion show differences to cases with the smaller type II (TII) deletion. METHOD: Ninety-six individuals with PWS were recruited from genetic centres and the PWS association. Forty-nine individuals were confirmed as having maternal UPD of chromosome 15 and were age and sex matched to 47 individuals with a deletion involving 15q11-13 (32 had the shorter (T II) deletion, and 14 had the longer (TI) deletion). Behavioural assessments were carried out blind to genetic status, using the Autism Diagnostic Observation Schedule (ADOS), the Autism Diagnostic Interview (ADI), the Autism Screening Questionnaire (ASQ), the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), the Vineland Adaptive Behaviour Scales (VABS), and measurements of intellectual ability, including the Wechsler and Mullen Scales and Raven's Matrices. RESULTS: UPD cases exhibited significantly more autistic-like impairments in reciprocal social interaction on questionnaire, interview and standardised observational measures. Comparison of TI and TII deletion cases revealed few differences, but ability levels tended to be lower in the TI deletion cases. CONCLUSIONS: Findings from a large study comparing deletion and UPD forms of Prader-Willi syndrome were consistent with other evidence in indicating that paternally imprinted genes in the 15q11-13 region constitute a genetic risk factor for aspects of autistic symptomatology. These genes may therefore play a role in the aetiology of autism. By contrast with another report, there was no clear-cut relationship between the size of the deletion and the form of cognitive and behavioural phenotype.     

人神经前体细胞移植治疗儿童广泛性发育障碍初探

目的：观察人神经前体细胞（hNPCs）移植治疗儿童广泛性发育障碍的安全性及疗效。方法：对22例广泛性发育障碍患儿进行研究,其中孤独症9例,Rett综合征13例,经颅骨钻孔侧脑室穿刺注射hNPCs治疗。分别于手术前、术后1个月、术后6个月、术后1年采用孤独症行为评定量表（ABC）对移植患儿进行评估。结果：治疗及随访过程中无严重不良事件发生。移植后22例患儿中,1例失访,17例患儿临床症状出现不同程度的改善,其中孤独症患儿8例,Rett综合征患儿9例。孤独症患儿行ABC量表评估后发现,术后6个月交往因子得分,以及术后1年ABC总分、交往及语言因子得分均低于术前,差异有统计学意义（P<0.05）。结论：临床应用hNPCs移植治疗儿童广泛性发育障碍是安全、可行的,并具有一定疗效,有必要扩大观察病例数进一步研究。     

可导致孤独症谱系障碍的肉碱缺乏症

孤独症谱系障碍是一组神经发育障碍性疾病, 导致社交障碍、 交流困难及行为异常, 病因复杂, 已知多种遗传和非遗传因素可导致多种类型的孤独症表现。左旋肉碱（左卡尼汀）是一种水溶性维生素亚类, 结构类似氨基酸, 参与多种物质代谢, 主要功能是将长链脂肪酸从胞浆转移到线粒体内质网进行β-氧化代谢。肉碱缺乏症可导致孤独症谱系障碍等精神行为异常, 一些患者发生心脏、 骨骼肌、 脑、 肝脏等多器官损伤, 严重者猝死。正常情况下, 机体通过饮食摄入、 内源合成、 肾脏排泄与重吸收来保证左卡尼汀的稳态。肉碱在机体的内源性合成通过线粒体内四步酶促反应完成, 三甲基赖氨酸羟化酶是肉碱合成中的一个关键酶。三甲基赖氨酸羟化酶缺乏症是一种X连锁遗传病, 引起肉碱合成障碍, 是导致孤独症谱系障碍病因之一。早期诊断, 早期补充左卡尼汀, 是改善三甲基赖氨酸羟化酶缺乏症所致孤独症患者预后的关键。     

The co-occurrence of autism spectrum disorder and attention-deficit/hyperactivity disorder symptoms in parents of children with ASD or ASD with ADHD

Background: Autism spectrum disorder (ASD) and attention‐deficit/hyperactivity disorder (ADHD) share about 50–72% of their genetic factors, which is the most likely explanation for their frequent co‐occurrence within the same patient or family. An additional or alternative explanation for the co‐occurrence may be (cross‐)assortative mating, e.g., the tendency to choose a partner that is similar or dissimilar to oneself. Another issue is that of parent‐of‐origin effect which refers to the possibility of parents differing in the relative quantity of risk factors they transmit to the offspring. The current study sets out to examine (cross‐)assortative mating and (cross‐)parent‐of‐origin effects of ASD and ADHD in parents of children with either ASD or ASD with ADHD diagnosis. Methods: In total, 121 families were recruited in an ongoing autism‐ADHD family genetics project. Participating families consisted of parents and at least one child aged between 2 and 20 years, with either autistic disorder, Asperger disorder or PDD‐NOS, and one or more biological siblings. All children and parents were carefully screened for the presence of ASD and ADHD. Results: No correlations were found between maternal and paternal ASD and ADHD symptoms. Parental ASD and ADHD symptoms were predictive for similar symptoms in the offspring, but with maternal hyperactive‐impulsive symptoms, but not paternal symptoms, predicting similar symptoms in daughters. ASD pathology in the parents was not predictive for ADHD pathology in the offspring, but mother’s ADHD pathology was predictive for offspring ASD pathology even when corrected for maternal ASD pathology. Conclusions: Cross‐assortative mating for ASD and ADHD does not form an explanation for the frequent co‐occurrence of these disorders within families. Given that parental ADHD is predictive of offspring’ ASD but not vice versa, risk factors underlying ASD may overlap to a larger degree with risk factors underlying ADHD than vice versa. However, future research is needed to clarify this issue.     

Further evidence for genetic heterogeneity in familial hemophagocytic lymphohistiocytosis (FHLH)

Familial hemophagocytic lymphohistiocytosis (FHLH; MIM #267700) is an autosomal recessive disorder of immune regulation characterized by fever, hepatosplenomegaly, and cytopenia that is fatal without bone marrow transplantation. Recent studies have suggested the existence of FHLH loci at 9q21.3-22 and t0q21-22 in Asian and European/African/Australian families, respectively. We studied two unrelated Canadian families in which first cousins were affected with FHLH. In an effort to localize the causative gene, we completed a genome-wide screen for homozygosity by descent by using an automated system to genotype 400 highly polymorphic dinucleotide repeat markers covering the genome with an average resolution of 10 centiMorgans (cM). We identified a total of three candidate loci that met the combined criteria for homozygosity by descent in one family and shared maternal alleles in the other family. One of these, D9S1690, had a cytogenetic localization (9q22.33) proximal to a previously reported inversion of chromosome 9 in an FHLH patient. However, additional closely linked flanking markers within 1-2 cM of all three candidates did not conform to the criteria for linkage in either family. Similarly, we excluded the linked 9q21.3-q22 and 10q21-22 regions recently reported in Asian and European/African/Australian families, respectively. The two families were then analyzed independently to encompass the possibility that they were segregating separate genes. Six additional candidate loci were identified on the basis of homozygosity for the same allele in all affected members of one family, but further analysis of closely linked flanking markers did not demonstrate similar homozygosity. Our data provide further evidence of genetic heterogeneity in FHLH and suggest the existence of at least a third locus for this disease.     

Office screening and early identification of children with autism

Autism spectrum disorders (ASDs), also called pervasive developmental disorders in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revised), constitute a group of neurodevelopmental disorders that coalesce around a common theme of impairments in social functioning, communication abilities, and repetitive or rigid behaviors. The ASDs considered here include autism/autistic disorder, Asperger disorder/Asperger syndrome (AS), and pervasive developmental disorder not otherwise specified. This article focuses on autism/autistic disorder screening and its early identification, with a brief mention for AS screening, as there are limited tools and no recommendation for universal screening for AS.     

Autism spectrum disorders: clinical and research frontiers

Autism spectrum disorders (ASD) are common neurodevelopmental disorders that occur along a broad continuum of severity with impairments in social interactions, communication and behaviour. This review highlights recent advances in autism research that shed light on the causes of the disorder and that have implications for clinical practice. It focuses on (1) the rising prevalence of ASD with attention given to recent epidemiological studies, (2) important genetic discoveries that may affect clinical evaluation of children with ASD, (3) active areas of research in cognitive neuroscience that seek to explain the underlying mechanisms of a complex disorder and (4) important studies on clinical populations with implications for screening and early identification of infants and toddlers with ASD.     

科学关注孤独症谱系障碍儿童的干预及全方位发展

孤独症谱系障碍是一种广泛发育障碍性疾病,临床主要以社会交往沟通障碍、刻板行为和狭窄兴趣为主要特征。随着更多孤独症谱系障碍相关知识的普及,我国接受干预的患儿也逐年增多,多集中在小年龄段的干预。儿科医务工作者应该关注干预方法的效果评价和这些孩子人生多个阶段所面临的问题,考虑到他们的全方位的发展。     

Clinical management of adolescents with autism

Autism spectrum disorder is a spectrum of neurodevelopmental disorders that includes autistic disorder and pervasive developmental disorder-not otherwise specified. This article provides the reader with an overview of the major psychosocial issues related to adolescents with autism. This discussion is followed by an interjection of medications that may be useful in maximizing the functioning of adolescents with autism.     

Autism: Fifty years on from Kanner

It is now 50 years since Leo Kanner first described autism as a distinctive pattern of symptoms in some children with severe developmental problems. Since then the assessment and diagnosis of children with pervasive disorders of development has been refined and much is known about the phenomenology and epidemiology. Autism is a biological disorder of the central nervous system (CNS) of unknown cause. It is associated with a number of organic disorders such as epilepsy and has comorbidity with other psychiatric disorders such as tic disorder. Cognitive abnormalities in social interactions, affect and language are present but there is still debate regarding which of these, if any, is the primary cognitive deficit. Special education and behavioural management has led to modest but important developmental improvement in many children with autism. Autism remains a life-long condition but patterns of symptoms change and skills develop from childhood into adult life.     

Editorial Perspective: Longitudinal research in autism – introducing the concept of ‘chronogeneity’

Autism Spectrum Disorder (ASD or autism) is a heterogeneous neurodevelopmental disorder. We are now at a critical juncture in autism research where we have the knowledge base and expertise to begin to think about studies that view heterogeneity, not as ‘statistical noise’ that can be ‘accounted for’ using data‐reduction techniques (such as group trajectories), but rather as ‘informative variance’ that can help form a more precise and dynamic picture of autism. In this Editorial we coin a new term and introduce the concept of ‘chronogeneity’ for the study of autism heterogeneity in relation to the dimension of time (chrono). Using examples of ongoing research and analytical advances we build the case for the potential utility of the concept of ‘chronogeneity’ and argue that a refined approach to the longitudinal investigation of autism (and other neurodevelopmental disorders) may move us closer to more precise and adaptive models of care for the children and youth affected by these disorders.     

Clinical features and molecular genetic analysis of a boy with Prader-Willi syndrome caused by an imprinting defect

Abstract Prader-Willi syndrome (PWS) is a neuroendocrine disorder caused by a non-functioning paternally derived gene(s) within the chromosome region 15q11-q13. Most cases result from microscopically visible deletions of paternal origin, or maternal uniparental disomy of chromosome 15. In both instances no recurrence has been reported. In rare cases, PWS is associated with lack of gene expression from the paternal allele due to an imprinting defect. We report the clinical features and the molecular genetic analysis of the first Danish child with PWS due to a defect of the putative imprinting centre (IC). When the imprinting mutation is inherited from a carrier father, the risk that future children will be affected is theoretically 50%. It is therefore important that these families are referred to a geneticist for counselling and further investigation. Prenatal diagnosis is currently only feasible when the mutation has been identified in the affected child.     

The familial aggregation of the lesser variant in biological and nonbiological relatives of PDD probands: a family history study

OBJECTIVE: To determine the risk of the lesser variant (or PDD-like traits) in the biological and nonbiological second- and third-degree relatives of PDD probands using a screening questionnaire and to investigate the extent to which the risk of the lesser variant differs according to various characteristics of the proband. METHOD: The sample consists of a series of 34 nuclear families with 2 affected PDD children (multiplex, MPX), 44 families with a single PDD child (simplex, SPX), and 14 families who adopted a PDD child. Data on characteristics of the lesser variant in 1362 biological and 337 nonbiological second- and third-degree relatives were collected from parents by telephone interview and from several maternal and paternal relatives by questionnaire. RESULTS: All components of the lesser variant were more common in biological relatives (BR) than nonbiological relatives (NBR), confirming the familial aggregation of the traits. Proband characteristics associated with an increased risk of the lesser variant in relatives were a higher level of functioning and coming from a MPX family. CONCLUSIONS: These findings on the familial aggregation of the lesser variant suggest that the genes for PDD also confer susceptibility to the lesser variant and that PDD may be a genetically heterogeneous disorder.     

Sensory Experiences Questionnaire: discriminating sensory features in young children with autism, developmental delays, and typical development

BACKGROUND: This study describes a new caregiver-report assessment, the Sensory Experiences Questionnaire (SEQ), and explicates the nature of sensory patterns of hyper- and hyporesponsiveness, their prevalence, and developmental correlates in autism relative to comparison groups. METHOD: Caregivers of 258 children in five diagnostic groups (Autism, PDD, DD/MR, Other DD, Typical) ages 5-80 months completed the SEQ. RESULTS: The SEQ's internal consistency was alpha' = .80. Prevalence of overall sensory symptoms for the Autism group was 69%. Sensory symptoms were inversely related to mental age. The Autism group had significantly higher symptoms than either the Typical or DD groups and presented with a unique pattern of response to sensory stimuli -hyporesponsiveness in both social and nonsocial contexts. A pattern of hyperresponsiveness was similar in the Autism and DD groups, but significantly greater in both clinical groups than in the Typical group. CONCLUSION: The SEQ was able to characterize sensory features in young children with autism, and differentiate their sensory patterns from comparison groups. These unique sensory patterns have etiological implications, as well as relevance for assessment and intervention practices.     

高功能与低功能学龄期孤独症儿童共患病研究

目的 了解学龄期高功能与低功能孤独症儿童共患病的发生情况。方法 采用横断面研究,对2011年9月至2011年11月北京大学精神卫生研究所门诊连续就诊、能够配合检查的62例孤独症儿童,年龄6～16岁、符合美国精神障碍诊断与统计手册第4版（DSM-IV）中孤独症诊断标准的儿童进行调查和评定。内容包括：一般状况调查、中国修订韦氏儿童智力量表（WISC）评定（不能进行韦氏测查者进行瑞文标准推理测验、比奈测验或图片词汇测验评定）、学龄儿童情感障碍和精神分裂症问卷（K-SADS-PL）评定、儿童总评问卷（C-GAS）评定、儿童孤独症评定量表（CARS）评定。结果 高功能孤独症组（IQ≥70）共患病终生共患率100%（29/29）,目前共患率为96.5%（28/29）。低功能孤独症组（IQ＜70）共患病终生共患率及目前共患率均为100%（33/33）。高功能孤独症组终生及目前共患情感障碍、焦虑障碍、广泛焦虑障碍、注意缺陷多动障碍、对立违抗障碍、抽动障碍的比例高于低功能孤独症组（P均＜0.05）。高功能孤独症组精神科用药史、目前上学比例高于低功能孤独症组,自幼发育落后比例低于低功能孤独症组（P均＜0.05）。高功能孤独症组CARS得分低于低功能孤独症组,C-GAS得分高于低功能孤独症组（P均＜0.05）。结论 共患病在学龄期高功能及低功能孤独症儿童中均非常常见。高功能孤独症患儿较低功能孤独症患儿具有更多的情绪行为障碍、较轻的孤独症症状、更多的精神科用药史,总体功能优于低功能孤独症患儿