Lessons from fragile X regarding neurobiology, autism, and neurodegeneration

The fragile X mental retardation 1 gene (FMR1) mutation causes two disorders: fragile X syndrome (FXS) in those with the full mutation and the fragile X-associated tremor/ataxia syndrome (FXTAS) in some older individuals with the premutation. FXS is caused by a deficiency of the FMR1 protein (FMRP) leading to dysregulation of many genes that create a phenotype with ADHD, anxiety, and autism. FXTAS is caused by the elevation of FMR1-mRNA to levels 2 to 8 times normal in the premutation. This causes an RNA gain of function toxicity leading to brain atrophy, white matter disease, neuronal and astrocytic inclusion formation, and subsequent ataxia, intention tremor, peripheral neuropathy, and cognitive decline. The neurobiology and pathophysiology of FXS and FXTAS are described in detail.     

智力低下和孤独症男童脆性X基因突变的研究

目的应用改良基因检测方法,探讨脆性X综合征致病基因(fragileXmentalretardation"1,FMR1)在中国人群智力低下和孤独症中的作用。方法收集2002～2006年小儿神经、遗传代谢门诊诊断的男性孤独症患儿44例、非家族性智力低下男性患儿40例,建立适用于男性的FMR1基因突变检查方法,对检查阳性者以pfxa3探针进行Southern杂交。结果在44例孤独症患儿中,发现1例pfxa3杂交片段约0.2kb,为FMR1前突变;40例智力低下患者中FMR1基因未见异常。结论在孤独症人群中发现的1例FMR1基因前突变,其致病意义有待进一步阐明。     

The Prader-Willi phenotype of fragile X syndrome

The Prader-Willi phenotype (PWP) of fragile X syndrome (FXS) is associated with obesity and hyperphagia similar to Prader-Willi syndrome (PWS), but without cytogenetic or methylation abnormalities at 15q11-13. Thirteen cases of PWP and FXS are reported here that were identified by obesity and hyperphagia. Delayed puberty was seen in 5 of 9 cases who had entered puberty, a small penis or testicles in seven of 13 cases, and infant hypotonia and/or a poor suck in seven of 13 cases. Autism spectrum disorder occurred in 10 of 13 cases, and autism was diagnosed in seven of 13 cases. We investigated cytoplasmic interacting FMR1 protein (CYFIP) expression, which is a protein that interacts with FMR1 protein (FMRP) because the gene for CYFIP is located at 15q11-13. CYFIP mRNA levels were significantly reduced in our patients with the PWP and FXS compared to individuals without FXS (p < .001) and also individuals with FXS without PWP (p = .03).     

Early acceleration of head circumference in children with fragile x syndrome and autism

OBJECTIVE: Head circumference (HC) growth has been shown in several studies to be accelerated early in life in both fragile X syndrome (FXS) and autism spectrum disorders (ASDs), but the rates of growth have not been compared between those with only FXS and those with FXS and ASD (FXS + ASD). METHODS: We hypothesized that individuals with FXS + ASD would have significantly larger HCs from individuals with only FXS and that there would be an early acceleration of HC in both the FXS-only and FXS + ASD groups. HC measurements were available retrospectively for 44 males, five and younger, with FXS, of whom 22 also had ASD. Measurements over time were available for 24 of the 44 children. HC percentiles were compared between the groups in two ways: by focusing on cross-sectional subsamples and by fitting hierarchical linear models to the full sample. RESULTS: Neither group differed significantly from the norm in the first year of life (p > 0.2). At 30 months, the FXS + ASD group was 27 percentile points above the norm (p = .0125), whereas the FXS-only group did not differ from the norm. At 60 months, the FXS-only group was 21 percentile points above the norm (p = .029), whereas the FXS + ASD group did not differ from the norm. CONCLUSION: The group difference in HC growth rate may differentiate brain development in individuals with FXS-only versus those with FXS + ASD.     

Fragile X syndrome: an overview of cause,characteristics, assessment and management

Fragile X syndrome (FXS) is the most common identifiable cause of inherited intellectual disability and autism spectrum conditions, and is associated with a range of physical, cognitive and behavioural characteristics. Alongside intellectual disability, heightened rates of autism spectrum disorder, anxiety disorders, attention-deficit-hyperactivity disorder, self-injury and aggression are reported. Timely identification of FXS as well as assessments of common co-morbid psychological conditions and underlying health problems are essential to ensure individuals with FXS receive appropriate support. This article provides an overview for clinicians of current literature on the cause of FXS as well as the key physical, cognitive, and behavioural characteristics with a focus on children and adolescents.     

Don’t miss patients with atypical FMR1 mutations: dysmorphism and clinical features in a boy with a partially methylated FMR1 full mutation

Fragile X syndrome characterized by intellectual disability (ID), facial dysmorphism, and postpubertal macroorchidism is the most common monogenic cause of ID. It is typically induced by an expansion of a CGG repeat in the fragile X mental retardation 1 (FMR1) gene on Xq27 to more than 200 repeats. Only rarely patients have atypical mutations in the FMR1 gene such as point mutations, deletions, or unmethylated/partially methylated full mutations. Most of these patients show a minor phenotype or even appear clinically healthy. Here, we report the dysmorphism and clinical features of a 17-year-old boy with a partially methylated full mutation of approximately 250 repeats. Diagnosis was made subsequently to the evaluation of a FMR1 premutation as the cause for maternal premature ovarian failure. Dysmorphic evaluation revealed no strikingly long face, no prominent forehead/frontal bossing, no prominent mandible, no macroorchidism, and a head circumference in the lower normal range. Acquisition of a driving license for mopeds and unaccompanied rides by public transport in his home province indicate rather mild ID (IQ?=?58). Conclusion: This adolescent demonstrates that apart from only minor ID, patients with a partially methylated FMR1 full mutation present less to absent pathognomonic facial dysmorphism, thus emphasizing the impact of family history for a straightforward clinical diagnosis.     

Understanding the biological underpinnings of fragile X syndrome

PURPOSE OF REVIEW: The purpose of this review is to present the latest findings on fragile X syndrome and to put them into perspective. Fragile X syndrome is a relatively common form of inherited mental retardation, caused by loss of function of the FMR1 gene on the long arm of the X chromosome. The molecular mechanisms underlying the syndrome are complex and continue to surprise researchers more than 12 years after the cloning of the gene. RECENT FINDINGS: We will specifically discuss the various aspects of the clinical phenotype, reassessed with the employment of functional imaging and electrophysiological techniques. The unexpected finding of a pathologic phenotype in premutation carriers is highlighted, as it represents a new and distinct condition with a different presentation in males and females. The third section deals briefly with the various functions of the FMRP protein, an RNA-binding protein interacting with multiple RNA molecules as well as proteins. It is important to realize that FMRP is probably changing partners several times, depending on its localization, on posttranslational modifications and on the available interacting proteins. In the following section, we present in short recent discoveries on the defective neuronal circuits in the fragile X syndrome. Most of these new data were made available by the study of animal models, mostly the Fmr1 knockout mouse, but also Drosophila. SUMMARY: We briefly discuss the alternative options for treating fragile X syndrome. Presently, a neuropharmacological approach acting on either critical receptors or aimed at reactivating the silenced FMR1 gene appears promising.     

Psychopathology and familial stress - comparison of boys with Fragile X syndrome and spinal muscular atrophy

BACKGROUND: Chronic illness and mental retardation are both associated with an increased rate of behavioural problems in children and with considerable emotional strain in families. The aim of the study was to analyse and compare the specific effects of two exemplary conditions on familial stress and coping. METHODS: Forty-nine boys with Fragile X syndrome (FXS) were compared with 46 boys with Spinal Muscular Atrophy (SMA) and 32 male controls. Intelligence was measured with the RAVEN or K-ABC tests. Psychopathology was assessed with the CBCL questionnaire and a structured psychiatric interview (Kinder-DIPS), parental stress with the QRS, coping with the F-COPES and social support with the F-SOZU questionnaires. RESULTS: The mean age of the FXS boys was 8.6, of the SMA boys 12.7 and of the controls 11.2 years. The mean IQ was 47 for the FXS, 112 for the SMA and 103 for the control groups. According to the CBCL, 89.8% of the FXS boys, 21.7% of the SMA and 15.7% of the controls had a total score in the borderline or clinical range. The rates were 63.3%, 34.8% and 21.9% for internalising and 67.3%, 10.9% and 18.8% for externalising behaviour, respectively. 81.6% of the FXS and 10.9% of the SMA patients had a DSM-IV or ICD-10 psychiatric diagnosis. The most common were ADHD (FXS: 36) and Separation Anxiety Disorder (SMA: 4). In total, parental stress was significantly higher in the FXS than in the SMA families (and in both compared to controls). There were no major inter-group differences regarding social support and familial coping. CONCLUSIONS: Children with FXS are severely mentally retarded and have a high rate of mainly externalising disorders. Despite good coping abilities and social support, this is associated with high familial stress. The SMA boys, with an intelligence in the upper normal range, are no more deviant than their healthy controls. Parental stress is lower in the SMA families with good coping abilities. In conclusion, families with mentally retarded children are in even greater need of help than those of children with severe chronic illness/physical handicap.     

DNA testing for fragile X syndrome in schools for learning difficulties.

Fragile X syndrome is the most common inherited cause of mental retardation. Early diagnosis is important not only for appropriate management of individuals but also to identify carriers who are unaware of their high risk of having an affected child. The disorder is associated with a cytogenetically visible fragile site (FRAXA) at Xq27.3, caused by amplification of a (CGG)n repeat sequence within the gene at this locus designated FMR1. Clinical and molecular studies have been undertaken to screen for fragile X syndrome in 154 children with moderate and severe learning difficulties of previously unknown origin. Southern blot analysis of peripheral blood showed the characteristic abnormally large (CGG)n repeat sequence associated with fragile X syndrome in four of the 154 children. The findings were confirmed by cytogenetic observation of the fragile site and by further molecular studies. The families of the affected children were offered genetic counselling and DNA tests to determine their carrier status. These findings show that there are still unrecognised cases of fragile X syndrome. Given the difficulty of making a clinical diagnosis and the implications for families when the diagnosis is missed, screening in high risk populations may be justified. The issues involved in screening all children in special schools for fragile X syndrome are discussed.     

DNA testing for fragile X syndrome in schools for learning difficulties

Fragile X syndrome is the most common inherited cause of mental retardation. Early diagnosis is important not only for appropriate management of individuals but also to identify carriers who are unaware of their high risk of having an affected child. The disorder is associated with a cytogenetically visible fragile site (FRAXA) at Xq27.3, caused by amplification of a (CGG)n repeat sequence within the gene at this locus designated FMR1. Clinical and molecular studies have been undertaken to screen for fragile X syndrome in 154 children with moderate and severe learning difficulties of previously unknown origin. Southern blot analysis of peripheral blood showed the characteristic abnormally large (CGG)n repeat sequence associated with fragile X syndrome in four of the 154 children. The findings were confirmed by cytogenetic observation of the fragile site and by further molecular studies. The families of the affected children were offered genetic counselling and DNA tests to determine their carrier status. These findings show that there are still unrecognised cases of fragile X syndrome. Given the difficulty of making a clinical diagnosis and the implications for families when the diagnosis is missed, screening in high risk populations may be justified. The issues involved in screening all children in special schools for fragile X syndrome are discussed.     

Verhaltensphänotyp des fragilen X-Syndroms

Aim of the study. As many phenotypic signs develop postpubertally, the aim of the study was to analyse the specific behavioural phenotype of the fragile X syndrome (FXS). In addition to that the practical relevance of the applied questionnaires was examined with respect to the pediatric practice. Methods. Parents of 49 boys with FXS and 16 boys with Tuberous Sclerosis filled out the “Child Behavior Checklist”(CBCL/4–18), the“Developmental Behavior Checklist”(DBC) and the “Fragebogen über Verhalten und soziale Kommunikation”(VSK). Results. 90% of boys with FXS had clinically relevant behavioural problems, mainly attentional and hyperactive symptoms.Also social problems and autistic behaviour are common,which can lead to a misdiagnosis of infantile autism.This pattern of behaviour is specific for FXS, even compared to other types of mental retardation. Conclusions. Boys with FXS show a specific behavioural phenotype with a high psychiatric comorbidity – both in comparison to children with normal intelligence and mental retardation.Parental questionnaires, especially for mentally retarded children (DBC), are highly relevant in assessing the behavioural phenotype and planing therapeutical interventions.     

Discovering fragile X syndrome: family experiences and perceptions

We used surveys from 274 families who had at least 1 child with fragile X syndrome (FXS) to determine their experiences in discovering FXS, factors associated with the timeliness of discovery, and the perceived consequences of obtaining this information. For families of male children who were born in the last decade, someone first became concerned about the child's development at an average age of 13 months. Professional confirmation of a developmental delay did not occur until an average age of 21 months, and a FXS diagnosis occurred at an average age of nearly 32 months. Families reported several barriers to discovering FXS and frustration with the process. Many families had additional children with FXS without knowing reproductive risk. A range of perceived benefits and challenges associated with the discovery were reported. We conclude that selected pediatric practices could promote earlier identification but in only a limited way and predict that disorders such as FXS will continue to challenge current criteria for determining viable candidate disorders for newborn screening.     

Autism medical comorbidities

Medical comorbidities are more common in children with autism spectrum disorders (ASD) than in the general population. Some genetic disorders are more common in children with ASD such as Fragile X syndrome, Down syndrome, Duchenne muscular dystrophy, neurofibromatosis type I, and tuberous sclerosis complex. Children with autism are also more prone to a variety of neurological disorders, including epilepsy, macrocephaly, hydrocephalus, cerebral palsy, migraine/headaches, and congenital abnormalities of the nervous system. Besides, sleep disorders are a significant problem in individuals with autism, occurring in about 80% of them. Gastrointestinal (GI) disorders are significantly more common in children with ASD; they occur in 46% to 84% of them. The most common GI problems observed in children with ASD are chronic constipation, chronic diarrhoea, gastroesophageal reflux and/or disease, nausea and/or vomiting, flatulence, chronic bloating, abdominal discomfort, ulcers, colitis, inflammatory bowel disease, food intolerance, and/or failure to thrive. Several categories of inborn-errors of metabolism have been observed in some patients with autism including mitochondrial disorders, disorders of creatine metabolism, selected amino acid disorders, disorders of folate or B12 metabolism, and selected lysosomal storage disorders. A significant proportion of children with ASD have evidence of persistent neuroinflammation, altered inflammatory responses, and immune abnormalities. Anti-brain antibodies may play an important pathoplastic mechanism in autism. Allergic disorders are significantly more common in individuals with ASD from all age groups. They influence the development and severity of symptoms. They could cause problematic behaviours in at least a significant subset of affected children. Therefore, it is important to consider the child with autism as a whole and not overlook possible symptoms as part of autism. The physician should rule out the presence of a medical condition before moving on to other interventions or therapies. Children who enjoy good health have a better chance of learning. This can apply to all children including those with autism.     

Fragile X syndrome: an update and review for the primary pediatrician

Fragile X syndrome (FXS) is the most common inherited cause of mental retardation. Since the initial identification of the responsible gene more than a decade ago, substantial progress has been made in both the clinical aspects of the disorder and its mechanistic basis; hence, it is important for primary care physicians to be familiar with these advances when providing anticipatory guidance. Timely diagnosis allows children to receive early intervention services and families to receive genetic counseling. Here the current state of knowledge is reviewed and a framework is provided for early recognition and diagnosis, along with counseling and treatment implications for the children and family members.     

Characteristics of autism spectrum disorder in Cornelia de Lange syndrome

Background: The prevalence of autism spectrum disorder (ASD) symptomatology is comparatively high in Cornelia de Lange syndrome (CdLS). However, the profile and developmental trajectories of these ASD characteristics are potentially different to those observed in individuals with idiopathic ASD. In this study we examine the ASD profile in CdLS in comparison to a matched group of individuals with ASD. Method: The Autism Diagnostic Observation Schedule (ADOS) was administered to 20 individuals with CdLS (mean age = 11.34; range = 6–13 years) and 20 individuals with idiopathic ASD (mean age = 10.42; range = 8–11 years). Participants were matched according to adaptive behaviour and receptive language skills. Results: Sixty‐five percent (N = 13) of individuals with CdLS met the cut‐off score for autism on the total ADOS score. Further analysis at domain and item level indicated that individuals with CdLS showed significantly less repetitive behaviour, (specifically sensory interests); more eye contact, more gestures and less stereotyped speech than the ASD group. The CdLS group also showed higher levels of anxiety. Conclusions: The comparison between CdLS and idiopathic ASD indicates subtle group differences in the profile of ASD symptomatology that are not accounted for by degree of intellectual disability or receptive language skills. These differences may not be evident when relying solely upon clinical and domain level scores, but may be distinguishing features of the ASD presentations in the two disorders. The findings have implications for the conceptualisation and assessment of ASD in individuals with genetic syndromes.     

Research review: structural language in autistic spectrum disorder - characteristics and causes

Background: Structural language anomalies or impairments in autistic spectrum disorder (ASD) are theoretically and practically important, although underrecognised as such. This review aims to highlight the ubiquitousness of structural language anomalies and impairments in ASD, and to stimulate investigation of their immediate causes and implications for intervention. Method: Studies of structural language in ASD are reviewed (based on a search of the literature and selected as meeting defined inclusion criteria), and explanatory hypotheses are discussed. Results: Some individuals with ASD never acquire language. Amongst those who do, language abilities range from clinically normal (ALN) to various degrees of impairment (ALI). Developmental trajectories and individual profiles are diverse, and minority subgroups have been identified. Specifically: language is commonly but not always delayed and delayed early language is always characterised by impaired comprehension and odd utterances, and sometimes by deviant articulation and grammar. Nevertheless, by school age an ‘ASD‐typical’ language profile emerges from group studies, with articulation and syntax least affected, and comprehension, semantics and certain facets of morphology most affected. Thus, even individuals with ALN have poor comprehension relative to expressive language; also semantic‐processing anomalies and idiosyncratic word usage. It is argued that impaired socio‐emotional‐communicative relating, atypical sensory‐perceptual processing, and uneven memory/learning abilities may underlie shared language anomalies across the spectrum; and that varying combinations of low nonverbal intelligence, semantic memory impairment and comorbidities including specific language impairment (SLI), hearing impairment, and certain medical syndromes underlie ALI and variation in individual profiles. Conclusions: Structural language is universally affected in ASD, due to a complex of shared and unshared causal factors. There is an urgent need for more research especially into the characteristics and causes of clinically significant language impairments.     

发根脆性X智力低下蛋白检测法诊断脆性X综合征

目的：至今已有多种筛查和诊断脆性X综合征(fragile X syndrome,FXS)的方法,以PCR法和Southern印迹方法应用最广,然而每种方法均存在各自的局限性。该研究探讨发根脆性X智力低下蛋白（fragile X mental retardation protein,FMRP）检测在诊断或筛查FXS中的可靠性,以建立一种快速、简便、价廉且可靠的诊断FXS的方法。方法：采用发根FMRP免疫组化的检测方法对80例健康儿童、40例不明原因智力低下儿童、已确诊FXS家系成员12例进行检查; 用7-deza-dGTP PCR 法进行对照,探讨其对诊断FXS的应用价值。结果：在80例健康儿童中,发根FMRP的表达率均在80%以上。40例不明原因智力低下患儿中,2例确诊为FXS患儿的发根FMRP表达率分别为10%和0,另38例非FXS患者发根FMRP的表达率均在80%以上。在FXS家系调查中,确诊的2例FXS患者的发根FMRP表达率均为0。结论：发根FMRP检测诊断FXS具有快速、简便、价廉、可靠等特点,值得进一步推广应用。［中国当代儿科杂志,2009,11（10）：817-820］     

Systemic and maxillofacial characteristics of 11 Japanese children with Russell–Silver syndrome

Russell–Silver syndrome (RSS) is a congenital anomaly characterized by intrauterine and postnatal growth retardation, typical facial features, fifth‐finger clinodactyly, and skeletal asymmetry. Although data on intrauterine and postnatal growth retardation have been reported, there are few reports concerning the typical maxillofacial morphology in individuals with RSS. The aim of this study was to describe the details of this systemic condition and to characterize maxillofacial morphology based on cephalograms in 11 Japanese patients (age range, 3.9–12.0 years) with RSS. All 11 individuals had intrauterine and postnatal growth retardation. In addition, most showed mandibular retrognathia and relative macrocephaly. Lateral cephalogram measurements showed that mandibular retrognathia resulted from short mandibular body length, whereas the depth of the cranial base was close to normal. Although asymmetry of hand, foot, and limb length were present in most individuals, obvious facial asymmetry was not common. Differences between left and right skeletal and dental age were not observed, indicating that children with RSS might show asymmetry because of quantitative differences in skeletal growth rather than delayed growth rate. Our findings not only provide important information about the maxillofacial characteristics of RSS, but also help to clarify the association between these characteristics and genetics, which will add to the body of information on clinical symptoms.     

Health supervision for children with fragile X syndrome

Fragile X syndrome (an FMR1-related disorder) is the most commonly inherited form of mental retardation. Early physical recognition is difficult, so boys with developmental delay should be strongly considered for molecular testing. The characteristic adult phenotype usually does not develop until the second decade of life. Girls can also be affected with developmental delay. Because multiple family members can be affected with mental retardation and other conditions (premature ovarian failure and tremor/ataxia), family history information is of critical importance for the diagnosis and management of affected patients and their families. This report summarizes issues for fragile X syndrome regarding clinical diagnosis, laboratory diagnosis, genetic counseling, related health problems, behavior management, and age-related health supervision guidelines. The diagnosis of fragile X syndrome not only involves the affected children but also potentially has significant health consequences for multiple generations in each family.     

Longitudinal follow-up of autism spectrum features and sensory behaviors in Angelman syndrome by deletion class

Background: Angelman syndrome (AS) is a neurogenetic disorder characterized by severe intellectual disability, lack of speech, and low threshold for laughter; it is considered a ‘syndromic’ form of autism spectrum disorder (ASD). Previous studies have indicated overlap of ASD and AS, primarily in individuals with larger (～6 Mb) Class I deletions of chromosome 15q11‐13. Questions remain regarding whether intellectual disability solely contributes to ASD features in AS and how ASD features in AS change over time. In this study, we used a dimensional approach to examine ASD symptom severity in individuals with AS Class I versus Class II deletions within the context of cognitive development over time. Methods: A total of 17 participants with a larger, Class I deletion and 25 participants with a smaller Class II deletion (～5 Mb) were enrolled (age range = 2–25 years; 5 years 5 months). Standardized measures of cognition, language, motor skills, adaptive skills, maladaptive behavior, autism, and sensory‐seeking behaviors/aversions were given at baseline and after 12 months. Results: Despite equivalent cognition and adaptive behavior, the results of repeated measures analyses of variance indicate that participants with Class I deletions have greater impairment in social affect (F = 8.65; p = .006) and more repetitive behaviors (F = 7.92; p = .008) compared to participants with Class II deletions. Although both groups improve in cognition over time, differences in ASD behaviors persist. Conclusions: Despite a lack of differences in cognition or adaptive behavior, individuals with Class I deletions have greater severity in ASD features and sensory aversions that remain over time. There are four genes (NIPA 1, NIPA 2, CYFIP1, and GCP5) missing in Class I and present in Class Il deletions, one or more of which may have a role in modifying the severity of social affect impairment, and level of restricted/repetitive behaviors in AS. Our results also suggest the utility of a dimensional, longitudinal approach to the assessment of ASD features in populations of individuals who are low functioning.