Definition of the neurological phenotype associated with dup (X)(p11.22-p11.23)

The aim of this study was to describe in detail the neurological features of nine patients carrying the recently reported microduplication at Xp11.22-11.23. Clinical and neurological examination, brain magnetic resonance imaging (except for two patients), electroencephalography and a neuropsychological assessment specific for language disturbances were performed in nine patients with microduplication at Xp11.22-11.23, disclosed by comparative genomic hybridisation array. Six patients were familial cases belonging to three unrelated pedigrees and three were sporadic cases. The patients had the following characteristics: mild dysmorphic facial features (except for two patients), mental retardation with moderate to severe global language deterioration, electroencephalographic epileptiform discharges during wakefulness and especially during sleep or electrical status epilepticus during slow sleep in younger cases, and negative brain magnetic resonance imaging. The main clinical features of this new microduplication syndrome were mild facial dysmorphisms, from increased electroencephalogram abnormalities during sleep to electrical status epilepticus during slow sleep, and mental retardation mainly involving language function in the absence of detectable brain lesions. In the absence of detectable brain lesions, speech delay may be associated with electrical status epilepticus during slow sleep or, alternatively, related to abnormal brain expression of a dosage-sensitive gene contained within the duplication region.     

Autism Spectrum Symptomatology Among Children with Duplication 7q11.23 Syndrome

Gold-standard diagnostic assessments of autism spectrum disorder (ASD) symptomatology were conducted on 63 children (mean CA: 8.81 years) with 7q11.23 duplication syndrome, one of the copy number variants identified by Sanders et al. (Neuron 70:863–885, 2011a) as associated with ASD. ASD classification rate was 39.6% for the Autism Diagnostic Interview-Revised and 25.4% for the Autism Diagnostic Observation Schedule-2 (ADOS-2). Based on these assessments combined with clinical judgment, 19.0% of children were diagnosed with ASD. Reasons for these discrepancies are discussed, as are differences in rate of diagnosis as a function of sex, age, and ADOS-2 module administered and differences in intellectual and adaptive behavior abilities as a function of presence or absence of ASD diagnosis and ADOS-2 module administered. Implications are addressed.     

Brief Report: Functional MRI of a Patient with 7q11.23 Duplication Syndrome and Autism Spectrum Disorder

The duplication of the Williams–Beuren syndrome (WBS) region (7q11.23) is a copy number variant associated with autism spectrum disorder (ASD). One of the most intriguing aspects is that the reciprocal microdeletion causes WBS, characterized by hypersociability, marked empathy, and a relative capacity in verbal short-term memory and language. Herein, we studied, by using functional morphological and volumetric magnetic resonance, a 17-year-old male patient who displays a de novo 7q11.23 duplication and ASD. The limbic system of the patient appeared hypo-functional, while the total brain volume was increased, thus contrasting, in an opposite and intriguing manner, with the global brain volume reduction reported in WBS. Even if these findings come from the analysis of a single patient and, therefore, have to be considered preliminary results, they encourage carrying on further functional and volumetric studies in patients with 7q11.23 duplication, to fully elucidate the role of this gene-dosage alteration on brain development and limbic system function.     

Xp22.3 genomic deletions involving the CDKL5 gene in girls with early onset epileptic encephalopathy

Purpose : Mutations of the X‐linked gene cyclin‐dependent kinase‐like 5 (CDKL5) cause an X‐linked encephalopathy with early onset intractable epilepsy, including infantile spasms and other seizure types, and a Rett syndrome (RTT)–like phenotype. Very limited information is available on the frequency and phenotypic spectrum associated with CDKL5 deletions/duplications. We investigated the role of CDKL5 deletions/duplications in causing early onset intractable epilepsy of unknown etiology in girls. Methods : We studied 49 girls with early onset intractable epilepsy, with or without infantile spasms, and developmental impairment, for whom no etiologic factors were obvious after clinical examination, brain magnetic resonance imaging (MRI) and expanded screening for inborn errors of metabolism. We performed CDKL5 gene mutation analysis in all and multiplex ligation dependent probe amplification assay (MLPA) in those who were mutation negative. Custom Array‐comparative genomic hybridization (CGH), breakpoint polymerase chain reaction (PCR) analysis, and X‐inactivation studies were performed in patients in whom MLPA uncovered a genomic alteration. Results : We found CDKL5 mutations in 8.2% (4 of 49) of patients and genomic deletions in 8.2% (4 of 49). Overall, abnormalities of the CDKL5 gene accounted for 16.3% (8 of 49) of patients. Discussion : CDKL5 gene deletions are an under‐ascertained cause of early onset intractable epilepsy in girls. Genetic testing of CDKL5, including both mutation and deletion/duplication analysis, should be considered in this clinical subgroup.     

Autism spectrum disorder phenotype and intellectual disability in females with epilepsy and PCDH-19 mutations

IntroductionAutism features and various degrees of cognitive deficit are reported in patients with PCDH-19 mutations and epilepsy. Autism spectrum disorder (ASD) and, often, cognitive profile are usually assessed clinically. We studied autism phenotype and cognitive outcome in a series of patients using standardized tools for development and ASD. We aimed to describe the phenotype of ASD in this series and to understand whether ASD is strictly linked to intellectual disability (ID) or is present as a comorbidity.MethodsEight females aged 5 to 17 years old with PCDH-19 mutations and epilepsy were recruited. For ASD diagnosis, the Autism Diagnostic Interview — Revised (ADI-R) and the Autism Diagnosis Observation Schedule (ADOS) were administered. Patients underwent a neuropsychological examination with tests measuring global intellectual efficiency (WPPSI-III and WISC-IV), language, and executive and social cognition abilities. Parental adaptive behavioral questionnaires were also obtained (VABS, CBCL, and BRIEF).ResultsSix out of eight patients presented with ASD and ID. Two patients had neither ASD nor ID, and both had the latest age of onset for their epilepsy. All cognitive functions were deficient, but theory-of-mind abilities compared to other cognitive features were even impaired. Features of ASD lacked major repetitive and stereotyped behaviors and show some differences with the classical ASD features related to ID.ConclusionOur results show a large spectrum of ID and a very high rate of ASD in patients with epilepsy and PCDH-19 mutations. Autism spectrum disorder seems to be a genuine comorbidity, more than a consequence of ID. It highlights the importance of standardized psychiatric and cognitive evaluation in order to establish a tailored rehabilitation program.     

The long-term outcome in two females with autism spectrum disorder

We describe the results of a long-term follow-up examination of two adult females diagnosed exhibiting an autism spectrum disorder in childhood. Over four decades after the initial diagnosis made by Gerhard Bosch, besides Leo Kanner and Hans Asperger, one of the first clinicians to describe cases of autistic behavior, the individuals had largely different psychiatric outcomes. Despite the fact that both females continuously showed definite autistic traits, one woman exhibited a generalized anxiety disorder, while the other was predominantly characterized by schizoaffective symptoms. The trajectories of the two cases are discussed in the light of research on possible associations and overlaps between autism spectrum disorders, psychosis and anxiety disorders. It is suggested that adult outcome studies in autism should consider a broader range of comorbidity.     

Central nervous system anomalies in two females with Borjeson-Forssman-Lehmann syndrome

Borjeson-Forssman-Lehmann syndrome (BFLS) is a rare disorder caused by mutations in the PHF6 gene. It manifests as syndromic X-linked recessive intellectual disability (ID) in males and as sporadic ID due to de novo mutations in females. Clinical features include variable ID and a range of somatic manifestations constituting a distinct phenotype in both males and females, respectively, including seizures in a few. Central nervous system (CNS) imaging data are largely unavailable for BFLS. Here we report on CNS MRI findings from two female individuals with BFLS due to a de novo duplication in PHF6 who presented with typical BFLS and epilepsy. Brain findings encompass an intriguing combination of structural abnormalities including a simplified gyral pattern and aspects resembling subcortical band heterotopia as signs of malformation of cortical development (MCD). This finding is of note, since PHF6 has been suggested to play pivotal roles in CNS development including neuronal migration.     

Autism in association with fragile X syndrome in females: implications for diagnosis and treatment in children

Fragile X syndrome is the second most common chromosomal cause of mental retardation (MR). The calculated incidence is 1/1000, making accurate and early diagnosis important for specific preventive, pharmacologic, and cognitive treatment. The timely diagnosis in males is facilitated by the characteristic phenotype and an association with autism. In contrast, in females heterozygous for fragile X, the characteristic phenotype and infantile autism are rarely reported. We present two females with cytogenetic expression of the fragile X chromosome for whom the studies were performed because of the presence of autism or prominent autistic features and a behavioral and physical phenotype consistent with fragile X syndrome. The first female, age three years, has autism, hyperactivity, echolalia, language delay, hand stereotypies, and mild MR. The characteristic phenotype was not present nor was there a family history of X-linked MR. Fragile X expression was 6% in the proband, 3% in the mother and 1% (normal) in the father. The second child, seven years old, has prominent autistic features, hyperactivity, mild MR, mild language disorder, and a family history consistent with X-linked MR. Fragile X expression was 3% in the proband and 0% in the mother. These cases support the occurrence of fragile X in autistic females and emphasize the importance of cytogenetic screening for fragile X in this high risk population. Early diagnosis of fragile X allows precise genetic counseling and more specific cognitive and pharmacologic treatment.     

Variable histological expression of dystrophinopathy in two females

We report two carriers of Xp21 muscular dystrophy with unusual clinical manifestations and striking variability of dystrophin deficiency within the same muscle biopsy. The first patient was a 60-year-old nun with recent onset of cramps and proximal weakness, mimicking an acquired myopathy. Muscle biopsy disclosed slight alterations in one sample and severe dystrophic changes in another; dystrophin was absent in 7% fibers in the former specimen and in 60% in the second. X inactivation was skewed with 90% cells inactivating the same X chromosome. The second patient was a 17-year-old girl with hyperCKemia, learning disability and a family history of X-linked muscular dystrophy. Muscle biopsy displayed slight fiber size variability and some internal nuclei; dystrophin was absent only in one muscle fiber. A second sample with the same morphological features demonstrated dystrophin deficiency with mosaic distribution. The pattern of X inactivation was normal. These cases emphasize the variability of histopathological changes and dystrophin deficiency in Xp21 muscular dystrophy carriers and the risk of sampling errors in muscle biopsy. Received: 26 August 1998 / Revised, accepted: 30 November 1998     

Autism as one of several disabilities in two children with congenital cytomegalovirus infection

Two children with congenital cytomegalovirus (CMV)-infection, severely disabled where autism was one of the disabilities are described. The characterization of the maternal infection have been possible and the connection between congenital CMV-infection and autism is discussed.     

Self-Reported Autism Symptoms in Adults with Autism Spectrum Disorders

Scores on the autism spectrum quotient (AQ) were examined in 65 adults with ASD. Maternal reports of symptoms were collected simultaneously using the autism diagnostic interview-revised (ADI-R) and the Vineland Screener. A slightly revised AQ administration procedure was used to accommodate adults with below average IQ. AQ scores were lower than in the original validation study, with only 11 adults (17%) scoring above the proposed diagnostic cut-off and 24 (27%) exceeding the screening cut-off. Adults with higher IQs endorsed more symptoms than those with below average intelligence, but even when analyses were restricted to the 39 adults with at least average IQ, only 44% met the screening cut-off. AQ scores were not significantly correlated with ADI-R or Vineland scores.     

Neuromuscular disease presentation with three genetic defects involving two genomes

An extensive range of molecular defects have been identified in the human mitochondrial genome (mtDNA), many associated with well-characterised, progressive neurological syndromes. We describe a patient who presented to a mitochondrial clinic with progressive bilateral ptosis, external opthalmoplegia and increasing difficulty with walking. He had previously been diagnosed with a dominant, demyelinating polyneuropathy due to PMP22 gene duplication and had also developed gout, presenting in acute renal failure, due to an X-linked recessive HPRT gene mutation. Muscle biopsy revealed many COX-deficient fibres which we show contain high levels of a third genetic defect – a novel, mitochondrial tRNA^Leu(CUN) (MTTL2) gene mutation.     

Reduced Bone Cortical Thickness in Boys with Autism or Autism Spectrum Disorder

Bone development, casein-free diet use, supplements, and medications were assessed for 75 boys with autism or autism spectrum disorder, ages 4–8 years. Second metacarpal bone cortical thickness (BCT), measured on hand-wrist radiographs, and % deviations in BCT from reference medians were derived. BCT increased with age, but % deviations evidenced a progressive fall-off (p = .02): +3.1 ± 4.7%, −6.5 ± 4.0%, −16.6 ± 3.4%, −19.4 ± 3.7%, −24.1 ± 4.4%, at ages 4–8, respectively, adjusting for height. The 12% of the boys on casein-free diets had an overall % deviation of −18.9 ± 3.7%, nearly twice that of boys on minimally restricted or unrestricted diets (−10.5 ± 1.3%, p < .04), although even for boys on minimally restricted or unrestricted diets the % deviation was highly significant (p < .001). Our data suggest that the bone development of autistic boys should be monitored as part of routine care, especially if they are on casein-free diets.     

Autism in children with congenital rubella

In the course of studying the behavioral characteristics of 243 preschool children with congenital rubella, we identified the syndrome of autism in 10 children and a partial syndrome of autism in an additional 8. These findings are discussed against the background of the behavioral investigations of rubella children. The methodology of our psychiatric study and the criteria for a diagnosis of autism are presented. The incidence of autism is considered with regard to the prevalence of other psychiatric disorders in this group and the physical status of the children. Two case histories of autistic rubella children are given and their behavioral characteristics are contrasted with nonautistic rubella children with matching sensory and other defects. The prevalence rate is compared with that found in two epidemiological studies and also with the rate indicated by other centers studying rubella children. Etiological implications of these findings are discussed. It is argued that these data support the concept of organic causation of the syndrome of autism.This study was done under a grant from the Children's Bureau, HEW No. H-220 (C2).     

Color Perception in Children with Autism

This study examined whether color perception is atypical in children with autism. In experiment 1, accuracy of color memory and search was compared for children with autism and typically developing children matched on age and non-verbal cognitive ability. Children with autism were significantly less accurate at color memory and search than controls. In experiment 2, chromatic discrimination and categorical perception of color were assessed using a target detection task. Children with autism were less accurate than controls at detecting chromatic targets when presented on chromatic backgrounds, although were equally as fast when target detection was accurate. The strength of categorical perception of color did not differ for the two groups. Implications for theories on perceptual development in autism are discussed.     

Sexual Behavior in Adults with Autism

A survey of the sexual behavior of 89 adults with autism living in group homes in North Carolina found that the majority of individuals were engaging in some form of sexual behavior. Masturbation was the most common sexual behavior. However, person-oriented sexual behaviors with obvious signs of arousal were also present in one third of the sample. The relationship between sexual behavior and demographic variables and other types of behaviors is explored. Information regarding group home sexuality policies and procedures are described.     

Recall Readiness in Children with Autism

When people are asked to learn information they need to judge when they have encoded the information accurately and will be able to retrieve it correctly. Making such a judgment is an aspect of metacognitive ability, and is referred to as recall readiness. Previous researchers have not considered recall readiness in children with autism, therefore we asked matched groups of children with autism, children with mental retardation, and normally developing children (mean mental age: 7 years) to study several pictures of objects until they felt ready to recall all the objects without error. Their recall was then tested. The children with autism and the children with mental retardation had impaired recall readiness compared to the normally developing children. We discuss this result with reference to other research into the metacognitive abilities of children with autism.