Kathleen Angkustsiri

Regression in Autism: Prevalence and Associated Factors in the CHARGE Study

OBJECTIVE The aim of this study was to examine the prevalence of regressive autism and associated demographic, medical, and developmental factors by using 2 different definitions of regression based on the Autism Diagnostic Interview, Revised. METHODS Subjects were aged 2 to 5 years, with autism (AU) or autism spectrum disorder (ASD) confirmed by standardized measures. Children with regression, defined as a) loss of both language and social skills or b) loss of either language or social skills, were compared with each other and to children with AU or ASD with no reported loss of skills on developmental and adaptive functioning. Parents reported on seizure, gastrointestinal, and sleep concerns. RESULTS Fifteen percent (50/333) of the combined AU-ASD group lost both language and social skills; 41% (138/333) lost either language or social skills. No differences were found between the 2 samples of children with regression. Few developmental, demographic, or medical differences were found between the combined regression group and children without loss of skills, in both the larger AU-ASD sample and the more homogeneous AU-only sample. Children with regression had significantly lower communication scores than children without regression. CONCLUSIONS The prevalence of regression in a large sample of young children with AU and ASD varies depending on the definition used; requiring loss of language significantly underestimates the frequency of developmental regression. Children with regression performed significantly less well than those without regression on 2 measures of communication, but the clinical meaningfulness of these differences is uncertain because of the small effect sizes.

Social Impairments in Chromosome 22q11.2 Deletion Syndrome (22q11.2DS): Autism Spectrum Disorder or a Different Endophenotype?

High prevalence of autism spectrum disorders (ASD) has been reported in 22q11.2DS, although this has been based solely on parent report measures. This study describes the presence of ASD using a procedure more similar to that used in clinical practice by incorporating history (Social Communication Questionnaire) AND a standardized observation measure (Autism Diagnostic Observation Schedule) and suggests that ASD is not as common as previously reported in 22q11.2DS. Differences in methodology, along with comorbid conditions such as anxiety, likely contribute to false elevations in ASD prevalence and information from multiple sources should be included in the evaluation of ASD.

Decreased DGCR8 expression and miRNA dysregulation in individuals with 22q11.2 deletion syndrome

Deletion of the 1.5–3 Mb region of chromosome 22 at locus 11.2 gives rise to the chromosome 22q11.2 deletion syndrome (22q11DS), also known as DiGeorge and Velocardiofacial Syndromes. It is the most common micro-deletion disorder in humans and one of the most common multiple malformation syndromes. The syndrome is characterized by a broad phenotype, whose characterization has expanded considerably within the last decade and includes many associated findings such as craniofacial anomalies (40%), conotruncal defects of the heart (CHD; 70–80%), hypocalcemia (20–60%), and a range of neurocognitive anomalies with high risk of schizophrenia, all with a broad phenotypic variability. These phenotypic features are believed to be the result of a change in the copy number or dosage of the genes located in the deleted region. Despite this relatively clear genetic etiology, very little is known about which genes modulate phenotypic variations in humans or if they are due to combinatorial effects of reduced dosage of multiple genes acting in concert. Here, we report on decreased expression levels of genes within the deletion region of chromosome 22, including DGCR8, in peripheral leukocytes derived from individuals with 22q11DS compared to healthy controls. Furthermore, we found dysregulated miRNA expression in individuals with 22q11DS, including miR-150, miR-194 and miR-185. We postulate this to be related to DGCR8 haploinsufficiency as DGCR8 regulates miRNA biogenesis. Importantly we demonstrate that the level of some miRNAs correlates with brain measures, CHD and thyroid abnormalities, suggesting that the dysregulated miRNAs may contribute to these phenotypes and/or represent relevant blood biomarkers of the disease in individuals with 22q11DS.

Utilization patterns of conventional and complementary/alternative treatments in children with autism spectrum disorders and developmental disabilities in a population-based study.

Objective: To compare the utilization of conventional treatments and utilization of complementary and alternative medicine in preschoolers with autism spectrum disorders (ASD) and other developmental disabilities (DD). Methods: Participants were 578 children who were part of an ongoing population-based, case-control study of 2- to 5-year olds with ASD, DD, and the general population. Parents completed an interview on past and current services. Results: Four hundred fifty-three children with ASD and 125 DD children were included. ASD families received more hours of conventional services compared with DD families (17.8 vs 11; p < .001). The use of psychotropic medications was low in both groups (approximately 3%). Overall, complementary and alternative medicine (CAM) use was not significantly different in ASD (39%) versus DD (30%). Hispanic families in both groups used CAM less often than non-Hispanic families. Variables such as level of function, immunization status, and the presence of an identified neurogenetic disorder were not predictive of CAM use. A higher level of parental education was associated with an increased CAM use in ASD and DD. Families who used >20 hours per week of conventional services were more likely to use CAM, including potentially unsafe or disproven CAM. Underimmunized children were marginally more likely to use CAM but not more likely to have received potentially unsafe or disproven CAM. Conclusion: Use of CAM is common in families of young children with neurodevelopmental disorders, and it is predicted by higher parental education and non-Hispanic ethnicity but not developmental characteristics. Further research should address how health care providers can support families in making decisions about CAM use.

An Examination of the Relationship of Anxiety and Intelligence to Adaptive Functioning in Children with Chromosome 22q11.2 Deletion Syndrome

Objective: This study investigates the relationship between anxiety symptoms and adaptive function in children with chromosome 22q11.2 deletion syndrome (22q11.2DS). Methods: Seventy-eight children between 7 and 14 years of age with 22q11.2DS and 36 typically developing (TD) children without known genetic syndromes participated in a larger study of neurocognition. Parents completed questionnaires about their childs anxiety symptoms (Behavior Assessment System for Children, 2nd edition [BASC-2] and Spence Childrens Anxiety Scale [SCAS]) and adaptive functioning (BASC-2 and Adaptive Behavior Assessment System, 2nd edition). Within the 22q11.2DS group, different DSM-IV anxiety domains were also analyzed using SCAS subscales. Results: Based on parent report, 19% of children with 22q11.2DS had a prior diagnosis of an anxiety disorder versus 58% with at least 1 elevated anxiety score (BASC-2 or SCAS). Mean BASC-2 anxiety scores were significantly higher in 22q11.2DS (55.6 ± 12.5) than in TD children (48.3 ± 10; p = .003), and a greater percentage of children with 22q11.2DS (37%) had an elevated BASC-2 anxiety scores compared with TD children (14%; p = .01). Higher anxiety scores were related to lower adaptive function (r = −.27; p = .015), but there was no relationship between Wechsler Intelligence Scale for Children, 4th edition Full Scale Intelligence Quotient and BASC-2 adaptive skills (r = −.06; p = .6) in the 22q11.2DS group. For the individual SCAS anxiety subscales, panic-agoraphobia (r = −.38; p = .03), physical injury (r = −.34; p = .05), and obsessive-compulsive disorder (r = −.47; p = .005) were significantly negatively related to adaptive function in 22q11.2DS. Conclusion: Despite the known risk, anxiety is underidentified in children with 22q11.2DS. The presence of anxiety symptoms, but not intelligence levels, in children with 22q11.2DS negatively correlated with adaptive function and impacts everyday living skills.

Mitochondrial Citrate Transporter-dependent Metabolic Signature in the 22q11.2 Deletion Syndrome

Background: The most common microdeletion congenital disorder, 22qDS, is the second risk factor for schizophrenia. Results: Plasma metabolomics in 22qDS consisted of an oxidative phosphorylation-to-glycolysis shift with altered 2-hydroxyglutaric acid, cholesterol, and fatty acid concentrations. Conclusion: Despite the haploinsufficiency of ∼30 genes, the 22qDS metabolic signature chiefly reflected deficits in the mitochondrial citrate transporter. Significance: Biochemical profiling of 22qDS unveiled the impact of SLC25A1 haploinsufficiency. The congenital disorder 22q11.2 deletion syndrome (22qDS), characterized by a hemizygous deletion of 1.5–3 Mb on chromosome 22 at locus 11.2, is the most common microdeletion disorder (estimated prevalence of 1 in 4000) and the second risk factor for schizophrenia. Nine of ∼30 genes involved in 22qDS have the potential of disrupting mitochondrial metabolism (COMT, UFD1L, DGCR8, MRPL40, PRODH, SLC25A1, TXNRD2, T10, and ZDHHC8). Deficits in bioenergetics during early postnatal brain development could set the basis for a disrupted neuronal metabolism or synaptic signaling, partly explaining the higher incidence in developmental and behavioral deficits in these individuals. Here, we investigated whether mitochondrial outcomes and metabolites from 22qDS children segregated with the altered dosage of one or several of these mitochondrial genes contributing to 22qDS etiology and/or morbidity. Plasma metabolomics, lymphocytic mitochondrial outcomes, and epigenetics (histone H3 Lys-4 trimethylation and 5-methylcytosine) were evaluated in samples from 11 22qDS children and 13 age- and sex-matched neurotypically developing controls. Metabolite differences between 22qDS children and controls reflected a shift from oxidative phosphorylation to glycolysis (higher lactate/pyruvate ratios) accompanied by an increase in reductive carboxylation of α-ketoglutarate (increased concentrations of 2-hydroxyglutaric acid, cholesterol, and fatty acids). Altered metabolism in 22qDS reflected a critical role for the haploinsufficiency of the mitochondrial citrate transporter SLC25A1, further enhanced by HIF-1α, MYC, and metabolite controls. This comprehensive profiling served to clarify the biochemistry of this disease underlying its broad, complex phenotype.

Mapping the deletion endpoints in individuals with 22q11.2 Deletion Syndrome by droplet digital PCR

BackgroundChromosome 22q11.2 deletion syndrome (22q11DS) is the most common human microdeletion syndrome and is associated with many cognitive, neurological and psychiatric disorders. The majority of individuals have a 3 Mb deletion while others have a nested 1.5 Mb deletion, but rare atypical deletions have also been described. To date, a study using droplet digital PCR (ddPCR) has not been conducted to systematically map the chromosomal breakpoints in individuals with 22q11DS, which would provide important genotypic insight into the various phenotypes observed in this syndrome.MethodsThis study uses ddPCR to assess copy number (CN) changes within the chromosome 22q11 deletion region and allows the mapping of the deletion endpoints. We used eight TaqMan assays interspersed throughout the deleted region of 22q11.2 to characterize the deleted region of chromosome 22 in 80 individuals known to have 22q11DS by FISH. Ten EvaGreen assays were used for finer mapping of the six identified individuals with 22q11DS atypical deletions and covering different regions of chromosome 22.ResultsddPCR provided non-ambiguous CN measurements across the region, confirmed the presence of the deletion in the individuals screened, and led to the identification of five differently sized and located deletions. The majority of the participants (n = 74) had the large 3 Mb deletions, whereas three had the smaller 1.5 Mb deletions, and the remaining three had an interstitial deletion of different size.ConclusionsThe lower cost, rapid execution and high reliability and specificity provided by ddPCR for CN measurements in the 22q11 region constitutes a significant improvement over the variable CN values generated by other technologies. The ability of the ddPCR approach, to provide a high resolution mapping of deletion endpoints may result in the identification of genes that are haplo-insufficient and play a role in the pathogenesis of 22q11DS. Finally, this methodology can be applied to the characterization of other microdeletions throughout the genome.

Two Boys With Fragile X Syndrome and Hepatic Tumors

Hepatic tumors are rare childhood neoplasms with uncertain etiology. We report the cooccurrence of hepatic tumors in 2 boys with fragile X syndrome, one with hepatoblastoma and another with desmoplastic nested spindle cell tumor of liver. The pathogenesis of fragile X syndrome involves silencing of the fragile X mental retardation 1 gene and consequent loss of FMR1 protein. We speculate regarding molecular pathways that might explain the cooccurrence of the 2 conditions. Further examination of a possible functional link between hepatic neoplasia and loss of FMRP is warranted.

A girl with fragile X premutation from sperm donation.

We present a girl with the fragile X premutation who obtained the premutation allele from donated sperm. Our patient has clinical characteristics of fragile X syndrome including emotional problems and neuropsychological difficulties presenting as learning disabilities. She is also at high risk for premature ovarian failure and low risk for the fragile X‐associated tremor ataxia (FXTAS). We suggest fragile X DNA screening in gamete donor candidates to decrease the chance of fragile X involvement in their offspring.

Fragile X syndrome with anxiety disorder and exceptional verbal intelligence.

Fragile X syndrome (FXS) is often characterized by mental retardation. However, FXS is also associated with significant emotional and psychiatric problems, including anxiety, depression, attention difficulties, and learning disabilities in the presence of a normal IQ. This report describes a unique woman with the full mutation of FXS who has an exceptional profile of above‐average intelligence combined with significant impairments due to anxiety and learning disability. Women with FXS can present primarily with learning and emotional problems, and clinicians should consider FXS in these women regardless of their IQ.