Adriana Lo-Castro

Epilepsy associated with autism and attention deficit hyperactivity disorder: Is there a genetic link?

Autism Spectrum Disorders (ASDs) and Attention Deficit and Hyperactivity Disorder (ADHD) are the most common comorbid conditions associated with childhood epilepsy. The co-occurrence of an epilepsy/autism phenotype or an epilepsy/ADHD phenotype has a complex and heterogeneous pathogenesis, resulting from several altered neurobiological mechanisms involved in early brain development, and influencing synaptic plasticity, neurotransmission and functional connectivity. Rare clinically relevant chromosomal aberrations, in addition to environmental factors, may confer an increased risk for ASDs/ADHD comorbid with epilepsy. The majority of the candidate genes are involved in synaptic formation/remodeling/maintenance (NRX1, CNTN4, DCLK2, CNTNAP2, TRIM32, ASTN2, CTNTN5, SYN1), neurotransmission (SYNGAP1, GABRG1, CHRNA7), or DNA methylation/chromatin remodeling (MBD5). Two genetic disorders, such as Tuberous sclerosis and Fragile X syndrome may serve as models for understanding the common pathogenic pathways leading to ASDs and ADHD comorbidities in children with epilepsy, offering the potential for new biologically focused treatment options.

ADHD and genetic syndromes

A high rate of Attention Deficit/Hyperactivity Disorder (ADHD)-like characteristics has been reported in a wide variety of disorders including syndromes with known genetic causes. In this article, we review the genetic and the neurobiological links between ADHD symptoms and some genetic syndromes such as: Fragile X Syndrome, Neurofibromatosis 1, DiGeorge Syndrome, Tuberous Sclerosis Complex, Turner Syndrome, Williams Syndrome and Klinefelter Syndrome. Although each syndrome may arise from different genetic abnormalities with multiple molecular functions, the effects of these abnormalities may give rise to common effects downstream in the biological pathways or neural circuits, resulting in the presentation of ADHD symptoms. Early diagnosis of ADHD allows for earlier treatment, and has the potential for a better outcome in children with genetic syndromes.

Deletion 2q37: An Identifiable Clinical Syndrome With Mental Retardation and Autism

Terminal deletion of the long arm of chromosome 2 is a rare chromosomal disorder characterized by low birth weight, delayed somatic and mental development, craniofacial defects, short neck, heart and lung congenital defects, and autistic features. We report on a girl with 46,XX.ish del(2)(q37.1) de novo karyotype, mental retardation, dysmorphic features, gastrointestinal anomalies, and autistic traits and compare her clinical manifestations with patients with the same deletion previously described in literature.

Sox11 Is Required to Maintain Proper Levels of Hedgehog Signaling during Vertebrate Ocular Morphogenesis

Ocular coloboma is a sight-threatening malformation caused by failure of the choroid fissure to close during morphogenesis of the eye, and is frequently associated with additional anomalies, including microphthalmia and cataracts. Although Hedgehog signaling is known to play a critical role in choroid fissure closure, genetic regulation of this pathway remains poorly understood. Here, we show that the transcription factor Sox11 is required to maintain specific levels of Hedgehog signaling during ocular development. Sox11-deficient zebrafish embryos displayed delayed and abnormal lens formation, coloboma, and a specific reduction in rod photoreceptors, all of which could be rescued by treatment with the Hedgehog pathway inhibitor cyclopamine. We further demonstrate that the elevated Hedgehog signaling in Sox11-deficient zebrafish was caused by a large increase in shha transcription; indeed, suppressing Shha expression rescued the ocular phenotypes of sox11 morphants. Conversely, over-expression of sox11 induced cyclopia, a phenotype consistent with reduced levels of Sonic hedgehog. We screened DNA samples from 79 patients with microphthalmia, anophthalmia, or coloboma (MAC) and identified two novel heterozygous SOX11 variants in individuals with coloboma. In contrast to wild type human SOX11 mRNA, mRNA containing either variant failed to rescue the lens and coloboma phenotypes of Sox11-deficient zebrafish, and both exhibited significantly reduced transactivation ability in a luciferase reporter assay. Moreover, decreased gene dosage from a segmental deletion encompassing the SOX11 locus resulted in microphthalmia and related ocular phenotypes. Therefore, our study reveals a novel role for Sox11 in controlling Hedgehog signaling, and suggests that SOX11 variants contribute to pediatric eye disorders.

Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin–Siris syndrome

Background SOX11 is a transcription factor proposed to play a role in brain development. The relevance of SOX11 to human developmental disorders was suggested by a recent report of SOX11 mutations in two patients with Coffin–Siris syndrome. Here we further investigate the role of SOX11 variants in neurodevelopmental disorders. Methods We used array based comparative genomic hybridisation and trio exome sequencing to identify children with intellectual disability who have deletions or de novo point mutations disrupting SOX11. The pathogenicity of the SOX11 mutations was assessed using an in vitro gene expression reporter system. Loss-of-function experiments were performed in xenopus by knockdown of Sox11 expression. Results We identified seven individuals with chromosome 2p25 deletions involving SOX11. Trio exome sequencing identified three de novo SOX11 variants, two missense (p.K50N; p.P120H) and one nonsense (p.C29*). The biological consequences of the missense mutations were assessed using an in vitro gene expression system. These individuals had microcephaly, developmental delay and shared dysmorphic features compatible with mild Coffin–Siris syndrome. To further investigate the function of SOX11, we knocked down the orthologous gene in xenopus. Morphants had significant reduction in head size compared with controls. This suggests that SOX11 loss of function can be associated with microcephaly. Conclusions We thus propose that SOX11 deletion or mutation can present with a Coffin–Siris phenotype.

Deletion 2p25.2: a cryptic chromosome abnormality in a patient with autism and mental retardation detected using aCGH.

We describe a 7-year-old patient with autism, moderate mental retardation, secondary microcephaly, agenesis of right optic nerve, and dysmorphic features carrying a de novo cryptic deletion of chromosome 2p25.2, detected by aCGH. Pure monosomies of 2p are very rare, and are usually observed as part of more complex aberrations involving other chromosomes. To the best of our knowledge, this is the first case presenting with a severe clinical phenotype and a de novo pure deletion of 2p25.2. The phenotypic effects of this rearrangement and the role of SOX11 gene, removed in our case, are herein discussed.

Neurobehavioral phenotype observed in KBG syndrome caused by ANKRD11 mutations

KBG syndrome is a rare disease characterized by typical facial dysmorphism, macrodontia of upper central incisors, skeletal abnormalities, and developmental delay. Recently, mutations in ANKRD11 gene have been identified in a subset of patients with KBG syndrome, while a contiguous gene deletion syndrome involving 16q24.3 region (including ANKRD11) was delineated in patients with facial dysmorphism, autism, intellectual disability, and brain abnormalities. Although numerous evidences point to a central causative role of ANKRD11 in the neurologic features of these patients, their neurocognitive and behavior phenotypes are still poorly characterized. Herein, we report the complete neurological and psychiatric features observed in two patients with KBG syndrome due to ANKRD11 mutations. Both patients show intellectual disabilities, severe impairment in communication skills, deficits in several aspects of executive functions and working memory and anxious traits. Their features are compared with those of previously reported patients with KBG syndrome aiding in the delineation of neurocognitive phenotype associated to ANKRD11 mutations.

De novo mosaic ring chromosome 18 in a child with mental retardation, epilepsy and immunological problems

Ring chromosome 18 [r(18)] is a disorder in which one or both ends of chromosome 18 are lost and joined forming a ring-shaped figures. R(18) patients can therefore show features of 18q-, 18p- syndrome or a combination of both, depending on the size of the 18p and 18q deleted regions. The phenotype of the r(18) is characterized by developmental delay/mental retardation, typical facial dysmorphisms, major abnormalities and immunological problems. Here we report a case of de novo mosaic r(18) with a characterization by array-based comparative genomic hybridization analysis, and discuss the phenotypic correlation in r(18) also through a comparison with previously described cases of the literature.

Attention-deficit hyperactivity disorder and binge eating disorder in a patient with 2q21.1-q22.2 deletion.

We report the case of a young male with attention-deficit hyperactivity disorder, oppositional defiant disorder, eating problems and overweight, and mild mental retardation. Karyotype analysis detected an apparently balanced translocation: t(1;2)(p34.1;q21.1) de novo. Array comparative genomic hybridization analysis defined a de-novo cryptic deletion of 2q21.1-q22.2 bands. The deletion, here first associated with this complex phenotype, encompasses several genes with a putative role in different domains of behavioral control and neurocognitive functions; their deregulated expression may influence metabolic pathways and the role of dopamine in reward, explaining the complex psychiatric phenotype and the pharmacotherapy response described in our patient.

Detecting anxiety symptoms in children and youths with neurofibromatosis type I

Children with Neurofibromatosis type 1 (NF1) are known to have cognitive, social, and behavioral deficits. Fifteen NF1‐subjects (5 boys, 10 girls, mean age = 13.4), and 15 healthy controls matched for age and sex were assessed on the presence of anxiety symptoms, using the Multidimensional Anxiety Scale for Children (MASC), self‐report questionnaire. Significant group differences emerged with regard to MASC total (Z = −2.058, P = 0.041) and anxiety disorder index (ADI; Z = −2.202, P = 0.026), but not with regard to single scales. When the severity and visibility of NF1 were considered, correlation between severity and social anxiety, and severity and MASC total was found. This is the first study assessing anxiety symptoms in NF1 children and youths. A precocious psychological survey and intervention in NF1 subjects, may contribute to reduce the risk of psychiatric disorders in adulthood.