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.

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.

Early Hippocampal i-LTP and LOX-1 Overexpression Induced by Anoxia: A Potential Role in Neurodegeneration in NPC Mouse Model.

Niemann-Pick type C disease (NPCD) is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol within the late endo-lysosomal compartment of cells. In the central nervous system, hypoxic insults could result in low-density lipoprotein (LDL) oxidation and Lectin-like oxidized LDL receptor-1 (LOX-1) induction, leading to a pathological hippocampal response, namely, ischemic long-term potentiation (i-LTP). These events may correlate with the progressive neural loss observed in NPCD. To test these hypotheses, hippocampal slices from Wild Type (WT) and NPC1-/- mice were prepared, and field potential in the CA1 region was analyzed during transient oxygen/glucose deprivation (OGD). Moreover, LOX-1 expression was evaluated by RT-qPCR, immunocytochemical, and Western blot analyses before and after an anoxic episode. Our results demonstrate the development of a precocious i-LTP in NPC1-/- mice during OGD application. We also observed a higher expression of LOX-1 transcript and protein in NPC1-/- mice with respect to WT mice; after anoxic damage to LOX-1 expression, a further increase in both NPC1-/- and WT mice was observed, although the protein expression seems to be delayed, suggesting a different kinetic of induction. These data clearly suggest an elevated susceptibility to neurodegeneration in NPC1-/- mice due to oxidative stress. The observed up-regulation of LOX-1 in the hippocampus of NPC1-/- mice may also open a new scenario in which new biomarkers can be identified.

Characterization of ANKRD11 mutations in humans and mice related to KBG syndrome.

Mutations in ANKRD11 have recently been reported to cause KBG syndrome, an autosomal dominant condition characterized by intellectual disability (ID), behavioral problems, and macrodontia. To understand the pathogenic mechanism that relates ANKRD11 mutations with the phenotype of KBG syndrome, we studied the cellular characteristics of wild-type ANKRD11 and the effects of mutations in humans and mice. We show that the abundance of wild-type ANKRD11 is tightly regulated during the cell cycle, and that the ANKRD11 C-terminus is required for the degradation of the protein. Analysis of 11 pathogenic ANKRD11 variants in humans, including six reported in this study, and one reported in the Ankrd11 (Yod/+) mouse, shows that all mutations affect the C-terminal regions and that the mutant proteins accumulate aberrantly. In silico analysis shows the presence of D-box sequences that are signals for proteasome degradation. We suggest that ANKRD11 C-terminus plays an important role in regulating the abundance of the protein, and a disturbance of the protein abundance due to the mutations leads to KBG syndrome.

Seizures induced by desloratadine, a second-generation antihistamine: clinical observations.

Some clinical experiences indicate that H1-antihistamines, especially first-generation H1-antagonists, occasionally provoke convulsions in healthy children as well as epileptic patients. Desloratadine is a frequently used second-generation antihistamine considered to be effective and safe for the treatment of allergic diseases. We describe four children who experienced epilepsy associated with the nonsedating H(1)-antagonist desloratadine and discuss the neurophysiologic role of the central histaminergic system in seizure susceptibility. In conclusion, we recommend caution in treating epileptic patients with the histamine H(1)-antagonists, including second- and third-generation drugs that are frequently referred because they are considered to be nonsedating antihistamines.

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.

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.

Neurologic aspects of microcephalic osteodysplastic primordial dwarfism type II.

Microcephalic osteodysplastic primordial dwarfism type II is a specific disorder characterized by severe intrauterine and postnatal growth retardation, acquired microcephaly, cerebrovascular abnormalities, progressive bone dysplasia, and a characteristic face. Whereas the diagnostic features of this syndrome are well-recognized, the neurologic aspects have not been clearly defined. We report on a detailed neurodevelopmental follow-up study of a new case of microcephalic osteodysplastic primordial dwarfism type II, followed from the first years of life to adolescence, and we discuss the neurocognitive features of our patient. We also review the neurologic aspects of this disorder compared with syndromes with overlapping phenotypes, such as microcephalic osteodysplastic primordial dwarfism types I and III and Seckel syndrome.

Interstitial deletion of a proximal 3p: a clinically recognisable syndrome.

Interstitial deletions of the proximal short arm of chromosome 3 occurring as constitutional aberrations are rare and a defined clinical phenotype is not established yet. We report on a 30-months-old girl with distinct facial features (square facies, plagiocephaly, broad forehead, broad nasal bridge, long philtrum and low set ears) and psychomotor/speech delay associated with an interstitial deletion of 3p12 chromosomal band, del(3)(p12p12). Clinical manifestations of our child were compared with those of other eight patients with the same deletion previously described to further delineate the proximal 3p deletion syndrome.

Role of ADHD symptoms as a contributing factor to obesity in patients with MC4R mutations.

Besides the crucial role of genetic susceptibility in the development of early-onset obesity, it has been shown that feeding behavior could contribute to increased body weight. A significant association between obesity/overweight and ADHD has been reported, suggesting that these two conditions, despite their heterogeneity, might share common molecular pathways. Although the co-occurrence of obesity and ADHD is increasingly supported by empirical evidence, the complex pathogenetic link between these two conditions is still unclear. Here, we focus on the relationship between MC4R gene mutations and ADHD in children with early-onset obesity. Mutations in the gene MC4R lead to the most common form of monogenic obesity. We hypothesize that dysregulated eating behavior in a subset of patients with MC4R mutation might be due to comorbid ADHD symptoms, underpinned by abnormal reward mechanisms. Therefore, we speculate that it is possible to prevent obesity in a subset of patients with MC4R mutation, even if these patients are genetically programmed to "be fat", via an appropriate treatment of ADHD symptoms. We hope that our paper will stimulate further studies testing if the early screening for ADHD symptoms and their appropriate treatment may be an effective way to prevent obesity in a subset of children with MC4R mutation.

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.

Planning deficit in children with neurofibromatosis type 1: a neurocognitive trait independent from attention-deficit hyperactivity disorder (ADHD)?

Neurofibromatosis type 1 is associated with executive dysfunctions and comorbidity with attention-deficit hyperactivity disorder (ADHD) in 30% to 50% of children. This study was designed to clarify the neurocognitive phenotype observed in neurofibromatosis type 1 by testing the hypothesis that children with neurofibromatosis type 1 have specific planning deficits independently from intellectual level and ADHD comorbidity. Eighteen children with neurofibromatosis type 1 were pair-matched to 18 children with ADHD and 18 healthy controls. All groups were assessed on the presence of ADHD symptoms (Conners Scales) and planning deficits (Tower of London). Compared with control group, groups with neurofibromatosis type 1 and ADHD demonstrated significant impairment of planning and problem solving. The lack of correlation between Tower of London results and Conners subscale scores in neurofibromatosis type 1 group confirmed that the planning and problem-solving deficit is not directly related to inattention level. These findings suggested that the executive impairment probably represents a peculiar trait of neurofibromatosis type 1 neurocognitive phenotype.

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.

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.

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.

"Idiopathic" mental retardation and new chromosomal abnormalities.

Mental retardation is a heterogeneous condition, affecting 1-3% of general population. In the last few years, several emerging clinical entities have been described, due to the advent of newest genetic techniques, such as array Comparative Genomic Hybridization. The detection of cryptic microdeletion/microduplication abnormalities has allowed genotype-phenotype correlations, delineating recognizable syndromic conditions that are herein reviewed. With the aim to provide to Paediatricians a combined clinical and genetic approach to the child with cognitive impairment, a practical diagnostic algorithm is also illustrated. The use of microarray platforms has further reduced the percentage of "idiopathic" forms of mental retardation, previously accounted for about half of total cases. We discussed the putative pathways at the basis of remaining "pure idiopathic" forms of mental retardation, highlighting possible environmental and epigenetic mechanisms as causes of altered cognition.

Late-onset epileptic spasms in children with Pallister-Killian syndrome: a report of two new cases and review of the electroclinical aspects.

Pallister-Killian syndrome is a rare syndrome of multiple congenital anomalies attributable to the presence of a mosaic supernumerary isochromosome (12p). Although the clinical manifestations of Pallister-Killian syndrome are variable, the most common anomalies include craniofacial dysmorphisms, limb deformities, progressive psychomotor development delay, severe hypotonia, and epilepsy. Standard karyotype is nearly always normal, but the isochromosome (12p) is present in a high percentage of skin fibroblasts. In this article, we report the case of 2 boys with Pallister-Killian syndrome having late-onset, drug-resistant epileptic spasms. Seizures have been reported in 40% of patients with Pallister-Killian syndrome but are poorly described. Epileptic spasms are not unusual in patients with brain malformations, chromosomal aberrations, and genetic syndromes, but epileptic spasms could be easily mistaken for behavioral manifestations. A better electroclinical characterization of epileptic seizures in Pallister-Killian syndrome using appropriate polygraphic tests (video-electroencephalography, electromyography) may lead to an early diagnosis and specific treatment for this form of epileptic spasms caused by this rare syndrome.

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.