TUBB Variants Underlying Different Phenotypes Result in Altered Vesicle Trafficking and Microtubule Dynamics.

Tubulinopathies are rare neurological disorders caused by alterations in tubulin structure and function, giving rise to a wide range of brain abnormalities involving neuronal proliferation, migration, differentiation and axon guidance. TUBB is one of the ten ß-tubulin encoding genes present in the human genome and is broadly expressed in the developing central nervous system and the skin. Mutations in TUBB are responsible for two distinct pathological conditions: the first is characterized by microcephaly and complex structural brain malformations and the second, also known as "circumferential skin creases Kunze type" (CSC-KT), is associated to neurological features, excess skin folding and growth retardation. We used a combination of immunocytochemical and cellular approaches to explore, on patients' derived fibroblasts, the functional consequences of two TUBB variants: the novel mutation (p.N52S), associated with basal ganglia and cerebellar dysgenesis, and the previously reported variant (p.M73T), linked to microcephaly, corpus callosum agenesis and CSC-KT skin phenotype. Our results demonstrate that these variants impair microtubule (MT) function and dynamics. Most importantly, our studies show an altered epidermal growth factor (EGF) and transferrin (Tf) intracellular vesicle trafficking in both patients' fibroblasts, suggesting a specific role of TUBB in MT-dependent vesicular transport.

A Comparison of Adaptive Functioning Between Children With Duplication 7 Syndrome and Williams-Beuren Syndrome: A Pilot Investigation.

Interstitial deletions of 7q11.23 cause the well-known Williams-Beuren Syndrome (WBS), while duplication of the same region leads to duplication 7 syndrome (Dup7). Children with WBS share a distinct neurobehavioral phenotype including mild to severe intellectual disability, severely impaired visual spatial abilities, relatively preserved verbal expressive skills, anxiety problems, enhanced social motivation (i.e., hypersociable behaviors) and socio-communicative problems. Children with Dup7 syndrome exhibit some "inverted" features when compared to those of individuals with WBS, such as reduced social motivation and impairment of expressive language. Direct comparison of WBS and Dup7 represents a unique opportunity for the neurobehavioral characterization of the 7q11.23 section. However, most of the available data come from qualitative analysis between different studies. To the best of our knowledge, there are no studies directly comparing features of two matched samples of individuals with WBS and Dup7 syndromes. In this pilot study, we compare the adaptive functioning - measured with the Vineland Adaptive Behavior Scales, Second Edition - of two relatively small samples of children with molecularly confirmed diagnosis of WBS and Dup7 matched for IQ and chronological age, with a particular attention to socialization domain and expressive subdomain. Contrary to our assumption, we have not found any significant difference on socialization domain and expressive subdomains. This pilot investigation suggests that, when matched for chronological age and cognitive level, children with WBS and Dup7 share more similarities than expected. The inverted features that emerge in clinical settings on expressive language and social motivation seem not to differently interfere with the daily abilities to communicate and socialize with meaningful others during daily lives. Differences highlighted by previous undirected comparisons could be due to general and non-specific factors such as cognitive level, which is more severely impaired in individuals with WBS than Dup7. Implications for assessment and treatment are discussed.

Differences and Similarities in Adaptive Functioning between Children with Autism Spectrum Disorder and Williams-Beuren Syndrome: A Longitudinal Study.

BACKGROUND: The last decade has seen a growing number of comparative studies on adaptive profiles between individuals with autism spectrum disorder (ASD) and Williams-Beuren syndrome (WBS), showing shared and syndrome-specific adaptive trajectories. Studies have revealed similarities in global adaptive profiles across conditions, while some differences have been found in preschoolers on the specific sub-domains of communication and socialization. However, the majority of studies that have focused on the differences in adaptive functioning across these two conditions used a cross-sectional design. To the best of our knowledge, there are no studies exploring the differences and similarities of adaptive functioning over time. METHODS: We compared longitudinal data of adaptive functioning measured by Vineland Adaptive Behavior Scales (VABS) between two samples of children and adolescents with ASD and WBS, matched for chronological age and cognitive/developmental level at the time of the first evaluation. RESULTS AND CONCLUSIONS: We did not find any difference on the global adaptive level, both at the first evaluation and over time. However, significant differences emerged on the socialization and communication levels at the time of recruitment. Longitudinal data show that only the socialization domain remains different over time, with individuals with WBS having better functioning than those with ASD. The results on shared and distinct patterns of adaptive functioning between disorders are discussed from a developmental perspective, thus contributing to the implementation of age-specific interventions.

Clinical and individual features associated with maternal stress in young adolescents with autism spectrum disorder.

Parents of people with autism spectrum disorder experience both negative stressful and positive events. Several clinical and socio-demographic features of children on the autism spectrum have been associated with parenting stress in their families. However, there have been few studies that focus on adolescents and the role of cognitive impairment has rarely been addressed. The main aim of the present research is to explore associations between autism symptoms, cognitive impairment, emotional and behavioral problems, socio-demographic features, and maternal stress in a sample of young adolescents with Autism Spectrum Disorder with and without cognitive impairment. Cognitive impairment and emotional and behavioral problems are associated with maternal stress, while autism symptoms seem to play a minor role. Maternal education and occupation are only associated with maternal stress in the group with cognitive impairment, while maternal age is stress-associated in the group of adolescents without cognitive impairment. Age-related implications for intervention and future research directions are discussed. LAY SUMMARY: Parents of individuals on the autism spectrum are exposed to both negative stressful and enriching experiences during their parenthood. While the influence of several child characteristics and socio-demographic features on parental stress during childhood has been widely explored in past studies, studies on teenagers are limited. The aim of the present research is to explore the influence of several characteristics on maternal stress levels in families with teenagers on the autism spectrum. We found that cognitive impairment and emotional and behavioral problems are associated with maternal stress, while autism symptoms seem to play a minor role. Socio-demographic features are not associated with maternal stress. Broadly speaking, the subjective perception of parental distress in both groups is less related to teenagers' characteristics then the perception of having a difficult interaction with the teenagers. We divided our participants into two groups (one group with cognitive impairment and the other group without). We found that mothers of teenagers with cognitive impairment are generally more stressed compared to the other group. Furthermore, we confirm that emotional and behavioral problems seem to play a major role in maternal stress (especially in the group without cognitive impairment), while autism symptoms seem to play a minor role. Furthermore, we found that maternal education/occupation and maternal age are associated with maternal stress in the group with and the group without cognitive impairment respectively. This research highlights the association between several variables and stress in mothers of adolescents on the spectrum. Results are discussed in the framework of previous findings highlighting the lack of adequate care and support services for families, especially for those of adolescents on the spectrum with cognitive impairment.

Cooperative Parent-Mediated Therapy in Children with Fragile X Syndrome and Williams Beuren Syndrome: A Pilot RCT Study of a Transdiagnostic Intervention-Preliminary Data.

Children with fragile X syndrome and William Beuren syndrome share several socio-communicative deficits. In both populations, around 30/35% of individuals meets criteria for autism spectrum disorder on gold standard instruments. Notwithstanding, few studies have explored feasibility and validity of therapy for socio-communicative deficits in individuals with these genetic conditions. In this study, we present preliminary data on a pilot RCT aimed to verify the effectiveness of cooperative parent-mediated therapy for socio-communicative deficits in a transdiagnostic perspective in a small sample of 12 participants. Our preliminary data showed that the experimental group had significant improvement in one socio-communicative skill (responsivity) and in clinical global impression, while the control group in an adaptive measure of socialization and word production. Implications of these results are then discussed.

Comparison of Adaptive Functioning in Children with Williams Beuren Syndrome and Autism Spectrum Disorder: A Cross-Syndrome Study.

Williams Beuren syndrome (WBS) and autism spectrum disorder (ASD) have been long considered as "polar opposite" disorders. Although children with WBS appears to be hypersociable, recent researches have revealed difficulties in socio-communicative skills such as shared attention, showing or giving objects, social relationships comprehension, pragmatic use of language, and emotion's recognition. The aim of this cross-syndrome study is to compare clinician-report adaptive profiles of two wide developmental range children by means of Vineland Adaptive Behavior Scales-Interview Edition, Survey Form. Eighty individuals, 40 with WBS and 40 with ASD (31 preschoolers and 49 scholars) with ASD and WBS matched for chronological age and developmental/cognitive level were recruited. Analysis of domains and subdomains have been reported. Results showed no significant difference in global adaptive level between WBS and ASD in both preschooler and scholar children. Communication domain significantly differ in preschoolers (higher in WBS children), but not in scholars. Expressive subdomain significantly differ in both preschoolers and scholars (higher in WBS children). Play and Leisure subdomain significantly differ in scholars (higher in WBS children), but not in preschoolers. Our results support hypothesis on a shared global adaptive impairment in children with WBS and ASD, by extending this findings to scholar-age children. Analysis of domains and subdomains differences highlight the need for interventions targeting social-pragmatic skills since first years of life. Differences in preschoolers and scholars adaptive profiles could be explained through a developmental perspective. LAY SUMMARY: Little is known about differences in adaptive profiles between Williams Beuren syndrome and autism spectrum disorder. Our results show similarities in global adaptive level and difference in communication level. Furthermore, expressive skills seem to be higher in Williams Beuren Syndrome. Autism Res 2021, 14: 748-758. © 2020 International Society for Autism Research and Wiley Periodicals LLC.

Manic and Depressive Symptoms in Children Diagnosed with Noonan Syndrome.

Noonan syndrome (NS) is a dominant clinically variable and genetically heterogeneous developmental disorder caused by germ-line mutations encoding components of the Ras-MAPK signaling pathway. A few studies have investigated psychopathological features occurring in individuals with NS, although they were poorly analyzed. The aim of the present work is to investigate the psychopathological features in children and adolescents with NS focusing on depressive and hypo-manic symptoms. Thirty-seven subjects with molecularly confirmed diagnosis were systematically evaluated through a psychopathological assessment. In addition, an evaluation of the cognitive level was performed. Our analyses showed a high recurrence of attention deficit and hyperactivity disorder symptoms, emotional dysregulation, irritability, and anxiety symptomatology. The mean cognitive level was on the average. The present study provides new relevant information on psychopathological features in individuals with NS. The implications for clinicians are discussed including the monitoring of mood disorders in a clinical evolution.

Further insight into the neurobehavioral pattern of children carrying the 2p16.3 heterozygous deletion involving NRXN1: Report of five new cases.

Increasing evidence links heterozygosity for NRXN1 gene deletions to a clinically wide spectrum of neurodevelopmental, psychiatric, and neurological disorders. However, to date, the neurocognitive and social communication features of children carrying this genomic rearrangement have not been assessed in detail. The cognitive and behavioral profiles of five children carrying a heterozygous NRXN1 deletion were investigated through systematic assessment of the cognitive and developmental levels, adaptive profile and presence of behavioral symptoms and autistic features. Furthermore, four transmitting parents were assessed by means of cognitive, psychopathological and parental stress tests. A below-average cognitive level was documented in all children, and defective adaptive levels were observed in four of them. Three of the five children were diagnosed as having autism spectrum disorder in comorbidity with intellectual disability/global developmental delay, with a major impairment in social communication skills. The remaining two children presented with isolated intellectual disability and an unclassifiable neurodevelopmental disorder, respectively. This study provide data contributing to a more accurate characterization of the neurobehavioral phenotype of individuals carrying heterozygous NRXN1 deletions. This analysis indicates that these structural rearrangements are associated with a variable expression of neuropsychiatric symptoms, and cast some doubts about the incomplete penetrance of the disorder.

7q11.23 Microduplication Syndrome: Clinical and Neurobehavioral Profiling.

7q11.23 Microduplication (dup7q11.23) syndrome is a rare autosomal dominant disorder due to a recurring 1.5 to 1.8 Mb duplication of the Williams-Beuren Syndrome critical region. Dup7q11.23 has been associated with several neuro-behavioral characteristics such as low cognitive and adaptive functioning, expressive language impairment, anxiety problems and autistic features. In the present study, we analyze the clinical features of ten individuals in which array-CGH detected dup7q11.23, spanning from 1.4 to 2.1 Mb. The clinical characteristics associated with dup7q11.23 are discussed with respect to its reciprocal deletion. Consistent with previous studies, we confirm that individuals with dup7q11.23 syndrome do not have a homogeneous clinical profile, although some recurring dysmorphic features were found, including macrocephaly, prominent forehead, elongated palpebral fissures, thin lip vermilion and microstomia. Minor congenital malformations include patent ductus arteriosus, cryptorchidism and pes planus. A common finding is hypotonia and joint laxity, resulting in mild motor delay. Neuropsychological and psychodiagnostic assessment confirm that mild cognitive impairment, expressive language deficits and anxiety are recurring neurobehavioral features. New insights into adaptive, psychopathological and neurodevelopmental profiles are discussed.