Refining the mutational spectrum and gene-phenotype correlates in pontocerebellar hypoplasia: results of a multicentric study.

BACKGROUND: Pontocerebellar hypoplasias (PCH) comprise a group of genetically heterogeneous disorders characterised by concurrent hypoplasia of the pons and the cerebellum and variable clinical and imaging features. The current classification includes 13 subtypes, with ~20 known causative genes. Attempts have been made to delineate the phenotypic spectrum associated to specific PCH genes, yet clinical and neuroradiological features are not consistent across studies, making it difficult to define gene-specific outcomes. METHODS: We performed deep clinical and imaging phenotyping in 56 probands with a neuroradiological diagnosis of PCH, who underwent NGS-based panel sequencing of PCH genes and MLPA for CASK rearrangements. Next, we conducted a phenotype-based unsupervised hierarchical cluster analysis to investigate associations between genes and specific phenotypic clusters. RESULTS: A genetic diagnosis was obtained in 43 probands (77%). The most common causative gene was CASK, which accounted for nearly half cases (45%) and was mutated in females and occasionally in males. The European founder mutation p.Ala307Ser in TSEN54 and pathogenic variants in EXOSC3 accounted for 18% and 9% of cases, respectively. VLDLR, TOE1 and RARS2 were mutated in single patients. We were able to confirm only few previously reported associations, including jitteriness and clonus with TSEN54 and lower motor neuron signs with EXOSC3. When considering multiple features simultaneously, a clear association with a phenotypic cluster only emerged for EXOSC3. CONCLUSION: CASK represents the major PCH causative gene in Italy. Phenotypic variability associated with the most common genetic causes of PCH is wider than previously thought, with marked overlap between CASK and TSEN54-associated disorders.

Symptoms of anxiety and depression and family's quality of life in children and adolescents with epilepsy.

INTRODUCTION: We studied children and adolescents with epilepsy (CAWE) and their families to evaluate symptoms of anxiety and depression, quality of life (QoL), and their correlations with epilepsy characteristics. MATERIAL AND METHODS: The study included 326 (52.5% females) 8 to 18years old CAWE. Anxiety and depression were assessed with the "Self-administered psychiatric scales for children and adolescents" (SAFA), and family's QoL with the parents' report "Impact of Epilepsy on QoL" (IEQoL). RESULTS: The CAWE exhibiting abnormal (T≥70) scores were 8.0% in the anxiety scale, 9.2% in the depression scale, and 4.6% in both scales. Social anxiety was the predominant anxiety symptom, while irritable mood and desperation were the most frequent symptoms of depression. Depressive symptoms were associated with parents' complaint of higher worries about the child's condition and future and lower well-being of the family. Severity and duration of the epilepsy and polypharmacy were independent from abnormal scores of anxiety and depression, but were associated with parents' worries about the child's condition and family's well-being. CONCLUSIONS: Anxiety and depression in CAWE are independent from the characteristics of the disease but are correlated to the lower well-being of the family. A search of these emotional problems is recommended for better care of the patients and their families.

Cognitive, adaptive, and behavioral features in Joubert syndrome.

Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by a distinctive cerebellar and brainstem malformation recognizable on brain imaging, the so-called molar tooth sign. The full spectrum of cognitive and behavioral phenotypes typical of JS is still far from being elucidated. The aim of this multicentric study was to define the clinical phenotype and neurobehavioral features of a large cohort of subjects with a neuroradiologically confirmed diagnosis of JS. Fifty-four patients aged 10 months to 29 years were enrolled. Each patient underwent a neurological evaluation as well as psychiatric and neuropsychological assessments. Global cognitive functioning was remarkably variable with Full IQ/General Quotient ranging from 32 to 129. Communication skills appeared relatively preserved with respect to both Daily Living and Socialization abilities. The motor domain was the area of greatest vulnerability, with a negative impact on personal care, social, and academic skills. Most children did not show maladaptive behaviors consistent with a psychiatric diagnosis but approximately 40% of them presented emotional and behavioral problems. We conclude that intellectual disability remains a hallmark but cannot be considered a mandatory diagnostic criterion of JS. Despite the high variability in the phenotypic spectrum and the extent of multiorgan involvement, nearly one quarter of JS patients had a favorable long-term outcome with borderline cognitive deficit or even normal cognition. Most of JS population also showed relatively preserved communication skills and overall discrete behavioral functioning in everyday life, independently from the presence and/or level of intellectual disability. © 2016 Wiley Periodicals, Inc.

Experiential virtual scenarios with real-time monitoring (interreality) for the management of psychological stress: a block randomized controlled trial.

BACKGROUND: The recent convergence between technology and medicine is offering innovative methods and tools for behavioral health care. Among these, an emerging approach is the use of virtual reality (VR) within exposure-based protocols for anxiety disorders, and in particular posttraumatic stress disorder. However, no systematically tested VR protocols are available for the management of psychological stress. OBJECTIVE: Our goal was to evaluate the efficacy of a new technological paradigm, Interreality, for the management and prevention of psychological stress. The main feature of Interreality is a twofold link between the virtual and the real world achieved through experiential virtual scenarios (fully controlled by the therapist, used to learn coping skills and improve self-efficacy) with real-time monitoring and support (identifying critical situations and assessing clinical change) using advanced technologies (virtual worlds, wearable biosensors, and smartphones). METHODS: The study was designed as a block randomized controlled trial involving 121 participants recruited from two different worker populations-teachers and nurses-that are highly exposed to psychological stress. Participants were a sample of teachers recruited in Milan (Block 1: n=61) and a sample of nurses recruited in Messina, Italy (Block 2: n=60). Participants within each block were randomly assigned to the (1) Experimental Group (EG): n=40; B1=20, B2=20, which received a 5-week treatment based on the Interreality paradigm; (2) Control Group (CG): n=42; B1=22, B2=20, which received a 5-week traditional stress management training based on cognitive behavioral therapy (CBT); and (3) the Wait-List group (WL): n=39, B1=19, B2=20, which was reassessed and compared with the two other groups 5 weeks after the initial evaluation. RESULTS: Although both treatments were able to significantly reduce perceived stress better than WL, only EG participants reported a significant reduction (EG=12% vs. CG=0.5%) in chronic "trait" anxiety. A similar pattern was found for coping skills: both treatments were able to significantly increase most coping skills, but only EG participants reported a significant increase (EG=14% vs CG=0.3%) in the Emotional Support skill. CONCLUSIONS: Our findings provide initial evidence that the Interreality protocol yields better outcomes than the traditionally accepted gold standard for psychological stress treatment: CBT. Consequently, these findings constitute a sound foundation and rationale for the importance of continuing future research in technology-enhanced protocols for psychological stress management. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01683617; http://clinicaltrials.gov/show/NCT01683617 (Archived by WebCite at http://www.webcitation.org/6QnziHv3h).

A Machine Learning Approach to the Diagnosis of Autism Spectrum Disorder and Multi-Systemic Developmental Disorder Based on Retrospective Data and ADOS-2 Score.

Early and accurate diagnosis of autism spectrum disorders (ASD) and tailored therapeutic interventions can improve prognosis. ADOS-2 is a standardized test for ASD diagnosis. However, owing to ASD heterogeneity, the presence of false positives remains a challenge for clinicians. In this study, retrospective data from patients with ASD and multi-systemic developmental disorder (MSDD), a term used to describe children under the age of 3 with impaired communication but with strong emotional attachments, were tested by machine learning (ML) models to assess the best predictors of disease development as well as the items that best describe these two autism spectrum disorder presentations. Maternal and infant data as well as ADOS-2 score were included in different ML testing models. Depending on the outcome to be estimated, a best-performing model was selected. RIDGE regression model showed that the best predictors for ADOS social affect score were gut disturbances, EEG retrievals, and sleep problems. Linear Regression Model showed that term pregnancy, psychomotor development status, and gut disturbances were predicting at best for the ADOS Repetitive and Restricted Behavior score. The LASSO regression model showed that EEG retrievals, sleep disturbances, age at diagnosis, term pregnancy, weight at birth, gut disturbances, and neurological findings were the best predictors for the overall ADOS score. The CART classification and regression model showed that age at diagnosis and weight at birth best discriminate between ASD and MSDD.

Challenges and resources in adult life with Joubert syndrome: issues from an international classification of functioning (ICF) perspective.

BACKGROUND: Joubert Syndrome (JS) is a rare inherited neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation (i.e. the molar tooth sign) and variable organ involvement. The aim of the present study was to describe functional limitations and disabilities in a large sample of adult patients with a diagnosis of JS. METHODS: We administered the International Classification of Functioning (ICF) checklist to thirty-six adult Italian patients with JS or their caregivers through telephone calls. RESULTS: None-to-mild impairment was documented for basic cognitive and mental functions, whereas severe deficit emerged for higher-order skills and language. A mismatch between individuals' capacity for daily activity and social participation and the actual performance in these fields emerged, suggesting that adults with JS may greatly benefit from external support from the caring environment. Indeed, specific facilitators were highlighted, including communication technologies as well as family members, healthcare professionals and peers support. Mild-to-severe barriers have been identified by adult patients with JS in the domains of services, systems and policies. CONCLUSIONS: These findings highlight challenges and barriers for adults with JS in areas of daily functioning that may be improved by investing in rehabilitation care models that embed social support programs and policies into clinical interventions.IMPLICATIONS FOR REHABILITATIONChildren with Joubert Syndrome, a child-onset rare inherited neurodevelopmental condition, are growing up and becoming adults; a life course approach in rehabilitation is needed;There is a substantial lack of information on the long-term adaptive daily functioning of children with a diagnosis of Joubert Syndrome;In this paper, the International Classification of Functioning (ICF) was applied to assess the daily functioning in people with JS;Severe deficits emerged for high-order skills and language, whereas the use of communication technologies and the engagement of family members were highlighted as key facilitators;These findings highlight the need for a change of paradigm in the care model of subjects with JS, with the embedding of social support in rehabilitation programs.

FARP-1 deletion is associated with lack of response to autism treatment by early start denver model in a multiplex family.

BACKGROUND: Children with autism spectrum disorder (ASD) display impressive clinical heterogeneity, also involving treatment response. Genetic variants can contribute to explain this large interindividual phenotypic variability. METHODS: Array-CGH (a-CGH) and whole genome sequencing (WGS) were performed on a multiplex family with two small children diagnosed with ASD at 17 and 18 months of age. Both brothers received the same naturalistic intervention for one year according to the Early Start Denver Model (ESDM), applied by the same therapists, yielding dramatically different treatment outcomes. RESULTS: The older sibling came out of the autism spectrum, while the younger sibling displayed very little, in any, improvement. This boy was subsequently treated applying a structured Early Intensive Behavioral Intervention paired with Augmentative Alternative Communication, which yielded a partial response within another year. The ESDM nonresponsive child carries a novel maternally inherited 65 Kb deletion at chr. 13q32.2 spanning FARP1. Farp1 is a synaptic scaffolding protein, which plays a significant role in neural plasticity. CONCLUSION: These results represent a paradigmatic example of the heuristic potential of genetic markers in predicting treatment response and possibly in supporting the targeted prescription of specific early intervention approaches.

3T Double Inversion Recovery Magnetic Resonance Imaging: diagnostic advantages in the evaluation of cortical development anomalies.

PURPOSE: The aim of this work was to investigate the diagnostic value of the DIR sequence at 3T MR imaging operating in the evaluation of cortical development anomalies. METHODS: We studied 40 patients, with a previous diagnosis of cortical dysplasia, by FLAIR-3D, DIR, FSE T2 and MPR-GE T1 sequences at 3T MRI. Two independent observers evaluated, for each sequence and lesion, some semiological aspects (cortical thickness, cortical signal intensity, white-gray matter blurring, subcortical white matter intensity). We made also a quantitative evaluation of the cortical signal intensity in lesion site, drawing a ROI on each MRI sequences and comparing them to the correspondent normal contralateral cortical area. RESULTS: We identified 44 cortical development anomalies. Qualitative analyses showed a high level of agreement between the observers concerning DIR potentialities in detecting and characterizing the cortical development disorders. Particularly DIR sequence was able to demonstrate the blurring and the subcortical white matter anomalies. The quantitative analyses didn't show a significant difference between DIR and traditional sequences in the evaluation of the cortical signal intensity. CONCLUSION: 3T MRI-DIR sequence is a useful and better suitable sequence compared to the traditional sequences in the characterization of some semiological aspects of the cortical development disorders, particularly blurring and subcortical white matter hyperintensity.

A rare case of cerebellar agenesis: a probabilistic Constrained Spherical Deconvolution tractographic study.

Aim of this study is to show the potential of probabilistic tractographic techniques, based on the Constrained Spherical Deconvolution (CSD) algorithms, in recognizing white matter fiber bundle anomalies in patients with complex cerebral malformations, such as cerebellar agenesis. The morphological and tractographic study of a 17-year-old male patient affected by cerebellar agenesis was performed by using a 3Tesla MRI scanner. Genetic and neuropsychological tests were carried out. An MRI morphological study showed the absence of both cerebellar hemispheres and the flattening of the anterior side of the pons. Moreover, it showed a severe vermian hypoplasia with a minimal vermian residual. The study recognized two thin cerebellar remnants, medially in contact with the small vermian residual, at the pontine level. The third ventricle, morphologically normal, communicated with a permagna cerebello-medullary cistern. Probabilistic CSD tractography identified some abnormal and aberrant infratentorial tracts, symmetrical on both sides. In particular, the transverse pontine fibers were absent and the following tracts with aberrant trajectories have been identified: "cerebello-thalamic" tracts; "fronto-cerebellar" tracts; and ipsilateral and contralateral "spino-cerebellar" tracts. Abnormal tracts connecting the two thin cerebellar remnants have also been detected. There were no visible alterations in the main supratentorial tracts in either side. Neuropsychiatric evaluation showed moderate cognitive-motor impairment with discrete adaptive compensation. Probabilistic CSD tractography is a promising technique that overcome reconstruction biases of other diffusion tensor-based approaches and allowed us to recognize, in a patient with cerebellar agenesis, abnormal tracts and aberrant trajectories of normally existing tracts.

Benign external hydrocephalus in infants. A single centre experience and literature review.

External hydrocephalus (EH) is a benign clinical entity in which macrocephaly is associated with an increase in volume of the subarachnoid space, especially overlying both frontal lobes, and a normal or only slight increase in volume of the lateral ventricles. Several pathogenic hypotheses have been proposed but the most accredited theory seems to be delayed maturation of the arachnoid villi. There is a consensus that this is a benign entity, correlated to a familial predisposition and, in some cases, inheritance. CT and MRI are very important to make a diagnosis but also to establish the prognosis in patients who encounter the rare complications such as subdural haematomas. In conclusion, CT and MRI can provide a highly accurate diagnosis in these patients, allowing a preliminary assessment of the prognosis, particularly regarding the enlarged subarachnoid space limits and the "cortical vein" sign which can predict a further complication. These results are obtained with the same examination performed in a standard CT or MRI study of the brain and no injection of contrast medium is needed.

Pontine Tegmental Cap Dysplasia: developmental and cognitive outcome in three adolescent patients.

Pontine Tegmental Cap Dysplasia (PTCD) is a recently described, rare disorder characterized by a peculiar cerebellar and brainstem malformation. Nineteen patients have been reported to date, of which only one in the adolescent age, and data on the clinical, cognitive and behavioural outcome of this syndrome are scarce. Here we describe three adolescent patients with PTCD. All presented bilateral deafness and multiple cranial neuropathies, variably associated with skeletal, cardiac and gastro-intestinal malformations. Feeding and swallowing difficulties, that are often causative of recurrent aspiration pneumonias and death in the first years of life, completely resolved with age in all three patients. Neuropsychological assessment showed borderline to moderate cognitive impairment, with delay in adaptive functioning, visual-spatial and language deficits. Two of three patients also showed mild behavioural problems, although their overall socialization abilities were well preserved. Cochlear implantation in two patients significantly improved their relational and learning abilities. Fibre tractography confirmed the abnormal bundle of transversely oriented fibres forming the typical pontine "tegmental cap" and absence of decussation of the superior cerebellar peduncles, supporting the hypothesis that PTCD results from abnormal axonal guidance and/or migration.These data indicate that PTCD may have a favourable long-term outcome, with borderline cognitive deficit or even normal cognition and partially preserved speech.