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.

Loss-Driven Topological Transitions in Lasing.

We experimentally observe lasing in a hexamer plasmonic lattice and find that, when tuning the scale of the unit cell, the polarization properties of the emission change. By a theoretical analysis, we identify the lasing modes as quasi-bound-states in continuum of topological charges of zero, one, or two. A T-matrix simulation of the structure reveals that the mode quality (Q) factors depend on the scale of the unit cell, with highest-Q modes favored by lasing. The system thus shows a loss-driven transition between lasing in modes of trivial and high-order topological charge.

Novel CTNNB1 variant leading to neurodevelopmental disorder with spastic diplegia and visual defects plus peripheral neuropathy: A case report.

Pathogenic variants in the ß1-catenin (CTNNB1) gene have been identified in patients with various diseases, including syndromic intellectual disability, autism spectrum disorder, familial exudative vitreoretinopathy, and neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV). We report on the clinical, genetic, neuroimaging, and neurophysiological data of a 15-year-old patient with complex hereditary spastic paraplegias with exotropia, dyskinesia, and cerebellar signs and a so-far unreported demyelinating (mainly sensory) polyneuropathy in her lower limbs. She carries the novel, de novo, likely pathogenic heterozygous c.603_605delinsAATA, p.(Met202Ilefs*6) frameshift variant in the CTNNB1 gene. Although peripheral neuropathy was not previously associated with NEDSDV, in light of the role of ß1-catenin as a junction protein in the peripheral as well as in the central nervous system documented in experimental studies, it might represent a causally linked and under-reported finding to be further explored.

Severe intellectual disability, absence of language, epilepsy, microcephaly and progressive cerebellar atrophy related to the recurrent de novo variant p.(P139L) of the CAMK2B gene: A case report and brief review.

The CAMK2B gene encodes the ß-subunit of calcium/calmodulin-dependent protein kinase II (CAMK2), an enzyme that has crucial roles in synaptic plasticity, especially in hippocampal and cerebellar neurons. Heterozygous variants in CAMK2B cause a rare neurodevelopmental disorder, with 40% of the reported cases sharing the same variant: c.416C>T, p.(P139L). This case report describes a 22-year-old patient with this recurrent variant, who presents with severe intellectual disability, absence of language, hypotonia, microcephaly, dysmorphic features, epilepsy, behavioral abnormalities, motor stereotypies, optic atrophy, and progressive cerebellar atrophy. Notably, this patient is the oldest reported so far and allows us to better delineate the clinical phenotype associated with this variant, adding clinical aspects never described before, such as epilepsy, optic atrophy, scoliosis, and neuroradiological changes characterized by progressive cerebellar atrophy.

Paediatric-onset hereditary spastic paraplegias: a retrospective cohort study.

AIM: To describe the clinical and neurogenetic spectrum of paediatric-onset hereditary spastic paraplegias (HSPs) diagnosed in our unit. METHOD: We report on 47 patients (30 males, 17 females; mean [SD] age 12y 7mo [6y 2mo], range 4-34y) clinically diagnosed with an HSP at the Child Neurology Unit, IRCCS-ASMN (Reggio Emilia, Italy) between 1990 and 2018, who were genetically investigated by means of single-gene direct sequencing and/or next-generation sequencing technologies (targeted panels, whole-exome sequencing [WES]). RESULTS: Complex forms prevailed slightly (n=26), autosomal dominant being the main inheritance pattern (n=11), followed by recessive (n=5) and X-linked (n=1). A definite genetic diagnosis was achieved in 17 patients. Spastic paraplegia 3A (n=4) was the most frequent cause of autosomal dominant HSP in our cohort, while no genetic variant prevailed in autosomal recessive forms and pathogenic/likely pathogenic variants were disclosed in a wide range of different genes. INTERPRETATION: We found wide phenotypic and genetic heterogeneity. With increasing accessibility to WES, a higher number of patients receive a diagnosis, allowing detection of variants in ultra-rare disease-causing genes and refining genotype-phenotype correlations. WHAT THIS PAPER ADDS: A genetic diagnosis of paediatric-onset hereditary spastic paraplegia was achieved in one-third of patients. Pathogenic/likely pathogenic variants in rare genes were found. Genotypic and phenotypic heterogeneity favours targeted panel/whole-exome sequencing for diagnosis.

Vagus nerve stimulation during pregnancy: an instructive case.

BACKGROUND: Little is known about the safety of vagus nerve stimulation during pregnancy. CASE REPORT: Herein we report the case of a young woman affected by childhood-onset partial epilepsy, obesity, and depression in which a malfunctioning of VNS was detected during pregnancy. Although device functioning was not optimal during the critical period of organogenesis, no morphological abnormalities of the fetus were detected. CONCLUSION: A confirmation of VNS safety may increase its use during pregnancy, thus reducing possible systemic effects of antiepileptic drugs and antidepressants on the women and the baby.

Quality of Life and Respiratory Performance in the Laryngectomized Patient: Role of the HME Filters during Physical Activity.

Background: Permanent tracheostomy because of total laryngectomy surgery entails significant consequences for patients regarding respiratory physiopathology, such as the loss of the filtering, humidifying, and heating of air by the nose. The use of special stomal filters can provide adequate protection of the tracheal-bronchopulmonary system with a reduction in respiratory pathologies. In fact, in most cases, laryngectomy patients are first cigarette smokers who for this reason also already have respiratory diseases such as chronic obstructive pulmonary disease (COPD). Despite the availability of tracheal filters, as reported in the literature, patients often tend to limit their use due to reported breathing difficulties, especially in conditions of intense breathing. Methods: The objective of this clinical study was to evaluate the most suitable stomal filter for laryngectomy patients during physical activity. The filters studied were an INHEALTH device (Blom-Singer SpeakFree HME); two ATOS devices (Provox® Life™ Energy HME and Provox® Life™ Home HME); and an FAHL device (Laryvox HME Sport). Results: For this purpose, the performances of 31 laryngectomy patients, subjected to medium-high physical effort, were analyzed through a standardized pneumological test, the Six Minute Walking Test (6MWT), which involves a sustained walk lasting six minutes, with an evaluation of heart rate, oxygen saturation, and meters traveled every 60 s; furthermore, we examined two subjective indices, namely, the basal and final dyspnea index and the initial and final muscular fatigue index. Conclusions: The multidisciplinary approach of the laryngectomee patient must also take pulmonary rehabilitation into consideration. It is the task of the medical team and speech therapy support to help the patient in the correct choice of HME filters taking into account daily needs.

Sport in the Laryngectomized Patient: A Literature Review and Single Case Presentation.

BACKGROUND: Total laryngectomy is an operation that involves numerous problems for the patient, especially in daily life: loss of the fact, loss of voice, evident scars and persistence of the tracheostoma. Much is known about rehabilitation programs involving the voice, swallowing, shoulder girdle rehabilitation; less explored is the field of sport and sports rehabilitation in the laryngectomized patient. METHODS: We conduced systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement in order to evaluate the possibilities of practicing sports for the patient after total laryngectomy. RESULTS: From an initial search of 4191 papers, we have come to include six papers for this literature review. We have also reported one of our clinical cases referring to a laryngectomized patient who swims competitively at an amateur level even after surgery with a particular device. The purpose of this work is to understand the role and importance of sport in rehabilitation and the possibilities that a frail patient like the laryngectomized patient has in practicing sport. Surely the best results are obtained in subjects who practiced sports before surgery. CONCLUSION: It is evident that sport is important in the psychological and motor recovery of the laryngectomized patient. There is still a lack of clear rehabilitation protocols, especially for water sports, which allow all laryngectomized patients to return to sports. We believe that early resumption of physical activity makes the experience of the disease less dramatic.

Voice rehabilitation and quality of life in laryngectomized patients.

BACKGROUND: Total laryngectomy represents the surgical procedure necessary for the treatment of some advanced neoplasms of the hypopharyngeal-laryngeal district and involves strong functional, physical and emotional repercussions. This research investigated the way in which the rehabilitation methods, used to improve the communicative needs of laryngectomized patients, influence their perceived quality of life. METHOD: The questionnaires "V-RQoL" and "SECEL" were administered to 45 patients divided into four groups on the basis of the type of vicarious voice: group TE (27 patients), group E (7 patients), group EL (2 patients), group NV (9 patients). RESULTS: Patients using electrical or tracheo-esophageal prostheses reported a better quality of life than patients with an erythromophonic voice. Regarding postoperative satisfaction, the group with esophageal voice was the most satisfied. CONCLUSIONS: The results lead us to emphasize the importance of preoperative counseling to make the patient as aware as possible of his future condition. KEY WORDS: Cancer, Laryngectomy, Vicarious Voice, Voice Rehabilitation, Quality of Life.

Extracapsular Tonsillectomy versus Intracapsular Tonsillotomy in Paediatric Patients with OSAS.

OBJECTIVE: The objective of our study was to compare our experience of intracapsular tonsillotomy performed with the help of a microdebrider usually used for adenoidectomy with results obtained from extracapsular surgery through dissection and from adenoidectomy in cases of people affected with OSAS, linked to adeno-tonsil hypertrophy, observed and treated in the last 5 years. METHODS: 3127 children with adenotonsillar hyperplasia and OSAS-related clinical symptoms (aged between 3 and 12 years) underwent tonsillectomy and/or adenoidectomy. A total of 1069 patients (Group A) underwent intracapsular tonsillotomy, while 2058 patients (Group B) underwent extracapsular tonsillectomy, from January 2014 to June 2018. The parameters considered in order to evaluate the effectiveness of the two different surgery techniques taken into consideration were as follows: the presence of possible postoperative complications, represented mainly by pain and perioperative bleeding; the level of postoperative respiratory obstruction compared with the original obstruction through night pulse oximetry, performed 6 months before and after the surgery; tonsillar hypertrophy relapse in Group A and/or the presence of residues in Group B with clinical evaluation performed 1 month, 6 months, and 1 year after the surgery; and postoperative life quality, evaluated through submitting to parents the same survey proposed before the surgery 1 month, 6 months, and 1 year after the surgery. RESULTS: Regardless of the technique used (extracapsular tonsillectomy or intracapsular tonsillotomy), there was a clear improvement in both the obstructive respiratory symptomatology and quality of life in both patient groups, as highlighted by the pulse oximetry and the OSA-18 survey submitted later. CONCLUSIONS: Intracapsular tonsillotomy surgery has improved in terms of a reduction in postoperative bleeding cases and pain reduction, with an earlier return to patients' usual lifestyle. Lastly, using a microdebrider with the intracapsular technique seems to be particularly effective in removing most of the tonsillar lymphatic tissue, leaving only a thin border of pericapsular lymphoid tissue and preventing lymphoid tissue regrowth during one year of follow-up.

Subjective Perception and Psychoacoustic Aspects of the Laryngectomee Voice: The Impact on Quality of Life.

PURPOSE: A retrospective study is presented to correlate the inter-judge consistency for the different psycho-perceptual parameters of the recently proposed Impression Noise Fluency Voicing (INFVo) perceptual rating scale for substitution voices, and the vocal function as perceived by the patient. METHODS: The scale Voice-Related Quality of Life (V-RQoL) and the Self Evaluation of Communication Experiences After Laryngectomy scale (SECEL)-a self-evaluation questionnaire of communicative experience after laryngectomy surgery-were administered to 89 total laryngectomees, subdivided in four groups depending on their type of alaryngeal voice (i.e., tracheoesophageal and esophageal speakers, electro larynx users, voiceless patients), in order to evaluate the impact of the impairment of the phonatory function on the quality of life. RESULTS: No significant differences exist among the various groups on their perception of QoL using subjective questionnaires, whereas the INFVo scale has proven to be a useful tool for the description and analysis of the psychoacoustic characteristics of the vocal signal and a reliable instrument to correctly classify the patients. It is also notable that the judgement of the patients on their own voice and those of the referees are highly significant. CONCLUSION: Although speech rehabilitation for the acquisition of a substitution voice offers a new way of communication for the laryngectomized patients, nonetheless, their QoL is not significantly related to the type of substitution voice. Therefore, improving the patient's adaptation to the new phonatory condition is mandatory.

Isolated neurofibromas of the great auricular nerve: A rare localization in a pediatric patient with neurofibromatosis type-1.

Peripheral nerve sheath tumors encompass a spectrum of well-defined clinicopathologic entities, ranging from benign tumors, such as neurofibromas, to high grade malignant neoplasms termed malignant peripheral nerve sheath tumors. Morphologic variability of these tumors is wide, and they engender some of the most controversial, difficult differential diagnoses. Localized neurofibromas often involve a major nerve and result typically in fusiform expansion of the nerve trunk (intraneural subtype). We report a case of circumscribed solitary neurofibromas in a 14-year-old boy with NF1 who presented to our department with a left neck swelling. The neurofibromas lesion involved the anterior branch of the great auricular nerve. The sensory symptoms initially reported by the patient (paresthesia and hyperesthesia) in the lower preauricular region. Surgical treatment represents the therapeutic method of choice in the approach to neurofibromas, considering functional disorders and possible aesthetic deformities. The case described presented difficulties in surgical excision, based on risk of functional and aesthetic results.

Quasi-BIC Mode Lasing in a Quadrumer Plasmonic Lattice.

Plasmonic lattices of metal nanoparticles have emerged as an effective platform for strong light-matter coupling, lasing, and Bose-Einstein condensation. However, the full potential of complex unit cell structures has not been exploited. On the other hand, bound states in continuum (BICs) have attracted attention, as they provide topologically protected optical modes with diverging quality factors. Here, we show that quadrumer nanoparticle lattices enable lasing in a quasi-BIC mode with a highly out-of-plane character. By combining theory with polarization-resolved measurements of the emission, we show that the lasing mode has a topological charge. Our analysis reveals that the mode is primarily polarized out-of-plane as a result of the quadrumer structure. The quality factors of the out-of-plane BIC modes of the quadrumer array can be exceedingly high. Our results unveil the power of complex multiparticle unit cells in creating topologically protected high-Q modes in periodic nanostructures.