Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly.

Telomere maintenance 2 (TELO2), Tel2 interacting protein 2 (TTI2), and Tel2 interacting protein 1 (TTI1) are the three components of the conserved Triple T (TTT) complex that modulates activity of phosphatidylinositol 3-kinase-related protein kinases (PIKKs), including mTOR, ATM, and ATR, by regulating the assembly of mTOR complex 1 (mTORC1). The TTT complex is essential for the expression, maturation, and stability of ATM and ATR in response to DNA damage. TELO2- and TTI2-related bi-allelic autosomal-recessive (AR) encephalopathies have been described in individuals with moderate to severe intellectual disability (ID), short stature, postnatal microcephaly, and a movement disorder (in the case of variants within TELO2). We present clinical, genomic, and functional data from 11 individuals in 9 unrelated families with bi-allelic variants in TTI1. All present with ID, and most with microcephaly, short stature, and a movement disorder. Functional studies performed in HEK293T cell lines and fibroblasts and lymphoblastoid cells derived from 4 unrelated individuals showed impairment of the TTT complex and of mTOR pathway activity which is improved by treatment with Rapamycin. Our data delineate a TTI1-related neurodevelopmental disorder and expand the group of disorders related to the TTT complex.

Speech-language pathologist, physical therapist, and occupational therapist experiences of interprofessional collaborations.

Interprofessional collaboration among speech-language pathology, physical therapy, and occupational therapy is considered to promote best practice in rehabilitation as it can enhance efficiency, patient outcomes, and clinician and patient satisfaction. Although clinician experiences with interprofessional collaboration have been studied in each of the rehabilitation professions separately, limited research has been conducted on the shared attitudes or experiences across speech-language pathology, physical therapy, and occupational therapy. The purpose of this study was to understand speech-language pathologist, physical therapist, and occupational therapist experiences of interprofessional collaborations. We conducted an exploratory cross-sectional online survey study. The survey included Likert-scale questions and open-ended questions that probed clinicians' general experiences with interprofessional practice and views and beliefs regarding barriers and facilitators to interprofessional collaboration. Responses from 213 clinician respondents were analyzed using descriptive quantitative methods and a qualitative content analysis. The results revealed overlap in attitudes and experiences across speech-language pathology, physical therapy, and occupational therapy about barriers and benefits to interprofessional collaboration. Perceived respect differed among the professions, with speech-language pathologists more frequently reporting that their role is often misunderstood or undervalued by other rehabilitation professionals. These results may guide future research focused upon the predictors of successful interprofessional collaborations and interactions.

Classification of accurate and misarticulated /ɑr/ for ultrasound biofeedback using tongue part displacement trajectories.

Ultrasound biofeedback therapy (UBT), which incorporates real-time imaging of tongue articulation, has demonstrated generally positive speech remediation outcomes for individuals with residual speech sound disorder (RSSD). However, UBT requires high attentional demands and may therefore benefit from a simplified display of articulation targets that are easily interpretable and can be compared to real-time articulation. Identifying such targets requires automatic quantification and analysis of movement features relevant to accurate speech production. Our image-analysis program TonguePART automatically quantifies tongue movement as tongue part displacement trajectories from midsagittal ultrasound videos of the tongue, with real-time capability. The present study uses such displacement trajectories to compare accurate and misarticulated American-English rhotic /ɑr/ productions from 40 children, with degree of accuracy determined by auditory perceptual ratings. To identify relevant features of accurate articulation, support vector machine (SVM) classifiers were trained and evaluated on several candidate data representations. Classification accuracy was up to 85%, indicating that quantification of tongue part displacement trajectories captured tongue articulation characteristics that distinguish accurate from misarticulated production of /ɑr/. Regression models for perceptual ratings were also compared. The simplest data representation that retained high predictive ability, demonstrated by high classification accuracy and strong correlation between observed and predicted ratings, was displacements at the midpoint of /r/ relative to /ɑ/ for the tongue dorsum and blade. This indicates that movements of the dorsum and blade are especially relevant to accurate production of /r/, suggesting that a predictive parameter and biofeedback target based on this data representation may be usable for simplified UBT.

ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder.

ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In vitro, ZMIZ1 showed impaired coactivation of the androgen receptor. In vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome.

Impact of vaccination on keratoplasty.

PURPOSE OF REVIEW: Corneal graft rejection has been reported after coronavirus disease 2019 (COVID-19) vaccination. The purpose of this review is to evaluate the literature regarding corneal graft rejection after vaccination, including rejection rates and risk factors. We aim to create a framework to identify patients who are at higher risk for graft rejection and may warrant consideration of prophylactic interventions. RECENT FINDINGS: Graft rejection has been reported following administration of mRNA, viral vector, and inactivated whole-virion COVID-19 vaccines. Most cases had additional risk factors associated with rejection. Vaccination increases circulation of proinflammatory cytokines, CD4+ and CD8+ T-cell responses, and antispike neutralizing antibody, all of which may contribute to graft rejection. Two prospective studies have found no relationship between recent vaccination and rejection but 20% of cornea specialists report to have seen a vaccine-associated rejection and 22% recommend delaying vaccination in certain circumstances. Many specialists recommend prophylactic topical corticosteroids before and after vaccination to mitigate rejection risk but there is no evidence to support this practice on a wider scale. SUMMARY: Our framework identified 96.8% of penetrating keratoplasty patients with vaccine-associated rejection as higher risk. Further research is needed in order to develop evidence-based guidelines.

Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.

Auditory-perceptual acuity in rhotic misarticulation: baseline characteristics and treatment response.

The rhotic sound /r/ is one of the latest-emerging sounds in English, and many children receive treatment for residual errors affecting /r/ that persist past the age of 9. Auditory-perceptual abilities of children with residual speech errors are thought to be different from their typically developing peers. This study examined auditory-perceptual acuity in children with residual speech errors affecting /r/ and the relation of these skills to production accuracy, both before and after a period of treatment incorporating visual biofeedback. Identification of items along an /r/-/w/ continuum was assessed prior to treatment. Production accuracy for /r/ was acoustically measured from standard/r/stimulability probes elicited before and after treatment. Fifty-nine children aged 9-15 with residual speech errors (RSE) affecting /r/ completed treatment, and forty-eight age-matched controls who completed the same auditory-perceptual task served as a comparison group. It was hypothesized that children with RSE would show lower auditory-perceptual acuity than typically developing speakers and that higher auditory-perceptual acuity would be associated with more accurate production before treatment. It was also hypothesized that auditory-perceptual acuity would serve as a mediator of treatment response. Results indicated that typically developing children have more acute perception of the /r/-/w/ contrast than children with RSE. Contrary to hypothesis, baseline auditory-perceptual acuity for /r/ did not predict baseline production severity. For baseline auditory-perceptual acuity in relation to biofeedback efficacy, there was an interaction between auditory-perceptual acuity and gender, such that higher auditory-perceptual acuity was associated with greater treatment response in female, but not male, participants.

Modelling category goodness judgments in children with residual sound errors.

This study investigates category goodness judgments of /r/ in adults and children with and without residual speech errors (RSEs) using natural speech stimuli. Thirty adults, 38 children with RSE (ages 7-16) and 35 age-matched typically developing (TD) children provided category goodness judgments on whole words, recorded from 27 child speakers, with /r/ in various phonetic environments. The salient acoustic property of /r/ - the lowered third formant (F3) - was normalized in two ways. A logistic mixed-effect model quantified the relationships between listeners' responses and the third formant frequency, vowel context and clinical group status. Goodness judgments from the adult group showed a statistically significant interaction with the F3 parameter when compared to both child groups (p < 0.001) using both normalization methods. The RSE group did not differ significantly from the TD group in judgments of /r/. All listeners were significantly more likely to judge /r/ as correct in a front-vowel context. Our results suggest that normalized /r/ F3 is a statistically significant predictor of category goodness judgments for both adults and children, but children do not appear to make adult-like judgments. Category goodness judgments do not have a clear relationship with /r/ production abilities in children with RSE. These findings may have implications for clinical activities that include category goodness judgments in natural speech, especially for recorded productions.

Delineation of the 9q31 deletion syndrome: Genomic microarray characterization of two patients with overlapping deletions.

Interstitial deletions of chromosome 9q31 are very rare. The deletions in most reported patients have been detected by conventional cytogenetics, with reported breakpoints ranging between 9q21 and 9q34. Therefore, an accurate description of a "9q31 deletion syndrome" could not be established. However, based on microarray studies, a small region of overlap has recently been proposed. We report clinical features of two unrelated individuals with overlapping 9q deletions identified by SNP microarray analysis. Patient 1 has a 9 Mb deletion, while Patient 2's deletion was 21.6 Mb. The clinical features common to our patients and those in the literature include developmental delay and short stature. Patient 2 shows additional features not reported in other 9q31 deletions, such as hearing loss, ventriculomegaly, cleft lip and palate, and small kidneys, which could be due to the larger size of the deletion, hence the influence of the genes in the region beyond the smallest region of overlap. Based on the comparison of these patients with the previously reported patients, we redefine the smallest region of overlap and characterize the clinical features of the 9q31 deletion syndrome.

A recurrent mutation in KCNA2 as a novel cause of hereditary spastic paraplegia and ataxia.

The hereditary spastic paraplegias (HSPs) are heterogeneous neurodegenerative disorders with over 50 known causative genes. We identified a recurrent mutation in KCNA2 (c.881G>A, p.R294H), encoding the voltage-gated K(+) -channel, KV 1.2, in two unrelated families with HSP, intellectual disability (ID), and ataxia. Follow-up analysis of > 2,000 patients with various neurological phenotypes identified a de novo p.R294H mutation in a proband with ataxia and ID. Two-electrode voltage-clamp recordings of Xenopus laevis oocytes expressing mutant KV 1.2 channels showed loss of function with a dominant-negative effect. Our findings highlight the phenotypic spectrum of a recurrent KCNA2 mutation, implicating ion channel dysfunction as a novel HSP disease mechanism. Ann Neurol 2016.

Neuroradiographic findings in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2DS) is a common genetic disorder with enormous phenotypic heterogeneity. Despite the established prevalence of developmental and neuropsychiatric issues in this syndrome, its neuroanatomical correlates are not as well understood. A retrospective chart review was performed on 111 patients diagnosed with 22q11.2DS. Of the 111 patients, 24 with genetically confirmed 22q11.2 deletion and brain MRI or MRA were included in this study. The most common indications for imaging were unexplained developmental delay (6/24), seizures of unknown etiology (5/24), and unilateral weakness (3/24). More than half (13/24) of the patients had significant radiographic findings, including persistent cavum septi pellucidi and/or cavum vergae (8/24), aberrant cortical veins (6/24), polymicrogyria or cortical dysplasia (4/24), inner ear deformities (3/24), hypoplastic internal carotid artery (2/24), and hypoplastic cerebellum (1/24). These findings reveal the types and frequencies of brain malformations in this case series, and suggest that the prevalence of neuroanatomical abnormalities in 22q11.2DS may be underestimated. Understanding indications for imaging and frequently encountered brain malformations will result in early diagnosis and intervention in an effort to optimize patient outcomes.

The molecular and phenotypic spectrum of IQSEC2-related epilepsy.

OBJECTIVE: IQSEC2 is an X-linked gene associated with intellectual disability (ID) and epilepsy. Herein we characterize the epilepsy/epileptic encephalopathy of patients with IQSEC2 pathogenic variants. METHODS: Forty-eight patients with IQSEC2 variants were identified worldwide through Medline search. Two patients were recruited from our early onset epileptic encephalopathy cohort and one patient from personal communication. The 18 patients who have epilepsy in addition to ID are the subject of this study. Information regarding the 18 patients was ascertained by questionnaire provided to the treating clinicians. RESULTS: Six affected individuals had an inherited IQSEC2 variant and 12 had a de novo one (male-to-female ratio, 12:6). The pathogenic variant types were as follows: missense (8), nonsense (5), frameshift (1), intragenic duplications (2), translocation (1), and insertion (1). An epileptic encephalopathy was diagnosed in 9 (50%) of 18 patients. Seizure onset ranged from 8 months to 4 years; seizure types included spasms, atonic, myoclonic, tonic, absence, focal seizures, and generalized tonic-clonic (GTC) seizures. The electroclinical syndromes could be defined in five patients: late-onset epileptic spasms (three) and Lennox-Gastaut or Lennox-Gastaut-like syndrome (two). Seizures were pharmacoresistant in all affected individuals with epileptic encephalopathy. The epilepsy in the other nine patients had a variable age at onset from infancy to 18 years; seizure types included GTC and absence seizures in the hereditary cases and GTC and focal seizures in de novo cases. Seizures were responsive to medical treatment in most cases. All 18 patients had moderate to profound intellectual disability. Developmental regression, autistic features, hypotonia, strabismus, and white matter changes on brain magnetic resonance imaging (MRI) were prominent features. SIGNIFICANCE: The phenotypic spectrum of IQSEC2 disorders includes epilepsy and epileptic encephalopathy. Epileptic encephalopathy is a main clinical feature in sporadic cases. IQSEC2 should be evaluated in both male and female patients with an epileptic encephalopathy.

New recessive truncating mutation in LTBP3 in a family with oligodontia, short stature, and mitral valve prolapse.

Latent TGFB-binding protein 3 (LTBP3) is known to increase bio-availability of TGFB. A homozygous mutation in this gene has previously been associated with oligodontia and short stature in a single family. We report on two sisters with homozygous truncating mutations in LTBP3. In addition to oligodontia and short stature, both sisters have mitral valve prolapse, suggesting a link between truncating LTBP3 mutations and mitral valve disease mediated through the TGFB pathway.

7q11.23 Duplication syndrome: Physical characteristics and natural history.

In order to describe the physical characteristics, medical complications, and natural history of classic 7q11.23 duplication syndrome [hereafter Dup7 (MIM 609757)], reciprocal duplication of the region deleted in Williams syndrome [hereafter WS (MIM 194050)], we systematically evaluated 53 individuals aged 1.25-21.25 years and 11 affected adult relatives identified in cascade testing. In this series, 27% of probands with Dup7 had an affected parent. Seven of the 26 de novo duplications that were examined for inversions were inverted; in all seven cases one of the parents had the common inversion polymorphism of the WS region. We documented the craniofacial features of Dup7: brachycephaly, broad forehead, straight eyebrows, broad nasal tip, low insertion of the columella, short philtrum, thin upper lip, minor ear anomalies, and facial asymmetry. Approximately 30% of newborns and 50% of older children and adults had macrocephaly. Abnormalities were noted on neurological examination in 88.7% of children, while 81.6% of MRI studies showed structural abnormalities such as decreased cerebral white matter volume, cerebellar vermis hypoplasia, and ventriculomegaly. Signs of cerebellar dysfunction were found in 62.3%, hypotonia in 58.5%, Developmental Coordination Disorder in 74.2%, and Speech Sound Disorder in 82.6%. Behavior problems included anxiety disorders, ADHD, and oppositional disorders. Medical problems included seizures, 19%; growth hormone deficiency, 9.4%; patent ductus arteriosus, 15%; aortic dilation, 46.2%; chronic constipation, 66%; and structural renal anomalies, 18%. We compare these results to the WS phenotype and offer initial recommendations for medical evaluation and surveillance of individuals who have Dup7.

This is your brain on sports. Measuring concussions in high school athletes in the Twin Cities metropolitan area.

Concussions can have a negative impact on students' ability to perform in the classroom as well as on their health and well-being. Therefore, timely treatment is especially important. To better understand the scope of the problem in Minnesota, the Minnesota Department of Health piloted an online sports-related concussion reporting system in 36 public high schools in the Twin Cities metropolitan area. In the 2013-2014 academic year, 730 concussions were reported to our system from certified athletic trainers working with those schools, with one out of every 100 athletes sustaining concussions. From this, we estimated that 2,974 sports-related concussions occurred among high school athletes statewide. This information is useful for evaluating and guiding prevention efforts and for informing clinicians on how to treat concussions.

The high cost of bath salts: a study of the health care burden of illicit synthetic drug use in Duluth, Minnesota.

The Minnesota Department of Health conducted an exploratory epidemiologic investigation into the health care burden of illicit synthetic drug (ISD) use in Duluth, Minnesota. Staff reviewed medical records of 78 patients with suspected ISD use who were treated in emergency departments at two Duluth-area hospitals from January through September 2013. Most (67%) were unemployed, 75% arrived at the hospital by ambulance or police escort and 57% were admitted to the hospital. Use of ISDs has the potential to create a significant burden on the health care system and public services. Therefore, effective prevention and response strategies need to be developed.

A Qualitative Analysis of Clinician Perspectives of Ultrasound Biofeedback for Speech Sound Disorders.

PURPOSE: Ultrasound biofeedback therapy (UBT) is a relatively new type of technology-assisted speech-language therapy and has shown promise in remediating speech sound disorders. However, there is a current lack of understanding of the barriers and benefits that may influence the usage behavior and clinical decision making for the implementation of UBT from a clinician perspective. In this qualitative study, we explore the perspectives of speech-language pathologists (SLPs) who have used ultrasound biofeedback in programs of speech sound therapy using the unified theory of acceptance and use of technology (UTAUT) model. METHOD: Seven SLPs who had clinical experience treating speech sound disorders with UBT participated. Semistructured in-depth interviews were conducted and video-recorded. Two coders coded and categorized the transcribed data, with consensus established with a third coder. Using thematic analysis, the data were exploratorily grouped into themes along components of the UTAUT model. RESULTS: The highest number of codes was sorted into the "effort expectancy" theme, followed by "performance expectancy," "social influence," and "facilitating conditions" themes of the UTAUT model. Clinicians identified multiple perceived barriers and benefits to the use of ultrasound technology. The top identified barrier was limited accessibility, and the top benefit was the ability to visualize a client's articulatory response to cues on a display. CONCLUSIONS: Clinicians prioritized "effort expectancy" and "performance expectancy" when reflecting on the use of ultrasound biofeedback for speech sound disorders. Clinicians spoke favorably about using UBT for speech sound disorder treatment but acknowledged institutional barriers and limitations at organizational and social levels.

Bilateral exudative retinal detachments and associated choroidal detachments in a patient on dapsone: a case report.

BACKGROUND: Dapsone is a synthetic sulfonamide used to treat numerous dermatologic conditions. Ocular side effects have been rarely reported and include retinal necrosis, optic atrophy, and macular infarction. We report the first known case of bilateral choroidal effusions and exudative retinal detachments associated with dapsone use. CASE PRESENTATION: A 57-year-old male with a past medical history of testicular seminoma presented with bilateral blurry vision for 2 months. His exam revealed bilateral choroidal effusions with bilateral exudative retinal detachments without evidence of intraocular tumor. The patient had recently been prescribed dapsone for urticarial vasculitis. The patient was instructed to discontinue dapsone and follow-up closely. Interval follow-up of 8 months demonstrated almost complete resolution of the choroidal effusions and retinal detachments with residual pigment epithelium changes after cessation of dapsone. The patient recovered his pre-detachment visual function. CONCLUSIONS: Patients on dapsone who present with new visual complaints should undergo a thorough ophthalmic evaluation given the multiple mechanisms by which dapsone can affect the eye.