A case with cardiac, skeletal, speech, and motor traits narrows the subtelomeric 19p13.3 microdeletion region to 46 kb.

Subtelomeric 19p13.3 deletions have been associated with diverse anatomical and developmental phenotypes. A recent study of eight patients with subtelomeric interstitial 19p13.3 microdeletions at 0.3-1.4 Mb (hg 19) showed associations with growth restrictions, skeletal deformities, craniofacial anomalies, congenital heart defects, renal malformations, hernias, immune system deficits, fine and gross motor delays, speech delays, and developmental and learning delays. The authors defined two small regions of overlap containing four and 11 genes, respectively, with potential haploinsufficiency. Here, we present a new case with a de novo 184 kb deletion containing eight genes, three of which fall into the second previously identified small region of overlap, reducing the shared region to 46 kb. Phenotypic traits include most of the core findings in the previously reported cases but not growth restrictions, craniofacial anomalies, renal malformation, and learning disability. A closer look at the speech and motor delays reveals apraxic speech and discoordination in the fine and gross motor domain, consistent with cerebellar involvement across motor systems. Findings are consistent with a role of AZU1 in the observed immune deficiencies and PTBP1 in the observed skeletal, abdominal, speech, language, motor, and sensory traits. This case thus contributes to a more nuanced understanding of the subtelomeric 19p13.3 deletion region.

Tools for standardized data collection: Speech, Language, and Hearing measurement protocols in the PhenX Toolkit.

The PhenX Toolkit (https://www.phenxtoolkit.org/) is an online catalog of recommended measurement protocols to facilitate cross-study analyses for biomedical research. An expert review panel (ERP) reviewed and updated the PhenX Toolkit Speech and Hearing domain to improve the precision and consistency of speech, language, and hearing disorder phenotypes. A three-member ERP convened in August 2018 to review the measurement protocols in the PhenX Speech and Hearing domain. Aided by three additional experts in voice assessment, vertigo, and stuttering, the ERP updated the 28 protocols to reflect the latest science and technology. ERP recommendations include six new protocols, five updated protocols (from the same source), and one retired protocol. New additions include two voice-related, three hearing-related, and two speech-related protocols. Additions reflect new phone/tablet applications for hearing and language, and clinical evaluations of voice. "Language" was added to the domain name, which is now "Speech, Language, and Hearing," to represent language-related protocols. These protocols can facilitate the assessment of speech, language, and hearing in clinical and population research. Common data elements (i.e., use of the same variables across studies) used by geneticists, otolaryngologists, audiologists, speech-language pathologists, and in other disciplines can lead to cross-study data integration and increased statistical power when studies are combined.

Three children with different de novo BCL11A variants and diverse developmental phenotypes, but shared global motor discoordination and apraxic speech: Evidence for a functional gene network influencing the developing cerebellum and motor and auditory cortices.

BCL11A is implicated in BCL11A-Related Intellectual Development Disorder (BCL11A-IDD). Previously reported cases had various types of BCL11A variants (copy-number variations [CNVs], singlenucleotide variants [SNVs]). Phenotypes included global, cognitive, and motor delays, autism spectrum disorder (ASD), craniofacial dysmorphology, and speech and language delays described generally, with only two reports specifying childhood apraxia of speech (CAS). Here, we present three additional children with CAS and de novo BCL11A variants, a p.Ala182Thr nonconservative missense and a p.GLu611.Ter nonsense variant, both in exon 4, and a 106 kb deletion harboring exons 1 and 2. All three children have fine and gross motor discoordination, feeding difficulties, and visual motor disorders. Intellectual and learning disabilities and disordered language skills were seen only in the child with the missense variant and the child with the deletion. These findings align with, and expand, previous findings in that BCL11A variants have significant and highly penetrant apraxic effects across motor systems, consistent with cerebellar involvement. The deletion of exons 1 and 2 is the smallest BCL11A CNV with the full phenotypic expression reported to date. The present results support previous findings in that BCL11A-IDD can result from BCL11A variants regardless of type (deletion, SNVs). A gene expression study shows that BCL11 is expressed highly in the early developing cerebellum and primary motor and auditory cortices. Significant co-expression rates in these regions with genes previously implicated in disorders of spoken language and in ASD support the phenotypic overlaps in children with BCL11A-IDD, CAS, and ASD.

Monoanionic C

A family of Pt(II) complexes bearing monoanionic C^N^N ligands as luminophoric units as well as a set of monodentate ligands derived from allenylidene and carbene species were synthesized and characterized in terms of structure and photophysical properties. In addition, we present the extraordinary molecular structure of a phosphorescent complex carrying an allenylidene ligand. Depending on the co-ligand, an effect can be observed in the photoluminescence lifetimes and quantum yields as well as in the radiative and radiation less deactivation rate constants. Their correlation with the substitution pattern was analyzed by comparing the photoluminescence in fluid solution at room temperature and in frozen glassy matrices at 77 K. Moreover, in order to gain a deeper understanding of the electronic states responsible for the optical properties, density functional theory calculations were performed. Finally, the cytotoxicity of the complexes was evaluated in vitro, showing that the cationic complexes exhibit strong effects at low micromolar concentrations. The calculated half-maximum effective concentrations (EC50 values) were 4 times lower in comparison to the established antitumor agent oxaliplatin. In contrast, the neutral species are less toxic, rendering them as potential bioimaging agents.

A New American University Model for Training the Future MCH Workforce Through a Translational Research Team.

OBJECTIVES: To describe the process of developing and implementing experiential learning through translational research teams that engage diverse undergraduate and graduate students. METHODS: After a college redesign, translational research teams were developed to foster multidisciplinary research and better integrate students with faculty research, community, and clinical activities. Three primary approaches were used to engage undergraduate and graduate students in the maternal and child health translational research team (MCH TrT). These included an undergraduate experiential learning course; participation in translational research team meetings and events; and mentorship activities including graduate student theses and supplementary projects. RESULTS: Since 2019, a total of 56 students have engaged with the MCH translational research team. The majority (64%) of students engaging in translational research were undergraduates. Racial and ethnic diversity was evident with 16% Latinx, 14% Black/African American, 12% Asian, 10% two or more races, and 4% Native American or Native Hawaiian. A large proportion (42%) of students indicated that they were first-generation college students, while 24% indicated they had a disability. Five themes emerged from student feedback about their involvement in the experiential learning course: the value of translational research, development of research skills, collaboration, practice development, and value for community partners. CONCLUSIONS FOR PRACTICE: Through an MCH translational research team, we have established a pathway to enhance diversity among the MCH workforce which will increase recruitment and retention of underrepresented groups, and ultimately improve MCH research and practice.

A phenotypically diverse family with an atypical 22q11.2 deletion due to an unbalanced 18q23;22q11.2 translocation.

The 22q11.2 deletion syndrome (22q11.2 DS) is the most common deletion syndrome in humans. In most cases, it occurs de novo. A rare family of three with 22q11.2 deletion syndrome (22q11.2 DS) resulting from an unbalanced 18q;22q translocation is reported here. Their deletion region is atypical in that it includes only 26 of the 36 genes in the minimal critical 22q11.2 DS region but it involves the loss of the centromeric 22q region and the entire p arm. The deletion region overlaps with seven other rare atypical cases; common to all cases was the loss of a region including SEPT5-GP1BB proximally and most of ARVCF distally. Interrogation of the deleted 22q region proximal to the canonical 22q11.2 deletion region in the DECIPHER database showed seven cases with isolated or combined traits of 22q11.2 DS, including three with clefts. The phenotypes in the present family thus may result from the loss of a subset of genes in the critical region, or alternatively the loss of other genes or sequences in the proximal 22q deletion region, or interactive effects among these. Despite the identical deletion locus in the three affected family members, expression of the 22q11.2 DS traits differed substantially among them. These three related cases thus contribute to knowledge of 22q11.2 DS in that their unusual deletion locus co-occurred with the cardinal features of the syndrome while their identical deletions are associated with variable phenotypic expression.

Spelling errors reveal underlying sequential and spatial processing deficits in adults with dyslexia.

Recent studies showed that some adults with dyslexia have difficulty processing sequentially arranged information. In a companion study, this deficit manifested as low accuracy during a word pair comparison task involving same/different decisions when two words differed in their letter sequences. This sequential deficit was associated with left/right spatial letter confusion. In the present study, we found the same underlying difficulty with sequential and spatial letter processing during word spelling. Participants were the same 22 adults with dyslexia and 20 age- and gender-matched controls as in the companion study. In the spelling task, sequential error rates were higher in the dyslexia group, compared to the controls. Measures of accuracy of serial letter order during the spelling task and the word comparison task were correlated. Only three participants, each with dyslexia, produced left/right letter reversals during spelling. These were the same participants who produced left/right errors when naming single letters. They also had profound difficulty with sequential and left/right letter processing in the spelling and word comparison tasks, and they had the most severe spelling impairment. We conclude that this pervasive, persistent difficulty with sequential and spatial reversals contributes to a severe dyslexia subtype. In the dyslexia group as a whole, additional and separate sources of errors were underspecified word representations in long-term memory and homophone errors that likely represent language-based deficits in word knowledge. In the participants, these three factors (sequential/spatial letter confusion, underspecified word form representation, language-based deficits) occurred either as single factors or in combination with each other.

Sequential and spatial letter reversals in adults with dyslexia during a word comparison task: demystifying the "was saw" and "db" myths.

Whether sequential and spatial letter reversals characterize dyslexia in children has been unclear, largely due to developmental variability of these errors in children with and without dyslexia. Here we demonstrate both types of reversals for the first time in adults with dyslexia (n = 22) but not in control adults (n = 20). Participants evaluated 576 word pairs that consisted of two identical words or two words that differed subtly, by categorizing them as same or different. Two subsets of word pairs differed in sequential (e.g. "two tow") and spatial (e.g. "cob cod") letter reversals. The adults with dyslexia were less accurate than the controls regarding both types of word pairs. Their accuracy during left/right letter reversals was lower, compared to both up/down letter reversals (e.g. "cub cup") and nonsymmetric letter similarities (e.g. "half halt"). Accuracy during left/right reversals was correlated with accuracy during sequential rearrangement in the word pair task as well as with a composite measure of sequential processing based on nonword repetition, nonword reading, and multisyllabic word repetition. It was also correlated with a composite measure of literacy skills. A subset of the dyslexia group who produced left/right errors during a rapid single letter naming task obtained lower accuracy than the dyslexia subgroup without such errors during both types of letter reversals, and their overall literacy skills were lower. We conclude that sequential and left/right letter reversals characterize a severe dyslexia subtype. These two types of reversal are associated, are part of a general deficit in sequential processing likely due to cerebellar deficits, and persist into adulthood.

Comparing global motor characteristics in children and adults with childhood apraxia of speech to a cerebellar stroke patient: evidence for the cerebellar hypothesis in a developmental motor speech disorder.

Individuals with childhood apraxia of speech (CAS) have motor deficits in systems beyond speech and also global deficits in sequential processing, consistent with cerebellar dysfunction. We investigated the cerebellar hypothesis of CAS in 18 children and adolescents with CAS, 11 typical controls, an adult with a probable CAS history, and an adult with a history of a cerebellar stroke. Compared to the controls, children and adolescents with CAS had the greatest difficulty with rapid syllable repetition when alternating between two different syllables types, less difficulty when switching among three different syllables, and no difficulty when repeating the same syllable. They also showed difficulty with alternating but not repetitive key tapping. Motor speeds during the syllable repetition and key tapping tasks where correlated, consistent with a central motor delimiter that governs both systems. Participants with CAS obtained low scores in a test of fine motor ability, where the tasks required rapid integration of complex hand movement sequences. The adult with the probable CAS history obtained motor performance scores that generally resembled those in the children and adolescents with CAS, consistent with motor deficits that persist into adulthood. The participant with the cerebellar stroke history showed deficits in tests of fine and gross motor ability as well as balance. His repetitive and alternating key tapping was slow in the ipsilateral hand relative to the stroke lesion. The shared deficits in sequential motor functions among all participants with CAS and the cerebellar stroke patient are consistent with persisting cerebellar dysfunctions in CAS.

Exome Sequencing of Two Siblings with Sporadic Autism Spectrum Disorder and Severe Speech Sound Disorder Suggests Pleiotropic and Complex Effects.

Recent studies of autism spectrum disorder (ASD) and childhood apraxia of speech (CAS) have resulted in conflicting conclusions regarding the comorbidity of these disorders on phenotypic grounds. In a nuclear family with two dually affected and one unaffected offspring, whole-exome sequences were evaluated for single nucleotide and indel variants and CNVs. The affected siblings but not the unaffected sibling share a rare deleterious compound heterozygous mutation in WWOX, implicated both in ASD and motor control. In addition, one of the affected children carries a rare deleterious de novo mutation in the ASD candidate gene RIMS1. The two affected children but not their unaffected sibling inherited deleterious variants with relevance for ASD and/or CAS. WWOX, RIMS1, and several of the genes harboring the inherited variants are expressed in the brain during prenatal and early postnatal development. Results suggest compound heterozygosity as a cause of ASD and CAS, pleiotropic gene effects, and potentially additional, complex genetic effects.

Dose-response relationship of intermittent normobaric hypoxia to stimulate erythropoietin in the context of health promotion in young and old people.

PURPOSE: Erythropoietin (EPO) has multifactorial positive effects on health and can be increased by intermittent normobaric hypoxia (IH). Recommendations about the intensity and duration of IH to increase EPO exist, but only for young people. Therefore, the aim of the study was to investigate the dose-response relationship regarding the duration of hypoxia until an EPO expression and the amount of EPO expression in old vs. young cohorts. METHODS: 56 young and 67 old people were assigned to two separate investigations with identical study designs (3-h hypoxic exposure) but with different approaches to adjust the intensity of hypoxia: (i) the fraction of inspired oxygen (FiO2) was 13.5%; (ii) the FiO2 was individually adjusted to an oxygen saturation of the blood of 80%. Age groups were randomly assigned to a hypoxia or control group (normoxic exposure). EPO was assessed before, during (90 and 180 min), and 30 min after the hypoxia. RESULTS: EPO increased significantly after 180 min in both cohorts and in both investigations [old: (i) + 16%, p = 0.007 and (ii) + 14%, p < 0.001; young: (i) + 27%, p < 0.001 and (ii) + 45%, p = 0.007]. In investigation (i), EPO expression was significantly higher in young than in old people after 180 min of hypoxic exposure (p = 0.024) and 30 min afterwards (p = 0.001). CONCLUSION: The results indicate that after a normobaric hypoxia of 180 min, EPO increases significantly in both age cohorts. The amount of EPO expression is significantly higher in young people during the same internal intensity of hypoxia than in old people.

The role of short-term memory impairment in nonword repetition, real word repetition, and nonword decoding: A case study.

In a companion study, adults with dyslexia and adults with a probable history of childhood apraxia of speech showed evidence of difficulty with processing sequential information during nonword repetition, multisyllabic real word repetition and nonword decoding. Results suggested that some errors arose in visual encoding during nonword reading, all levels of processing but especially short-term memory storage/retrieval during nonword repetition, and motor planning and programming during complex real word repetition. To further investigate the role of short-term memory, a participant with short-term memory impairment (MI) was recruited. MI was confirmed with poor performance during a sentence repetition and three nonword repetition tasks, all of which have a high short-term memory load, whereas typical performance was observed during tests of reading, spelling, and static verbal knowledge, all with low short-term memory loads. Experimental results show error-free performance during multisyllabic real word repetition but high counts of sequence errors, especially migrations and assimilations, during nonword repetition, supporting short-term memory as a locus of sequential processing deficit during nonword repetition. Results are also consistent with the hypothesis that during complex real word repetition, short-term memory is bypassed as the word is recognized and retrieved from long-term memory prior to producing the word.

Sequential processing deficit as a shared persisting biomarker in dyslexia and childhood apraxia of speech.

The purpose of this study was to investigate the hypothesis that individuals with dyslexia and individuals with childhood apraxia of speech share an underlying persisting deficit in processing sequential information. Levels of impairment (sensory encoding, memory, retrieval, and motor planning/programming) were also investigated. Participants were 22 adults with dyslexia, 10 adults with a probable history of childhood apraxia of speech (phCAS), and 22 typical controls. All participants completed nonword repetition, multisyllabic real word repetition, and nonword decoding tasks. Using phonological process analysis, errors were classified as sequence or substitution errors. Adults with dyslexia and adults with phCAS showed evidence of persisting nonword repetition deficits. In all three tasks, the adults in the two disorder groups produced more errors of both classes than the controls, but disproportionally more sequencing than substitution errors during the nonword repetition task. During the real word repetition task, the phCAS produced the most sequencing errors, whereas during the nonword decoding task, the dyslexia group produced the most sequencing errors. Performance during multisyllabic motor speech tasks, relative to monosyllabic conditions, was correlated with the sequencing error component during nonword repetition. The results provide evidence for a shared persisting sequential processing deficit in the dyslexia and phCAS groups during linguistic and motor speech tasks. Evidence for impairments in sensory encoding, short-term memory, and motor planning/programming was found in both disorder groups. Future studies should investigate clinical applications regarding preventative and targeted interventions towards cross-modal treatment effects.

Two unrelated children with overlapping 6q25.3 deletions, motor speech disorders, and language delays.

Interstitial and terminal 6q25 deletions are associated with developmental delays, hypotonia, eye pathologies, craniofacial dysmorphologies, and structural brain anomalies. In most cases, speech and language deficits are not described in detail. We report on a case (Patient 1, age 7 years) with a de novo 6q25.3-qter deletion, 11.1 Mb long and encompassing 108 genes, and a case (Patient 2, age 5 years) with an inherited interstitial 6q25.3 deletion, located within Patient 1's deletion region and 403 kb long, the smallest 6q25 deletion reported to date. Both children have hypotonia, motor speech disorders, and expressive language delays. Patient 1's speech was characterized by childhood apraxia of speech (CAS) and dysarthria. Other findings include developmental delay, ataxic cerebral palsy, optic nerve dysplagia, and atypical brain morphologies regarding the corpus callosum and gyration patterns, a clinical profile that closely matches a previously reported case with a nearly identical deletion. Patient 2 had speech characterized by CAS and typical nonverbal processing abilities. His father, a carrier, had typical speech and language but showed difficulties with complex motor speech and hand motor tasks, similar to other adults with residual signs of CAS. The small deletion in this family contains the IGF2R-AIRN-SLC22A2-SLC22A3 gene cluster, which is associated with imprinting and maternal-specific expression of Igf2R, Slc22a2, and Slc22a3 in mice, whereas imprinting in humans is a polymorphic trait. The shared phenotypes in the two patients might be associated with the deletion of the gene cluster.

De novo microdeletion of BCL11A is associated with severe speech sound disorder.

In 10 cases of 2p15p16.1 microdeletions reported worldwide to date, shared phenotypes included growth retardation, craniofacial and skeletal dysmorphic traits, internal organ defects, intellectual disability, nonverbal or low verbal status, abnormal muscle tone, and gross motor delays. The size of the deletions ranged from 0.3 to 5.7 Mb, where the smallest deletion involved the BCL11A, PAPOLG, and REL genes. Here we report on an 11-year-old male with a heterozygous de novo 0.2 Mb deletion containing a single gene, BCL11A, and a phenotype characterized by childhood apraxia of speech and dysarthria in the presence of general oral and gross motor dyspraxia and hypotonia as well as expressive language and mild intellectual delays. BCL11A is situated within the dyslexia susceptibility candidate region 3 (DYX3) candidate region on chromosome 2. The present case is the first to involve a single gene within the microdeletion region and a phenotype restricted to a subset of the traits observed in other cases with more extensive deletions.

Joint exome and metabolome analysis in individuals with dyslexia: Evidence for associated dysregulations of olfactory perception and autoimmune functions.

Dyslexia is a learning disability that negatively affects reading, writing, and spelling development at the word level in 5%-9% of children. The phenotype is variable and complex, involving several potential cognitive and physical concomitants such as sensory dysregulation and immunodeficiencies. The biological pathogenesis is not well-understood. Toward a better understanding of the biological drivers of dyslexia, we conducted the first joint exome and metabolome investigation in a pilot sample of 30 participants with dyslexia and 13 controls. In this analysis, eight metabolites of interest emerged (pyridoxine, kynurenic acid, citraconic acid, phosphocreatine, hippuric acid, xylitol, 2-deoxyuridine, and acetylcysteine). A metabolite-metabolite interaction analysis identified Krebs cycle intermediates that may be implicated in the development of dyslexia. Gene ontology analysis based on exome variants resulted in several pathways of interest, including the sensory perception of smell (olfactory) and immune system-related responses. In the joint exome and metabolite analysis, the olfactory transduction pathway emerged as the primary pathway of interest. Although the olfactory transduction and Krebs cycle pathways have not previously been described in dyslexia literature, these pathways have been implicated in other neurodevelopmental disorders including autism spectrum disorder and obsessive-compulsive disorder, suggesting the possibility of these pathways playing a role in dyslexia as well. Immune system response pathways, on the other hand, have been implicated in both dyslexia and other neurodevelopmental disorders.

Effects of intermittent hypoxia on cognitive performance and quality of life in elderly adults: a pilot study.

BACKGROUND: Physical exercise has a positive effect on cognitive performance and quality of life (QoL). One reason for this is the upregulation of brain-derived neurotrophic factor, which improves brain plasticity. Intermittent hypoxia promotes first the proliferation of endogenous neuroprogenitors which leads to an increased number of newborn neurons and second the expression of brain-derived neurotrophic factor in the adult hippocampus. Intermittent hypoxia may, therefore, support synaptic plasticity, the process of learning and provoke antidepressant-like effects. Hence, intermittent hypoxia might also lead to improved cognitive functioning and QoL. OBJECTIVE: This study aims to evaluate to what extent physical activity with preceded intermittent hypoxic training is more effective than solely strength-endurance training on cognitive performance and QoL. METHODS: 34 retired people aged between 60 and 70 years were randomly assigned to a control group or intervention group. Contrarily to the control group, which was supplied with a placebo air mixture, the intervention group was supplied with an intermittent hypoxic training prior to a strength-endurance exercise program. The cognitive performance of individuals was examined using the d2 test and the Number Combination Test (ZVT) both before and after the exercise program. We assessed QoL with the Medical Outcomes Study Short-Form 36-Item Health Survey (SF-12) and Pittsburgh Sleep Quality Index (PSQI) and the strength-endurance capacity using the Spring test. RESULTS: Regarding the d2 test, a time × group effect was observed. Speed of cognitive performance in seconds was measured using ZVT. Here, no interaction effect was discovered. An interaction effect was not found in the Physical Component Summary scores (SF-12). Regarding the Mental Component Summary, an interaction effect just failed to become statistically significant. Furthermore, we determined sleep quality with the PSQI. Here, an interaction effect was observed. The analysis of the strength-endurance test revealed no interaction effects. CONCLUSION: The data of the current study suggest that an additional intermittent hypoxic training combined with physical exercise augments the positive effects of exercise on cognitive performance and QoL in elderly humans.

Associations among measures of sequential processing in motor and linguistics tasks in adults with and without a family history of childhood apraxia of speech: a replication study.

The purpose of this study was to address the hypothesis that childhood apraxia of speech (CAS) is influenced by an underlying deficit in sequential processing that is also expressed in other modalities. In a sample of 21 adults from five multigenerational families, 11 with histories of various familial speech sound disorders, 3 biologically related adults from a family with familial CAS showed motor sequencing deficits in an alternating motor speech task. Compared with the other adults, these three participants showed deficits in tasks requiring high loads of sequential processing, including nonword imitation, nonword reading and spelling. Qualitative error analyses in real word and nonword imitations revealed group differences in phoneme sequencing errors. Motor sequencing ability was correlated with phoneme sequencing errors during real word and nonword imitation, reading and spelling. Correlations were characterized by extremely high scores in one family and extremely low scores in another. Results are consistent with a central deficit in sequential processing in CAS of familial origin.

Deficits in sequential processing manifest in motor and linguistic tasks in a multigenerational family with childhood apraxia of speech.

The purpose of this study was to evaluate a global deficit in sequential processing as candidate endophenotypein a family with familial childhood apraxia of speech (CAS). Of 10 adults and 13 children in a three-generational family with speech sound disorder (SSD) consistent with CAS, 3 adults and 6 children had past or present SSD diagnoses. Two preschoolers with unremediated CAS showed a high number of sequencing errors during single-word production. Performance on tasks with high sequential processing loads differentiated between the affected and unaffected family members, whereas there were no group differences in tasks with low processing loads. Adults with a history of SSD produced more sequencing errors during nonword and multisyllabic real word imitation, compared to those without such a history. Results are consistent with a global deficit in sequential processing that influences speech development as well as cognitive and linguistic processing.