Abnormal Tone Research Articles

Motor phenotypes associated with genetic neurodevelopmental disorders.

There is a growing number of monogenic disorders implicated in neurodevelopmental disorders (NDDs), including autism spectrum disorder and intellectual disability. Motor impairment is frequently seen in these disorders, although not clearly defined. We aimed to characterize the motor phenotype of genetic NDDs. We analyzed data from Simons Searchlight, collecting information on patients with genetic NDDs. Data analyzed included Vineland Adaptive Behavior Scales Second Edition (Vineland-II) motor standard scores, motor milestones and tone abnormalities. In total, 959 patients with 57 genetic disorders were included. Disorders associated with Vineland-II motor standard score <56 included GRIN2B-related disorder (mean standard score = 53.5), HNRNPH2-related disorder (mean standard score = 55.8) and SCN2A-related disorder (mean standard score = 49.9). The only genetic condition with a mean age of sitting unsupported ≥18 months was GRIN1-related disorder (mean age = 26.3 months). Genetic conditions with a mean age of walking independently ≥36 months included CTNNB1-related disorder (mean age = 37.4 months) and HNRNPH2-related disorder (mean age = 41.9 months). Tone abnormalities included hypotonia in 83% (577/696), hypertonia in 16% (112/696), a diagnosis of cerebral palsy (CP) in 10% (73/696) and a diagnosis specifically of spastic CP in 3% (23/696). Patients with genetic NDDs have a spectrum of motor impairment, which warrant further characterization.

Strategic tone management in ESG reports and ESG risk

In this study, we investigate whether strategic tone management in environmental, social, and governance (ESG) reports can serve as an indicator of future ESG risk. Our baseline results reveal a positive association between abnormal positive tone in ESG reports and future ESG risk. The findings suggest that firms employ impression management strategy in their ESG reports to provide misleading information. Analyst coverage and media attention can mitigate this positive association. Heterogeneity analysis reveals that the positive correlation is stronger for firms mandated to disclose ESG reports and those adhering to the Global Reporting Initiative guidelines. Additional tests indicate that abnormal positive tone is positively associated only with future environmental risk, not with future social and governance risk. We observe this positive association exclusively in government-reported ESG risk, not in media-reported ESG risk. Our results offer valuable implications for mitigating the adverse impact of strategic tone management on corporate sustainability practices.

Basic helix-loop-helix transcription factor BHLHE22 monoallelic and biallelic variants cause a neurodevelopmental disorder with agenesis of the corpus callosum, intellectual disability, tone and movement abnormalities.

BHLHE22 encodes a Class II basic helix-loop-helix transcription factor (bHLH). It is expressed exclusively in the retina and central nervous system (CNS), and functions as an important regulator of retinogenesis and neuronal differentiation. Mice lacking bhlhe22 show nearly complete loss of three brain comminsure, including the corpus callosum. Here we report eleven individuals from nine unrelated families with BHLHE22 variants, with a neurodevelopmental disorder presenting with absent or limited speech, severely impaired motor abilities, intellectual disability (ID), involuntary movements, autistic traits with stereotypies, abnormal muscle tone. The majority of individuals have partial or complete agenesis of the corpus callosum (ACC). Additional symptoms comprised epilepsy, variable dysmorphic features, and eye anomalies. One additional individual had spastic paraplegia without delayed development and ACC, expanding the phenotype to milder and later onset forms. Four individuals carry de novo missense variants within the highly conserved helix-loop-helix domain while seven individuals from five unrelated families carry a recurrent homozygous frameshift variant, p.(Gly74Alafs*18). Our findings implicate BHLHE22 variants in causing a previously unidentified autosomal dominant and recessive neurodevelopmental disorder associated with ACC, severe motor, language, and cognitive delays, abnormal tone, and involuntary movements. To our knowledge, this is the first report of Class II bHLH variants in humans shown to significantly disrupt brain development, cognition, and movement.

Ambiguity of tone in annual reports and bank risk taking

AbstractIn this paper, we examine whether abnormal ambiguity of tone in banks' 10‐K filings is associated with banks' risk‐taking behaviour. We estimate abnormal ambiguous tone using residual of a tone model that disentangles the obfuscation component from the information component in the ambiguous tone. We find that banks that intentionally use more ambiguous tone in 10‐K filings exhibit higher risk taking subsequently, consistent with the argument that an intentional ambiguous tone adds to the opacity of financial statements, which potentially masks managerial risk‐taking activities and curbs market discipline from external stakeholders. Our results remain robust to alternative model specifications and sensitivity tests which address potential endogeneity concerns. Furthermore, banks with higher abnormal ambiguous tone are associated with more aggressive investment decisions. Together, our findings suggest that abnormal ambiguous tone in annual reports is informative of banks' risk‐taking activities.

Neuromotor and Neurosensory Impairment among High Risk Infants at One Year of Age – Risk Factor Analysis

Background: Improvement in the quality of perinatal care in the last few decades has led on to improve newborn survival. Sick neonates who have survived are exposed to high risk factors in the prenatal period and are termed as high risk infants (HRIn). This study aimed at determining the proportion of neuromotor and neurosensory impairments among HRIn. Methods: This prospective observational study was conducted in a tertiary care centre in South India between January 2020 and December 2021. Study population comprised of intramural high risk infants fulfilling the criteria. At discharge infants were stratified as mild, moderate or severe risk for developing neurodevelopmental disorders and follow up plan was given. The subjects were assessed at 4, 6, 8 and 12 month for impairments. Results: Total 138 infants were enrolled and 88 completed follow up. Lost for follow up was 36.2%. The impairments detected with respect to motor and vision were 12.5% and 1.1% respectively. Sepsis, seizures, birth asphyxia and preterm were robust prognostic factors for neuromotor impairment. Risk of tone abnormality was 13 times higher in infants who had sepsis. At risk for developmental delay was noticed in 11.4% of the study for which significant association was with prematurity, sepsis and birth asphyxia. Discussion: HRIn are susceptible for neurodevelopmental impairments. Hence early identification and enrolment in intervention programs will ensure favorable outcomes.

Environmental, social and governance (ESG) performance and abnormal positive tone

Purpose The purpose of this study is to explore the relationship between environmental, social and governance (ESG) performance and tone management in the annual report. This is based on the notion that managers, driven by personal interests, may use their ESG accomplishments by using an abnormal positive tone to enhance their reputation or career prospects. Design/methodology/approach Using panel data from Chinese listed companies from 2010 to 2022, this study first investigates the relationship between ESG performance and abnormal tone management. The study then uncovers this relationship is mediated through the mechanisms of equity-based incentive and analyst coverage. The conclusions of this paper hold even after a series of robustness tests, such as propensity score matching, Heckman two-stage method and two-stage least squares with instrumental variables. Findings This study finds a positive correlation between ESG performance and the presence of abnormal positive tone in annual reports. Furthermore, the mechanistic analysis reveals that managers in companies with strong ESG performance are motivated to use an overly positive tone, largely due to their vested interests in equity-based compensation. Moreover, in an effort to alleviate the pressure stemming from heightened financial analyst coverage and enhance the impression conveyed through analysts' reports, managers with superior ESG performance also tend to inflate the tone within their annual reports. Practical implications This study provides significant insights into the ongoing dialogue surrounding ESG-related equity incentives, which incentivize managerial manipulation of stock prices through the use of abnormal positive tone. The findings call upon investors to exercise greater vigilance in examining narrative information in annual reports, as abnormally positive tones may not always faithfully represent performance but rather reflect managerial self-interest. Social implications There is an emphasis on the importance of robust oversight mechanisms within corporate governance bodies to curb the manipulation of tone for managers’ personal gain. Originality/value This study enhances the theoretical foundation of ESG studies, offering a holistic perspective on the intricate interplay among ESG performance, managerial behavior and financial markets, with potential implications for researchers, investors and regulators.

Muscle Tone Assessment by Machine Learning Using Surface Electromyography

Muscle tone is defined as the resistance to passive stretch, but this definition is often criticized for its ambiguity since some suggest it is related to a state of preparation for movement. Muscle tone is primarily regulated by the central nervous system, and individuals with neurological disorders may lose the ability to control normal tone and can exhibit abnormalities. Currently, these abnormalities are mostly evaluated using subjective scales, highlighting a lack of objective assessment methods in the literature. This study aimed to use surface electromyography (sEMG) and machine learning (ML) for the objective classification and characterization of the full spectrum of muscle tone in the upper limb. Data were collected from thirty-nine individuals, including spastic, healthy, hypotonic and rigid subjects. All of the classifiers applied achieved high accuracy, with the best reaching 96.12%, in differentiating muscle tone. These results underscore the potential of the proposed methodology as a more reliable and quantitative method for evaluating muscle tone abnormalities, aiming to address the limitations of traditional subjective assessments. Additionally, the main features impacting the classifiers’ performance were identified, which can be utilized in future research and in the development of devices that can be used in clinical practice.

Systemic complications of Aicardi Goutières syndrome using real-world data

ObjectiveAicardi Goutières Syndrome (AGS) is a rare genetic interferonopathy associated with diverse multisystemic complications. A critical gap exists in our understanding of its longitudinal, systemic disease burden, complicated by delayed diagnosis. To address this need, real-world data extracted from existing medical records were used to characterize the longitudinal disease burden. MethodsAll subjects (n = 167) with genetically confirmed AGS enrolled in the Myelin Disorders Biorepository Project (MDBP) were included. As available in medical records, information was collected on subject demographics, age of onset, and disease complications. Information from published cases of AGS (2007–2022; n = 129) with individual-level data was also collected. Neurologic severity at the last available encounter was determined by retrospectively assigning the AGS Severity Scale [severe (0–3), moderate (4–8), and mild (9–11)]. ResultsThe genotype frequency in the natural history cohort was TREX1 (n = 26, 15.6 %), RNASEH2B (n = 50, 29.9 %), RNASEH2C (n = 3, 1.8 %), RNASEH2A (n = 7, 4.2 %), SAMHD1 (n = 25, 15.0 %), ADAR (n = 34, 20.4 %), IFIH1 (n = 19, 11.4 %), and RNU7–1 (n = 3, 1.8 %). The median age of systemic onset was 0.15 years [IQR = 0.67 years; median range by genotype: 0 (TREX1) - 0.62 (ADAR) years], while the median neurological onset was 0.33 years [IQR = 0.82 years; median range by genotype: 0.08 (TREX1) - 0.90 (ADAR) year].The most common early systemic complications were gastrointestinal, including dysphagia or feeding intolerance (n = 124) and liver abnormalities (n = 67). Among postnatal complications, thrombocytopenia appeared earliest (n = 29, median 0.06 years). Tone abnormalities (axial hypotonia: n = 145, 86.8 %; dystonia: n = 123, 73.7 %), irritability (n = 115, 68.9 %), and gross motor delay (n = 112, 7.1 %) emerged as the most prevalent neurological symptoms. Previously published case reports demonstrated similar patterns.The median AGS score for the entire cohort was 4 (IQR = 7). The most severe neurologic phenotype occurred in TREX1-related AGS (n = 19, median AGS severity score 2, IQR = 2). Time to feeding tube placement, chilblains, early gross motor delay, early cognitive delay, and motor regression were significantly associated with genotype (Fleming-Harrington log-rank: p = 0.0002, p < 0.0001, p = 0.0038, p < 0.0001, p = 0.0001, respectively). Microcephaly, feeding tube placement, and seizures were associated with lower AGS scores (All: Wilcoxon rank sum test, p < 0.0001).Among the qualifying case reports (n = 129), tone abnormalities were the most prevalent disease feature, with spastic quadriplegia reported in 37 of 96 cases (38.5 %) and dystonia in 30 of 96 cases (31.2 %). ConclusionsAGS is a heterogeneous disease with multi-organ system dysfunction that compounds throughout the clinical course, resulting in profound neurological and extra-neurological disease impact. Systemic symptoms precede neurologic disease features in most cases. Disease onset before the age of one year, microcephaly, feeding tube placement, and seizures were associated with worse neurological outcomes. This work will inform evidence-based clinical monitoring guidelines and clinical trial design.

Does data asset disclosure contribute to the market efficiency? Evidence from China

Information regarding firms' data assets and stock pricing has been more closely related when data is integrated into firms' value creation processes. However, since data asset disclosure can also be engaged in impression management by firms, its contribution to market efficiency may be impeded. Using a sample of Chinese A-share listed firms from 2014 to 2020, this study examines the impact of increased data asset information disclosure on the subsequent stock price volatility. The findings suggest that more data asset disclosure reduces stock return idiosyncratic volatility. The mechanism analysis shows that data asset disclosure reduces idiosyncratic volatility of stock prices by mitigating analyst forecast dispersion and noise trading induced by buy-sell imbalances. Moreover, this mitigating effect is more pronounced in firms with more analyst following, observable digital investments, and higher liquidity. But the effect is diminished if firms use a more positive abnormal tone in their annual reports.

Analysis of genetic etiology of 234 deaths in the pediatric intensive care unit with suspected genetic diseases

Objective: To explore the genetic etiology of pediatric intensive care unit (PICU) mortality cases and summarize their clinical characteristics. Methods: This was a retrospective cohort study. The study population consisted of 234 children who died within 7 d after admitted to the PICU of Children's Hospital of Fudan University from January 2017 to December 2021. The clinical diagnoses, laboratory test results, and genetic testing results were collected. These patients were divided into the pathogenic gene variation positive (PGVP) group and the pathogenic gene variation negative (PGVN) group according to the results of genetic testing. The Mann-Whitney U test and Pearson's chi-square test or Fisher's exact probability method were used to compare the clinical characteristics between the groups. Results: A total of 234 cases were enrolled, including 139 (59.4%) males and 95 (40.6%) females. The age at death was 1.0 (0.4, 3.7) years old and the length of PICU stay was 16 (6, 33) days. There were 62 cases (26.5%) PGVP, and the mutated pathogenic genes included immune genes (23 cases (37.1%)), metabolic genes (11 cases (17.7%)), neuromuscular genes (11 cases (17.7%)), cardiovascular genes (4 cases (6.5%)), and genes of other systems (13 cases (21.0%)). The age at death in PGVP cases was significantly lower than in PGVN cases (0.6 (0.3, 1.4) vs. 1.3(0.5, 4.3) years old, Z=3.85, P<0.001). Compared with the PGVN group, the PGVP group had a higher incidence of family history and chronic complex conditions (CCC) than the PGVN group (6.5% (4/62) vs. 0.6% (1/172) and 93.5% (58/62) vs. 76.2% (131/172), χ2=8.87, P=0.018 and 0.003, respectively). Children in the PGVP group were admitted with higher incidence of severe infection, decreased consciousness or coma, moderate-to-severe anemia, thrombocytopenia, protracted diarrhea, and abnormalities in muscle strength or tone than those in the PGVN group (74.2%(46/62) vs. 45.9%(79/172), 50.0%(31/62) vs. 35.5%(61/172), 32.3%(20/62) vs. 18.0%(31/172), 21.0%(13/62) vs. 10.5%(18/172), 25.8%(16/62) vs. 4.1%(7/172), 16.1%(10/62) vs. 5.2%(9/172), χ2=14.63, 4.04, 5.41, 4.37, 24.30, 7.25, all P<0.05). Pathogenic genes that occurred more than twice included IL2RG (5 cases), SMN1 (4 cases), and SH2D1A (3 cases, including 2 single gene varients and 1 copy number varient). Conclusions: Among the deceased cases in the PICU, the main genetic causes are immune-related, metabolic, and neuromuscular genetic disorders. Critically ill children with a family history, CCC, and early features such as severe infections, decreased consciousness or coma, moderate to severe anemia, thrombocytopenia, protracted diarrhea, or abnormalities in muscle strength or tone should be closely monitored and undergo early genetic testing.

Cerebral palsy in children: A clinical practice review

Cerebral palsy is a disorder characterized by abnormal tone, posture, and movement. In clinical practice, it is often useful to approach cerebral palsy based on the predominant motor system findings – spastic hemiplegia, spastic diplegia, spastic quadriplegia, extrapyramidal or dyskinetic, and ataxic. The prevalence of cerebral palsy is between 1.5 and 3 per 1,000 live births with higher percentage of cases in low to middle income countries and geographic regions. Pre-term birth and low birthweight are recognized as the most frequent risk factors for cerebral palsy; other risk factors include hypoxic-ischemic encephalopathy, maternal infections, and multiple gestation. In most cases of cerebral palsy, the initial injury to the brain occurs during early fetal brain development. Intracerebral hemorrhage and periventricular leukomalacia are the main pathologic findings found in preterm infants who develop spastic cerebral palsy. The diagnosis of cerebral palsy is primarily based on clinical findings. Early recognition of infants at risk for cerebral palsy as well as those with cerebral palsy is possible based on a combination of clinical history, use of standardized neuromotor assessment and findings on magnetic resonance imaging; however, in clinical practice, cerebral palsy is more reliably diagnosed by 2 years of age. Magnetic resonance imaging scan is indicated to delineate the extent of brain lesions and to identify congenital brain malformations. Genetic testing and tests for inborn errors of metabolism are indicated to identify specific disorders, especially treatable disorders. Because cerebral palsy is associated with multiple associated and secondary medical conditions, its management requires a sustained and consistent collaboration among multiple disciplines and specialties. With appropriate support, most children with cerebral palsy grow up to be adults with good functional abilities.

Financial fraud detection for Chinese listed firms: Does managers' abnormal tone matter?

This study introduces a novel perspective on financial fraud detection by exploring the utility of managers' abnormal tone. To mitigate bias in indicator selection, we implement a feature selection process involving a comprehensive set of 301 indicators, including financial, non-financial, and textual, and various machine learning algorithms. The dataset contains 6077 pairs of fraudulent and non-fraudulent samples in China. Our findings underscore the significance of abnormal tone in fraud detection, establishing it as a prominent factor in the feature selection process. The accuracy outcomes from eight machine learning models further confirm that incorporating abnormal tone can enhance fraud detection performance.

Post-term Birth and Developmental Coordination Disorder: A Narrative Review of Motor Impairments in Children.

A prevalent long-term medical condition in children that is rarely understood and acknowledged in educational contexts is developmental coordination disorder (DCD), which is one of the most prevalent conditions in school-aged children. Mild-to-severe abnormalities in muscle tone, posture, movement, and the learning of motor skills are associated with motor disorders. Early detection of developmental abnormalities in children is crucial as delayed motor milestones during infancy might indicate a delay in both physical and neurological development. To overcome the current condition of motor impairment, obstructing their risk factors is important to prevent the development of disability, which is already determined in the prenatal and perinatal period. Concerning the relationship with gestational age, the majority of the studies reported a relationship between DCD and preterm children. However, the entire range of gestational age, including post-term birth, has not been studied. The risk of developmental consequences such as cognitive impairments, major mental diseases, attention-deficit/hyperactivity disorder, autism spectrum disorder, and other behavioral and emotional problems increases in post-term birth, according to prior studies. Thus, this review aims to provide an overview of information linking post-term birth to children's motor impairment, with a focus on DCD. A thorough systemic review was conducted on online databases, and only a few studies were found on the association with post-term children. Insufficient evidence made it necessary to examine more post-term cohorts in adolescence to fully determine the long-term health concerns and develop therapies to mitigate the detrimental effects of post-term deliveries.

Progressive Thrombocytopenia, Splenomegaly, and Abnormal Tone in an Infant With Growth Faltering.

A 4-month-old full-term female presented with growth faltering associated with progressive feeding difficulty, rash, abdominal distension, and developmental delays. She was found to have disconjugate gaze, abnormal visual tracking, mixed tone, bruising, and splenomegaly on examination. Initial workup was notable for thrombocytopenia and positive cytomegalovirus (CMV) immunoglobulin G and immunoglobulin M antibodies. She initially presented to the infectious diseases CMV clinic, where she was noted to have severe malnutrition, prompting referral to the emergency department for hospital admission to optimize nutrition with nasogastric tube feeding and facilitate additional evaluation. An active CMV infection with viruria and viremia was confirmed, but elements of her presentation and workup including brain magnetic resonance imaging were not consistent with isolated CMV infection. To avoid premature diagnostic closure, a multidisciplinary workup was initiated and ultimately established her diagnosis.

Explicit training through neurodevelopmental therapy improves tone and postural control in hemiplegic stroke-A Systematic review protocol

Introduction Hemiplegia is the common term used to describe a multitude of clinical problems associated with a stroke. Hemiplegic stroke accounts for 70-85% of all first strokes. Trunk stability is impaired due to hypertonia and weakness in hemiplegia. Impaired trunk control leads to gait and postural abnormalities which if left untreated causes permanent disability in hemiplegics. Objective To investigate the scope of research on the benefits of explicit training using Neurodevelopmental Therapy (NDT) for enhancing tone and postural control in subjects with hemiplegic stroke. Methods In order to adhere to established protocols of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework, the systematic review will be carried out to find pertinent studies published up to the search date, and a thorough search strategy will be applied across popular electronic databases including PubMed/Medline, Scopus, and Cochrane Library. This systematic review methodology has been registered in PROSPERO for rigorous and transparent dissemination of study search, synthesis, and analysis. Discussion As the motor impairments due to abnormal tone and postural impairment in hemiplegic stroke substantially impact a stroke survivor’s quality of life, this study will provide a thorough and methodical approach to synthesize and report the merits and demerits on the effectiveness of NDT in enhancing tone and postural control, considering the potential variability in interventions and outcomes, and the methodological rigor of particular studies. The review also intends to provide significant insights for clinicians, researchers, and policymakers by critically analysing and summarizing the present state of research in this domain. This will facilitate evidence-based decision-making in rehabilitation techniques for patients with hemiplegic stroke. Systematic Review Registration number CRD42023476137

Discretionary tone in reward-based crowdfunding: Do project owners talk their way to success?

This study examines the relationship between abnormal tone and project performance of reward-based crowdfunding (RBC) using the Kickstarter data from 2009 to 2020. We document a negative relationship between abnormal tone and the success of a project in the RBC campaign section, while a positive impact in the Risks and Challenges section. This outcome remains robust to a variety of sensitivity tests and after accounting for potential endogeneity concerns. Cross-sectional analyses reveal that the effect of abnormal tone in RBC on project success is contingent on project quality and legal jurisdiction. Further investigation of the concurrent effect of abnormal tone in the two sections shows that an increase in the discretionary tone, given that it is overly optimistic, has a negative effect on funding performance. Last, based on a machine learning Sent-Latent Dirichlet Allocation model, we explore up to 70 specific risk categories embedded in Kickstarter projects, and we find that eight of them are strongly and negatively associated with project success. Our paper provides valuable insights into the significance of disclosure and sheds light on the ongoing and increased regulations on crowdfunding platforms.

Strategic forward-looking nonearnings disclosure and overinvestment

We examine whether tone management in different aspects of forward-looking statements (FLSs) is related to managers' self-serving overinvestments. Using data for U.S.-listed firms between 2003 and 2019, we provide novel evidence that the abnormal tone of nonearnings-related qualitative FLSs' is significantly and positively related to firms' overinvestments but that other aspects of FLSs are insignificant to overinvestments. Moreover, this relation is more substantial in financially unconstrained firms. Our findings reveal the heterogeneous roles of different aspects of FLSs in firms' opportunistic disclosures concerning future overinvestments. Further analyses also indicate that this relationship is more pronounced for firms with less monitoring and managers with greater career concerns. We also employ instrumental variables with a two-stage least-square approach and a Heckman selection model to mitigate the endogeneity issue. Our results are robust after conducting a battery of robustness tests. Overall, our findings provide robust evidence that managers are likely to strategically manipulate nonearnings-related qualitative FLSs to mislead investors’ perception of firms' future fundamentals to achieve self-serving purposes.

Assessing the Impact of Fencing on Postural Parameters: Observational Study Findings on Elite Athletes.

The aim of the study was to evaluate whether the static stabilometric parameters among elite fencers, were affected by prolonged, asymmetric training regimen. A sample of 26 elite fencers of both genders, aged 19.15 ± 2.24 years, practising one of the three disciplines foil, épée, or sabre, was recruited for the study. Anthropometric measurements including thigh and calf circumferences and postural assessment based on the weight distribution on a stabilimeter platform were performed. Postural tone, as indicated by measures such as sway length and sway area ratio was calculated.. No notable anthropometric asymmetries were detected within the examined group The weight distribution patterns on the support quadrants in static stabilometric measurements did not suggest clinically significant issues. There were no significant differences among subgroups based on gender and lower limb dominance for both anthropometric and stabilimeter variables. However, 30.8% of participants showed anomalies in postural tone (hypertonic and hypotonic condition). Five out of eight athletes found with abnormal postural tone were foil fencers, suggesting a potential discipline-specific effect. Individual adjustments were found in foil fencers. These findings provide insights into the potential effects of fencing training on postural parameters among elite athletes.

First report of Tunisian patients with CDKL5-related encephalopathy.

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) are associated with a wide spectrum of clinical presentations. Early-onset epileptic encephalopathy (EOEE) is the most recognized phenotype. Here we describe phenotypic features in eight Tunisian patients with CDKL5-related encephalopathy. We included all cases with clinical features consistent with CDKL5-related encephalopathy: infantile epileptic spasm, acquired microcephaly, movement disorders and visual impairment. We collected data about seizure types, electroencephalogram, magnetic resonance imaging, and metabolic analysis. The diagnosis of CDKL5 mutation was made thanks to Sanger sequencing with an ABI PRISM 3100-Avant automated DNA sequencer using a Big Dye Terminator Cycle Sequencing Reaction Kit v1.1. and Next Generation Sequencing (NGS) since the development of a gene panel responsible for DEE within the framework of "Strengthening the Sfax University Expertise for diagnosis and management of epileptic encephalopathies". We collected four boys and four girls aged meanly 6 years old with confirmed mutation on CDKL5 gene. Overall, we identified five de novo CDKL5 mutations including three Frame-shift mutations, one missense mutation, and a splicing variant. The mean age at first seizure onset was 4 months. The first seizure type was infantile epileptic spasm (4/8) followed by tonic (2/8) and myoclonic seizures (2/8). Out of eight cases, four exhibited two stages epileptic course while epilepsy in three other patients progressed on three stages. Regarding development, most cases (6/8) had psychomotor retardation from the start whilst the two others showed psychomotor regression with the onset of seizures. Additional clinical features included visual impairment (7/8), tone abnormalities (7/8), stereotypies (7/8), and acquired microcephaly (6/8). Our present report delineates an unusual phenotype of CDKL5-related encephalopathy with male gender predominance and delayed onset epilepsy. It interestingly described new phenotypic features and uncommon benign developmental profiles in boys, different patterns of CDKL5-epilepsy, neuroimaging findings, and CDKL5 mutational spectrum.

Ambulatory electrocardiographic longitudinal monitoring in a canine model for Duchenne muscular dystrophy identifies decreased very low frequency power as a hallmark of impaired heart rate variability.

Duchenne muscular dystrophy (DMD) patients exhibit a late left ventricular systolic dysfunction preceded by an occult phase, during which myocardial fibrosis progresses and some early functional impairments can be detected. These latter include electrocardiographic (ECG) and heart rate variability (HRV) abnormalities. This longitudinal study aimed at describing the sequence of ECG and HRV abnormalities, using Holter ECG in the GRMD (Golden retriever muscular dystrophy) dog model, known to develop a DMD-like disease, including cardiomyopathy. Most of the known ECG abnormalities described in DMD patients were also found in GRMD dogs, including increased heart rate, prolonged QT and shortened PR intervals, ventricular arrhythmias, and several of them could be detected months before the decrease of fractional shortening. The HRV was impaired like in DMD patients, one of the earliest evidenced abnormalities being a decrease in the very low frequency (VLF) component of the power spectrum. This decrease was correlated with the further reduction of fractional shortening. Such decreased VLF probably reflects impaired autonomic function and abnormal vasomotor tone. This study provides new insights into the knowledge of the GRMD dog model and DMD cardiomyopathy and emphasizes the interest to monitor the VLF power in DMD patients, still unexplored in this disease, whilst it is highly predictive of deleterious clinical events in many other pathological conditions.