Search Results (15)

The 22q11.2 deletion syndrome (DS) can have a significant impact on functionality. The purpose was to describe 22q11.2DS children with functioning from a biopsychosocial perspective, focusing on the impact of children’s health condition from domains of the International Classification of Functioning, Disability, and Health (ICF). Methods: A descriptive, cross-sectional case series study with seven 22q11.2DS children. A questionnaire with an ICF checklist for 22q11.2DS was completed using a structured interview. The Wechsler Abbreviated Scale of Intelligence (WASI) was used to determine the Intelligence Quotient (IQ). Results: Seven participants from 7 to 12 years old, presented some level of IQ impairment. It was observed that 22q11.2DS children experience significant intellectual, cognitive, and speech impairments across ICF Body Function domains. Impairments related to nose and pharynx were found in only one patient. The most relevant categories considered limitations in the Activity and Participation components pertained to producing nonverbal messages, communication, handling stress, and social interaction. Family, health professionals, and acquaintances were perceived as facilitators in the component Environmental Factors. Conclusion: The sample has its functioning affected by aspects that go beyond impairments in body structure and function. The organization of information from the perspective of the ICF is a different approach that helps clinical reasoning. Full article

Parent-of-origin-dependent gene expression of a few hundred human genes is achieved by differential DNA methylation of both parental alleles. This imprinting is required for normal development, and defects in this process lead to human disease. Induced pluripotent stem cells (iPSCs) serve as a valuable tool for in vitro disease modeling. However, a wave of de novo DNA methylation during reprogramming of iPSCs affects DNA methylation, thus limiting their use. The DNA methyltransferase 3B (DNMT3B) gene is highly expressed in human iPSCs; however, whether the hypermethylation of imprinted loci depends on DNMT3B activity has been poorly investigated. To explore the role of DNMT3B in mediating de novo DNA methylation at imprinted DMRs, we utilized iPSCs generated from patients with immunodeficiency, centromeric instability, facial anomalies type I (ICF1) syndrome that harbor biallelic hypomorphic DNMT3B mutations. Using a whole-genome array-based approach, we observed a gain of methylation at several imprinted loci in control iPSCs but not in ICF1 iPSCs compared to their parental fibroblasts. Moreover, in corrected ICF1 iPSCs, which restore DNMT3B enzymatic activity, imprinted DMRs did not acquire control DNA methylation levels, in contrast to the majority of the hypomethylated CpGs in the genome that were rescued in the corrected iPSC clones. Overall, our study indicates that DNMT3B is responsible for de novo methylation of a subset of imprinted DMRs during iPSC reprogramming and suggests that imprinting is unstable during a specific time window of this process, after which the epigenetic state at these regions becomes resistant to perturbation. Full article

Multidimensional assessments are important in evaluating the overall health of older adults. The comprehensive geriatric assessment (CGA) is a representative framework; however, the burden associated with the CGA has led to the development of simplified multidimensional tools. Comparing these tools to the CGA can help utilize them effectively. However, a direct comparison is challenging owing to the conceptual nature of the CGA. In this study, we conducted a web-based survey to identify essential CGA components by linking International Classification of Functioning, Disability, and Health (ICF) category level 2 items and “not defined/not covered” (nd/nc) items. Healthcare professionals and individuals aged >65 years participated in a two-stage Delphi study. In total, 182 respondents (7 geriatricians, 22 nurses, 20 therapists, and 4 case managers) completed the survey. Sixty-one essential components for CGA were identified, including 55 ICF categories. Additionally, personal factors (i.e., proactiveness) and nd/nc items (i.e., subjective perceptions) were aggregated. The results suggest that the CGA includes objective conditions of intrinsic capacity, functional ability, and environment as well as subjective perceptions and proactiveness toward those conditions. Thus, CGA is not merely expected to assess geriatric syndrome but also to estimate broader concepts, such as interoception, resilience, and quality of life. Full article

The role of transcranial magnetic stimulation (TMS) measures as biomarkers of fibromyalgia syndrome (FMS) phenotypes is still unclear. We aimed to determine the clinical correlates of TMS measures in FMS patients. We conducted a cross-sectional analysis that included 58 patients. We performed standardized TMS assessments, including resting motor threshold (MT), motor-evoked potential (MEP), short intracortical inhibition (SICI), and intracortical facilitation (ICF). Sociodemographic, clinical questionnaires, and quantitative sensory testing were collected from all of the patients. Univariate and multivariate linear regression models were built to explore TMS-associated factors. We found that SICI did not significantly correlate with pain levels but was associated with sleepiness, comorbidities, disease duration, and anxiety. On the other hand, ICF showed a positive correlation with pain levels and a negative correlation with body mass index (BMI). BMI was a negative effect modifier of the ICF and pain association. The clinical correlates of MT and MEP were scarce. Our results suggest that SICI and ICF metrics are potential phenotyping biomarkers in FMS related to disease compensation and levels of pain perception, respectively. The clinical translation of TMS paired-pulse protocols represents an opportunity for a mechanistic understanding of FMS and the future development of precision treatments. Full article

Understanding functioning and disabilities in children with Congenital Zika Syndrome (CZS) is essential for health planning. We describe disabilities present in children with CZS followed in a reference hospital in Rio de Janeiro, Brazil, based on the biopsychosocial model of the International Classification of Functioning, Disability and Health (ICF). This was a cohort study of children >3 years of age with CZS. Disability was characterized through outcomes related to ICF components assessed via clinical and motor development evaluations. Among 50 children, with a median age of 40 months, 47 (94%) presented with severe impairment and 46 (92%) had microcephaly. Damage to the head and neck was found in most children, with abnormal central nervous system imaging universally present. Most children had cognitive impairment (92%), muscle tone problems (90%), and speech deficits (94%). We found movement limitations in all categories but more pervasively (80–94%), in postural transfers and displacements. The main environmental factors identified in the ICF model were the use of products or substances for personal consumption and access to health services. Children with CZS have extremely high rates of disability beyond aged 3 years, particularly regarding motor activity. ICF-based models can contribute to the assessment of health domains. Full article

Robust, tightly regulated DNA repair is critical to maintaining genome stability and preventing cancer. Eukaryotic DNA is packaged into chromatin, which has a profound, yet incompletely understood, regulatory influence on DNA repair and genome stability. The chromatin remodeler HELLS (helicase, lymphoid specific) has emerged as an important epigenetic regulator of DNA repair, genome stability, and multiple cancer-associated pathways. HELLS belongs to a subfamily of the conserved SNF2 ATP-dependent chromatin-remodeling complexes, which use energy from ATP hydrolysis to alter nucleosome structure and packaging of chromatin during the processes of DNA replication, transcription, and repair. The mouse homologue, LSH (lymphoid-specific helicase), plays an important role in the maintenance of heterochromatin and genome-wide DNA methylation, and is crucial in embryonic development, gametogenesis, and maturation of the immune system. Human HELLS is abundantly expressed in highly proliferating cells of the lymphoid tissue, skin, germ cells, and embryonic stem cells. Mutations in HELLS cause the human immunodeficiency syndrome ICF (Immunodeficiency, Centromeric instability, Facial anomalies). HELLS has been implicated in many types of cancer, including retinoblastoma, colorectal cancer, hepatocellular carcinoma, and glioblastoma. Here, we review and summarize accumulating evidence highlighting important roles for HELLS in DNA repair, genome maintenance, and key pathways relevant to cancer development, progression, and treatment. Full article

(1) Introduction: Multiple studies have shown that peak oxygen consumption is reduced in the majority of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS )patients, using the gold standard for measuring exercise intolerance: cardiopulmonary exercise testing (CPET). A 2-day CPET protocol has shown different results on day 2 in ME/CFS patients compared to sedentary controls. No comparison is known between ME/CFS and idiopathic chronic fatigue (ICF) for 2-day CPET protocols. We compared ME/CFS patients with patients with chronic fatigue who did not fulfill the ME/CFS criteria in a male population and hypothesized a different pattern of response would be present during the 2nd day CPET. (2) Methods: We compared 25 male patients with ICF who had completed a 2-day CPET protocol to an age-/gender-matched group of 26 male ME/CFS patients. Measures of oxygen consumption (VO₂), heart rate (HR), systolic and diastolic blood pressure, workload (Work), and respiratory exchange ratio (RER) were collected at maximal (peak) and ventilatory threshold (VT) intensities. (3) Results: Baseline characteristics for both groups were similar for age, body mass index (BMI), body surface area, (BSA), and disease duration. A significant difference was present in the number of patients with fibromyalgia (seven ME/CFS patients vs. zero ICF patients). Heart rate at rest and the RER did not differ significantly between CPET 1 and CPET 2. All other CPET parameters at the ventilatory threshold and maximum exercise differed significantly (p-value between 0.002 and <0.0001). ME/CFS patients showed a deterioration of performance on CPET2 as reflected by VO₂ and workload at peak exercise and ventilatory threshold, whereas ICF patients showed improved performance on CPET2 with no significant change in peak workload. (4) Conclusion: This study confirms that male ME/CFS patients have a reduction in exercise capacity in response to a second-day CPET. These results are similar to published results in male ME/CFS populations. Patients diagnosed with ICF show a different response on day 2, more similar to sedentary and healthy controls. Full article

Chronic pain syndromes present a subversion of both functional and structural nociceptive networks. We used transcranial magnetic stimulation (TMS) to evaluate changes in cortical excitability and plasticity in patients with chronic migraine (CM) treated with botulinum neurotoxin type A (BoNT/A). We enrolled 11 patients with episodic migraine (EM) and 11 affected by CM. Baseline characteristics for both groups were recorded using single- and paired-pulse TMS protocols. The same TMS protocol was repeated in CM patients after four cycles of BoNT/A completed in one year. At baseline, compared with EM patients, patients with CM had a lower threshold in both hemispheres (right hemisphere: 46% ± 7.8 vs. 52% ± 4.28, p = 0.03; left hemisphere: 52% ± 4.28 vs. 53.54% ± 6.58, p = 0.02). In EM, paired-pulse stimulation elicited a physiologically shaped response, whereas in CM, physiological intracortical inhibition (ICI) between 1 and 3 ms intervals was absent at baseline. On the contrary, increasing intracortical facilitation (ICF) was observed for all interstimulus intervals (ISIs). In CM, cortical excitability was partially reduced after BoNT/A treatment, along with a significant decrease observed in MIDAS score (from 20.7 to 9.8; p = 0.008). The lower motor threshold in CM reflects a higher cortical hyperexcitability. The lack of physiological ICI in CM could indicate sensitisation of the trigeminovascular system. Although reduced, this type of response is still observable after treatment, despite a marked clinical improvement. Our study suggests a long-term alteration of cortical plasticity due to chronic pain. Full article

Management of COVID-19 post-acute syndrome is an emerging health issue in rehabilitation. This article aims to present a proposal, based on the principles of clinical governance, health management and information technology (IT), and to respond to the need for a structured organization model for post-acute COVID-19 rehabilitation. The authors present a regional-based model of a network of clinicians and healthcare managers using a dedicated IT platform to achieve both effectiveness and efficiency objectives, to ensure coordination of the available resources and the most appropriate rehabilitative treatment for patients. The proposed post-acute COVID-19 rehabilitation network has been designed according to the model of a clinical management project within the Italian national healthcare system, and its context is an easily adjustable model for the European healthcare systems. The authors base the project on current laws and scientific guidelines in rehabilitation in Italy and in Europe and use the SWOT analysis technique to assess the proposal feasibility. The primary aims of the project are: (1) standardizing the minimum assessment tools of post-COVID-19 patients with disabilities; (2) ensuring an individual rehabilitation project for each patient with international classification of functioning, disability and health (ICF) coding and (3) reporting the activity performance with appropriate indicators. The secondary aims are: (1) developing educational programs for patients and care givers also aimed at acquiring better empowerment and positive behavior; (2) creating a regional database for data collection and (3) improving IT, and specifically tele-rehabilitation, as a suitable approach during the COVID-19 emergency and also in the future. Expected results are: continuum of care; effectiveness, efficacy and appropriateness in the delivery of rehabilitation treatments through a standardized minimum assessment and the wording of the individual rehabilitation project and a precise reporting of performance indicators to measure the effectiveness of clinical activities and the satisfaction of patients and caregivers. The assessment of results will be analyzed at three and six months to implement corrective actions according to the concept of continuous improvement of the Deming cycle. The IT remote approach allows the patient to meet the needs of proximity of care and empowerment, and, at the same time, to contain the spread of infection. This project could have a significant healthcare impact ensuring a more efficient and effective management of the demand of rehabilitation post-acute COVID-19, expanding the professional skills of the rehabilitation team members, improving both clinical and process data, in addition to optimal allocation of available economic resources. Full article

(1) Objective: The World Health Organization’s (WHO) International Classification of Functioning, Disability and Health (ICF) classification is a unified framework for the description of health and health-related states. This study aimed to use the ICF framework to classify outcome measures used in follow-up studies of coronavirus outbreaks and make recommendations for future studies. (2) Methods: EMBASE, MEDLINE, CINAHL and PsycINFO were systematically searched for original studies assessing clinical outcomes in adult survivors of severe acute respiratory distress syndrome (SARS), middle east respiratory syndrome (MERS) and coronavirus disease-19 (COVID-19) after hospital discharge. Individual items of the identified outcome measures were linked to ICF second-level and third-level categories using ICF linking rules and categorized according to an ICF component. (3) Results: In total, 33 outcome measures were identified from 36 studies. Commonly used (a) ICF body function measures were Pulmonary Function Tests (PFT), Impact of event scale (IES-R) and Hospital Anxiety and Depression Scale (HADS); (b) ICF activity was 6-Minute Walking Distance (6MWD); (c) ICF participation measures included Short Form-36 (SF-36) and St George’s Respiratory Questionnaire (SGRQ). ICF environmental factors and personal factors were rarely measured. (4) Conclusions: We recommend future COVID-19 follow-up studies to use the ICF framework to select a combination of outcome measures that capture all the components for a better understanding of the impact on survivors and planning interventions to maximize functional return. Full article

Facioscapulohumeral muscular dystrophy (FSHD) has been associated with the genetic and epigenetic molecular features of the CpG-rich D4Z4 repeat tandem array at 4q35. Reduced DNA methylation of D4Z4 repeats is considered part of the FSHD mechanism and has been proposed as a reliable marker in the FSHD diagnostic procedure. We considered the assessment of D4Z4 DNA methylation status conducted on distinct cohorts using different methodologies. On the basis of the reported results we conclude that the percentage of DNA methylation detected at D4Z4 does not correlate with the disease status. Overall, data suggest that in the case of FSHD1, D4Z4 hypomethylation is a consequence of the chromatin structure present in the contracted allele, rather than a proxy of its function. Besides, CpG methylation at D4Z4 DNA is reduced in patients presenting diseases unrelated to muscle progressive wasting, like Bosma Arhinia and Microphthalmia syndrome, a developmental disorder, as well as ICF syndrome. Consistent with these observations, the analysis of epigenetic reprogramming at the D4Z4 locus in human embryonic and induced pluripotent stem cells indicate that other mechanisms, independent from the repeat number, are involved in the control of the epigenetic structure at D4Z4. Full article

Immunodeficiency, centromeric instability and facial anomalies syndrome 2 (ICF2) is a rare autosomal recessive primary immunodeficiency disorder. So far, 27 patients have been reported. Here, we present three siblings with ICF2 due to a homozygous ZBTB24 gene mutation (c.1222 T>G, p. (Cys408Gly)). Immune deficiency in these patients ranged from late-onset combined immunodeficiency (CID) with severe respiratory tract infections and recurrent shingles to asymptomatic selective antibody deficiency. Evident clinical heterogeneity manifested despite a common genetic background, suggesting the pathogenic relevance of epigenetic modification. Immunological follow-up reveals a previously unidentified gradual depletion of B and CD4⁺ T cells in all three presented patients with transition of a common variable immunodeficiency (CVID)-like disease to late-onset-CID in one of them. Considering all previously published cases with ICF2, we identify inadequate antibody responses to vaccines and reduction in CD27⁺ memory B cells as prevalent immunological traits. High mortality among ICF2 patients (20%) together with the progressive course of immunodeficiency suggest that hematopoietic stem cell transplantation (HSCT) should be considered as a treatment option in due time. Full article

Maintenance of an intact genome is essential for cellular and organismal homeostasis. The centromere is a specialized chromosomal locus required for faithful genome inheritance at each round of cell division. Human centromeres are composed of large tandem arrays of repetitive alpha-satellite DNA, which are often sites of aberrant rearrangements that may lead to chromosome fusions and genetic abnormalities. While the centromere has an essential role in chromosome segregation during mitosis, the long and repetitive nature of the highly identical repeats has greatly hindered in-depth genetic studies, and complete annotation of all human centromeres is still lacking. Here, we review our current understanding of human centromere genetics and epigenetics as well as recent investigations into the role of centromere DNA in disease, with a special focus on cancer, aging, and human immunodeficiency–centromeric instability–facial anomalies (ICF) syndrome. We also highlight the causes and consequences of genomic instability at these large repetitive arrays and describe the possible sources of centromere fragility. The novel connection between alpha-satellite DNA instability and human pathological conditions emphasizes the importance of obtaining a truly complete human genome assembly and accelerating our understanding of centromere repeats’ role in physiology and beyond. Full article

The correct establishment and maintenance of DNA methylation patterns are critical for mammalian development and the control of normal cell growth and differentiation. DNA methylation has profound effects on the mammalian genome, including transcriptional repression, modulation of chromatin structure, X chromosome inactivation, genomic imprinting, and the suppression of the detrimental effects of repetitive and parasitic DNA sequences on genome integrity. Consistent with its essential role in normal cells and predominance at repetitive genomic regions, aberrant changes of DNA methylation patterns are a common feature of diseases with chromosomal and genomic instabilities. In this context, the functions of DNA methyltransferases (DNMTs) can be affected by mutations or alterations of their expression. DNMT3B, which is involved in de novo methylation, is of particular interest not only because of its important role in development, but also because of its dysfunction in human diseases. Expression of catalytically inactive isoforms has been associated with cancer risk and germ line hypomorphic mutations with the ICF syndrome (Immunodeficiency Centromeric instability Facial anomalies). In these diseases, global genomic hypomethylation affects repeated sequences around centromeric regions, which make up large blocks of heterochromatin, and is associated with chromosome instability, impaired chromosome segregation and perturbed nuclear architecture. The review will focus on recent data about the function of DNMT3B, and the consequences of its deregulated activity on pathological DNA hypomethylation, including the illicit activation of germ line-specific genes and accumulation of transcripts originating from repeated satellite sequences, which may represent novel physiopathological biomarkers for human diseases. Notably, we focus on cancer and the ICF syndrome, pathological contexts in which hypomethylation has been extensively characterized. We also discuss the potential contribution of these deregulated protein-coding and non-coding transcription programs to the perturbation of cellular phenotypes. Full article

Genome manipulation of human induced pluripotent stem (iPS) cells is essential to achieve their full potential as tools for regenerative medicine. To date, however, gene targeting in human pluripotent stem cells (hPSCs) has proven to be extremely difficult. Recently, an efficient genome manipulation technology using the RNA-guided DNase Cas9, the clustered regularly interspaced short palindromic repeats (CRISPR) system, has been developed. Here we report the efficient generation of an iPS cell model for immunodeficiency, centromeric region instability, facial anomalies syndrome (ICF) syndrome using the CRISPR system. We obtained iPS cells with mutations in both alleles of DNA methyltransferase 3B (DNMT3B) in 63% of transfected clones. Our data suggest that the CRISPR system is highly efficient and useful for genome engineering of human iPS cells. Full article