Genetic and phenotypic findings in 34 novel Spanish patients with DDX3X neurodevelopmental disorder.

DDX3X is a multifunctional ATP-dependent RNA helicase involved in several processes of RNA metabolism and in other biological pathways such as cell cycle control, innate immunity, apoptosis and tumorigenesis. Variants in DDX3X have been associated with a developmental disorder named intellectual developmental disorder, X-linked syndromic, Snijders Blok type (MRXSSB, MIM #300958) or DDX3X neurodevelopmental disorder (DDX3X-NDD). DDX3X-NDD is mainly characterized by intellectual disability, brain abnormalities, hypotonia and behavioral problems. Other common findings include gastrointestinal abnormalities, abnormal gait, speech delay and microcephaly. DDX3X-NDD is predominantly found in females who carry de novo variants in DDX3X. However, hemizygous pathogenic DDX3X variants have been also found in males who inherited their variants from unaffected mothers. To date, more than 200 patients have been reported in the literature. Here, we describe 34 new patients with a variant in DDX3X and reviewed 200 additional patients previously reported in the literature. This article describes 34 additional patients to those already reported, contributing with 25 novel variants and a deep phenotypic characterization. A clinical review of our cohort of DDX3X-NDD patients is performed comparing them to those previously published.

Seven Additional Patients with SOX17 Related Pulmonary Arterial Hypertension and Review of the Literature.

Pulmonary arterial hypertension (PAH) is an infrequent disorder characterized by high blood pressure in the pulmonary arteries. It may lead to premature death or the requirement for lung and/or heart transplantation. Genetics plays an important and increasing role in the diagnosis of PAH. Here, we report seven additional patients with variants in SOX17 and a review of sixty previously described patients in the literature. Patients described in this study suffered with additional conditions including large septal defects, as described by other groups. Collectively, sixty-seven PAH patients have been reported so far with variants in SOX17, including missense and loss-of-function (LoF) variants. The majority of the loss-of-function variants found in SOX17 were detected in the last exon of the gene. Meanwhile, most missense variants were located within exon one, suggesting a probable tolerated change at the amino terminal part of the protein. In addition, we reported two idiopathic PAH patients presenting with the same variant previously detected in five patients by other studies, suggesting a possible hot spot. Research conducted on PAH associated with congenital heart disease (CHD) indicated that variants in SOX17 might be particularly prevalent in this subgroup, as two out of our seven additional patients presented with CHD. Further research is still necessary to clarify the precise association between the biological pathway of SOX17 and the development of PAH.

Snijders Blok-Campeau Syndrome: Description of 20 Additional Individuals with Variants in CHD3 and Literature Review.

Snijders Blok-Campeau syndrome (SNIBCPS, OMIM# 618205) is an extremely infrequent disease with only approximately 60 cases reported so far. SNIBCPS belongs to the group of neurodevelopmental disorders (NDDs). Clinical features of patients with SNIBCPS include global developmental delay, intellectual disability, speech and language difficulties and behavioral disorders like autism spectrum disorder. In addition, patients with SNIBCPS exhibit typical dysmorphic features including macrocephaly, hypertelorism, sparse eyebrows, broad forehead, prominent nose and pointed chin. The severity of the neurological effects as well as the presence of other features is variable among subjects. SNIBCPS is caused likely by pathogenic and pathogenic variants in CHD3 (Chromodomain Helicase DNA Binding Protein 3), which seems to be involved in chromatin remodeling by deacetylating histones. Here, we report 20 additional patients with clinical features compatible with SNIBCPS from 17 unrelated families with confirmed likely pathogenic/pathogenic variants in CHD3. Patients were analyzed by whole exome sequencing and segregation studies were performed by Sanger sequencing. Patients in this study showed different pathogenic variants affecting several functional domains of the protein. Additionally, none of the variants described here were reported in control population databases, and most computational predictors suggest that they are deleterious. The most common clinical features of the whole cohort of patients are global developmental delay (98%) and speech disorder/delay (92%). Other frequent features (51-74%) include intellectual disability, hypotonia, hypertelorism, abnormality of vision, macrocephaly and prominent forehead, among others. This study expands the number of individuals with confirmed SNIBCPS due to pathogenic or likely pathogenic variants in CHD3. Furthermore, we add evidence of the importance of the application of massive parallel sequencing for NDD patients for whom the clinical diagnosis might be challenging and where deep phenotyping is extremely useful to accurately manage and follow up the patients.

Lamb-Shaffer syndrome: 20 Spanish patients and literature review expands the view of neurodevelopmental disorders caused by SOX5 haploinsufficiency.

Lamb-Shaffer Syndrome (LSS; OMIM #616803; ORPHA #313892; ORPHA #313884) is an infrequent genetic disorder that affects multiple aspects of human development especially those related to the development of the nervous system. LSS is caused by variants in the SOX5 gene. At the molecular level, SOX5 gene encodes for a transcription factor containing a High Mobility Group (HMG) DNA-Binding domain with relevant functions in brain development in different vertebrate species. Clinical features of Lamb-Shaffer syndrome may include intellectual disability, delayed speech and language development, attention deficits, hyperactivity, autism spectrum disorder, visual problems and seizures. Additionally, patients with the syndrome may present distinct facial dimorphism such as a wide mouth with full lips, small chin, broad nasal bridge, and deep-set eyes. Other physical features that have been reported in some patients include short stature, scoliosis, and joint hypermobility. Here, we report the clinical and molecular characterization of a Spanish LSS cohort of new 20 patients and review all the patients published so far which amount for 111 patients. The most frequent features included developmental delay, intellectual disability, visual problems, poor speech development and facial dysmorphic features. Strikingly, pain insensitivity and hypermetropia seems to be more frequent than previously reported, based on the frequency seen in the Spanish cohort. Eighty-three variants have been reported so far, single nucleotide variants (SNV) and copy number variants represent 47% and 53%, respectively, from the total of variants reported. Similarly to previous reports, the majority of the SNVs variants of the novel patients reported herein fall in the HMG domain of the protein. However, new variants, affecting other functional domains, were also detected. In conclusion, LLS is a rare genetic disorder mostly characterized by a wide range of developmental and neurological symptoms. Early diagnosis would allow to start of care programs, clinical follow up, prospective studies and appropriate genetic counseling, to promote clinical and social improvement to have profound lifelong benefits for patients and their families. Further research is needed to better understand the underlying mechanisms of the syndrome related to SOX5 haploinsufficiency.

Clinical Heterogeneity and Different Phenotypes in Patients with SETD2 Variants: 18 New Patients and Review of the Literature.

SETD2 belongs to the family of histone methyltransferase proteins and has been associated with three nosologically distinct entities with different clinical and molecular features: Luscan-Lumish syndrome (LLS), intellectual developmental disorder, autosomal dominant 70 (MRD70), and Rabin-Pappas syndrome (RAPAS). LLS [MIM #616831] is an overgrowth disorder with multisystem involvement including intellectual disability, speech delay, autism spectrum disorder (ASD), macrocephaly, tall stature, and motor delay. RAPAS [MIM #6201551] is a recently reported multisystemic disorder characterized by severely impaired global and intellectual development, hypotonia, feeding difficulties with failure to thrive, microcephaly, and dysmorphic facial features. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and potentially endocrine. Three patients who carried the missense variant p.Arg1740Gln in SETD2 were reported with a moderately impaired intellectual disability, speech difficulties, and behavioral abnormalities. More variable findings included hypotonia and dysmorphic features. Due to the differences with the two previous phenotypes, this association was then named intellectual developmental disorder, autosomal dominant 70 [MIM 620157]. These three disorders seem to be allelic and are caused either by loss-of-function, gain-of-function, or missense variants in the SETD2 gene. Here we describe 18 new patients with variants in SETD2, most of them with the LLS phenotype, and reviewed 33 additional patients with variants in SETD2 that have been previously reported in the scientific literature. This article offers an expansion of the number of reported individuals with LLS and highlights the clinical features and the similarities and differences among the three phenotypes associated with SETD2.

Adult experiences in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth and epigenetic disorder caused by changes on chromosome 11p15. The primary features requiring management in childhood include macroglossia, omphalocele, lateralized overgrowth, hyperinsulinism, and embryonal tumors. Management guidelines have not been developed for adults with BWS and there have been few studies to assess the clinical needs of these patients. Furthermore, there have been few studies on the psychosocial implications of BWS in children or adults. Here, we present a descriptive summary of data gathered from two separate adult BWS cohorts. The first, a patient-based survey cohort, includes self-reported health information and recollections about BWS experiences, while the second provides results of a medical record-based assessment from patients in an overgrowth registry. Results highlight the clinical features and medical issues affecting two large independent cohorts of adults with BWS while noting similarities. Open-ended questions asked of the survey cohort yielded themes to guide future qualitative studies. Finally, the study demonstrated the reliability of patient-reported data and the utility of international partnerships in this context.

Conditioned Medium from H2O2-Preconditioned Human Adipose-Derived Stem Cells Ameliorates UVB-Induced Damage to Human Dermal Fibroblasts.

Human skin exposure to ultraviolet B (UVB) radiation can result in acute photodamage through oxidative modifications of cellular components and biomolecules involved in the metabolism of dermal cells. Recently, the therapeutic potential of human adipose-derived stem cells (hASCs) has been investigated as a novel strategy for photoprotection due to their pro-angiogenic properties, protective activity against oxidative stress and paracrine effect on dermal cells. To enhance these therapeutic properties, hASCs can be preconditioned by exposing them to sublethal cellular stressors. In this study, we first analyzed response capacity against UVB-induced oxidative stress in H2O2-preconditioned hASCs (called HC016 cells); and second, we evaluated the photoprotective effect of HC016-conditioned medium (CM) in an in vitro UVB irradiation model in cultured human foreskin fibroblasts (hFFs). The results demonstrated that HC016 cells have a greater capacity to respond efficiently to UVB-induced oxidative stress, evidenced by higher Nrf2 antioxidant system activity and enhanced viability and migration capacity. Further, HC016-CM treatment increased viability, migratory capacity and collagen type I synthesis in hFFs exposed to UVB radiation, as well as reducing their cytotoxicity, apoptosis, senescence and IL-6 secretion. Collectively, these findings support the view that HC016 cells could protect against UVB-induced photodamage via paracrine mechanisms.

Primary results of the Spanish Cryoballoon Ablation Registry: acute and long-term outcomes of the RECABA study.

Cryoablation is safe and effective for the treatment of atrial fibrillation (AF) in controlled clinical trials, but contemporary real-world usage and outcomes are limited. The Report of the Spanish Cryoballoon Ablation Registry (RECABA) was designed to evaluate acute and 12-month outcomes of cryoballoon ablation for the treatment of AF in Spain. Patients from 27 Spanish centers were prospectively enrolled. Patients were treated with cryoballoon ablation and managed according to standard of care protocols at each center. The primary endpoint was ≥ 30 s freedom from AF at 12-month after a 3-month blanking period. Secondary endpoints included a description of patient characteristics, cryoablation procedural strategy and safety, and predictors of efficacy. In total, 1742 patients (71.4% PAF, 68.8% male, mean age 58.02 ± 10.40 years, 76.1% overweight or obese, CHA2DS2-VASc index 1.40 ± 1.28) were enrolled. Patients received 7.2 ± 2.67 cryo-applications. PV potentials could be detected in 61% of the PVs during ablation, with a mean time to block of 52.9 ± 37.02 s. Acute PVI was observed in 97% of PVs with 75.8% isolated with the first cryo-application. Mean procedural time was 113 ± 41 min. Acute complications occurred in 4.4% of the cases. With follow-up in 1628 patients, AF-free survival was 78.5% (PAF: 80.6% vs PersAF 73.3%; p < 0.001). Left atrium enlargement, female sex, non-PAF, and early recurrence were independent predictors of AF recurrence (p < 0.05). RECABA provides detailed insight into current dosing practices and demonstrates cryoablation is safe and effective in real-world use.ClinicalTrials.gov number: NCT02785991.

Hydrogen Peroxide-Preconditioned Human Adipose-Derived Stem Cells Enhance the Recovery of Oligodendrocyte-Like Cells after Oxidative Stress-Induced Damage.

Oxidative stress associated with neuroinflammation is a key process involved in the pathophysiology of neurodegenerative diseases, and therefore, has been proposed as a crucial target for new therapies. Recently, the therapeutic potential of human adipose-derived stem cells (hASCs) has been investigated as a novel strategy for neuroprotection. These cells can be preconditioned by exposing them to mild stress in order to improve their response to oxidative stress. In this study, we evaluate the therapeutic potential of hASCs preconditioned with low doses of H2O2 (called HC016 cells) to overcome the deleterious effect of oxidative stress in an in vitro model of oligodendrocyte-like cells (HOGd), through two strategies: i, the culture of oxidized HOGd with HC016 cell-conditioned medium (CM), and ii, the indirect co-culture of oxidized HOGd with HC016 cells, which had or had not been exposed to oxidative stress. The results demonstrated that both strategies had reparative effects, oxidized HC016 cell co-culture being the one associated with the greatest recovery of the damaged HOGd, increasing their viability, reducing their intracellular reactive oxygen species levels and promoting their antioxidant capacity. Taken together, these findings support the view that HC016 cells, given their reparative capacity, might be considered an important breakthrough in cell-based therapies.

Multifunctional nanofibrous patches composed of nanocellulose and lysozyme nanofibers for cutaneous wound healing.

Cutaneous wounds frequently require the use of patches to promote healing, nevertheless, most commercial products are fabricated with non-biodegradable synthetic substrates that pose environmental problems upon disposal. Herein, the partnership between two biobased nanofibrous polymers, namely a polysaccharide (nanofibrillated cellulose (NFC)) and a protein (lysozyme nanofibers (LNFs)), is explored to design sustainable fibrous patches with good mechanical performance and biological functionalities for wound healing applications. Two patches with different morphologies were prepared by vacuum filtration of a water-based suspension of both nanofibers and by sequential filtration of the separated suspensions (layered patch). The resultant freestanding patches exhibited high thermal stability (up to 250 °C), mechanical performance (Young's modulus ≥3.7 GPa), and UV-barrier properties. The combination of the bioactive LNFs with the mechanically robust NFC conveyed antioxidant activity (76-79% DPPH scavenging) and antimicrobial activity against Staphylococcus aureus (3.5-log CFU mL-1 reduction), which is a major benefit to prevent microbial wound infections. Moreover, these patches are biocompatible towards L929 fibroblast cells, and the in vitro wound healing assay evidenced a good migration capacity leading to an almost complete wound occlusion. Therefore, the partnership between the two naturally derived nanofibrous polymers represents a potential blueprint to engineer sustainable multifunctional patches for cutaneous wound healing.

H2O2-preconditioned human adipose-derived stem cells (HC016) increase their resistance to oxidative stress by overexpressing Nrf2 and bioenergetic adaptation.

BACKGROUND: Mesenchymal stem cells, including those derived from human adipose tissue (hASCs), are currently being widely investigated for cell therapy. However, when transplanted at the site of injury, the survival and engraftment rates of hASCs are low, mainly due to the harsh microenvironment they encounter, characterized by inflammation and oxidative stress. To overcome these therapeutic limitations, cell preconditioning with low-concentration of hydrogen peroxide (H2O2) has been proposed as a plausible strategy to increase their survival and adaptation to oxidative stress. Nonetheless, the underlying mechanisms of this approach are not yet fully understood. In this study, we analyzed molecular and bioenergetic changes that take place in H2O2 preconditioned hASCs. METHODS: Long-term exposure to a low concentration of H2O2 was applied to obtain preconditioned hASCs (named HC016), and then, their response to oxidative stress was analyzed. The effect of preconditioning on the expression of Nrf2 and its downstream antioxidant enzymes (HO-1, SOD-1, GPx-1, and CAT), and of NF-κB and its related inflammatory proteins (COX-2 and IL-1ß), were examined by Western blot. Finally, the Seahorse XF96 Flux analysis system was used to evaluate the mitochondrial respiration and glycolytic function, along with the total ATP production. RESULTS: We found that under oxidative conditions, HC016 cells increased the survival by (i) decreasing intracellular ROS levels through the overexpression of the transcription factor Nrf2 and its related antioxidant enzymes HO-1, SOD-1, GPx-1, and CAT; (ii) reducing the secretion of pro-inflammatory molecules COX-2 and IL-1ß through the attenuation of the expression of NF-κB; and (iii) increasing the total ATP production rate through the adaption of their metabolism to meet the energetic demand required to survive. CONCLUSIONS: H2O2 preconditioning enhances hASC survival under oxidative stress conditions by stimulating their antioxidant response and bioenergetic adaptation. Therefore, this preconditioning strategy might be considered an excellent tool for strengthening the resistance of hASCs to harmful oxidative stress.

On the Use of Dance as a Rehabilitation Approach for Children with Cerebral Palsy: A Single Case Study.

Cerebral Palsy (CP) is the most common motor disability in childhood. It is a group of permanent disorders that affect child development causing disorders of movement and posture and activity limitations. The impairment of psychomotor skills of children with Cerebral Palsy is attributed to a permanent alteration occurred in non-progressive brain development of the fetus or nursing infant. Some motor related symptoms can be treated using proper physical therapy. However, one of the biggest problems of the usual physical therapy is adherence to therapy. Ballet can be an alternative or a complement to physiotherapy, with the added attraction of not being part of a to therapy, but a fun activity with the extra reward associated with the realization of an artistic activity. For some years the ballet is used as therapeutically valuable for both children with cerebral palsy: Intensive ballet training can generate changes in the sensorimotor cortex. Ballet is characterized by a complex process of movements that have to be in a musical rhythm (hence have to be precise), in which there is an overall coordination of the muscles. It is also a highly motivating and rewarding activity that allows many children with CP sharing the activities of their peers without special needs. Objective measurements of the Full Port de Bras movement has been chosen as an index of improvement. The results shows progressive improvements of the execution in a single case.

Correlation between pain, disability, and quality of life in patients with common low back pain.

STUDY DESIGN: Correlation among previously validated questionnaires. OBJECTIVES: To determine the correlation between pain, disability, and quality of life in patients with low back pain. SUMMARY OF BACKGROUND DATA: The Visual Analogue Scale (VAS), and the Roland-Morris (RMQ), Oswestry (OQ), and EuroQol (EQ) Questionnaires are validated instruments to assess pain, low back pain-related disability, and quality of life. METHODS: The study was done in the primary care setting, in Mallorca, with 195 patients who visited their physician for LBP. Individuals were given the VAS, RMQ, OQ, and EQ on their first visit and 14 days later. RESULTS: Median duration of pain when entering the study was 10 days (P25,P75: 3, 40). On day 1, simple correlation was r = 0.347 between VAS and RMQ, r = -0.422 between VAS and EQ, and r = -0.442 between RMQ and EQ. On day 15, simple correlation was r = 0.570 between VAS and RMQ, r = -0.672 between VAS and EQ, and r = -0.637 between RMQ and EQ. Multiple linear regression models showed that, on day 1, the VAS score explains 12% of the RMQ score and the VAS and RMQ scores explain 27% of the EQ score. On day 15, the VAS score explains 33% of the RMQ score, and the VAS and RMQ scores explain 58% of the EQ score. On day 1, a 10% increase in VAS worsens disability by 3.3% and quality of life by 2.65%. On day 15, a 10% increase in VAS worsens disability by 4.99% and quality of life by 3.80%. Prestudy duration of pain had no influence on any model. All these correlation coefficients and models are significant at the P < 0.001 level. The OQ had lower correlation values with the other three scales, and only two of them were significant. CONCLUSION: Clinically relevant improvements in pain may lead to almost unnoticeable changes in disability and quality of life. Therefore, these variables should be assessed separately when evaluating the effect of any form of treatment for low back pain. The influence of pain and disability on quality of life progresses while they last, and doubles in 14 days. In acute and subacute patients, this increase is not dependent on the previous duration of pain.