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BioRxiv : the Preprint Server For... Jun 2024ADP-ribosylation is a post-translational modification involving the transfer of one or more ADP-ribose units from NAD+ to target proteins. Dysregulation of...
PURPOSE
ADP-ribosylation is a post-translational modification involving the transfer of one or more ADP-ribose units from NAD+ to target proteins. Dysregulation of ADP-ribosylation is implicated in neurodegenerative diseases. Here we report a novel homozygous variant in the gene (c.545A>G, p.His182Arg) encoding the mono(ADP-ribosyl) hydrolase ARH3 found in 2 patients with childhood-onset neurodegeneration with stress-induced ataxia and seizures (CONDSIAS).
METHODS
Genetic testing via exome sequencing was used to identify the underlying disease cause in two siblings with developmental delay, seizures, progressive muscle weakness, and respiratory failure following an episodic course. Studies in a cell culture model uncover biochemical and cellular consequences of the identified genetic change.
RESULTS
The ARH3 variant affects a highly conserved residue in the active site of ARH3, leading to protein instability, degradation, and reduced expression. ARH3 additionally fails to localize to the nucleus. The combination of reduced expression and mislocalization of ARH3 resulted in accumulation of mono-ADP ribosylated species in cells.
CONCLUSIONS
The children's clinical course combined with the biochemical characterization of their genetic variant develops our understanding of the pathogenic mechanisms driving CONDSIAS and highlights a critical role for ARH3-regulated ADP ribosylation in nervous system integrity.
PubMed: 38915701
DOI: 10.1101/2024.06.14.597428 -
PloS One 2024Neurofibromatosis type 1 (NF1) is a complex genetic disorder that affects a range of tissues including muscle and bone. Recent preclinical and clinical studies have...
Neurofibromatosis type 1 (NF1) is a complex genetic disorder that affects a range of tissues including muscle and bone. Recent preclinical and clinical studies have shown that Nf1 deficiency in muscle causes metabolic changes resulting in intramyocellular lipid accumulation and muscle weakness. These can be subsequently rescued by dietary interventions aimed at modulating lipid availability and metabolism. It was speculated that the modified diet may rescue defects in cortical bone as NF1 deficiency has been reported to affect genes involved with lipid metabolism. Bone specimens were analyzed from wild type control mice as well as Nf1Prx1-/- (limb-targeted Nf1 knockout mice) fed standard chow versus a range of modified chows hypothesized to influence lipid metabolism. Mice were fed from 4 weeks to 12 weeks of age. MicroCT analysis was performed on the cortical bone to examine standard parameters (bone volume, tissue mineral density, cortical thickness) and specific porosity measures (closed pores corresponding to osteocyte lacunae, and larger open pores). Nf1Prx1-/- bones were found to have inferior bone properties to wild type bones, with a 4-fold increase in the porosity attributed to open pores. These measures were rescued by dietary interventions including a L-carnitine + medium-chain fatty acid supplemented chow previously shown to improve muscle histology function. Histological staining visualized these changes in bone porosity. These data support the concept that lipid metabolism may have a mechanistic impact on bone porosity and quality in NF1.
Topics: Animals; Neurofibromatosis 1; Mice; Disease Models, Animal; Mice, Knockout; Phenotype; Neurofibromin 1; Porosity; Bone and Bones; Lipid Metabolism; X-Ray Microtomography; Male; Bone Density; Diet
PubMed: 38913608
DOI: 10.1371/journal.pone.0304778 -
Journal of Orthopaedic Case Reports Jun 2024The results of primary total knee replacement (TKR) using hinge implants performed in the Indian population with post-polio residual paresis (PPRP) are unknown. The...
INTRODUCTION
The results of primary total knee replacement (TKR) using hinge implants performed in the Indian population with post-polio residual paresis (PPRP) are unknown. The purpose of this study was to report the outcome of primary rotating hinge TKR in Indian patients with PPRP at a minimum follow-up of 12 months.
MATERIALS AND METHODS
We retrospectively reviewed the clinical and radiological records of six patients treated with primary rotating hinge TKR. Pre-and post-operative (at final follow-up) knee range of motion (ROM), knee sagittal deformity, knee society score (KSS), and Oxford knee score (OKS) were compared to determine improvement in function.
RESULTS
Six rotating hinge TKRs (five female and one male patient) were analyzed for this study. At a mean follow-up of 27 ± 22 months (range, 12-71 months), the mean pre-operative KSS of 50.6 ± 2.5 significantly improved (P < 0.0001) to 72.5 ± 1.6, and the mean pre-operative OKS of 23.6 ± 1.6 significantly improved (P < 0.0001) to 35.3 ± 1.7. The mean pre-operative knee ROM of 94° ± 10° changed to 92° ± 4° (P = 0.64) and the mean pre-operative sagittal deformity of 7° ± 23.5° changed to -3° ± 2.5° (P = 0.32) at final follow-up. None of the knees had any intra- or post-operative complications or showed radiologic evidence of post-operative loosening, subsidence, or periprosthetic radiolucent lines at the final follow-up.
CONCLUSION
Rotating hinge TKR gave excellent clinical and radiological results at a mean follow-up of 27 months in the present study. Despite TKR being a technically challenging procedure in patients with poliomyelitis-affected limbs, a rotating hinge design, along with meticulous surgical technique, can significantly improve function in such patients.
PubMed: 38910982
DOI: 10.13107/jocr.2024.v14.i06.4542 -
Cureus May 2024Moebius syndrome is a rare disease characterized by unilateral or bilateral facial nerve palsies with/without other cranial nerve palsy. It manifests clinically with...
Moebius syndrome is a rare disease characterized by unilateral or bilateral facial nerve palsies with/without other cranial nerve palsy. It manifests clinically with facial muscle weakness and/or ophthalmoplegia and can be associated with other physical anomalies such as various limb deformities and orofacial malformation. Herein, we have described the clinical and radiological features of Moebius syndrome in a 9-year-old female child who presented with left-side facial palsy and bilateral complete horizontal gaze palsy.
PubMed: 38910704
DOI: 10.7759/cureus.60887 -
Cureus May 2024Atlantoaxial dislocations (AAD) are a diverse set of C1-C2 rotatory subluxations that include the inferior and superior axial facet articulations. C1-C2 segments are...
Atlantoaxial dislocations (AAD) are a diverse set of C1-C2 rotatory subluxations that include the inferior and superior axial facet articulations. C1-C2 segments are both covered by cranial-cervical ligaments, indicating that AAD would damage both joints. Whenever the posterior elements are missing or impaired, lateral mass screw fixation has replaced alternative posterior cervical fixation procedures as the preferred treatment for securing the sub-axial cervical spine. An increase in muscle tone, hyperreflexia, pathological reflexes, digit/hand clumsiness, and gait deviations caused by spinal cord compression at the cervical level are the most common clinical features. A 23-year-old female patient came with the chief complaint of weakness, tingling sensation, and numbness in both upper and lower limbs along with imbalance while walking. She had a history of falls which was managed conservatively. As the symptoms progressed, an MRI, a CT scan, and an X-ray of the neck were done to rule out the level of injury which revealed AAD, and the patient was operated on for C1-C2 lateral mass fixation. Post-operatively, the patient was referred to the physiotherapy department for further management. The patient's quality of life and daily functioning were positively affected after undergoing early intervention as measured by the Functional Independence Measure, Neck Disability Index, Berg Balance Scale, and Dynamic Gait Index.
PubMed: 38910634
DOI: 10.7759/cureus.60913 -
Cureus May 2024Several large longitudinal studies on myotonic dystrophy type 1 (DM1) patients have revealed that proximal muscles show more gradual muscle weakness than distal muscles...
Several large longitudinal studies on myotonic dystrophy type 1 (DM1) patients have revealed that proximal muscles show more gradual muscle weakness than distal muscles and that the progression of muscle weakness might differ between the sexes. However, these longitudinal studies were based on two follow-up time points. The present report aimed to verify the longitudinal characteristics of muscle strength and various movement abilities in a case of DM1 by examining the results of 44 repeated evaluations for approximately two years. A 40-year-old male patient with DM1 could walk independently without any aid. We recorded the longitudinal changes in his muscle strength and movement ability during outpatient rehabilitation. During follow-up, he had a fall and was diagnosed with a right ankle sprain. To evaluate the effects of the fall, we examined his recorded data. He had a significant decrease in right knee extensor muscle strength after the fall, suggesting muscle weakness due to disuse syndrome. Although his right knee extensor muscle strength and walking speed decreased, the timed up-and-go test score was improved, and walking endurance in the 2-minute walk test was maintained. In the present case, there were some motor tasks in which the movement ability was maintained or improved, likely due to the use of compensation by residual function, even when muscle weakness was present. Regular and repeated evaluations of patients with DM1 lead to reveal longitudinal characteristics of their dysfunction and movement ability.
PubMed: 38910617
DOI: 10.7759/cureus.60818 -
Journal of Cardiothoracic Surgery Jun 2024This manuscript aims to describe the symptoms, demographics, surgical approaches and techniques, the volume of surgical interventions, histological results, intra- and...
BACKGROUND
This manuscript aims to describe the symptoms, demographics, surgical approaches and techniques, the volume of surgical interventions, histological results, intra- and postoperative complications, and postoperative results in patients with anterior mediastinal tumors of thyroid origin (AMTTO).
METHODS
Twenty patients with AMTTO were operated between 2017 and 2021. Fifteen were women and 5 were men. The mean age was 66.8 years.
RESULTS
The most common histology was nodular micro- and macrofollicular goiter (15/20, 75%). Kocher cervicotomy (65%) was the preferred approach. Total thyroidectomy was performed in 95% of patients. Intraoperative complications were identified in 25% (5/20), and in 2 patients a tracheostomy was required. Early postoperative complications were established in 65% and the most common was unilateral transient recurrent nerve paresis or paralysis and dysphonia (25%).
CONCLUSIONS
Commonly resection of AMTTO is a challenge due to its complexities associated with high-risk cases, emphasizing the need for experienced centers in managing such cases.
Topics: Humans; Male; Female; Aged; Mediastinal Neoplasms; Thyroidectomy; Middle Aged; Thyroid Neoplasms; Retrospective Studies; Postoperative Complications; Treatment Outcome; Adult; Intraoperative Complications; Thyroid Gland; Aged, 80 and over
PubMed: 38907269
DOI: 10.1186/s13019-024-02831-7 -
BMC Neurology Jun 2024Congenital myasthenic syndromes (CMS) are among the most challenging differential diagnoses in the neuromuscular domain, consisting of diverse genotypes and phenotypes.... (Review)
Review
BACKGROUND
Congenital myasthenic syndromes (CMS) are among the most challenging differential diagnoses in the neuromuscular domain, consisting of diverse genotypes and phenotypes. A mutation in the Docking Protein 7 (Dok-7) is a common cause of CMS. DOK7 CMS requires different treatment than other CMS types. Regarding DOK7's special considerations and challenges ahead of neurologists, we describe seven DOK7 patients and evaluate their response to treatment.
METHODS
The authors visited these patients in the neuromuscular clinics of Tehran and Kerman Universities of Medical Sciences Hospitals. They diagnosed these patients based on clinical findings and neurophysiological studies, which Whole Exome Sequencing confirmed. For each patient, we tried unique medications and recorded the clinical response.
RESULTS
The symptoms started from birth to as late as the age of 33, with the mean age of onset being 12.5. Common symptoms were: Limb-girdle weakness in 6, fluctuating symptoms in 5, ptosis in 4, bifacial weakness in 3, reduced extraocular movement in 3, bulbar symptoms in 2 and dyspnea in 2 3-Hz RNS was decremental in 5 out of 6 patients. Salbutamol was the most effective. c.1124_1127dupTGCC is the most common variant; three patients had this variant.
CONCLUSION
We strongly recommend that neurologists consider CMS in patients with these symptoms and a similar familial history. We recommend prescribing salbutamol as the first-choice treatment option for DOK7 patients.
Topics: Humans; Myasthenic Syndromes, Congenital; Male; Female; Muscle Proteins; Adult; Young Adult; Adolescent; Child; Mutation
PubMed: 38907197
DOI: 10.1186/s12883-024-03713-0 -
Frontiers in Oncology 2024Chemotherapy-induced peripheral neurotoxicity (CIPN) is a dose-limiting side effect observed in breast cancer patients. Its primary clinical manifestations include limb...
BACKGROUND
Chemotherapy-induced peripheral neurotoxicity (CIPN) is a dose-limiting side effect observed in breast cancer patients. Its primary clinical manifestations include limb numbness, tingling sensations, hypoesthesia, or paresthesia. In severe instances, some patients may also encounter muscle cramps, weakness, and pain, leading to potential paralysis. The onset of CIPN significantly impacts the quality of life for cancer patients. Hence, it is imperative to explore preventive strategies for managing CIPN.
METHODS
We searched for relevant randomized controlled trials (RCTs) and non-randomized controlled trials (non-RCTs) in several databases. The primary outcome measures encompassed the Patient Neurotoxicity Questionnaire (PNQ), the Functional Assessment of Cancer Therapy-Taxane (FACT-Taxane), and the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). Secondary outcomes aimed to evaluate the quality of life and the tolerability of ice gloves. Meta-analysis was conducted using RevMan 5.3 software to determine the relative risk ratio (RR) and 95% confidence interval (CI).
RESULTS
We conducted an analysis involving 372 patients across seven trials. In our meta-analysis, the use of ice gloves demonstrated non-significant results in reducing the incidence of both motor and sensory neuropathy, as assessed through CTCAE (sensory: RR: 0.94; 95% CI: 0.85 to 1.02; P = 0.15; motor: RR: 1.04; 95% CI: 0.88 to 1.22; P = 0.64). Similarly, when evaluated using the PNQ, there was no significant reduction observed in the incidence of sensory and motor neuropathy (sensory: RR: 0.49; 95% CI: 0.20 to 1.20; P = 0.12; motor: RR: 0.71; 95% CI: 0.26 to 1.99; P = 0.52). Consistently, our conclusions remained unchanged when employing the FACT-Taxane assessment. Regarding the evaluation of the quality of life, our observations suggested a potential improvement with the use of ice gloves, and participants exhibited moderate tolerance towards them.
CONCLUSION
Ice gloves are a reasonable option for the treatment of CIPN in patients undergoing chemotherapy for breast cancer. However, the effectiveness of ice gloves in combating CIPN remains inconclusive at this time due to the low quality and limited number of clinical trials on this topic.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023457045, identifier CRD42023457045.
PubMed: 38903710
DOI: 10.3389/fonc.2024.1366782 -
Frontiers in Neuroscience 2024Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons characterized by muscle weakness, muscle twitching, and muscle wasting.... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons characterized by muscle weakness, muscle twitching, and muscle wasting. ALS is regarded as the third-most frequent neurodegenerative disease, subsequent to Alzheimer's disease (AD) and Parkinson's disease (PD). The World Health Organization (WHO) in 2007 declared that prolonged use of statins may induce development of ALS-like syndrome and may increase ALS risk. Subsequently, different studies have implicated statins in the pathogenesis of ALS. In contrast, results from preclinical and clinical studies highlighted the protective role of statins against ALS neuropathology. Recently, meta-analyses and systematic reviews illustrated no association between long-term use of statins and ALS risk. These findings highlighted controversial points regarding the effects of statins on ALS pathogenesis and risk. The neuroprotective effects of statins against the development and progression of ALS may be mediated by regulating dyslipidemia and inflammatory changes. However, the mechanism for induction of ALS neuropathology by statins may be related to the dysregulation of liver X receptor signaling (LXR) signaling in the motor neurons and reduction of cholesterol, which has a neuroprotective effect against ALS neuropathology. Nevertheless, the exact role of statins on the pathogenesis of ALS was not fully elucidated. Therefore, this narrative review aims to discuss the role of statins in ALS neuropathology.
PubMed: 38903602
DOI: 10.3389/fnins.2024.1422912