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Journal of Medical Genetics Mar 2024Mutations in the tropomyosin receptor kinase fused () gene are associated with various neurological disorders, including autosomal recessive hereditary spastic...
BACKGROUND
Mutations in the tropomyosin receptor kinase fused () gene are associated with various neurological disorders, including autosomal recessive hereditary spastic paraplegia (HSP), autosomal dominant hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) and autosomal dominant type of Charcot-Marie-Tooth disease type 2.
METHODS
Whole genome sequencing and whole-exome sequencing were used, followed by Sanger sequencing for validation. Haplotype analysis was performed to confirm the inheritance mode of the novel mutation in a large Chinese family with HSP. Additionally, another family diagnosed with HMSN-P and carrying the reported mutation was studied. Clinical data and muscle pathology comparisons were drawn between patients with HSP and patients with HMSN-P. Furthermore, functional studies using skin fibroblasts derived from patients with HSP and patients with HMSN-P were conducted to investigate the pathomechanisms of mutations.
RESULTS
A novel heterozygous variant (NM_006070.6: c.125G>A (p.R42Q)) was identified and caused pure HSP. We further confirmed that the well-documented recessively inherited spastic paraplegia, caused by homozygous mutations, exists in a dominantly inherited form. Although the clinical features and muscle pathology between patients with HSP and patients with HMSN-P were distinct, skin fibroblasts derived from both patient groups exhibited reduced levels of autophagy-related proteins and the presence of TFG-positive puncta.
CONCLUSIONS
Our findings suggest that autophagy impairment may serve as a common pathomechanism among different clinical phenotypes caused by mutations. Consequently, targeting autophagy may facilitate the development of a uniform treatment for TFG-related neurological disorders.
Topics: Humans; Spastic Paraplegia, Hereditary; Proteins; Hereditary Sensory and Motor Neuropathy; Mutation; Nervous System Diseases; Pedigree; Paraplegia; Vesicular Transport Proteins
PubMed: 37890998
DOI: 10.1136/jmg-2023-109485 -
Spinal Cord Aug 2023Retrospective multicenter study.
STUDY DESIGN
Retrospective multicenter study.
OBJECTIVES
Although surgery is frequently selected for the treatment of idiopathic spinal cord herniation (ISCH), its impact on functional outcomes has yet to be fully understood given the limited number of patients in previous studies. This study aims to evaluate the symptomatic history and surgical outcomes of ISCH.
SETTING
Three institutions in Japan.
METHODS
A total of 34 subjects with ISCH were retrospectively enrolled and followed up for at least 2 years. Demographic information, imaging findings, and clinical outcomes were collected. Functional status was assessed using the JOA score.
RESULTS
The types of neurologic deficit were monoparesis, Brown-Sequard, and paraparesis in 5, 17, and 12 cases, with their mean disease duration being 1.2, 4.2, and 5.8 years, respectively. Significant differences in disease duration were observed between the monoparesis and Brown-Sequard groups (p < 0.01) and between the monoparesis and paraparesis groups (p = 0.04). Surgery promoted significantly better recovery rates from baseline. Correlations were observed between age at surgery and recovery rate (p < 0.01) and between disease duration and recovery rate (p = 0.04). The mean recovery rates were 82.6%, 51.6%, and 29.1% in the monoparesis, Brown-Sequard, and paraparesis groups, respectively. The monoparesis group had a significantly higher recovery rate than did the Brown-Sequard (p = 0.045) and paraparesis groups (p < 0.01).
CONCLUSIONS
Longer disease duration was correlated with the progression of neurologic deficit. Older age, and worse preoperative neurologic status hindered postoperative functional recovery. These results highlight the need to consider surgical timing before neurologic symptoms deteriorate.
Topics: Humans; Spinal Cord Diseases; Retrospective Studies; Magnetic Resonance Imaging; Spinal Cord Injuries; Hernia; Spinal Cord; Paresis; Paraparesis; Treatment Outcome; Brown-Sequard Syndrome
PubMed: 37380759
DOI: 10.1038/s41393-023-00904-3 -
JPMA. the Journal of the Pakistan... Oct 2023Neurogenic bladder is one of the negative consequences following a spinal cord injury (SCI). SCI patients who have neurogenic bladder depend on alternative methods to... (Review)
Review
Neurogenic bladder is one of the negative consequences following a spinal cord injury (SCI). SCI patients who have neurogenic bladder depend on alternative methods to drain urine from their bladder. These include indwelling catheters, reflex voiding , suprapubic tapping and intermittent catheterisation. This review summarizes evidence from the literature of five selected complications (renal failure, urinary tract infections, calculi, urethral stricture, and bladder cancer) that could result from use of the different bladder drainage methods. There is inconsistent evidence to support the superiority of intermittent over indwelling catheterisation on risk of renal impairment, urethral stricture, and renal calculi. Indwelling catheterisations are associated with higher risk of bladder calculi and cancer. Caution needs to be taken when interpreting this review, as many of its findings are from retrospective studies, and more than a decade old. Clinicians need to communicate the evidence to their patients when making the decision on method of bladder drainage.
Topics: Humans; Urinary Bladder; Urinary Bladder, Neurogenic; Urinary Catheterization; Retrospective Studies; Urethral Stricture; Catheters, Indwelling; Urinary Tract Infections; Spinal Cord Injuries; Drainage
PubMed: 37876089
DOI: 10.47391/JPMA.23-77 -
Molecular Cell Apr 2024Cells respond to lysosomal membrane permeabilization by membrane repair or selective macroautophagy of damaged lysosomes, termed lysophagy, but it is not fully...
Cells respond to lysosomal membrane permeabilization by membrane repair or selective macroautophagy of damaged lysosomes, termed lysophagy, but it is not fully understood how this decision is made. Here, we uncover a pathway in human cells that detects lipid bilayer perturbations in the limiting membrane of compromised lysosomes, which fail to be repaired, and then initiates ubiquitin-triggered lysophagy. We find that SPG20 binds the repair factor IST1 on damaged lysosomes and, importantly, integrates that with the detection of damage-associated lipid-packing defects of the lysosomal membrane. Detection occurs via sensory amphipathic helices in SPG20 before rupture of the membrane. If lipid-packing defects are extensive, such as during lipid peroxidation, SPG20 recruits and activates ITCH, which marks the damaged lysosome with lysine-63-linked ubiquitin chains to initiate lysophagy and thus triages the lysosome for destruction. With SPG20 being linked to neurodegeneration, these findings highlight the relevance of a coordinated lysosomal damage response for cellular homeostasis.
Topics: Humans; Autophagy; Intracellular Membranes; Lipids; Lysosomes; Macroautophagy; Ubiquitin
PubMed: 38503285
DOI: 10.1016/j.molcel.2024.02.029 -
The Journal of Neuroscience : the... Jul 2023Hereditary spastic paraplegia (HSP) is a severe neurodegenerative movement disorder, the underlying pathophysiology of which remains poorly understood. Mounting evidence...
Hereditary spastic paraplegia (HSP) is a severe neurodegenerative movement disorder, the underlying pathophysiology of which remains poorly understood. Mounting evidence has suggested that iron homeostasis dysregulation can lead to motor function impairment. However, whether deficits in iron homeostasis are involved in the pathophysiology of HSP remains unknown. To address this knowledge gap, we focused on parvalbumin-positive (PV) interneurons, a large category of inhibitory neurons in the central nervous system, which play a critical role in motor regulation. The PV interneuron-specific deletion of the gene encoding transferrin receptor 1 (TFR1), a key component of the neuronal iron uptake machinery, induced severe progressive motor deficits in both male and female mice. In addition, we observed skeletal muscle atrophy, axon degeneration in the spinal cord dorsal column, and alterations in the expression of HSP-related proteins in male mice with deletion in the PV interneurons. These phenotypes were highly consistent with the core clinical features of HSP cases. Furthermore, the effects on motor function induced by ablation in PV interneurons were mostly concentrated in the dorsal spinal cord; however, iron repletion partly rescued the motor defects and axon loss seen in both sexes of conditional mutant mice. Our study describes a new mouse model for mechanistic and therapeutic studies relating to HSP and provides novel insights into iron metabolism in spinal cord PV interneurons and its role in the regulation of motor functions. Iron is crucial for neuronal functioning. Mounting evidence suggests that iron homeostasis dysregulation can induce motor function deficits. Transferrin receptor 1 (TFR1) is thought to be the key component in neuronal iron uptake. We found that deletion of in parvalbumin-positive (PV) interneurons in mice induced severe progressive motor deficits, skeletal muscle atrophy, axon degeneration in the spinal cord dorsal column, and alterations in the expression of hereditary spastic paraplegia (HSP)-related proteins. These phenotypes were highly consistent with the core clinical features of HSP cases and partly rescued by iron repletion. This study describes a new mouse model for the study of HSP and provides novel insights into iron metabolism in spinal cord PV interneurons.
Topics: Male; Female; Animals; Mice; Spastic Paraplegia, Hereditary; Parvalbumins; Proteins; Phenotype; Interneurons; Atrophy
PubMed: 37308296
DOI: 10.1523/JNEUROSCI.2277-22.2023 -
Journal of Neuroimmunology Oct 2023Neurologic manifestations of mpox (monkeypox) infection are common. Rarely, transverse myelitis has been associated with mpox infection. We describe a case of...
Neurologic manifestations of mpox (monkeypox) infection are common. Rarely, transverse myelitis has been associated with mpox infection. We describe a case of longitudinally extensive transverse myelitis in a patient with recently diagnosed mpox, presenting as acute flaccid paraplegia. The patient underwent an extensive work-up that included serological and cerebrospinal fluid (CSF) testing and magnetic resonance imaging (MRI). They were treated with tecoviromat, high dose steroids, and intravenous immunoglobulin, followed by plasma exchange. Despite these interventions, there was minimal neurologic improvement. This case underscores the importance of instituting measures designed to prevent mpox infection, including public education initiatives.
Topics: Humans; Myelitis, Transverse; Mpox (monkeypox); Immunoglobulins, Intravenous; Steroids
PubMed: 37689031
DOI: 10.1016/j.jneuroim.2023.578190 -
Occupational Therapy International 2023People with disabilities face considerable obstacles when exercising, which precludes them from the social and health benefits of physical activity. Especially for... (Review)
Review
BACKGROUND
People with disabilities face considerable obstacles when exercising, which precludes them from the social and health benefits of physical activity. Especially for individuals with paraplegia with spinal cord injuries, it is necessary to maintain continuous participation in physical activity even after discharge, as it helps to maintain mobility and daily living activities through upper body strength. However, the participation rate of people with disabilities in physical activity in Korea is still low, mainly due to the lack of exercise equipment and facilities.
OBJECTIVES
The aim of this study is to identify aspects that can be improved for better accessibility to exercise equipment for individuals with paraplegia with spinal cord injuries and to reach a consensus on possible guidelines for accessible exercise equipment.
METHODS
This study reviews and evaluated the usability of four existing upper-body exercise equipment for individuals with paraplegia with spinal cord injuries. To assess usability, task performance scores and time were measured, and a survey was conducted on safety and satisfaction. Based on these results, areas for improvement were identified. Through literature review, usability results, and opinions from various stakeholders, eight requirements for universal accessibility were proposed.
RESULTS
It is necessary to consider how wheelchair users access the exercise equipment. The access method to the exercise area (facility regulations, auxiliary equipment to be provided, etc.) and placement of exercise equipment should also be considered. Information such as explanations of the exercise equipment and how to use it should be located within the wheelchair user's field of vision. Considering the participation rate in sports for people with disabilities in Korea, it is necessary to explain the exact exercise equipment and exercise method. It is also necessary to consider how wheelchair users transfer from the wheelchair to the seat of the exercise equipment. Parts that require manipulation of each exercise equipment must be within the wheelchair user's range of motion. Various supports or assistive devices that provide body support according to each piece of equipment are needed. In addition to the wheelchair's own brake, it is necessary to provide a fixing device so that the wheelchair does not move during the exercise.
CONCLUSION
For people with spinal cord injuries, the arm ergometer, aerobic exercise equipment, showed higher scores in performance, stability, and satisfaction compared to other exercise equipment. Among the strength exercise equipment, shoulder press had an effect on performance, seated lat pull-down had an effect on stability, and seated chest press had an effect on satisfaction. Therefore, when selecting exercise equipment, it is necessary to recommend aerobic and strength exercise equipment according to the preferences of people with spinal cord injuries. When developing strength exercise equipment, it is necessary to consider usability evaluation factors for individuals with spinal cord injury.
Topics: Humans; Exercise; Occupational Therapy; Paraplegia; Republic of Korea; Spinal Cord Injuries; Wheelchairs
PubMed: 38161738
DOI: 10.1155/2023/6652703 -
Preparing the spinal cord - priming or preconditioning? A systematic review of experimental studies.Scandinavian Cardiovascular Journal :... Dec 2023Paraplegia is devastating complication associated with thoracic and thoracoabdominal aortic aneurysm repair. Vast evidence has been gathered on pre-, peri- and... (Review)
Review
Paraplegia is devastating complication associated with thoracic and thoracoabdominal aortic aneurysm repair. Vast evidence has been gathered on pre-, peri- and postoperative protective adjuncts aiming to minimize spinal cord ischemia. This review focuses on the pretreatment phase of open surgical or endovascular aortic procedures and gathers the experimental data on the interventional preconditioning and priming methods that increase the spinal cord ischemic tolerance. By the start of March 2021, a systematic review was performed in PubMed, Scopus and Web of Science core collection to identify the articles that reported (i) either an ischemic preconditioning, remote ischemic preconditioning or priming method prior to (ii) experimental spinal cord ischemia performed in endovascular or open surgical fashion mimicking either thoracic, abdominal or thoracoabdominal aortic aneurysm procedures. (iii) The outcomes were reported neurological, motor-evoked potential, somatosensory-evoked potential, histopathological, immunohistochemical, physiological analysis, or in different combinations of these measurements. The search yielded 7802 articles, and 57 articles were included in the systematic review. The articles were assessed by the evaluated species, the utilized pretreatment, the measured protective effects, and the suggested underlying mechanisms. The reviewed articles showed several possible mechanisms in ischemic and remote ischemic preconditioning for prevention of spinal cord ischemia. The main suggested method for priming was arteriogenetic stimulus. Future studies should confirm these hints of arteriogenetic stimulus with more precise quantification of the protective recruitment process.
Topics: Humans; Aortic Aneurysm, Thoracic; Spinal Cord Ischemia; Paraplegia; Ischemia; Endovascular Procedures; Aortic Aneurysm, Thoracoabdominal
PubMed: 36660818
DOI: 10.1080/14017431.2023.2166100 -
Neurological Sciences : Official... Sep 2023Progressive muscular atrophy (PMA) is a rare adult-onset neurological disease that is characterized by isolated lower motor neuron degeneration. While it is still...
BACKGROUND
Progressive muscular atrophy (PMA) is a rare adult-onset neurological disease that is characterized by isolated lower motor neuron degeneration. While it is still disputable whether PMA is a subtype of amyotrophic lateral sclerosis (ALS) or an isolated disorder, it is well-established as a clinically defined entity. About 5% of PMA cases are monogenic, and the implicated genes largely overlap with those causing monogenic ALS.
CASE DESCRIPTION
Here we describe a 68-year-old female patient with progressive and asymmetric upper-limb weakness throughout an 18-month period, with muscle atrophy, dysphagia and slurring of speech. The lower limbs were unaffected, and there was no sign of upper motor neuron dysfunction. Comprehensive genetic testing for single nucleotide and copy-number variants revealed a pathogenic monoallelic variant c.1529C>T, p.(Ala510Val) in the SPG7 gene.
DISCUSSION
Pathogenic biallelic SPG7 variants have been originally associated with hereditary spastic paraplegia, but other phenotypes are nowadays known to be linked to these variants, such as ALS. However, there is no report of this (or any) other SPG7 variant in association with PMA, whether it progressed to ALS or not. In conclusion, we present the first known case of PMA associated with a monoallelic SPG7 mutation.
Topics: Female; Humans; Amyotrophic Lateral Sclerosis; Muscular Atrophy, Spinal; Mutation; Genetic Testing; Spastic Paraplegia, Hereditary; ATPases Associated with Diverse Cellular Activities; Metalloendopeptidases
PubMed: 37213040
DOI: 10.1007/s10072-023-06867-w -
Journal of Neuroimmunology Oct 2023Hypertrophic pachymeningitis (HP) is a relatively rare disease of the central nervous system characterized by local or diffuse fibrous thickening of the dura mater. At... (Review)
Review
Hypertrophic pachymeningitis (HP) is a relatively rare disease of the central nervous system characterized by local or diffuse fibrous thickening of the dura mater. At present, there is still insufficient research on the pathogenesis and treatment strategies of this disease. We reported a continuous case series of seven patients with idiopathic HP (IHP), and also details one case of immunoglobulin G4-related HP requiring surgical intervention. Early diagnosis and appropriate surgical intervention for IHP could prevent the progression of permanent neurological damage and spinal cord paraplegia.
Topics: Humans; Dura Mater; Hypertrophy; Meningitis; Spinal Cord
PubMed: 37660537
DOI: 10.1016/j.jneuroim.2023.578191