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An implanted neurotrophin-3 (NT3)-chitosan scaffold can recruit endogenous neural stem cells to migrate to a lesion region and differentiate into mature neurons after adult spinal cord injury (SCI). However, the identities of these newborn neurons and whether they can form functional synapses and circuits to promote recovery after paraplegia remain unknown. By using combined advanced technologies, we revealed here that the newborn neurons of several subtypes received synaptic input from the corticospinal tract (CST), rubrospinal tract (RST), and supraspinal tracts. They formed a functional neural circuit at the injured spinal region, further driving the local circuits beneath the lesion. Our results showed that the NT3-chitosan scaffold facilitated the maturation of spinal neurons and the reestablishment of the spinal neural circuit in the lesion region 12 weeks after SCI. Transsynaptic virus experiments revealed that these newborn spinal neurons received synaptic connections from the CST and RST and drove the neural circuit beneath the lesion via newly formed synapses. These re-established circuits successfully recovered the formation and function of the neuromuscular junction (NMJ) beneath the lesion spinal segments. These findings suggest that the NT3-chitosan scaffold promotes the formation of relay neural circuits to accommodate various types of brain descending inputs and facilitate functional recovery after paraplegia., Competing Interests: Declaration of Competing interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

PNS and CNS myelin contain large amounts of galactocerebroside and sulfatide with 2-hydroxylated fatty acids. The underlying hydroxylation reaction is catalyzed by fatty acid 2-hydroxylase (FA2H). Deficiency in this enzyme causes a complicated hereditary spastic paraplegia, SPG35, which is associated with leukodystrophy. Mass spectrometry-based proteomics of purified myelin isolated from sciatic nerves of Fa2h-deficient (Fa2h -/- ) mice revealed an increase in the concentration of the three proteins Cadm4, Mpp6 (Pals2), and protein band 4.1G (Epb41l2) in 17-month-old, but not in young (4 to 6-month-old), Fa2h -/- mice. These proteins are known to form a complex, together with the protein Lin7, in Schmidt-Lanterman incisures (SLIs). Accordingly, the number of SLIs was significantly increased in 17-month-old but not 4-month-old Fa2h -/- mice compared to age-matched wild-type mice. On the other hand, the relative increase in the SLI frequency was less pronounced than expected from Cadm4, Lin7, Mpp6 (Pals2), and band 4.1G (Epb41l2) protein levels. This suggests that the latter not only reflect the higher SLI frequency but that the concentration of the Cadm4 containing complex itself is increased in the SLIs or compact myelin of Fa2h -/- mice and may potentially play a role in the pathogenesis of the disease. The proteome data are available via ProteomeXchange with identifier PXD030244., (© 2022. The Author(s).)

Abstract: This study investigated causes of attenuation of cerebrospinal fluid (CSF) signal on heavily T2-weighted (T2W) images in dogs with thoracolumbar disc extrusion. Medical records and magnetic resonance images were retrospectively reviewed. Dogs were classified into the following grades; grade 1, non-ambulatory paraparesis; grade 2, paraplegia with deep pain perception and grade 3, paraplegia without deep pain perception. The length of intramedullary T2W hyperintensity of the spinal cord, cranial/ caudal expansion of extradural compressive materials (ECM), and the CSF signal attenuation were measured. Ratios to the second lumbar vertebra (L2) were calculated for the length of intramedullary T2W hyperintensity (T2W:L2), cranial/caudal expansion of ECM (ECML:L2), and CSF signal attenuation (CSF:L2). The dogs were classified into focal or extended T2W hyperintensity groups according to the length [focal, shorter than length of L2; extended, longer than L2]. The area of EMC and the spinal canal were measured on transverse images at the lesion deriving occupancy ratio. The correlation between CSF:L2 and other data were analysed, and CSF:L2 was compared between the grades. In dogs with intramedullary T2W hyperintensity, the locations of CSF attenuation and the hyperintensity were compared if those locations were matched. Fifty-five dogs were included, 36 of which showed intramedullary T2W hyperintensity. Twenty-two of 36 dogs were considered as match of the location of the CSF attenuation and hyperintensity. CSF:L2 was significantly correlated with T2W:L2 in dogs with extended T2W hyperintensity ( p = 0.0002), while CSF:L2 was significantly correlated with ECML:L2 in dogs with focal or no T2W hyperintensity ( p = 0.0103 and p = 0.0364, respectively). CSF:L2 in grade 3 was significantly greater than those in patients who were grade 1 or 2 (both p < 0.001). In conclusion, higher CSF:L2, which was frequently seen in grade 3, would be most consistent with a higher T2W:L2 which might indicate spinal cord swelling., (Copyright© Authors.)

Transverse myelitis typically extends two or less spinal segments, whereas longitudinal extensive transverse myelitis (LETM) extends three or more spinal segments in length and may occasionally span all the segments of the spinal cord. We present a case of spinal tuberculosis presenting with LETM with true lower motor neuron-type flaccid paraplegia.

In several neurodegenerative disorders, axonal pathology may originate from impaired oligodendrocyte-to-axon support of energy substrates. We previously established transgenic mice that allow measuring axonal ATP levels in electrically active optic nerves. Here, we utilize this technique to explore axonal ATP dynamics in the Plpnull/y mouse model of spastic paraplegia. Optic nerves from Plpnull/y mice exhibited lower and more variable basal axonal ATP levels and reduced compound action potential (CAP) amplitudes, providing a missing link between axonal pathology and a role of oligodendrocytes in brain energy metabolism. Surprisingly, when Plpnull/y optic nerves are challenged with transient glucose deprivation, both ATP levels and CAP decline slower, but recover faster upon reperfusion of glucose. Structurally, myelin sheaths display an increased frequency of cytosolic channels comprising glucose and monocarboxylate transporters, possibly facilitating accessibility of energy substrates to the axon. These data imply that complex metabolic alterations of the axon-myelin unit contribute to the phenotype of Plpnull/y mice., Competing Interests: The authors have declared that no competing interests exist.

FBXO7 is implicated in the ubiquitin-proteasome system and parkin-mediated mitophagy. FBXO7defects cause a levodopa-responsive parkinsonian-pyramidal syndrome(PPS)., Methods: We investigated the disease molecular bases in a child with PPS and brain iron accumulation., Results: A novel homozygous c.368C>G (p.S123*) FBXO7 mutation was identified in a child with spastic paraplegia, epilepsy, cerebellar degeneration, levodopa nonresponsive parkinsonism, and brain iron deposition. Patient's fibroblasts assays demonstrated an absence of FBXO7 RNA expression leading to impaired proteasome degradation and accumulation of poly-ubiquitinated proteins., Conclusion: This novel FBXO7 phenotype associated with impaired proteasome activity overlaps with neurodegeneration with brain iron accumulation disorders., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Hereditary spastic paraplegias (HSP) are neurodegenerative disorders characterized by lower limb spasticity and weakness, with or without additional symptoms. Mutations in ATP13A2, known to cause Kufor-Rakeb syndrome (KRS), have been recently implicated in HSP., Methods: Whole-exome sequencing was done in a Canada-wide HSP cohort., Results: Three additional patients with homozygous ATP13A2 mutations were identified, representing 0.7% of all HSP families. Spastic paraplegia was the predominant feature, all patients suffered from psychiatric symptoms, and one patient had developed seizures. Of the identified mutations, c.2126G>C;(p.[Arg709Thr]) is novel, c.2158G>T;(p.[Gly720Trp]) has not been reported in ATP13A2-related diseases, and c.2473&#95;2474insAAdelC;p.[Leu825Asnfs*32]) has been previously reported in KRS but not in HSP. Structural analysis of the mutations suggested a disruptive effect, and enrichment analysis suggested the potential involvement of specific pathways., Conclusion: Our study suggests that in HSP patients with psychiatric symptoms, ATP13A2 mutations should be suspected, especially if they also have extrapyramidal symptoms., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Objectives: Delayed paraplegia developed postoperatively after thoracoabdominal aneurysm surgery is primarily associated with spinal cord ischemia/reperfusion injury. Our previous study suggested that spinal cord stimulation postconditioning protected the spinal cord from ischemia/reperfusion injury through microglia inhibition. In this study, we further investigated whether α7 nicotinic acetylcholine receptors were involved in the neuroprotective mechanism of spinal cord stimulation., Methods: Rabbits were randomly assigned to sham, control, 2 Hz, α-bungarotoxin, and 2 Hz-α-bungarotoxin groups (n = 24/group). Transient spinal cord ischemia was performed on all rabbits except rabbits in the sham group. Rabbits in the control group received no further intervention, rabbits in the 2 Hz group were given 2 Hz spinal cord stimulation, rabbits in the α-bungarotoxin group received prescribed intrathecal α-bungarotoxin (α-bungarotoxin, a specific α7 nicotinic acetylcholine receptor antagonist) injections, and rabbits in the 2 Hz-α-bungarotoxin group received both α-bungarotoxin injections and 2 Hz spinal cord stimulation. Hind-limb neurologic function was assessed, and spinal cord histologic examination, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining, and microglia staining were performed at 8 hours, 1 day, 3 days, and 7 days of reperfusion., Results: Rabbits in the 2 Hz group had significantly better neurologic functions, more α-motor neurons, and lower terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive neuron rates and microglia area/anterior horn area ratios (microglia area ratios) than the control group. The neurologic functions of the α-bungarotoxin group were significantly worse than those of the control group, whereas other results were not significantly different from the control group. The results of the 2 Hz-α-bungarotoxin group were insignificant to the control group except for the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive neuron rates, which were significantly lower than in the control group., Conclusions: The neuroprotective effects of spinal cord stimulation postconditioning against spinal cord ischemia/reperfusion injury were partially mediated by activating α7 nicotinic acetylcholine receptors., (Copyright © 2019. Published by Elsevier Inc.)

Background: Alterations of vacuolar protein sorting-associated protein 13 (VPS13) family members including VPS13A, VPS13B, and VPS13C lead to chorea acanthocytosis, Cohen syndrome, and parkinsonism, respectively. Recently, VPS13D mutations were identified as a cause of VPS13D-related movement disorders, which show several phenotypes including chorea, dystonia, spastic ataxia, and spastic paraplegia., Methods: We applied whole-exome analysis for a patient with a complicated form of hereditary spastic paraplegia (HSP) and her unaffected parents. Then, we screened the candidate genes in 664 Japanese families with HSP in Japan., Results: We first found a compound heterozygote VPS13D mutation and a heterozygote ABHD4 variation in a sporadic patient with spastic paraplegia. Then, we found three patients with VPS13D mutations in two Japanese HSP families. The three patients with homozygous mutations (p.Thr1118Met/p.Thr1118Met and p.Thr2945Ala/p.Thr2945Ala) in the VPS13D showed an adult onset pure form of HSP. Meanwhile, the patient with a compound heterozygous mutation (p.Ser405Arg/p.Arg3141Ter) in the VPS13D showed a childhood onset complicated form of HSP associated with cerebellar ataxia, cervical dystonia, cataracts, and chorioretinal dystrophy., Conclusion: In the present study, we found four patients in three Japanese families with novel VPS13D mutations, which may broaden the clinical and genetic findings for VPS13D-related disorders., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Mutations in WASHC5 (also known as KIAA0196 ) cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG8. WASHC5, commonly called strumpellin, is a core component of the Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex that activates actin nucleation at endosomes. Although various other cellular roles for strumpellin have also been described, none account for how SPG8-associated mutations lead to HSP. Here, we identified protein interactors of the WASH complex by immunoprecipitation and mass spectrometry and assessed the functions of strumpellin in cultured cells using both overexpression and RNA interference along with cell-spreading assays to investigate cell adhesion. We uncovered a decrease in CAV1 protein abundance as well as endosomal fission defects resulting from pathogenic SPG8 mutations. CAV1, a key component of caveolae, interacted with strumpellin in cells, and strumpellin inhibited the lysosomal degradation of CAV1. SPG8-associated missense mutations in strumpellin did not rescue endosomal tubulation defects, reduction in CAV1 protein abundance, or integrin-mediated cell adhesion in strumpellin-deficient cells. Mechanistically, we demonstrated that the WASH complex maintained CAV1 and integrin protein amounts by inhibiting their lysosomal degradation through its endosomal actin nucleation activity. In addition, the interaction of strumpellin with CAV1 stimulated integrin recycling, thereby promoting cell adhesion. These findings provide a molecular link between WASHC5 mutations and impairment of CAV1- and integrin-mediated cell adhesion, providing insights into the cellular pathogenesis of SPG8., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: X-linked adrenoleukodystrophy (ALD) is one of the most common peroxisomal disorders characterized by abnormal accumulation of very long-chain fatty acids (VLCFA) in plasma and tissues and caused by mutations within ABCD1. Clinically, ALD present with various phenotypes, ranging from asymptomatic type to rapidly progressive childhood cerebral form. However, no remarkable abnormality in cerebral white matter usually makes it difficult to distinguish adult ALD from hereditary spastic paraplegia (HSP)., Methods: We analyzed the features of seven Chinese ALD patients who had a primary phenotype of spastic paraplegia. Sequencing was performed in the probands and their familial members. Detailed clinical, VLCFAs test, hormone test, magnetic resonance imaging, and electromyogram are presented., Results: We reported seven ALD patients from a Chinese cohort of 142 HSP patients. Genetic investigations revealed five known ABCD1 mutations (c.346G>C, c.521A>G, c.829G>T, c.1415&#95;1416delAG, and c.1849C>T) and two novel mutations (c.454C>G, c.1452&#95;1482del). Further auxiliary testing revealed that they had higher VLCFA and/or adrenal insufficiency., Conclusions: Our findings expand the mutation spectrum of ABCD1 and indicate that ALD represent a significant portion (4.9%, 7/142) of the spastic paraplegia entities. ALD should be considered in male patients with spastic paraplegia, even if there was no positive family history., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Primitive neuroectodermal tumor (PNET) is a rare and highly malignant neoplasm composed of small round cells, which frequently occurs in children and adolescents. PNET originating from the prostate is even rarer. We report a case of PNET of the prostate with notalgia and paraplegia as the initial symptoms. Positron emission tomography-computed tomography scanning showed hypodense and hypermetabolism on the prostate; subsequently, we ascertained the diagnosis by transrectal ultrasound-guided biopsy. The patient underwent local vertebral radiotherapy combined with five courses of systematic chemotherapy. Disease progressed after 11 months, and the overall survival was 17 months.

Background: Congenital disorders of glycosylation (CDGs) are genetic diseases caused by pathogenic variants of genes involved in protein or lipid glycosylation. De novo variants in the SLC35A2 gene, which encodes a UDP-galactose transporter, are responsible for CDGs with an X-linked dominant manner. Common symptoms related to SLC35A2 variants include epilepsy, psychomotor developmental delay, hypotonia, abnormal facial and skeletal features, and various magnetic resonance imaging (MRI) findings., Methods: Whole-exome sequencing was performed on the patient's DNA, and candidate variants were confirmed by Sanger sequencing. cDNA analysis was performed to assess the effect of the splice site variant using peripheral leukocytes. The X-chromosome inactivation pattern was studied using the human androgen receptor assay., Results: We identified a de novo splice site variant in SLC35A2 (NM&#95;005660.2: c.274+1G>A) in a female patient who showed severe developmental delay, spastic paraplegia, mild cerebral atrophy, and delayed myelination on MRI, but no seizures. The variant led to an aberrant splicing resulting in an in-frame 33-bp insertion, which caused an 11-amino acid insertion in the presumptive cytoplasmic loop. X-inactivation pattern was random. Partial loss of galactose and sialic acid of the N-linked glycans of serum transferrin was observed., Conclusion: This case would expand the phenotypic spectrum of SLC35A2-related disorders to delayed myelination with spasticity and no seizures., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Anatomical studies of spinal cord injury (SCI) using magnetic resonance imaging (MRI) report diverging observations, from "no changes" to "tissue atrophy in motor and non-motor regions." These discrepancies among studies can be attributed to heterogeneity in extent, level, and post-injury duration observed within the SCI population. But, no studies have investigated structural changes associated with different levels of injury (paraplegia vs. tetraplegia). High-resolution MRI images were processed using a voxel-based morphometry technique to compare regional gray matter volume (GMV) between 16 complete paraplegia and 7 complete tetraplegia SCI subjects scanned within 2 years of injury when compared to 22 age-matched healthy controls using one-way analysis of covariance (ANCOVA). A post-hoc analysis using a region of interest-based approach was utilized to quantify GMV differences between healthy controls and subgroups of SCI. A voxel-wise one-sample t -test was also performed to evaluate the mean effect of post-injury duration on GMV of the SCI group. ANCOVA resulted in altered GMV in inferior frontal gyrus, bilateral mid orbital gyrus extending to rectal gyrus, and anterior cingulate cortex. Post-hoc analysis, in general, indicated GM atrophy after SCI, but tetraplegia showed a greater decrease in GMV when compared to paraplegia and healthy controls. Further, the GMV of the middle frontal gyrus, superior frontal gyrus, inferior frontal gyrus, insula, mid-orbital gyrus, and middle temporal gyrus was positively correlated with post-injury duration in both paraplegia and tetraplegia groups. GM atrophy after SCI is affected by level of cord injury, with higher levels of injury resulting in greater loss of GMV. Magnitude of GMV loss in the frontal cortex after SCI also appears to be dynamic within the first 2 years of injury. Understanding the effect of injury level and injury duration on structural changes after SCI can help to better understand the mechanisms leading to positive and negative clinical outcome in SCI patients.

Over the past decade, many medical lower limb exoskeletons have been developed and exploited. The advantage of such a systems is to ensure the mobility of paraplegic patients, as well as their physical rehabilitation. However, existing solutions have not been widely available among the disabled population, particularly adolescents, due to the limitations of their conception caused by the rapid physical growth and morphological variation of this population.In this paper, a new scalable structure of the exoskeleton is proposed as a feasible solution to the problem of morphological changes. As this is the first time the generic term "scalability" has been used, its requirements and design methods, including the morphological changes and alignment, are presented in detail to better meet the growing needs for such a promising device. The evaluation of the proposed scalable structure shows a promising utility that is illustrated by several experimental scenarios: the load capacity of the structure, the efficiency of the fixation mechanisms, the validation of the hip alignment mechanism and finally the validation of the evolutionary structure.

Purpose To investigate metabolic changes in chronic spinal cord injury (SCI) by applying MR spectroscopy in the cervical spinal cord. Materials and Methods Single-voxel short-echo spectroscopic data in study participants with chronic SCI and healthy control subjects were prospectively acquired in the cervical spinal cord at C2 above the level of injury between March 2016 and January 2017 and were compared between groups. Concentrations of total N-acetylaspartate (tNAA), myo-inositol (mI), total choline-containing compounds (tCho), creatine, and glutamine and glutamate complex were estimated from the acquired spectra. Participants were assessed with a comprehensive clinical evaluation investigating sensory and motor deficits. Correlation analysis was applied to investigate relationships between observed metabolic differences, lesion severity, and clinical outcome. Results There were 18 male study participants with chronic SCI (median age, 51 years; range, 30-68 years) and 11 male healthy control subjects (median age, 45 years; range, 30-67 years). At cervical level C2, tNAA/mI and tCho/mI ratios were lower in participants with SCI (tNAA/mI: -26%, P = .003; tCho/mI: -18%; P = .04) than in healthy control subjects. The magnitude of difference was greater with the severity of cord atrophy (tNAA/mI: R 2 = 0.44, P = .003; tCho/mI: R 2 = 0.166, P = .09). Smaller tissue bridges at the lesion site correlated with lower ratios of tNAA/mI (R 2 = 0.69, P = .006) and tCho/mI (R 2 = 0.51, P = .03) at the C2 level. Lower tNAA/mI and tCho/mI ratios were associated with worse sensory and motor outcomes (P < .05). Conclusion Supralesional metabolic alterations are observed in chronic spinal cord injury, likely reflecting neurodegeneration, demyelination, and astrocytic gliosis in the injured cervical cord. Lesion severity and greater clinical impairment are both linked to the biochemical changes in the atrophied cervical cord after spinal cord injury. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Lin in this issue.

Objectives: Spinal cord ischemia secondary to trauma or a vascular occlusive event is a threatening phenomenon. The neuroprotective properties of minocycline have been shown in several models of central nervous system diseases and after spinal cord ischemia; however, the benefit of using the drug requires additional confirmation in different animal models. Astrocytes are essential as regulators of neuronal functions and for providing nutrients. The authors hypothesized that astrocytes in the spinal cord may be an important target for minocycline action after ischemia and thus in the prevention of secondary spreading damage., Design: A prospective, randomized animal study., Setting: University research laboratory, single institution., Participants: Adult male Sprague Dawley rats, weighing between 400 and 450 g., Interventions: A model of spinal cord ischemia in the rat was used for this study to determine whether a single, high-dose (10 mg/kg) of minocycline protects against damage to the neuronal cytoskeleton, both in the white and gray matter, and whether it reduces glial fibrillary acidic protein levels, which is an index for prevention of astrocyte activation during ischemia. Thirty minutes before thoracic aorta occlusion, minocycline was administered for 18 minutes using a 2 F Fogarty catheter., Measurements and Main Results: Minocycline given prophylactically significantly mitigated severe hindlimb motor impairment and reduced glial fibrillary acidic protein plus astrocytosis in both the white and gray matter of the spinal cord, caudal to the occlusion. Neuronal histologic cytoarchitecture, which was severely and significantly compromised in control animals, was preserved in the minocycline-treated animals., Conclusions: This study's data imply that minocycline may attenuate reactive astrocytosis in response to injury with better neurologic outcome in a model of spinal cord ischemia in rats. The data suggest that future use of minocycline, clinically, might be advantageous in surgeries with a potential risk for paraplegia due to spinal cord ischemia., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Study Design: Cross-sectional OBJECTIVE: To investigate the association between skeletal muscle mass and spasticity in people with spinal cord injury (SCI)., Setting: Tertiary level hospital in Seoul, Korea METHODS: Spasticity was evaluated in 69 participants with SCI using the spasticity sum score (SSS), Penn Spasm Frequency Scale (PSFS), and Spinal Cord Assessment Tool for Spastic Reflexes (SCATS). Skeletal muscle mass was measured using a dual-energy X-ray absorptiometry scanner, and skeletal muscle index was calculated by dividing skeletal muscle mass by height squared. Laboratory parameters including hemoglobin, albumin, creatinine, fasting glucose, and cholesterol were measured. Spearman's correlation analysis was performed to assess the association between the skeletal muscle mass and spasticity scales. Multiple linear regression analysis was used to present the independent association between them., Results: The participants' mean age was 41.8 years; 54 (78.3%) were male, and 46 (66.7%) were tetraplegic. Skeletal muscle index of lower extremities was significantly correlated with all spasticity scales. Spearman's correlation coefficients were 0.468, 0.467, 0.555, 0.506, and 0.474 for SSS, PSFS, SCATS clonus, SCATS flexor, and SCATS extensor with p-values < 0.001, respectively. After adjustment for age, sex, level of injury, body mass index, and serum creatinine, all spasticity scales were significantly associated with skeletal muscle index of lower extremities in multiple regression analysis. Standardized coefficients were 0.228, 0.274, 0.294, 0.210, and 0.227 for SSS, PSFS, SCATS clonus, SCATS flexor, and SCATS extensor., Conclusions: Spasticity was significantly correlated with the skeletal muscle mass even after adjusting for possible confounders. Spasticity may need to be considered as an influencing factor in interventions such as electrical stimulation to preserve skeletal muscle mass.

Objective/background: To assess frequency domain heart rate variability (HRV) parameters at rest and in response to postural autonomic provocations in individuals with spinal cord injury (SCI) and investigate the autonomic influences on the heart of different physical activities., Design: Cross-sectional study., Methods: Ten subjects with complete cervical SCI and fourteen subjects with complete low thoracic SCI were prospectively recruited from the community and further divided in sedentary and physically active groups, the latter defined as regular weekly 4 hour physical activity for the preceding 3 months. Sixteen healthy individuals matched for sex and age were recruited to participate in the control group. The Low Frequency (LF), High Frequency (HF) powers and the LF/HF ratio of HRV were measured from continuous electrocardiogram (ECG) recordings at rest and after sitting using a fast Fourier transformation., Outcome Measures: The LF,HF, and the LF/HF ratio at rest and after sitting., Results: A significant decrease in all HRV parameters in patients with SCI was found compared to controls. The change in HF, LF and LF/HF following sitting maneuver was significantly greater in controls as compared with the SCI group and greater in subjects with paraplegia as compared to subjects with tetraplegia. Better HRV values and enhanced vagal activity appears to be related to the type of physical activity in active subjects with paraplegia., Conclusion: In this cohort of subjects spectral parameters of HRV were associated with the level of the injury. Passive standing was associated with higher HRV values in subjects with paraplegia.

The tropomyosin-receptor kinase fused gene (TFG) has recently been implicated in several distinct hereditary disorders, including the autosomal-recessive form of complicated hereditary spastic paraplegia called SPG57. Previously, three homozygous variants of the TFG gene were reported in five families with SPG57, in which early onset spastic paraplegia, optic atrophy, and peripheral neuropathy were variably identified. Here, we present the first Japanese patient with SPG57, and have added a homozygous p.Ile66Thr variant as the fourth SPG57 genotype.

Delayed paraplegia complicates the recovery from spinal cord ischemia or traumatic spinal cord injury. While delayed motor neuron apoptosis is implicated in the pathogenesis, no effective treatment or preventive measures is available for delayed paraplegia. Hydrogen sulfide exerts anti-apoptotic effects. Here, we examined effects of hydrogen sulfide breathing on the recovery from transient spinal cord ischemia. Breathing hydrogen sulfide starting 23 h after reperfusion for 5 h prevented delayed paraplegia after 5 min of spinal cord ischemia. Beneficial effects of hydrogen sulfide were mediated by upregulation of anti-apoptotic Bcl-XL and abolished by nitric oxide synthase 2 deficiency. S-nitrosylation of NFkB p65 subunit, which is induced by nitric oxide derived from nitric oxide synthase 2, facilitated subsequent sulfide-induced persulfidation of p65 and transcription of anti-apoptotic genes. These results uncover the molecular mechanism of the anti-apoptotic effects of sulfide based on the interaction between nitric oxide and sulfide. Exploitation of the anti-apoptotic effects of delayed hydrogen sulfide breathing may provide a new therapeutic approach for delayed paraplegia., (Copyright © 2018 Elsevier Inc. All rights reserved.)

1. NAME OF DISEASE (SYNONYMS): Pontocerebellar hypoplasia type 9 (PCH9) and spastic paraplegia-63 (SPG63). 2. OMIM# OF THE DISEASE: 615809 and 615686. 3. NAME OF THE ANALYSED GENES OR DNA/CHROMOSOME SEGMENTS: AMPD2 at 1p13.3. 4. OMIM# OF THE GENE(S): 102771.

An increasing number of mitochondrial diseases are found to be caused by pathogenic variants in nuclear encoded mitochondrial aminoacyl-tRNA synthetases. FARS2 encodes mitochondrial phenylalanyl-tRNA synthetase (mtPheRS) which transfers phenylalanine to its cognate tRNA in mitochondria. Since the first case was reported in 2012, a total of 21 subjects with FARS2 deficiency have been reported to date with a spectrum of disease severity that falls between two phenotypes; early onset epileptic encephalopathy and a less severe phenotype characterized by spastic paraplegia. In this report, we present an additional 15 individuals from 12 families who are mostly Arabs homozygous for the pathogenic variant Y144C, which is associated with the more severe early onset phenotype. The total number of unique pathogenic FARS2 variants known to date is 21 including three different partial gene deletions reported in four individuals. Except for the large deletions, all variants but two (one in-frame deletion of one amino acid and one splice-site variant) are missense. All large deletions and the single splice-site variant are in trans with a missense variant. This suggests that complete loss of function may be incompatible with life. In this report, we also review structural, functional, and evolutionary significance of select FARS2 pathogenic variants reported here., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Inflammatory pseudotumor is a histologically proven benign tumor-like lesion of unknown etiopathogenesis. It is less commonly found in central nervous system, and least commonly in the spinal canal. Spinal epidural inflammatory pseudotumor is a rarely reported entity., Case Description: We report a patient who presented with paraplegia, in whom a spinal epidural mass was diagnosed as an inflammatory pseudotumor after surgical excision followed by histopathology., Conclusions: It was a radiologic dilemma; thus, complete excision was required for diagnosis and a better outcome., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Assisted-treadmill training, may be helpful in promoting muscle mass preservation after incomplete spinal cord injury (SCI). However, biological mechanism involved in this process is still not fully understood. This study investigated the effects of locomotor treadmill training on muscle trophism mediated by protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K) in paraplegic rats. Adult female Wistar rats underwent an incomplete thoracic SCI induced by compression using an aneurysm clip. After 7 days, injured animals started a 3-week locomotor treadmill training with body weight-support and manual step help. Soleus trophism was measured by muscle weight and transverse myofiber cross-sectional area (CSA). An enzyme-linked immunosorbent assay (ELISA) and western blot analysis were used to detect brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB), Akt, mTOR and p70S6K in paretic soleus. Trained animals did not show locomotor improved, but present an increase in muscle weight and myofiber CSA. Furthermore, the levels of Akt, p70S6K phosphorylation, mTOR and TrkB receptor were increased by training in soleus. In contrast, muscle BDNF levels were significantly reduced after training. The results suggest locomotor treadmill training partially reverts/prevents soleus muscle hypotrophy in rats with SCI. Furthermore, this study provided the first evidence that morphological muscle changes were caused by Akt/mTOR/p70S6K signaling pathway and TrkB up-regulation, which may increase the sensitivity of muscle, reducing autocrine signaling pathway demand of BDNF for cell growth.

Objectives: Capillary hemangiomas are benign vascular tumors. They are commonly founded in the vertebral bodies but very seldom in the spinal cord. The most common symptom at onset is long-lasting axial pain without neurologic deficit. In rare cases, the onset may be acute with neurological deficit due to an intratumoral hemorrhage., Patient and Methods: We report a case of a 58-year-old male with a history of 15 days upper back pain triggered by a mild traumatism that evolves acutely to paraplegia and urinary and fecal retention. An urgent MR showed an intradural lesion with signs of intratumoral haemorrhage., Results: Urgent surgical intervention was performed and the anatomopathological results were capillary hemangioma. The symptoms of the patient improved after the surgery., Conclusions: Intradural capillary hemangioma with acute intratumoral hemorrhage is a rare pathology, but it must be kept in mind because early diagnosis and treatment are key to achieve a good outcome. As far as we know, this is the first case reported of an intradural-extramedular capillary hemangioma that presents sudden neurologic deficit due to intratumoral bleeding., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A large, highly prolific swine farm in Hungary had a 2-year history of neurologic disease among newly weaned (25- to 35-day-old) pigs, with clinical signs of posterior paraplegia and a high mortality rate. Affected pigs that were necropsied had encephalomyelitis and neural necrosis. Porcine astrovirus type 3 was identified by reverse transcription PCR and in situ hybridization in brain and spinal cord samples in 6 animals from this farm. Among tissues tested by quantitative RT-PCR, the highest viral loads were detected in brain stem and spinal cord. Similar porcine astrovirus type 3 was also detected in archived brain and spinal cord samples from another 2 geographically distant farms. Viral RNA was predominantly restricted to neurons, particularly in the brain stem, cerebellum (Purkinje cells), and cervical spinal cord. Astrovirus was generally undetectable in feces but present in respiratory samples, indicating a possible respiratory infection. Astrovirus could cause common, neuroinvasive epidemic disease.

Brown adipose tissues (BAT) burn lipids to generate heat through uncoupled respiration, thus representing a powerful target to counteract lipid accumulation and obesity. The tumor suppressor liver kinase b1 (Lkb1) is a key regulator of cellular energy metabolism; and adipocyte-specific knockout of Lkb1 (Ad-Lkb1 KO) leads to the expansion of BAT, improvements in systemic metabolism and resistance to obesity in young mice. Here we report the unexpected finding that the Ad-Lkb1 KO mice develop hindlimb paralysis at mid-age. Gene expression analyses indicate that Lkb1 KO upregulates the expression of inflammatory cytokines in interscapular BAT and epineurial brown adipocytes surrounding the sciatic nerve. This is followed by peripheral neuropathy characterized by infiltration of macrophages into the sciatic nerve, axon degeneration, reduced nerve conductance, and hindlimb paralysis. Mechanistically, Lkb1 KO reduces AMPK phosphorylation and amplifies mammalian target-of-rapamycin (mTOR)-dependent inflammatory signaling specifically in BAT but not WAT. Importantly, pharmacological or genetic inhibition of mTOR ameliorates inflammation and prevents paralysis. These results demonstrate that BAT inflammation is linked to peripheral neuropathy., (Copyright © 2017. Published by Elsevier B.V.)

Mutations in the mitochondrial aminoacyl-tRNA synthetases (mtaaRSs) can cause profound clinical presentations, and have manifested as diseases with very selective tissue specificity. To date most of the mtaaRS mutations could be phenotypically recognized, such that clinicians could identify the affected mtaaRS from the symptoms alone. Among the recently reported pathogenic variants are point mutations in FARS2 gene, encoding the human mitochondrial PheRS. Patient symptoms range from spastic paraplegia to fatal infantile Alpers encephalopathy. How clinical manifestations of these mutations relate to the changes in three-dimensional structures and kinetic characteristics remains unclear, although impaired aminoacylation has been proposed as possible etiology of diseases. Here, we report four crystal structures of HsmtPheRS mutants, and extensive MD simulations for wild-type and nine mutants to reveal the structural changes on dynamic trajectories of HsmtPheRS. Using steady-state kinetic measurements of phenylalanine activation and tRNA Phe aminoacylation, we gained insight into the structural and kinetic effects of mitochondrial disease-related mutations in FARS2 gene., (© 2017 The Protein Society.)

Background Aims: Cell transplantation in patients suffering spinal cord injury (SCI) is in its initial stages, but currently there is confusion about the results because of the disparity in the techniques used, the route of administration, and the criteria for selecting patients., Methods: We conducted a clinical trial involving 12 patients with complete and chronic paraplegia (average time of chronicity, 13.86 years; SD, 9.36). The characteristics of SCI in magnetic resonance imaging (MRI) were evaluated for a personalized local administration of expanded autologous bone marrow mesenchymal stromal cells (MSCs) supported in autologous plasma, with the number of MSCs ranging from 100 × 10(6) to 230 × 10(6). An additional 30 × 10(6) MSCs were administered 3 months later by lumbar puncture into the subarachnoid space. Outcomes were evaluated at 3, 6, 9 and 12 months after surgery through clinical, urodynamic, neurophysiological and neuroimaging studies., Results: Cell transplantation is a safe procedure. All patients experienced improvement, primarily in sensitivity and sphincter control. Infralesional motor activity, according to clinical and neurophysiological studies, was obtained by more than 50% of the patients. Decreases in spasms and spasticity, and improved sexual function were also common findings. Clinical improvement seems to be dose-dependent but was not influenced by the chronicity of the SCI., Conclusion: Personalized cell therapy with MSCs is safe and leads to clear improvements in clinical aspects and quality of life for patients with complete and chronically established paraplegia., (Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Introduction: Inflammatory pseudotumors (IPTs) are benign lesions with unknown etiology, probably an immunological reaction to a traumatic or an infective insult or sometimes considered as an IgG4-related autoimmune disorder. It can occur as an isolated or multi-centric lesion and are reported to involve almost all parts of the human body. Although lung and orbital IPTs are reported commonly, central nervous system involvement is a rare occurrence. Only seven cases of spinal epidural IPTs have been reported to date. These are clinically and radiologically a diagnosis of exclusion. It is an exclusive histopathological diagnosis., Case Report: We present here a 49-year-old female with 2 months history of progressive weakness in lower limbs, with no history suggestive of any traumatic, infective, inflammatory, or neoplastic pathology. Both clinical and radiological investigations were inconclusive. There was a mass lesion in the epidural space (predominantly in the posterior and right lateral space) at T1-T3 vertebral levels compressing the thoracic spinal cord. Considering the progressive nature of her neurological deficit, an emergency decompressive laminectomies of T1-T3 vertebrae were done with excision of the compressive mass lesion. Histopathological examination showed a rich lympho-plasmacytic cell infiltrates with storiform spindle cells and dense fibrosis, which was diagnostic of IPT. Post-operatively there was a rapid recovery in neurology and she became ambulatory at the end of 2 weeks. The purpose of this case report is to discuss the clinical, histopathological and radiological features, differential diagnosis, management, and prognosis of spinal IPT on the background of relevant literature review.

Background and Purpose: SPG7 is one of the most common forms of autosomal recessive hereditary spastic paraplegia. The phenotype has been shown to be heterogeneous, varying from a complex spastic ataxia to pure spastic paraplegia or pure ataxia. The aim of this study was to clinically and genetically characterize patients with SPG7 in Norway., Methods: Six Norwegian families with a clinical diagnosis of hereditary spastic paraplegia were diagnosed with SPG7 through Sanger sequencing and whole-exome sequencing. Haplotypes were established to identify a possible founder mutation. All patients were thoroughly examined and the clinical and molecular findings are described., Results: The core phenotype was spastic paraparesis with ataxia, bladder disturbances and progressive external ophthalmoplegia. The variant p.H701P was identified in homozygous state in one family and in compound heterozygous state in three families. Haplotype analysis of seven surrounding single nucleotide polymorphisms supports that this variant resides on a founder haplotype. Four of the families were compound heterozygous for the previously well-described p.A510V variant., Conclusion: SPG7 is a common subgroup of hereditary spinocerebellar disorders in Norway. The broad phenotype in the Norwegian SPG7 population illustrates the challenges with the traditional dichotomous classification of hereditary spinocerebellar disorders into hereditary spastic paraplegia or hereditary ataxia. A Norwegian founder mutation p.H701P was identified in four out of six families, making it a major cause of SPG7 in Norway., (© 2016 EAN.)

Background: Extradural spinal angiolipomas are extremely rare benign neoplasms made up of mature lipocytes with abnormal blood vessels. Spinal angiolipomas represent only 0.14-1.2% of all spinal axis tumours., Case Presentation: A case of thoracic spinal extradural angiolipoma producing acute spinal cord compression in a 35-year old housewife is presented. Patient presented with sudden onset of lower limbs paralysis and urinary incontinence for 1 month after vaginal delivery. Patient was diagnosed as dorsal spine angiolipoma which was treated surgically with excellent outcome., Conclusions: Spinal angiolipomas are rare tumours but it is mandatory to include it in the differential diagnosis of the spinal extradural space occupying lesions. Pregnancy and vaginal delivery may suddenly exacerbate the condition. The best investigation to choose to diagnose these lesions is definitely magnetic resonance imaging of the spine. The aim of treatment of extradural angiolipomas of the spine is to resect the tumour in Toto surgically with no need of adjuvant therapy, surgery alone can lead to excellent outcome.

Introduction: A marker predictive of hematoma expansion in the central nervous system could aid the selection of patients for hemostatic or surgical treatment., Case Report: Here, we present a 83-year-old patient with acute spinal subdural hematoma with paraparesis progressing to paraplegia. A contrast extravasation within the intraspinal hematoma was visualized on spinal MR indicating active bleeding (spinal spot sign). A second acquisition of contrast-enhanced MR images showed progression of contrast extravasation helping to different active bleeding from spinal arteriovenous malformations/fistula., Conclusions: A "spinal spot sign" may be important for treatment decisions, notably in patients with incomplete neurological deficits at the time of imaging.

Hyperargininemia is caused by deficiency of arginase 1, which catalyzes the hydrolysis of L-arginine to urea as the final enzyme in the urea cycle. In contrast to other urea cycle defects, arginase 1 deficiency usually does not cause catastrophic neonatal hyperammonemia but rather presents with progressive neurological symptoms including seizures and spastic paraplegia in the first years of life and hepatic pathology, such as neonatal cholestasis, acute liver failure, or liver fibrosis. Some patients have developed hepatocellular carcinoma. A usually mild or moderate hyperammonemia may occur at any age. The pathogenesis of arginase I deficiency is yet not fully understood. However, the accumulation of L-arginine and the resulting abnormalities in the metabolism of guanidine compounds and nitric oxide have been proposed to play a major pathophysiological role. This article provides an update on the first patients ever described, gives an overview of the distinct clinical characteristics, biochemical as well as genetical background and discusses treatment options.

Hereditary spastic paraplegias (HSP) are rare neurodegenerative diseases sharing the degeneration of the corticospinal tracts as the main pathological characteristic. They are considered one of the most heterogeneous neurological disorders. All modes of inheritance have been described for the 84 different loci and 67 known causative genes implicated up to now. Recent advances in molecular genetics have revealed clinico-genetic heterogeneity of these disorders including their clinical and genetic overlap with other diseases of the nervous system. The systematic analysis of a large set of genes, including exome sequencing, is unmasking unusual phenotypes or inheritance modes associated with mutations in HSP genes and related genes involved in various neurological diseases. A new nosology may emerge after integration and understanding of these new data to replace the current classification. Collectively, functions of the known genes implicate the disturbance of intracellular membrane dynamics and trafficking as the consequence of alterations of cytoskeletal dynamics, lipid metabolism and organelle structures, which represent in fact a relatively small number of cellular processes that could help to find common curative approaches, which are still lacking.

A 73-year-old woman (height : 155 cm, weight : 55 kg) was scheduled to undergo a laparotomic hepatectomy and radiofrequency ablation for hepatocellular carcinoma. Her medical history did not include any relevant conditions such as cardiovascular or neurological disorders. A thoracic epidural catheter was introduced at T8-9 before the induction of anesthesia with intravenous propofol. General anesthesia was maintained with the inhalation of oxygen, air, and desflurane, and the continuous infusion of remifentanil. Several intraoperative episodes of mild hypotension occurred, each of which was successfully treated with intravenous ephedrine, but otherwise her anesthetic course was uneventful, and she recovered from the anesthesia smoothly. Her postoperative pain was well controlled with continuous epidural infusion of levobupivacaine and fentanyl, and she could walk by herself on postoperative day (POD) 1. However, she suffered weakness in her lower extremities on POD2 and subsequently fell into complete paraplegia with sensory loss below the T4 level on POD3. A magnetic resonance imaging scan taken on POD4 showed an idiopathic spinal cord infarction (SCI) involving levels T1 through T4, although no epidural abnormalities, e.g., hematomas, were detected. Immediate treatment with methylprednisolone, ozagrel, and edaravone failed to resolve her symptoms. We suggest that it is of great importance to consider SCI as a differential diagnosis as soon as possible in cases of unanticipated postoperative paraplegia.

Objectives: Prevention of the development of paraplegia during the repair of the damage caused by descending thoracic and thoracoabdominal aneurysms remains an important issue. Therefore, we investigated the protective effect of atorvastatin on ischemia-induced spinal cord injury in a rabbit model., Method: Thirty-two rabbits were divided into the following four equally sized groups: group I (control), group II (ischemia-reperfusion), group III (atorvastatin treatment) and group IV (atorvastatin withdrawal). Spinal cord ischemia was induced by clamping the aorta both below the left renal artery and above the iliac bifurcation. Seventy-two hours postoperatively, the motor function of the lower limbs of each animal was evaluated according to the Tarlov score. Spinal cord and blood samples were obtained for histopathological and biochemical analyses., Results: All of the rabbits in group II exhibited severe neurological deficits. Atorvastatin treatment (groups III and IV) significantly reduced the level of motor dysfunction. No significant differences were observed between the motor function scores of groups III and IV at the evaluated time points. Light microscopic examination of spinal cord tissue samples obtained at the 72nd hour of reperfusion indicated greater tissue preservation in groups III and IV than in group II., Conclusion: This study demonstrates the considerable neuroprotective effect of atorvastatin on the neurological, biochemical and histopathological status of rabbits with ischemia-induced spinal cord injury. Moreover, the acute withdrawal of atorvastatin therapy following the induction of spinal cord ischemia did not increase the neuronal damage in this rabbit model.