Whole-exome sequencing confirms implication of VPS13D as a potential cause of progressive spastic ataxia.

BACKGROUND: VPS13D is a large ubiquitin-binding protein playing an essential role in mitophagy by regulating mitochondrial fission. Recently, VPS13D biallelic pathogenic variants have been reported in patients displaying variable neurological phenotypes, with an autosomic recessive inheritance. The objectives of the study were to determine the genetic etiology of a patient with early onset sporadic progressive spastic ataxia, and to investigate the pathogenicity of VPS13D variants through functional studies on patient's skin fibroblasts. CASE PRESENTATION: We report the case of a 51-year-old patient with spastic ataxia, with an acute onset of the disease at age 7. Walking difficulties slowly worsened over time, with the use of a wheelchair since age 26. We have used trio-based whole-exome sequencing (WES) to identify genes associated with spastic ataxia. The impact of the identified variants on mitochondrial function was assessed in patient's fibroblasts by imaging mitochondrial network and measuring level of individual OXPHOS complex subunits. Compound heterozygous variants were identified in VPS13D: c.946C > T, p.Arg316* and c.12416C > T, p.(Ala4139Val). Primary fibroblasts obtained from this patient revealed an altered mitochondrial morphology, and a decrease in levels of proteins from complex I, III and IV. CONCLUSIONS: Our findings confirmed implication of VPS13D in spastic ataxia and provided further support for mitochondrial defects in patient's skin fibroblasts with VPS13D variants. This report of long-term follow up showed a slowly progressive course of the spastic paraplegia with cerebellar features. Furthermore, the performed functional studies could be used as biomarker helping diagnosis of VPS13D-related neurological disorders when molecular results are uneasy to interpret.

Sacral Anterior Root Stimulation and Visceral Function Outcomes in Spinal Cord Injury-A Systematic Review of the Literature Over Four Decades.

OBJECTIVE: Sacral anterior root stimulation (SARS) was developed 40 years ago to restore urinary and bowel functions to individuals with spinal cord injury. Mostly used to restore lower urinary tract function, SARS implantation is coupled with sacral deafferentation to counteract the problems of chronic detrusor sphincter dyssynergia and detrusor overactivity. In this article, we systematically review 40 years of SARS implantation and assess the medical added value of this approach in accordance with the PRISMA guidelines. We identified 4 axes of investigation: 1) impact on visceral functions, 2) implantation safety and device reliability, 3) individuals' quality of life, and 4) additional information about the procedure. METHODS: A systematic review was performed. Three databases were consulted: PubMed, EBSCOhost, and Pascal. A total of 219 abstracts were screened and 38 articles were retained for analysis (1147 implantations). RESULTS: The SARS technique showed good clinical results (85.9% of individuals used their implant for micturition and 67.9% to ease bowel movements) and improved individual quality of life. Conversely, several sources of complications were reported after implantation (e.g., surgical complications and failure). CONCLUSIONS: Despite promising results, a decline in implantations was observed. This decline can be linked to the complication rate, as well as to the development of new therapeutics (e.g., botulinum toxin) and directions for research (spinal cord stimulation) that may have an impact on people. Nevertheless, the lack of alternatives in the short-term suggests that the SARS implant is still relevant for the restoration of visceral functions after spinal cord injury.

A new phenotype of choreic syndrome associating severe freezing of gait and chorea.

The early onset of gait akinesia should not rule out the diagnosis of hereditary chorea. It would be helpful to proceed to a whole-genome and long-read sequencing in order to track a new pathogenic variant including noncoding repeat expansion.

Coexistence of schwannomatosis and glioblastoma in two families.

Schwannomatosis is a rare affection predisposing to multiple peripheral neurologic tumors development. Approximatively, one third of patients with schwannomatosis are carriers of a germline mutation in LZTR1 (Leucin Zipper Transcription Regulator 1). Tumorigenesis in schwannomatosis responds to a somatic 5-hit/3-step mechanism resulting in a loss of function (LOF) of LZTR1 and the contiguous genes of locus 22q11.2q12.2. Effectively, LZTR1 is mapped on 22q11.2 and centromeric to SMARCB1 also implicated in the determinism of schwannomatosis and NF2, responsible for neurofibromatosis type 2. On a somatic point of view, LZTR1 mutations are known to drive with a significant frequency glioblastoma (GB) development. We report here two families in which segregate both multiple schwannomas and GB. In the first family, the proband received a diagnosis with of schwannomatosis after a surgery for a lumbar schwannoma at age 43, molecularly confirmed by identification of a germline heterozygous mutation in LZTR1. Her father, having unremarkable medical history deceased from an apparently isolated GB at age 59. In the second family, LZTR1-related schwannomatosis was diagnosed in the index case at age 70 after multiple schwannomas surgeries. Her elder sister had no neurological medical history before occurrence of a lethal GB at age 78. Molecular analysis of GB sample from both affected relatives showed the presence of the familial mutation. These observations hypothesize a potential link between schwannomatosis and the GB development.

Validation of a methodology for neuro-urological and lumbosacral stimulation studies in domestic pigs: a humanlike animal model.

OBJECTIVESpinal cord injuries (SCIs) result in loss of movement and sensory feedback, but also organ dysfunction. Nearly all patients with complete SCI lose bladder control and are prone to kidney failure if intermittent catheterization is not performed. Electrical stimulation of sacral spinal roots was initially considered to be a promising approach for restoring continence and micturition control, but many patients are discouraged by the need for surgical deafferentation as it could lead to a loss of sensory functions and reflexes. Nevertheless, recent research findings highlight the renewed interest in spinal cord stimulation (SCS). It is thought that synergic recruitment of spinal fibers could be achieved by stimulating the spinal neural networks involved in regulating physiological processes. Paradoxically, most of these recent studies focused on locomotor issues, while few addressed visceral dysfunction. This could at least partially be attributed to the lack of methodological tools. In this study, the authors aim to fill this gap by presenting a comprehensive method for investigating the potential of SCS to restore visceral functions in domestic pigs, a large-animal model considered to be a close approximation to humans.METHODSThis methodology was tested in 7 female pigs (Landrace pig breed, 45-60 kg, 4 months old) during acute experiments. A combination of morphine and propofol was used for anesthesia when transurethral catheterization and lumbosacral laminectomy (L4-S4) were performed. At the end of the operation, spinal root stimulation (L6-S5) and urodynamic recordings were performed to compare the evoked responses with those observed intraoperatively in humans.RESULTSNervous excitability was preserved despite long-term anesthesia (mean 8.43 ± 1.5 hours). Transurethral catheterization and conventional laminectomy were possible while motor responses (gluteus muscle monitoring) were unaffected throughout the procedure. Consistent detrusor (approximately 25 cm H2O) and sphincter responses were obtained, whereas spinal root stimulation elicited detrusor and external urethral sphincter co-contractions similar to those observed intraoperatively in humans.CONCLUSIONSPigs represent an ideal model for SCS studies aimed at visceral function investigation and restoration because of the close similarities between female domestic pigs and humans, both in terms of anatomical structure and experimental techniques implemented. This article provides methodological keys for conducting experiments with equipment routinely used in clinical practice.

Number of botulinum toxin injections needed to stop requests for treatment for chronic lateral epicondylar tendinopathy. A 1-year follow-up study.

BACKGROUND: Epicondylar tendinopathy ("tennis elbow") is a serious issue in manual labourers. Symptoms can persist over months or even more than 1 year, even when treated with trinitrine patches, acupuncture, sclerosis of neovessels, shock-wave therapy, autologous blood injections, platelet-rich plasma or hyaluronic acid. Botulinum toxin (BoNT-A) injections showed promising short-term results, but the long-term beneficial effects are not yet known. OBJECTIVE: We aimed to assess the long-term effect, side effects and recurrence rate after BoNT-A injections on chronic lateral epicondylar tendinopathy during 1 year. METHODS: This open study followed a 3-month randomized controlled trial. We included 50 patients followed at day 0 (V0), 90 (V1), 180-270 (V2) and 365 (V3). The main judgment criterion was the number of BoNT-A injections required to achieve pain relief with no further request for treatment by the patient. RESULTS: After one BoNT-A injection, 22/50 (44%) patients did not ask for further treatment during follow-up because of complete pain relief, and 20/50 (40%) asked for a second BoNT-A injection. For 20 patients with a second injection, 18 (90%) did not ask for further treatment during follow-up. Only 1 patient had a recurrence of pain after an initial pain relief of greater than 75%. Quality of life, and painful and maximal gripping force improved significantly at V1, V2 and V3 as compared with V0, and repercussions on daily and professional activities decreased significantly (P<0.05). CONCLUSIONS: One or 2 BoNT-A injections has favourable results for chronic epicondylar tendinopathy.

Functional Selectivity of Lumbosacral Stimulation: Methodological Approach and Pilot Study to Assess Visceral Function in Pigs.

Nearly all spinal cord injured (SCI) individuals lose bladder control and are prone to kidney complications if intermittent catheterization is not applied. Electrical stimulation of the sacral anterior roots with an implantable neuroprosthesis is one means to restore continence and control micturition. However, only a small percentage of the SCI population benefits from this solution because of its drawbacks, e.g., section of sacral posterior roots with loss of spared sensitivity. There has been renewed interest in spinal cord stimulation in recent years, but most studies have focused on locomotion and only few have reported the impact on visceral functions. Moreover, even though the lumbosacral spinal cord is the location of many pre-cabled neural networks (involved in locomotion, bladder, and bowel management), the functional selectivity of spinal stimulations has never been investigated in detail. Here, we present: 1) a methodology designed to study lumbosacral epispinal-intradural stimulation selectivity; 2) preliminary results assessing the impact of epispinal stimulation on bladder and bowel functions in two domestic pigs; and 3) a comparison of these visceral responses with abdominal and lower limb activities. Our experiments resulted in selective bladder and rectal responses, i.e., without hind paw responses, thus reaffirming the rehabilitation potential of spinal cord stimulation.

Impact of direct epispinal stimulation on bladder and bowel functions in pigs: A feasibility study.

AIMS: This study assesses the potential of epispinal (subdural) stimulation application in the treatment of urinary and bowel neurological disorders. Acute experiments were performed on a large animal model - the domestic pig - to develop a new methodology facilitating future results and technology transfers to human. METHODS: After rectal and bladder catheterization, four Landrace pigs (45-50 kg) underwent spinal cord surgery - that is, lumbosacral incision, laminectomy [L4-S4], dural opening and microsurgical arachnoid dissection. Three successive electrical stimulation sessions were carried out: 1) nerve roots stimulation, 2) epispinal stimulation with a matrix electrode, 3) epispinal stimulation with a small diameter needle electrode. Changes in rectal and bladder pressures were monitored throughout the various procedures to identify spinal areas inducing responses while evaluating the influence of electrode contacts size in the measured responses amplitudes. RESULTS: An interesting area was identified in the upper portion of the spinal myelomeres (ie, spinal cord segment delimited by two successive pairs of spinal roots) directly adjoining root with best pressures (either rectal or vesical). Significant responses (up to 40 cmH2 O) were also obtained with a needle electrode. Furthermore, bowel evacuation was triggered in one of the animals. Despite the use of smaller electrode contacts, no detrusor or rectum selective responses were observed in none of the sessions. CONCLUSION: This study showed, for the first time, that epispinal stimulation causes significant detrusor and rectal responses in pigs and allows considering further studies with the objective of treating urinary and rectal disorders in spinal cord injury patients.

An Intermediate Animal Model of Spinal Cord Stimulation.

Spinal cord injuries (SCI) result in the loss of movement and sensory feedback as well as organs dysfunctions. For example, nearly all SCI subjects loose their bladder control and are prone to kidney failure if they do not proceed to intermittent (self-) catheterization. Electrical stimulation of the sacral spinal roots with an implantable neuroprosthesis is a promising approach, with commercialized products, to restore continence and control micturition. However, many persons do not ask for this intervention since a surgical deafferentation is needed and the loss of sensory functions and reflexes become serious side effects of this procedure. Recent results renewed interest in spinal cord stimulation. Stimulation of existing pre-cabled neural networks involved in physiological processes regulation is suspected to enable synergic recruitment of spinal fibers. The development of direct spinal stimulation strategies aiming at bladder and bowel functions restoration would therefore appear as a credible alternative to existent solutions. However, a lack of suitable large animal model complicates these kinds of studies. In this article, we propose a new animal model of spinal stimulation -pig- and will briefly introduce results from one first acute experimental validation session.

Functional variability of sacral roots in bladder control.

OBJECT: Sacral roots are involved in sensory, autonomic, and motor innervation of the lower limbs and perineum. Theoretically, it can be assumed that the S-3 root level innervates the bladder; however, clinical practice shows that this distribution can vary. Few researchers have studied this variability. METHODS: The authors conducted a retrospective study involving 40 patients who underwent surgery requiring an electrophysiological exploration of the sacral roots. They performed stimulations for the monitoring of muscular (3 Hz, 1 V) and bladder responses under cystomanometry (30 Hz, 10 V). RESULTS: Although the S-3 roots were involved in bladder innervation in all cases, they were exclusively involved (i.e., the only nerve roots involved) in only 8 of 40 cases. In the remaining 32 cases, other sacral nerve roots were involved. The most common association was S-3+S-4 (12 cases), followed by S-2+S-3 (6 cases), S-2+S-3+S-4 (5 cases), and S-3+S-4+S-5 (2 cases). Stimulation of S-2 could sometimes induce bladder contraction (15 cases, 40%); however, the amplitude was often low. S-4 nerve roots were involved in 24 of 40 cases (60%) in the bladder motor function, whereas S-5 roots were only involved 7 times (17%). Occasionally, we noticed a horizontal asymmetry in the response, with a predominant response from the right side in 6 of 7 cases, always with a major S-3 response. CONCLUSIONS: This is the first study showing a significant horizontal and vertical variability in the functional distribution of sacral roots in bladder innervation. These results show the variability of cauda equina syndromes and their forensic implications. These data should help with the monitoring of sacral roots and the performance of several tasks during surgery, including neurostimulation and neuromodulation.

Safety and self-reported efficacy of botulinum toxin for adult spasticity in current clinical practice: a prospective observational study.

OBJECTIVE: To determine the safety and the self-reported efficacy of botulinum toxin injections for adult spasticity in current clinical practice. DESIGN: A prospective observational study. SUBJECTS: A total of 406 adult patients with focal spasticity received of 1136 series botulinum toxin injections at Bordeaux University Hospital from January 2007 to December 2009. METHODS: Adverse events following botulinum toxin injections were reported. Their severity and the therapeutic efficacy of botulinum toxin injections were estimated with a four-point self-reporting scale (0 to 3). Latency and duration of adverse events and subjective improvement were also noted. RESULTS: The data of 640 series of injections were analyzed. Forty-six (7.2%) adverse events were reported, of which 36 (78%) were local. There were 18 (39%) cases of local muscular weakness with an average duration of 30.0 (SD 38.2) days, and an average severity score of 1.0 (SD 0.97). Among systemic adverse events, there were 8 (17%) cases of excessive fatigue without global muscular weakness and 2 (4%) cases of transitory generalized muscular weakness. The average subjective improvement score was 1.89 (SD 0.97) and was higher for upper, than for lower, limbs (P=0.007). CONCLUSION: Self-reported adverse events following botulinum toxin injections in spasticity are rare, often benign and of short duration in current clinical practice. Botulinum toxin is considered effective by patients in treating spasticity of the upper and lower limbs.