Novel mutation of SPG4 gene in a Chinese family with hereditary spastic paraplegia:A case report

BACKGROUND Hereditary spastic paraplegia(HSP)is a group of neurogenetic diseases of the corticospinal tract,accompanied by distinct spasticity and weakness of the lower extremities.Mutations in the spastic paraplegia type 4(SPG4)gene,encoding the spastin protein,are the major cause of the disease.This study reported a Chinese family with HSP caused by a novel mutation of the SPG4 gene.CASE SUMMARY A 44-year-old male was admitted to our hospital for long-term right lower limb weakness,leg stiffness,and unstable walking.His symptoms gradually worsened,while no obvious muscle atrophy in the lower limbs was found.Neurological examinations revealed that the muscle strength of the lower limbs was normal,and knee reflex hyperreflexia and bilateral positive Babinski signs were detected.Members of his family also had the same symptoms.Using mutation analysis,a novel heterozygous duplication mutation,c.1053dupA,p.(Gln352Thrfs*15),was identified in the SPG4 gene in this family.CONCLUSION A Chinese family with HSP had a novel mutation of the SPG4 gene,which is autosomal dominant and inherited as pure HSP.The age of onset,sex distribution,and clinical manifestations of all existing living patients in this family were analyzed.The findings may extend the current knowledge on the existing mutations in the SPG4 gene.

A Case of Cerebrospinal Drainage for Paraplegia Complicated by Acute Aortic Dissection (Stanford B) Followed by TEVAR in the Subacute Phase

The patient is 50-year-old man. He was admitted to our hospital with a strong back pain and diagnosed as an acute type B aortic dissection. On the second day of hospitalization, he developed symptoms of paraplegia, and we considered TEVAR, but we were concerned that TEVAR intervention in the acute phase might worsen the dissection, so we first placed a cerebrospinal drainage (CSFD) device, which resulted in improvement of his symptoms. Thereafter, although his lower limb mobility was fine, he underwent thoracic stent graft aortic repair (TEVAR) in the subacute phase due to worsening ULP. The patient had a good postoperative course and was discharged home unassisted. The initial placement of CSFD was effective in reducing the incidence of paraplegia as a complication of TEVAR and in bringing the timing of TEVAR intervention from the acute phase to the subacute phase.

Rescue axonal defects by targeting mitochondrial dynamics in hereditary spastic paraplegias

Impaired axonal development and degeneration underlie debilitating neurodegenerative diseases including hereditary spastic paraplegia, a large group of inherited diseases. Hereditary spastic paraplegia is caused by retrograde degeneration of the long corticospinal tract axons, leading to progressive spasticity and weakness of leg and hip muscles. There are over 70 subtypes with various underlying pathophysiological processes, such as defective vesicular trafficking, lipid metabolism, organelle shaping, axonal transport, and mitochondrial dysfunction. Although hereditary spastic paraplegia consists of various subtypes with different pathological characteristics, defects in mitochondrial morphology and function emerge as one of the common cellular themes in hereditary spastic paraplegia. Mitochondrial morphology and function are remodeled by mitochondrial dynamics regulated by several key fission and fusion mediators. However, the role of mitochondrial dynamics in axonal defects of hereditary spastic paraplegia remains largely unknown. Recently, studies reported perturbed mitochondrial morphology in hereditary spastic paraplegia neurons. Moreover, downregulation of mitochondrial fission regulator dynamin-related protein 1, both pharmacologically and genetically, could rescue axonal outgrowth defects in hereditary spastic paraplegia neurons, providing a potential therapeutic target for treating these hereditary spastic paraplegia. This mini-review will describe the regulation of mitochondrial fission/fusion, the link between mitochondrial dynamics and axonal defects, and the recent progress on the role of mitochondrial dynamics in axonal defects of hereditary spastic paraplegia.

Proteolipid protein 1 gene sequencing of hereditary spastic paraplegia

PCR amplification and sequencing of whole blood DNA from an individual with hereditary spastic paraplegia, as well as family members, revealed a fragment of proteolipid protein 1 （PLP1） gene exon 1, which excluded the possibility of isomer 1 expression for this family. The fragment sequence of exon 3 and exon 5 was consistent with the proteolipid protein 1 sequence at NCBI. In the proband samples, a PLP1 point mutation in exon 4 was detected at the basic group of position 844, T→C, phenylalanine→leucine. In proband samples from a male cousin, the basic group at position 844 was C, but gene sequencing signals revealed mixed signals of T and C, indicating possible mutation at this locus. Results demonstrated that changes in PLP1 exon 4 amino acids were associated with onset of hereditary spastic paraplegia.

A Patient with Malignant Spinal Epidural Lymphoma with Initial Rapidly Aggravating Paraplegia

We report the case of a 51-year-old female with rapid neurological deterioration as an initial presentation of non-Hodgkin’s lymphoma. Paraplegia occurred suddenly after a 4-day history of weakness and numbness of the lower extremity. MRI revealed a dorsal epidural mass from T10 to T11 that compressed the spinal cord. There was neither bone destruction nor a paravertebral mass. Emergency decompressive laminectomy and tumor resection were performed. Histological analysis of the surgical specimen indicated diffuse large B cell lymphoma. The clinical stage was IV on CT and complete remission was achieved by subsequent chemotherapy. Spinal cord compression occurs in the course of non-Hodgkin’s lymphoma in 0.1% - 6.5% of cases, but this situation usually develops in the late phase with bone destruction and/or a paravertebral mass. Cord compression and especially the severe symptoms such as paraplegia are rare as the initial presentation of lymphoma.

THE EFFECT OF ACUPUNCTURE ON URINARY BLADDER DYSFUNCTION OF PATIENTS WITH TRAUMATIC PARAPLEGIA

62 patients with traumatic paraplegia were treated with acupuncture(GovernorVessel electro-stimulation),according to the theories of TCM such as dredging the meridians,regu-lating vital energy and blood,improving blood circulation,reinforcing marrow and replenishing brain.The effect of acupuncture on urinary bladder disturbance was studied.The results indicated that totaleffect rate was 96.8%(Ⅰ—Ⅲ),marked effect rate was 66.1%(Ⅰ—Ⅱ).The marked effect rate incomplete paraplegia was significantly different from that in imcomplete paraplegia;it was 63.0% and87.5% respectively.Furthermore,the results suggested that the degree of spinal cord injury was veryimprotant factor that affected the effect of acupuncture therapy.

Novel ATL1 mutation in a Chinese family with hereditary spastic paraplegia: A case report and review of literature

BACKGROUND Hereditary spastic paraplegias (HSPs) refer to a group of heterogeneous neurodegenerative diseases characterized by lower limbs spasticity and weakness. So far, over 72 genes have been found to cause HSP (SPG1-SPG72). Among autosomal dominant HSP patients, spastic paraplegia 4 (SPG4/SPAST) gene is the most common pathogenic gene, and atlastin-1 (ATL1) is the second most common one. Here we reported a novel ATL1 mutation in a Chinese spastic paraplegia 3A (SPG3A) family, which expands the clinical and genetic spectrum of ATL1 mutations. CASE SUMMARY A 9-year-old boy with progressive spastic paraplegia accompanied by right hearing loss and mental retardation for five years was admitted to our hospital.Past history was unremarkable. The family history was positive, and his grandfather and mother had similar symptoms. Neurological examinations revealed hypermyotonia in his lower limbs, hyperreflexia in knee reflex, bilateral positive Babinski signs and scissors gait. The results of blood routine test, liver function test, blood glucose test, ceruloplasmin test and vitamin test were all normal. The serum lactic acid level was significantly increased. The testing for brainstem auditory evoked potential demonstrated that the right side hearing was impaired while the left was normal. Magnetic resonance imaging showed mild atrophy of the spinal cord. The gene panel test revealed that the proband carried an ATL1 c.752A>G p.Gln251Arg (p.Q251R) mutation, and Sanger sequencing confirmed the existence of family co-segregation. CONCLUSION We reported a novel ATL1 Q251R mutation and a novel clinical phenotype of hearing loss in a Chinese SPG3A family.

Apoptosis of motor neurons in the spinal cord after ischemia reperfusion injury delayed paraplegia in rabbits

Objective To clarify the pathologic change of the motor neuron on spinal cord ischemia reperfusion injury delayed paraplegia.Methods The infrarenal aorta of White New Zealand rabbits(n=24) was occluded for 26 minutes using two bulldog clamps.Rabbits were killed after 8,24,72,or 168 hours(n=6 per group),respectively.The clamps was placed but never clamped in sham-operated rabbits(n=24).The lumbar segment of the spinal cord(L5 to L7) was used for morphological studies,including hematoxylin and eosin staining,the expression of bcl-2 and bax proteins in spinal cord was detected with immunohistochemistry.The apoptotic neurons in spinal cord were measured with terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end-labeling of DNA fragments(TUNEL) staining.Results Delayed paraplegia occurred in all rabbits of ischemia reperfusion group at 16-24 hours,but not in sham groups.Motor neurons were selectively lost at 7 days after transient ischemia.After ischemia,the positive expression of bcl-2 protein were in the sham controls but decreased significantly as compared with that of the IR group(P<0.01),especially in 72 hours reperfusion.The positive expression of bax protein were also in the sham controls, but increased in the IR group,especially in 72 hours reperfusion;In addition, TUNEL study demonstrated that no cells were positively labeled until 24 hours after ischemia,but nuclei of some motor neurons were positively labeled at peak after ischemia reperfusion at 72 hours.Conclusion Spinal cord ischemia in rabbits induces morphological and biochemical changes suggestive of apoptosis.These data raise the possibility that apoptosis contributes to neuronal cell death after spinal cord ischemia reperfusion.

Clinical presentation of gastric Burkitt lymphoma presenting with paraplegia and acute pancreatitis:A case report

BACKGROUND The incidence of gastric Burkitt lymphoma(BL),presenting as paraplegia and acute pancreatitis,is extremely low.BL is a great masquerader that presents in varied forms and in atypical locations,and it is prone to misdiagnosis and missed diagnosis.The prognosis of BL remains poor because of the difficulty in early diagnosis and the limited advances in chemotherapy.CASE SUMMARY A 53-year-old man was referred to our hospital from the local county hospital due to abdominal pain for two weeks and weakness in the lower extremities for one day.Magnetic resonance imaging of the abdomen and lumbar spine showed a swollen pancreas and gallbladder,with peripancreatic exudation and liquid collection,indicating acute pancreatitis and acute cholecystitis.Additionally,we observed abnormally thickened lesions of the gastric wall,multiple enlarged retroperitoneal lymph nodes and a well-demarcated,posterolateral extradural mass lesion between T9 and T12,with extension through the spinal foramen and definite bony destruction,suggesting metastasis in gastric malignancy.Subsequent whole-body positron emission tomography/computed tomography examination showed multifocal malignant lesions in the stomach,pancreas,gallbladder,bone,bilateral supraclavicular fossa,anterior mediastinum,bilateral axillary and retroperitoneal lymph nodes.Gastroduodenal endoscopy revealed primary BL with massive involvement of the gastric body and duodenum.The patient refused chemotherapeutic treatment and died one week later due to upper gastrointestinal hemorrhage.Afterward,we reviewed the characteristics of 11 patients with BL involving the stomach,pancreas or spinal cord.CONCLUSION Clinicians should be aware that BL can be the potential cause of acute pancreatitis or a rapidly progressive spinal tumor with accompanying paraplegia.For gastric BL,gastroscopy biopsies and pathology are necessary for a definite diagnosis.

Paraplegia from spinal intramedullary tuberculosis:A case report

BACKGROUND Tuberculosis (TB) mostly attacks the lungs, and extrapulmonary TB involving thecentral nervous system is uncommon;among these cases, spinal intramedullaryTB is even more rare. The clinical manifestations of spinal intramedullary TB aresimilar to those of intramedullary spinal cord tumors. Therefore, it is necessary tomake a careful differential diagnosis of spinal intramedullary lesions to achievethe appropriate treatment and favorable prognosis. We report a rare case of ayoung male patient with paraplegia due to spinal intramedullary TB, which isuncommon and regrettable.CASE SUMMARY A 23-year-old male presented with fever accompanied by nausea and vomitinglasting for 2 mo and was then diagnosed with tubercular meningitis. After anti-TBtreatment, his symptoms were significantly improved. However, 2 mo after thediagnosis of tubercular meningitis, the patient felt numbness below the costal archlevel, which lasted for 1 wk, and he paid no attention to this symptom. Whatfollowed was paraplegia and urine/fecal incontinence. Magnetic resonanceimaging of the thoracic spine showed a ring-enhanced intramedullary cord lesionat T8-T9. Lesion exploration showed enlargement of the spinal cord at T8-T9, andthe lesion could be observed by incision. The lesion was adhered to the peripheraltissue and was grayish-white and tough with a poor blood supply and a diameterof approximately 0.8 cm. The lesion was resected completely. The results ofpathological examination by both hematoxylin-eosin staining and acid-fast bacillistaining confirmed TB, accompanied by acute and chronic suppurativeinflammation and granulation tissue formation. The patient was instructed tocontinue anti-TB treatment after the operation, but he did not follow the medicaladvice. Follow-up continued for ten years, the patient had persistent paraplegia,the numbness disappeared and urine/fecal sensation recovered.CONCLUSION Although TB is a kind of benign disease, some cases progress rapidly. Moreover,spinal intramedullary TB may seriously endanger quality of life and still needstimely diagnosis and proper treatment.

Chinese Herbal Medicine and Acupuncture Used for Rehabilitation of the Impaired Urinary System in Patients with Paraplegia—A Report of 52 Cases

Infection of the urinary system is frequently seen in the paraplegic patients with urinary complications,which is one of the main reasons for the late death in such cases. The effects of the therapeutic method adopted for the urinary rehabilitation are directly related to the life quality and survival time of the paraplegic patients. Since 1999-2002, the authors had applied Chinese herbal medicine combined with acupuncture for the urinary rehabilitation in 52 paraplegic patients, with quite good therapeuticresults as reported in the following.

ACUPUNCTURE TREATMENT OF COMPLETE TRAUMATIC PARAPLEGIA——Analysis of 261 Cases

Traumatic paraplegia is commonly seenin cases with the spinal cord injured. Basedon the significant therapeutic effectivenessobtained from our acupuncture treatment offacial paralysis. monoplegia. hemiplegia andmultiple neuritis, we started to treattraumatic paraplegia with acupuncture in1963. From 1976 to 1993, 428 patients

Unexpected Postoperative Paraplegia after Thoracotomy in Lung Cancer: Incidental Migration of Oxidized Regenerated Cellulose Used for Hemostasis of Intercostal Space Bleeding

Background: We experienced a very rare complication, that is, an unexpected postoperative paraplegia due to the incidental migration of oxidized regenerated cellulose used for hemostasis of intercostal space bleeding. Patients and Methods: The objective is to analyze the cause and to take measures against the very rare complication from an empirical analysis and the literature. For a 78-year-old male with suspected lung cancer in the right upper lobe (S1), a thoracotomy was performed. For hemostasis of the bleeding from the 5th intercostal thoracotomy space, we used and placed oxidized regenerated cellulose at the continuous oozing bleeding sites. On the 3rd postoperative day, paralysis beneath thoracic vertebrae level 6 was observed. Immediate computed-tomographic (CT) scanning and magnetic resonance imaging (MRI) displayed a 17 × 9 × 14 mm epidural hematoma in the spinal canal at level 5 of the thoracic vertebrae. An emergent laminectomy for the thoracic vertebra was performed to remove the oxidative cellulose and haematoma, and the compression was released. The paraplegia gradually began to recover and maintain a standing position. After 1 year from the event, the patient can walk by himself with a crutch. Results: The causes were that the oxidative cellulose materials were used for the intercostal bleeding at the open thoracotomy. The migration of the oxidative cellulose materials into the epidural space and into thoracic spinal canal through the intervertebral foramen, or gradual penetration of the oxidative cellulose materials into the spinal canal due to respiratory costal movement. As a measurement of prevention, the hemostat materials should be completely removed after finishing of the hemostasis. In the case of a difficult hemostasis, consultation of an orthopedist or neurosurgeon to perform the appropriate hemostasis in good cooperation is required. Conclusion: If postoperative paraplegia is suspected, immediate CT scanning and/or MRI examination would become powerful diagnostic procedures as soon as possible to start an interventional treatment.

Paraplegia by Acute Cervical Disc Herniation after Shoulder Arthroscopic Surgery in Beach-Chair Position

Paraplegia after non-cervical spine surgery under general anesthesia is a rare devastating postoperative complication [1]. A patient with shoulder pain was scheduled for shoulder arthroscopy due to rotator cuff repair. Arthroscopic shoulder surgery was performed with the patient in the beach-chair. Postoperatively, patients complained the weakness of both lower leg and marked numbness and tingling in the both arms. MRI showed a herniated intervertebral disc between C6 and C7 with spinal cord compression. Despite urgent discectomy, the patient remained dysesthesia of both upper extremities for 6 months. The purpose of this report is to introduce our case with a paraplegia observed after arthroscopic shoulder surgery in beach-chair position because of acute cervical herniation.

The prevalence of cognitive dysfunction in the estonian population of the hereditary spastic paraplegia

The hereditary spastic paraplegias (HSPs) are neu-rodegenerative disorders of the motor system. The information about the prevalence of the cognitive dysfunction in HSP is inconsistent. The aim of the study was to describe the prevalence of cognitive dysfunction and the cognitive profiles of persons with HSP (pwHSP) compared to healthy controls. Subjects. Participating in the cognition study were 48 persons with HSP from the epidemiological study and 48 healthy controls. Of those with HSP, 81% (39/48) had pure and 19% (9/48) had complex forms. Among pwHSP, 20.8% (10/48) had pathogenic and 14.6% (7/48) had non-pathogenic mutations in the SPAST gene. There were no mutations detected in 31 persons with the SPAST gene. Methods. Neuropsychological test battery, MMSE Results. The results of the neuropsychological tests were significantly lower in persons with HSP than in the controls (Bonferroni correction, p < 0.00625). There were statistically significant differences in subtests measuring consistent long term retrieval (p < 0.001), later recall (p = 0.004) in verbal memory and symbol digit modalities (p = 0.0015). Five persons with HSP had an MMSE score of 24 or less. Conclusions. Our results demonstrate that cognitive dysfunction is present in 16.7 to 33.3% of persons with HSP, depending on the criteria applied. There was cognitive dysfunction in 30% of persons with a known pathogenic mutation in the SPAST gene. The most frequently damaged functions in HSP are consistent long term retrieval and later recall in verbal memory and symbol digit modalities tests that discriminate between controls and pwHSP with dysfunction (1.5 SD) in three or more domains. Dementia in HSP is rare.

Acute Paraplegia Due to <i>Salmonella brandenburg</i>Spondylodiscitis: Case Report

The authors present the case of a 48-year-old man admitted for acute onset of paraplegia in a patient suffering from backaches for 1 week. The rapidly progressive motor disturbances had been evolving for approximately 12 hours. The entire spinal MRI showed an epidural mass at T4-T6 associated with extensive lesions of spondylodiscitis and a T7-T8 vertebral body loss of height. A large six-level laminectomy was performed. A tumoral etiology couldn’t be entirely excluded intraoperatively so that no fusion has been done at that time. The pathological exam revealed acute inflammatory lesions with no argument in favor of a tumoral process. Bacteriological exam of the pathological specimen and stools cultures were positive for Salmonella brandenburg. An episode of gastroenteritis after the ingestion of a pizza has been evoked. The antibiotic medication was prescribed for 12 weeks. Postoperative evolution was favorable with a possible march between bars 6 weeks after. The authors emphasize the pseudo-tumoral presentation in an immunocompetent patient, the lack of complications and the post-ingestion mechanism.

Case report of tubercular spondylodiscitis with paraplegia managed by posterior transpedicular decompression and pedicle screw fixation

Pott’s paraplegia is still prevalent in this part of the world. Early onset paraplegia can be improved by timely surgical intervention under ATT cover. The disease mostly affects the thoraco-lumbar spine. Classically, the diseased area is addressed by anterior thoracic or thoraco-lumbar approach and after curettage of the diseased and necrotic material the anterior column is reconstructed by rib or fibular strut graft or metallic cage and supplemented by posterior instrumentation and fusion. Laminectomy, as a method of decompression, was greatly discouraged in spinal tuberculosis with compressive myelopathy except in posterior element involvement. We present a case of a 35 years old lady with Pott’s paraplegia treated by hemilaminectomy and transpedicular limited anterior decompression of the cord and pedicle screw fixation with fusion who improved vastly in terms of motor power.

Verification of the Validity of the NPT Treatment in Hereditary Spastic Paraplegia: An Investigation Performed by Application of Random Matrix Theory

We have applied the Random Matrix Theory in order to examine the validity of the NPT treatment in HSP. We have investigated the pathology examining the sEMG recorded signal for about eight minutes. We have performed standard electromyographic investigations as well as we have applied the RMT method of analysis. We have investigated the sEMG signals before and after the NPT treatment. The application of a so robust method as the RMT evidences that the NPT treatment was able to induce a net improvement of the disease respect to the pathological status before NPT.

Awake rabbit model of ischemic spinal cord injury with delayed paraplegia:The role of ambient temperature

Background:Paraplegia after spinal cord ischemia is a devastating condition in the clinic.Here,we develop an awake rabbit model of spinal cord ischemia with delayed paraplegia and explore the influence of ambient temperature on the outcomes after injury.Methods:A total of 47 male rabbits were involved in the present study.Transient spinal cord ischemia was induced by occluding the infrarenal abdominal aorta of awake rabbits at different ambient temperatures.To find the optimal conditions for developing delayed paraplegia,hindlimb motor function after ischemia was evaluated between experiments.Results:The onset and magnitude of ischemic injury varied with the ambient temperature maintained during the peri-i schemia period.More serious spinal cord injury occurred when ischemia was induced at higher temperatures.At 18°C,25-minute ischemia resulted in 74%of rabbits developing delayed paraplegia.At a temperature of 28°C or higher,most of the animals developed acute paraplegia immediately.While at 13°C,rabbits usually regained normal motor function without paraplegia.Conclusion:This awake rabbit model is highly reproducible and will be helpful in future studies of delayed paraplegia after spinal cord ischemia.The ambient temperature must be considered while using this model during investigation of therapeutic interventions.

Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.