Sacsin Deletion Induces Aggregation of Glial Intermediate Filaments

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder commonly diagnosed in infants and characterized by progressive cerebellar ataxia, spasticity, motor sensory neuropathy and axonal demyelination. ARSACS is caused by mutations in the SACS gene that lead to truncated or defective forms of the 520 kDa multidomain protein, sacsin. Sacsin function is exclusively studied on neuronal cells, where it regulates mitochondrial network organization and facilitates the normal polymerization of neuronal intermediate filaments (i.e., neurofilaments and vimentin). Here, we show that sacsin is also highly expressed in astrocytes, C6 rat glioma cells and N9 mouse microglia. Sacsin knockout in C6 cells (C6Sacs−/−) induced the accumulation of the glial intermediate filaments glial fibrillary acidic protein (GFAP), nestin and vimentin in the juxtanuclear area, and a concomitant depletion of mitochondria. C6Sacs−/− cells showed impaired responses to oxidative challenges (Rotenone) and inflammatory stimuli (Interleukin-6). GFAP aggregation is also associated with other neurodegenerative conditions diagnosed in infants, such as Alexander disease or Giant Axonal Neuropathy. Our results, and the similarities between these disorders, reinforce the possible connection between ARSACS and intermediate filament-associated diseases and point to a potential role of glia in ARSACS pathology.

Severe Generalized Weakness, Paraplegia following administration of Oxaliplatin in a patient with refractory T-cell non-Hodgkin lymphoma: A case report

Introduction Oxaliplatin is a third-generation platinum compound that used extensively for the treatment of various types of cancer especially gastrointestinal neoplasms. The main dose-limiting toxicities of oxaliplatin are hematological toxicity and peripheral sensory neuropathy. Case report A 42-year-old man with refractory peripheral T-cell lymphoma (PTCL) was admitted to receive GEMOX chemotherapy regimen (gemcitabine, oxaliplatin). Three days after receiving his third cycle of chemotherapy regimen, he was re-admitted to the emergency department with complaint of severe generalized weakness, and paraplegia in the lower extremities. According to clinical and para-clinical findings, chronic sensorimotor polyneuropathy with ongoing axonal loss was confirmed. Management & Outcome Intravenous dexamethasone 8 mg three times daily was started at the time of admission for the patient. Muscle weakness and sensory impairment improved dramatically within 10 days and the patient was able to walk with assistance. Discussion Several cases of neuropathy following oxaliplatin and only one case with gemcitabine-based chemotherapy regimen have been previously reported. However, motor symptoms are rare unless in the setting of acute neuropathy due to oxaliplatin. The most striking finding of our study was the incidence of a chronic sensorimotor axonaldemyelinating polyneuropathy in a patient who were subjected to oxaliplatin therapy. In conclusion, we report a case of severe generalized weakness and paraplegia following administration of Oxaliplatin.

Falciparum malaria associated acute kidney injury with polyneuropathy and intra-arterial thrombosis (stroke)

Background Malaria is still major problem in developing countries, such as Pakistan. Besides fever, body ache and vomiting it can present with acute kidney injury, proteinuria, hematuria and cerebral manifestations which are more common with falciparum malaria. Neurological manifestations are rare presentation of malaria and should be consider in patients who are admitting with features of neuropathy and stroke. Case presentation We describe an unusual case of falciparum malaria, complicated by acute kidney injury who developed Polyneuropathy and intra-arterial thrombosis in middle cerebral artery territory. Our patient recovered his renal functions during admission and recovered his power and sensation in his limbs as well after 1 month. Conclusion Malaria cause neurological manifestations including axonal and sensory neuropathy, cerebral venous and arterial thrombosis, PMNS, cerebellar signs and symptoms, psychosis, etc. With prompt diagnosis and early treatment they can be cure and regain their motor and sensory functions to normal level.

Edukasi Penggunaan Monofilament dalam Deteksi Dini Neuropati Sensori Diabetes Mellitus Tipe 2 Pada Kader di Tengah Pandemi Covid-19 Kelurahan Kolo Kota Bima

ABSTRAKNeuropati atau sering disebut sebagai gangguan sensasi merupakan salah satu komplikasi yang sering ditemukan pada pasien diabetes Mellitus tipe 2. Kejadian neuropati sering tidak disadari oleh pasien sehingga mengakibatkan munculnya Diabetic Foot Ulcer. Deteksi dini neuropati diabetic sangat penting pada pasien dengan DM karena pencegahan bisa menurunkan morbiditas dan mortalitas.. Metode yang dilakukan meliputi tahap persiapan, tahap pelaksanaan, monitoring dan evaluasi. strategi pelaksanaan dengan melakukan pre test sebelum kegiatan dilaksanakan, kemudian membagikan modul dan video penggunaan alat pengecekan gula darahdan penggunaan monofilament test, setelah itu di evaluasi dengan post test. Hasil yang didapatkan 90% kader yang hadir mememahami dan bisa mempraktekan cara pengecekan gula darah secara mandiri dan menggunkan monofilament tes. Sedangkan kegaiatan dengan 50 penyandang diabetes 40% mengalami gangguan neuropati sensori, maka dapat disimpulakan adanya peningkatan pengetahuan dan keterampilan para kader tentang deteksi dini neuropati pada pasien diabetes mellitus tipe 2 yang meliputi, pengertian DM, tanda dan gejala, penatalaksanaan, komplikasi, tanda gangguan neuropati dan cara mendeteksinya, ditandai dengan kemampuan kader dan penyandang diabetes mampu menjawab dan mempraktikan pertanyaan dari pengabdi. Kata Kunci: Edukasi, Pelatihan, Monofilament tes, Neuropati. ABSTRACT Neuropathy or often referred to as impaired sensation is one of the complications that are often found in patients with type 2 diabetes mellitus. Early detection of diabetic neuropathy is very important in patients with DM because prevention can reduce morbidity and mortality. The methods used include the preparation stage, implementation stage, monitoring and evaluation. the implementation strategy was to do a pre test before the activity was carried out, then distribute modules and videos on the use of blood sugar checking tools and the use of monofilament tests, after which they were evaluated with a post test. The results obtained were 90% of the cadres who attended understood and could practice how to independently check blood sugar and use the monofilament test. While activities with 50 people with diabetes 40% experiencing sensory neuropathy disorders, it can be concluded that there is an increase in knowledge and skills of cadres about early detection of neuropathy in patients with type 2 diabetes mellitus which includes understanding of DM, signs and symptoms, management, complications, signs of neuropathic disorders. and how to detect it, is marked by the ability of cadres and people with diabetes to be able to answer and practice questions from the servants. Keywords: Education, Training, Monofilament test, Neuropathy

CASE REPORT OF ADULT-ONSET CHARCOT MARIE TOOTH TYPE X

Charcot-Marie-Tooth (CMT) or Hereditary Motor and Sensory Neuropathy (HMSN) is the most common hereditary peripheral nerve disease with progressive chronic weakness, muscle atrophy, and sensory disturbances. There are several types and subtypes of CMT with their respective clinical manifestations. In this article, we reported a patient with of CMT type X. A 43-year-old male patient was referred to a neurology clinic with weakness in both limbs for 2 years, accompanied by tingling and sensory disturbance in both hands and feet. There are several of his family members who had similar complaints. Lumbosacral magnetic resonance imaging (MRI) examination revealed mild nucleus pulposus herniation. Electroneuromyography (ENMG) examination revealed demyelinating sensory motor polyneuropathy. Histopathological examination of nerve biopsy showed demyelination of the sural nerve. It is hard to make a diagnosis of CMT, because it requires high suspicion from clinicians once encounter a suspected case and also need to supported by sophisticated equipment such as electrophysiological examinations, nerve biopsy examinations, and genetic examinations. It is vital for clinicians for being able to diagnose CMT correctly and provide treatment as soon as possible in order to maintain the patients’ quality of life.

Investigation of a Novel NTRK1 Variation Causing Congenital Insensitivity to Pain With Anhidrosis

Background: Congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive sensory neuropathy, was caused mainly by biallelic mutations in the NTRK1 gene. The pathogenesis of CIPA still needs further elucidation.Methods: Here, we recruited a CIPA case and introduced whole-exome sequencing (WES) to identify the causative variation. Subsequently, an in silico molecular dynamic (MD) analysis was performed to explore the intramolecular impact of the novel missense variant. Meanwhile, in vitro functional study on the novel variant from a metabolomic perspective was conducted via the liquid chromatography–mass spectrometry (LC-MS) approach, of which the result was verified by quantitative real-time PCR (qRT-PCR).Results: A novel compound heterozygous variation in NTRK1 gene was detected, consisting of the c.851–33T > A and c.2242C > T (p.Arg748Trp) variants. MD result suggested that p.Arg748Trp could affect the intramolecular structure stability. The results of the LC-MS and metabolic pathway clustering indicated that the NTRK1Arg748Trp variant would significantly affect the purine metabolism in vitro. Further analysis showed that it induced the elevation of NT5C2 mRNA level.Conclusion: The findings in this study extended the variation spectrum of NTRK1, provided evidence for counseling to the affected family, and offered potential clues and biomarkers to the pathogenesis of CIPA.

Ipatasertib plus paclitaxel for PIK3CA/AKT1/PTEN-altered hormone receptor-positive HER2-negative advanced breast cancer: primary results from cohort B of the IPATunity130 randomized phase 3 trial

Purpose PI3K/AKT pathway alterations are frequent in hormone receptor-positive (HR+) breast cancers. IPATunity130 Cohort B investigated ipatasertib–paclitaxel in PI3K pathway-mutant HR+ unresectable locally advanced/metastatic breast cancer (aBC). Methods Cohort B of the randomized, double-blind, placebo-controlled, phase 3 IPATunity130 trial enrolled patients with HR+ HER2-negative PIK3CA/AKT1/PTEN-altered measurable aBC who were considered inappropriate for endocrine-based therapy (demonstrated insensitivity to endocrine therapy or visceral crisis) and were candidates for taxane monotherapy. Patients with prior chemotherapy for aBC or relapse < 1 year since (neo)adjuvant chemotherapy were ineligible. Patients were randomized 2:1 to ipatasertib (400 mg, days 1–21) or placebo, plus paclitaxel (80 mg/m2, days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). Results Overall, 146 patients were randomized to ipatasertib–paclitaxel and 76 to placebo–paclitaxel. In both arms, median investigator-assessed PFS was 9.3 months (hazard ratio, 1.00, 95% CI 0.71–1.40) and the objective response rate was 47%. Median paclitaxel duration was 6.9 versus 8.8 months in the ipatasertib–paclitaxel versus placebo–paclitaxel arms, respectively; median ipatasertib/placebo duration was 8.0 versus 9.1 months, respectively. The most common grade ≥ 3 adverse events were diarrhea (12% with ipatasertib–paclitaxel vs 1% with placebo–paclitaxel), neutrophil count decreased (9% vs 7%), neutropenia (8% vs 9%), peripheral neuropathy (7% vs 3%), peripheral sensory neuropathy (3% vs 5%) and hypertension (1% vs 5%). Conclusion Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered HR+ HER2-negative aBC. The ipatasertib–paclitaxel safety profile was consistent with each agent’s known adverse effects. Trial registration NCT03337724.