Cytochemical Characterization of Cerebrospinal Fluid Macrophage Inclusions in Pediatric Patients Receiving Intrathecal Nusinersen (SPINRAZA®) for Spinal Muscular Atrophy

2021 ◽  
pp. 1-6
Author(s):  
Kristian T. Schafernak ◽  
Jeffrey R. Jacobsen ◽  
Dulce Hernandez ◽  
Robin D. Kaye ◽  
Sylvia E. Perez
Keyword(s):  
Cerebrospinal Fluid ◽  
Spinal Muscular Atrophy ◽  
Pediatric Patients ◽  
Muscular Atrophy ◽  
Exon Skipping ◽  
Neuromuscular Disorder ◽  
Case Presentation ◽  
Smn Protein

<b><i>Introduction:</i></b> Spinal muscular atrophy (SMA) is a debilitating neuromuscular disorder caused by biallelic deletion of the <i>SMN1</i> gene. Nusinersen, an antisense oligonucleotide delivered intrathecally, binds to the pre-mRNA of <i>SMN1</i>’s pseudogene, <i>SMN2</i>, to prevent exon skipping and produce functional SMN protein to compensate for the deficiency caused by <i>SMN1</i> deletion. <b><i>Case Presentation:</i></b> We reviewed 15 cerebrospinal fluid (CSF) cytology specimens from 8 patients receiving nusinersen for SMA. Macrophages with peculiar inclusions (“nusinophages”) were seen in 8 specimens from 4 of the patients: 1 infant and 3 children with SMA type 1. This finding has only previously been reported in adults with SMA types 2 and 3 and in 2 infants with SMA type 1. <b><i>Discussion/Conclusion:</i></b> Specimens containing nusinophages had a significantly higher proportion of macrophages and lower proportion of lymphocytes than those in which nusinophages were not detected. The macrophage inclusions do not represent iron or microorganisms and instead are composed, at least in part, of glycosaminoglycans. Because CSF is a common specimen type, cytotechnologists and cytopathologists need to be aware of these inclusions, so they do not interpret them erroneously as evidence of infection or hemorrhage, especially in light of the fact that oligonucleotide therapy has been approved for a variety of conditions and is currently under investigation for intrathecal delivery in several other neurodegenerative disorders.

scholarly journals Nusinersen Modulates Proteomics Profiles of Cerebrospinal Fluid in Spinal Muscular Atrophy Type 1 Patients

2021 ◽  
Vol 22 (9) ◽  
pp. 4329
Author(s):  
Laura Bianchi ◽  
Maria Sframeli ◽  
Lorenza Vantaggiato ◽  
Gian Luca Vita ◽  
Annamaria Ciranni ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Spinal Muscular Atrophy ◽  
Disease Progression ◽  
Muscular Atrophy ◽  
Protein Pattern ◽  
Neuromuscular Disorder ◽  
Survival Motor Neuron ◽  
Apolipoprotein A1 ◽  
Proteomic Approach

Spinal muscular atrophy (SMA) type 1 is a severe infantile autosomal-recessive neuromuscular disorder caused by a survival motor neuron 1 gene (SMN1) mutation and characterized by progressive muscle weakness. Without supportive care, SMA type 1 is rapidly fatal. The antisense oligonucleotide nusinersen has recently improved the natural course of this disease. Here, we investigated, with a functional proteomic approach, cerebrospinal fluid (CSF) protein profiles from SMA type 1 patients who underwent nusinersen administration to clarify the biochemical response to the treatment and to monitor disease progression based on therapy. Six months after starting treatment (12 mg/5 mL × four doses of loading regimen administered at days 0, 14, 28, and 63), we observed a generalized reversion trend of the CSF protein pattern from our patient cohort to that of control donors. Notably, a marked up-regulation of apolipoprotein A1 and apolipoprotein E and a consistent variation in transthyretin proteoform occurrence were detected. Since these multifunctional proteins are critically active in biomolecular processes aberrant in SMA, i.e., synaptogenesis and neurite growth, neuronal survival and plasticity, inflammation, and oxidative stress control, their nusinersen induced modulation may support SMN improved-expression effects. Hence, these lipoproteins and transthyretin could represent valuable biomarkers to assess patient responsiveness and disease progression.

scholarly journals Growth patterns in children with spinal muscular atrophy

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Ramona De Amicis ◽  
Giovanni Baranello ◽  
Andrea Foppiani ◽  
Alessandro Leone ◽  
Alberto Battezzati ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Neuromuscular Disorder ◽  
Severe Form ◽  
Growth Patterns ◽  
Standards Of Care ◽  
Growth Standards ◽  
Treatment Naïve

Abstract Background Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle atrophy and weakness. SMA type 1 (SMA1) is the most severe form: affected infants are unable to sit unaided; SMA type 2 (SMA2) children can sit, but are not able to walk independently. The Standards of Care has improved quality of life and the increasing availability of disease-modifying treatments is progressively changing the natural history; so, the clinical assessment of nutritional status has become even more crucial. Aims of this multicenter study were to present the growth pattern of treatment-naïve SMA1 and SMA2, and to compare it with the general growth standards. Results Body Weight (BW, kg) and Supine Length (SL, cm) were collected using a published standardized procedure. SMA-specific growth percentiles curves were developed and compared to the WHO reference data. We recruited 133 SMA1 and 82 SMA2 (48.8% females). Mean ages were 0.6 (0.4–1.6) and 4.1 (2.1–6.7) years, respectively. We present here a set of disease-specific percentiles curves of BW, SL, and BMI-for-age for girls and boys with SMA1 and SMA2. These curves show that BW is significantly lower in SMA than healthy peers, while SL is more variable. BMI is also typically lower in both sexes and at all ages. Conclusions These data on treatment-naïve patients point toward a better understanding of growth in SMA and could be useful to improve the clinical management and to assess the efficacy of the available and forthcoming therapies not only on motor function, but also on growth.

scholarly journals Gene therapy for spinal muscular atrophy: the Qatari experience

Gene Therapy ◽  
2021 ◽  
Author(s):  
Hossamaldein Gaber Ali ◽  
Khalid Ibrahim ◽  
Mahmoud Fawzi Elsaid ◽  
Reem Babiker Mohamed ◽  
Mahmoud I. A. Abeidah ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Spinal Muscular Atrophy ◽  
Troponin I ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Neuromuscular Disorder ◽  
Progressive Muscle Weakness ◽  
Elevated Bilirubin

AbstractSpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by hypotonia, progressive muscle weakness, and wasting. Onasemnogene abeparvovec (Zolgensma®) is a novel gene therapy medicine, FDA-approved in May 2019 for the treatment of SMA. This study aimed to describe Qatari experience with onasemnogene abeparvovec by reviewing the clinical outcomes of 9 SMA children (7 SMA type 1 and 2 with SMA type 2) aged 4‒23 months treated between November 2019 and July 2020. Children <2 years with 5q SMA with a bi-allelic mutation in the SMN1 gene were eligible for gene therapy. Liver function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and total bilirubin), platelet count, coagulation profile, troponin-I levels, and motor scores (Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders [CHOP INTEND]), were regularly monitored following gene therapy. All patients experienced elevated AST or ALT, two experienced high prothrombin time, and one experienced elevated bilirubin; all of these patients were asymptomatic. Furthermore, one event of vomiting after infusion was reported in one patient. Significant improvements in CHOP INTEND scores were observed following therapy. This study describes the short-term outcomes and safety of onasemnogene abeparvovec, which is well tolerated and shows promise for early efficacy.

scholarly journals Ultrastructural characterization of peripheral denervation in a mouse model of Type III spinal muscular atrophy

2021 ◽  
Author(s):  
Federica Fulceri ◽  
Francesca Biagioni ◽  
Fiona Limanaqi ◽  
Carla L. Busceti ◽  
Larisa Ryskalin ◽  
...  
Keyword(s):  
Mouse Model ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Disease Onset ◽  
Muscle Spindles ◽  
Neuromuscular Disorder ◽  
Type Iii ◽  
Smn Protein

AbstractSpinal muscular atrophy (SMA) is a heritable, autosomal recessive neuromuscular disorder characterized by a loss of the survival of motor neurons (SMN) protein, which leads to degeneration of lower motor neurons, and muscle atrophy. Despite SMA being nosographically classified as a motor neuron disease, recent advances indicate that peripheral alterations at the level of the neuromuscular junction (NMJ), involving the muscle, and axons of the sensory-motor system, occur early, and may even precede motor neuron loss. In the present study, we used a mouse model of slow progressive (type III) SMA, whereby the absence of the mouse SMN protein is compensated by the expression of two human genes (heterozygous SMN1A2G, and SMN2). This leads to late disease onset and prolonged survival, which allows for dissecting slow degenerative steps operating early in SMA pathogenesis. In this purely morphological study carried out at transmission electron microscopy, we extend the examination of motor neurons and proximal axons towards peripheral components, including distal axons, muscle fibers, and also muscle spindles. We document remarkable ultrastructural alterations being consistent with early peripheral denervation in SMA, which may shift the ultimate anatomical target in neuromuscular disease from the spinal cord towards the muscle. This concerns mostly mitochondrial alterations within distal axons and muscle, which are quantified here through ultrastructural morphometry. The present study is expected to provide a deeper knowledge of early pathogenic mechanisms in SMA.

scholarly journals Distal Spinal Muscular Atrophy: An Overlooked Etiology of Weaning Failure in Children with Respiratory Insufficiency

2018 ◽  
Vol 07 (03) ◽  
pp. 159-162 ◽  
Author(s):  
Asgar Eghbalkhah ◽  
Kamyar Kamrani ◽  
Nahid Khosroshahi ◽  
Hossein Yousefimanesh ◽  
Zahra Eskandarizadeh ◽  
...  
Keyword(s):  
Respiratory Distress ◽  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Respiratory Insufficiency ◽  
Muscular Atrophy ◽  
Pediatric Intensive Care ◽  
Neuromuscular Disorder ◽  
Weaning Failure ◽  
Life Threatening

AbstractSpinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder that involves the anterior horn motor neurons. It is a disease with a poor prognosis presenting with progressive distal motor weakness and respiratory insufficiency from diaphragmatic paralysis followed by distal muscle weakness before 6 months of age. With the intent to spread the awareness of this rare and life-threatening disease, we report a 2.5-month-old female infant with a subsequent diagnosis of SMARD1, who was admitted in our pediatric intensive care unit with chief complaint of progressive respiratory distress and poor feeding.

scholarly journals Combining multi-omics and drug perturbation profiles to identify novel treatments that improve disease phenotypes in spinal muscular atrophy

2019 ◽  
Author(s):  
Katharina E. Meijboom ◽  
Viola Volpato ◽  
Jimena Monzón-Sandoval ◽  
Joseph M. Hoolachan ◽  
Suzan M. Hammond ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Neuromuscular Disorder ◽  
Survival Motor Neuron ◽  
Muscle Pathology ◽  
Drug Candidates ◽  
Novel Treatments ◽  
Disease Phenotypes ◽  
Parallel Data ◽  
Smn Protein

ABSTRACTSpinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss of survival motor neuron (SMN) protein. While SMN restoration therapies are beneficial, they are not a cure. We aimed to identify novel treatments to alleviate muscle pathology combining transcriptomics, proteomics and perturbational datasets. This revealed potential drug candidates for repurposing in SMA. One of the lead candidates, harmine, was further investigated in cell and animal models, improving multiple disease phenotypes, including SMN expression and lifespan. Our work highlights the potential of multiple, parallel data driven approaches for development of novel treatments for use in combination with SMN restoration therapies.

Cervical puncture to deliver nusinersen in patients with spinal muscular atrophy

Neurology ◽  
2018 ◽  
Vol 91 (7) ◽  
pp. e620-e624 ◽  
Author(s):  
Aravindhan Veerapandiyan ◽  
Ria Pal ◽  
Stephen D'Ambrosio ◽  
Iris Young ◽  
Katy Eichinger ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Spinal Fusion ◽  
Tissue Concentration ◽  
Muscular Atrophy ◽  
Retrospective Chart Review ◽  
Neuromuscular Disorder ◽  
Spinal Cord Tissue ◽  
Posterior Aspect ◽  
Feasible Alternative

ObjectiveTo report our experience delivering intrathecal nusinersen through cervical puncture in patients with spinal muscular atrophy (SMA) with no lumbar access.BackgroundSMA is a neuromuscular disorder characterized by profound muscle weakness, atrophy, and paralysis due to degeneration of the anterior horn cells. Nusinersen, the first Food and Drug Administration–approved treatment for SMA, is administered intrathecally via lumbar puncture; however, many patients with SMA have scoliosis or solid spinal fusion with hardware that makes lumbar access impossible. Studies in primates have demonstrated better spinal cord tissue concentration with intrathecal injections than with intracerebral ventricular injections. Therefore we have used C1/C2 puncture as an alternative to administer nusinersen.MethodRetrospective chart review.ResultsIntrathecal nusinersen via cervical puncture was given to 3 patients who had thoracic and lumbosacral spinal fusion: a 12-year-old girl with type 1 SMA and 2 17-year-old girls with type 2 SMA. Cervical puncture was performed without deep sedation under fluoroscopic guidance using a 25-G or a 24-G Whitacre needle in the posterior aspect of C1-C2 interspace and full dose of nusinersen (12 mg/5 mL) was injected after visualizing free CSF flow. Patients completed their 4 loading doses and first maintenance dose of nusinersen, and 15 procedures were successful and well-tolerated.ConclusionCervical puncture is a feasible alternative delivery route to administer intrathecal nusinersen in patients with longstanding SMA and spine anatomy precluding lumbar access when done by providers with expertise in this procedure.

scholarly journals Treatment with nusinersen in a girl with spinal muscular atrophy type 1 - Case report

2020 ◽  
Vol 89 (5-6) ◽  
pp. 320-326
Author(s):  
Tanja Loboda ◽  
Tita Butenko ◽  
Tanja Golli ◽  
Damjan Osredkar
Keyword(s):  
Spinal Muscular Atrophy ◽  
Respiratory Infections ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Neuromuscular Disorder ◽  
Natural Course ◽  
Dramatic Improvement ◽  
Serious Adverse Events ◽  
Spinal Muscular Atrophy Type

We report the case of a girl with spinal muscular atrophy (SMA) type 1, who is the first patient with SMA in Slovenia treated with nusinersen, the first disease modifying therapy available for these patients. SMA is an autosomal recessive neuromuscular disorder characterized by muscle weakness, atrophy and paralysis due to the degeneration of the anterior horn cells, leading to premature death, most commonly due to respiratory infections. Nusinersen, an antisense oligonucleotide, was clinically approved based on clinical trials showing dramatic improvement in the natural course of infantile-onset SMA. After the genetic confirmation of SMA, our girl was the first child in Slovenia to receive nusinersen, which was provided through an expanded access programme. She received intrathecal applications of nusinersen according to the protocol. No serious adverse events were observed. Assessment of her motor skills was performed using The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP – INTEND) before the beginning of treatment and after completing the first 7 applications of nusinersen. She scored 21/64 points before the introduction of treatment and 32/64 after the completion of treatment. In conclusion, nusinersen improved the CHOP – INTEND motor function score and has been effective in delaying the expected natural course of SMA in our patient.

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