scholarly journals Glial Fibrillary Acidic Protein in Cerebrospinal Fluid of Nusinersen-Treated Patients with Spinal Muscular Atrophy

2021 ◽  
Author(s):  
Maren Freigang ◽  
Petra Steinacker ◽  
Claudia Diana Wurster ◽  
Olivia Schreiber-Katz ◽  
Alma Osmanovic ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Glial Fibrillary Acidic Protein ◽  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Muscular Atrophy ◽  
Gene Replacement ◽  
Adult Patients ◽  
Acidic Protein ◽  
Specialist Care ◽  
Predict Treatment Response

Abstract BackgroundActivated astroglia is involved in the pathophysiology of neurodegenerative diseases and has also been described in animal models of spinal muscular atrophy (SMA). Given the urgent need of biomarkers for treatment monitoring of new RNA-modifying and gene replacement therapies in SMA, we examined glial fibrillary acidic protein (GFAP) concentrations as a marker of astrogliosis in the cerebrospinal fluid (CSF) of children and adult patients with SMA before and during treatment with nusinersen.Methods58 adult patients and 21 children with genetically confirmed 5q-associated SMA from 4 German motor neuron disease specialist care centers and 30 age- and sex-matched controls were prospectively included in this study. GFAP concentration was measured in CSF and motor performance and disease severity were assessed.ResultsCSF GFAP concentrations did not differ from controls but showed higher levels in more severely affected patients after adjustment for patients’ age. Within 14 months of nusinersen treatment, CSF GFAP concentrations did not change significantly.ConclusionsGFAP concentration in CSF of patients with long-standing SMA is not useful to assess disease severity or predict treatment response, but might support the hypothesis that glial activation is involved in SMA pathology.

scholarly journals Cerebrospinal Fluid Parameters in Antisense Oligonucleotide-Treated Adult 5q-Spinal Muscular Atrophy Patients

2021 ◽  
Vol 11 (3) ◽  
pp. 296
Author(s):  
Lars Hendrik Müschen ◽  
Alma Osmanovic ◽  
Camilla Binz ◽  
Konstantin F. Jendretzky ◽  
Gresa Ranxha ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Spinal Muscular Atrophy ◽  
Total Protein ◽  
Antisense Oligonucleotide ◽  
Muscular Atrophy ◽  
Neurological Diseases ◽  
Clinical Signs ◽  
Central Nervous System Disease ◽  
Oligoclonal Bands ◽  
System Disease

Approval of nusinersen, an intrathecally administered antisense oligonucleotide, for the treatment of 5q-spinal muscular atrophy (SMA) marked the beginning of a new therapeutic era in neurological diseases. Changes in routine cerebrospinal fluid (CSF) parameters under nusinersen have only recently been described in adult SMA patients. We aimed to explore these findings in a real-world setting and to identify clinical and procedure-associated features that might impact CSF parameters. Routinely collected CSF parameters (leukocyte count, lactate, total protein, CSF/serum albumin quotient (QAlbumin), oligoclonal bands) of 28 adult SMA patients were examined for up to 22 months of nusinersen treatment. Total protein and QAlbumin values significantly increased in the first 10 months, independent of the administration procedure. By month 14, no further increases were detected. Two patients developed transient pleocytosis. In two cases, positive oligoclonal bands were found in the beginning and in four patients throughout the whole observation period. No clinical signs of inflammatory central nervous system disease were apparent. Our data confirm elevated CSF total protein and QAlbumin during nusinersen treatment. These alterations may be caused by both repeated lumbar punctures and the interval between procedures rather than by the medication itself. Generally, there were no severe alterations of CSF routine parameters. These results further underline the safety of nusinersen therapy.

SMN mRNA and protein levels in peripheral blood

Neurology ◽  
2006 ◽  
Vol 66 (7) ◽  
pp. 1067-1073 ◽  
Author(s):  
C. J. Sumner ◽  
S. J. Kolb ◽  
G. G. Harmison ◽  
N. O. Jeffries ◽  
K. Schadt ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Peripheral Blood ◽  
Muscular Atrophy ◽  
Gene Copy ◽  
Blood Levels ◽  
Type I ◽  
Protein Levels ◽  
Smn Protein

Background: Clinical trials of drugs that increase SMN protein levels in vitro are currently under way in patients with spinal muscular atrophy.Objective: To develop and validate measures of SMN mRNA and protein in peripheral blood and to establish baseline SMN levels in a cohort of controls, carriers, and patients of known genotype, which could be used to follow response to treatment.Methods: SMN1 and SMN2 gene copy numbers were determined in blood samples collected from 86 subjects. Quantitative reverse transcription PCR was used to measure blood levels of SMN mRNA with and without exon 7. A cell immunoassay was used to measure blood levels of SMN protein.Results: Blood levels of SMN mRNA and protein were measured with high reliability. There was little variation in SMN levels in individual subjects over a 5-week period. Levels of exon 7-containing SMN mRNA and SMN protein correlated with SMN1 and SMN2 gene copy number. With the exception of type I SMA, there was no correlation between SMN levels and disease severity.Conclusion: SMN mRNA and protein levels can be reliably measured in the peripheral blood and used during clinical trials in spinal muscular atrophy, but these levels do not necessarily predict disease severity.

Serum glial fibrillary acidic protein correlates with multiple sclerosis disease severity

2018 ◽  
Vol 26 (2) ◽  
pp. 210-219 ◽  
Author(s):  
Heidi Högel ◽  
Eero Rissanen ◽  
Christian Barro ◽  
Markus Matilainen ◽  
Marjo Nylund ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Nervous System ◽  
Glial Fibrillary Acidic Protein ◽  
Disease Progression ◽  
Disease Severity ◽  
Single Molecule ◽  
Progressive Disease ◽  
Disease Duration ◽  
Acidic Protein ◽  
Csf Levels

Background: Cerebrospinal fluid (CSF) levels of two soluble biomarkers, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL), have been shown to associate with multiple sclerosis (MS) disease progression. Now, both biomarkers can be detected reliably in serum, and importantly, their serum levels correlate well with their CSF levels. Objective: To evaluate the usability of serum GFAP measurement as a biomarker of progressive disease and disease severity in MS. Methods: Clinical course, Expanded Disability Status Scale (EDSS), disease duration, patient age and magnetic resonance imaging (MRI) parameters were reviewed in 79 MS patients in this cross-sectional hospital-based study. Serum samples were collected for measurement of GFAP and NfL concentrations using single molecule array (Simoa) assay. A cohort of healthy controls was evaluated for comparison. Results: Higher serum concentrations of both GFAP and NfL were associated with higher EDSS, older age, longer disease duration, progressive disease course and MRI pathology. Conclusion: Earlier studies have demonstrated that GFAP, unlike NfL, is not increased in association with acute focal inflammation-related nervous system damage. Our work suggests that GFAP serum level associates with disease progression in MS and could potentially serve as an easily measurable biomarker of central nervous system (CNS) pathology related to disease progression in MS.

Cerebrospinal fluid neurofilament and glial fibrillary acidic protein in patients with cerebral vasculitis

2002 ◽  
Vol 67 (6) ◽  
pp. 844-851 ◽  
Author(s):  
K. Nylén ◽  
J-E. Karlsson ◽  
C. Blomstrand ◽  
A. Tarkowski ◽  
E. Trysberg ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Glial Fibrillary Acidic Protein ◽  
Cerebral Vasculitis ◽  
Acidic Protein

Reader Response: Nusinersen in Adult Patients With Spinal Muscular Atrophy: Observations From a Single Center

Neurology ◽  
2021 ◽  
Vol 96 (22) ◽  
pp. 1061.2-1062
Author(s):  
Tim Hagenacker ◽  
Maggie Christine Walter ◽  
Valeria Sansone ◽  
Eugenio Mercuri
Keyword(s):  
Spinal Muscular Atrophy ◽  
Reader Response ◽  
Muscular Atrophy ◽  
Adult Patients ◽  
Single Center

scholarly journals Cerebrospinal fluid proteomic profiling in nusinersen‐treated patients with spinal muscular atrophy

2020 ◽  
Vol 153 (5) ◽  
pp. 650-661 ◽  
Author(s):  
Tobias Kessler ◽  
Pauline Latzer ◽  
Dominic Schmid ◽  
Uwe Warnken ◽  
Afshin Saffari ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Proteomic Profiling

scholarly journals Patient-Reported Prevalence of Non-motor Symptoms Is Low in Adult Patients Suffering From 5q Spinal Muscular Atrophy

2019 ◽  
Vol 10 ◽  
Author(s):  
René Günther ◽  
Claudia Diana Wurster ◽  
Isabell Cordts ◽  
Jan Christoph Koch ◽  
Christoph Kamm ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Adult Patients ◽  
Motor Symptoms ◽  
Patient Reported ◽  
Non Motor Symptoms

scholarly journals Twenty-Five Years of Spinal Muscular Atrophy Research: From Phenotype to Genotype to Therapy, and What Comes Next

2020 ◽  
Vol 21 (1) ◽  
pp. 231-261 ◽  
Author(s):  
Brunhilde Wirth ◽  
Mert Karakaya ◽  
Min Jeong Kye ◽  
Natalia Mendoza-Ferreira
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Gene Replacement ◽  
Efficient Treatment ◽  
The Road ◽  
Cellular Pathways ◽  
On The Road ◽  
Or Gene ◽  
Novel Therapeutic Strategies ◽  
Homozygous Deletions

Twenty-five years ago, the underlying genetic cause for one of the most common and devastating inherited diseases in humans, spinal muscular atrophy (SMA), was identified. Homozygous deletions or, rarely, subtle mutations of SMN1 cause SMA, and the copy number of the nearly identical copy gene SMN2 inversely correlates with disease severity. SMA has become a paradigm and a prime example of a monogenic neurological disorder that can be efficiently ameliorated or nearly cured by novel therapeutic strategies, such as antisense oligonucleotide or gene replacement therapy. These therapies enable infants to survive who might otherwise have died before the age of two and allow individuals who have never been able to sit or walk to do both. The major milestones on the road to these therapies were to understand the genetic cause and splice regulation of SMN genes, the disease's phenotype–genotype variability, the function of the protein and the main affected cellular pathways and tissues, the disease's pathophysiology through research on animal models, the windows of opportunity for efficient treatment, and how and when to treat patients most effectively.This review aims to bridge our knowledge from phenotype to genotype to therapy, not only highlighting the significant advances so far but also speculating about the future of SMA screening and treatment.

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