scholarly journals Serum creatinine is a biomarker of progressive denervation in spinal muscular atrophy

Neurology ◽  
2019 ◽  
Vol 94 (9) ◽  
pp. e921-e931 ◽  
Author(s):  
Christiano R.R. Alves ◽  
Ren Zhang ◽  
Alec J. Johnstone ◽  
Reid Garner ◽  
Pann H. Nwe ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Lean Mass ◽  
Muscular Atrophy ◽  
Compound Muscle Action Potential ◽  
Survival Motor Neuron ◽  
Mixed Effect

ObjectiveIdentifying simple biomarkers that can predict or track disease progression in patients with spinal muscular atrophy (SMA) remains an unmet clinical need. To test the hypothesis that serum creatinine (Crn) could be a prognostic biomarker for monitoring progression of denervation in patients with SMA, we determined whether serum Crn concentration correlates with disease severity in patients with SMA.MethodsWe examined a cohort of 238 patients with SMA with 1,130 Crn observations between 2000 and 2016. Analyses were corrected for age, and 156 patients with SMA had dual-energy x-ray absorptiometry data available for correction for lean mass. We investigated the relationship between Crn and SMA type, survival motor neuron 2 (SMN2) copies, and Hammersmith Functional Motor Scale (HFMS) score as primary outcomes. In addition, we tested for associations between Crn and maximum ulnar compound muscle action potential amplitude (CMAP) and motor unit number estimation (MUNE).ResultsPatients with SMA type 3 had 2.2-fold (95% confidence interval [CI] 1.93–2.49; p < 0.0001) higher Crn levels compared to those with SMA type 1 and 1.7-fold (95% CI 1.52–1.82; p < 0.0001) higher Crn levels compared to patients with SMA type 2. Patients with SMA type 2 had 1.4-fold (95% CI 1.31–1.58; p < 0.0001) higher Crn levels than patients with SMA type 1. Patients with SMA with 4 SMN2 copies had 1.8-fold (95% CI 1.57–2.11; p < 0.0001) higher Crn levels compared to patients with SMA with 2 SMN2 copies and 1.4-fold (95% CI 1.24–1.58; p < 0.0001) higher Crn levels compared to patients with SMA with 3 SMN2 copies. Patients with SMA with 3 SMN2 copies had 1.4-fold (95% CI 1.21–1.56; p < 0.0001) higher Crn levels than patients with SMA with 2 SMN2 copies. Mixed-effect model revealed significant differences in Crn levels among walkers, sitters, and nonsitters (p < 0.0001) and positive associations between Crn and maximum CMAP (p < 0.0001) and between Crn and MUNE (p < 0.0001). After correction for lean mass, there were still significant associations between Crn and SMA type, SMN2 copies, HFMS, CMAP, and MUNE.ConclusionsThese findings indicate that decreased Crn levels reflect disease severity, suggesting that Crn is a candidate biomarker for SMA progression. We conclude that Crn measurements should be included in the routine analysis of all patients with SMA. In future studies, it will be important to determine whether Crn levels respond to molecular and gene therapies.

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.

Nusinersen in patients older than 7 months with spinal muscular atrophy type 1

Neurology ◽  
2018 ◽  
Vol 91 (14) ◽  
pp. e1312-e1318 ◽  
Author(s):  
Karolina Aragon-Gawinska ◽  
Andreea M. Seferian ◽  
Aurore Daron ◽  
Elena Gargaun ◽  
Carole Vuillerot ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Function ◽  
Treatment Initiation ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Survival Motor Neuron ◽  
Spinal Muscular Atrophy Type ◽  
Nutritional Data

ObjectiveTo evaluate the safety and clinical efficacy of nusinersen in patients older than 7 months with spinal muscular atrophy type 1 (SMA1).MethodsPatients with SMA1 were treated with nusinersen by intrathecal injections as a part of the Expanded Access Program (EAP; NCT02865109). We evaluated patients before treatment initiation (M0) and at 2 months (M2) and 6 months (M6) after treatment initiation. Survival, respiratory, and nutritional data were collected. Motor function was assessed with the modified Hammersmith Infant Neurologic Examination Part 2 (HINE-2) and physiotherapist scales adjusted to patient age (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and the Motor Function Measure 20 or 32).ResultsWe treated 33 children ranging in age from 8.3 to 113.1 months between December 2016 and May 2017. All patients were alive and were continuing treatment at M6. Median progress on the modified HINE-2 score was 1.5 points after 6 months of treatment (p < 0.001). The need for respiratory support significantly increased over time. There were no statistically significant differences between patients presenting with 2 and those presenting with 3 copies of the survival motor neuron 2 (SMN2) gene.ConclusionsOur results are in line with the phase 3 study for nusinersen in patients with SMA1 treated before 7 months of age and indicate that patients benefit from nusinersen even at a later stage of the disease.ClinicalTrials.gov identifier:NCT02865109.Classification of evidenceThis study provides Class IV evidence that for patients with SMA1 who are older than 7 months, nusinersen is beneficial.

scholarly journals Observations from a nationwide vigilance program in medical care for spinal muscular atrophy patients in Chile

2019 ◽  
Vol 77 (7) ◽  
pp. 470-477
Author(s):  
Karin ALVAREZ ◽  
Bernardita SUAREZ ◽  
María Angélica PALOMINO ◽  
Cecilia HERVIAS ◽  
Giancarlo CALCAGNO ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Copy Number ◽  
Muscular Atrophy ◽  
Genetic Diagnosis ◽  
Standards Of Care ◽  
Scoliosis Surgery ◽  
Timely Access ◽  
Type 3

ABSTRACT Spinal muscular atrophy (SMA) has gained much attention in the last few years because of the approval of the first intrathecal treatment for this neurodegenerative disease. Latin America needs to develop the demographics of SMA, timely access to diagnosis, and appropriate following of the standards of care recommendations for patients. These are essential steps to guide health policies. Methods This was a descriptive study of a cohort of SMA patients from all over Chile. We analyzed the clinical, motor functional, and social data, as well as the care status of nutritional, respiratory and skeletal conditions. We also measured the SMN2 copy number in this population. Results We recruited 92 patients: 50 male; 23 SMA type-1, 36 SMA type-2 and 33 SMA type-3. The median age at genetic diagnosis was 5, 24 and 132 months. We evaluated the SMN2 copy number in 57 patients. The SMA type-1 patients were tracheostomized and fed by gastrostomy in a 69.6 % of cases, 65% of SMA type-2 patients received nocturnal noninvasive ventilation, and 37% of the whole cohort underwent scoliosis surgery. Conclusion Ventilatory care for SMA type-1 is still based mainly on tracheostomy. This Chilean cohort of SMA patients had timely access to genetic diagnosis, ventilatory assistance, nutritional support, and scoliosis surgery. In this series, SMA type-1 is underrepresented, probably due to restrictions in access to early diagnosis and the high and early mortality rate.

scholarly journals Prevalensi, Spektrum Klinis dan Gambaran Neurofisiologi Kasus Neuromuskular

Sari Pediatri ◽  
2019 ◽  
Vol 20 (4) ◽  
pp. 214 ◽  
Author(s):  
Mia Milanti Dewi ◽  
Dwi Putro Widodo ◽  
Roy Amardiyanto ◽  
Nurcahaya Sinaga ◽  
Nurul Hidayah
Keyword(s):  
Muscular Dystrophy ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Axonal Neuropathy ◽  
Demyelinating Polyneuropathy ◽  
Acute Motor Axonal Neuropathy ◽  
Spinal Muscular Atrophy Type ◽  
Guillain Barré

Latar belakang. Sebagian kasus neuromuskular dapat ditegakkan berdasarkan klinis. Pemeriksaan penunjang, pemeriksaan imunologi dan analisis genetik sangat penting diperiksa untuk memastikan diagnosis. Ini merupakan penelitian pertama mengenai prevalensi penyakit neuromuskular di Indonesia.Tujuan. Mengetahui prevalensi, spektrum klinis, dan gambaran neurofisiologi kasus neuromuskular di RSCM periode Januari – Desember 2017.Metode. Penelitian ini bersifat retrospektif dari Januari – Desember 2017.Hasil. Di tahun 2017 terdapat 179 pasien (usia 1 bulan – 18 tahun) yang dirujuk untuk dilakukan pemeriksaan elektromiografi, dan 130 pasien memenuhi kriteria diagnostik penyakit neuromuskular. Dari seluruh pasien kelainan neuromuskular yang sering ditemukan berturut-turut adalah neuropati perifer (22,2%), Duchenne muscular dystrophy (15,6%), brachialis plexus injury (15,2%), Bell’s palsy (7,6%), Erb Palsy (6,1%), chronic inflamatory demyelinating polyneuropathy (5,4 %), spinal muscular atrophy type 1 (4,6 %), spinal muscular atrophy type 2 (3,8%), miastenia gravis okular (3,8%), Limb Girdle muscular dystrophy (3,1%), sindrom Guillain Barre (3,1%), sindrom Guillain Barre-tipe acute motor axonal neuropathy (2,3%), sindrom Guillain Barre-tipe acute motor-sensory axonal neuropathy (1,5%), miastenia gravis umum (1,5%), Charcot Marie tooth (1,5%), miotonia kongenital (1,5%), dan miositis viral akut (1,5%). Kesimpulan. Prevalensi kelainan neuromuskular anak RSCM sebesar 2,6 % dari seluruh pasien yang dilakukan datang ke poli saraf anak. Lima terbanyak kelainan neuromuskular adalah neuropati perifer, Ducchenne Muscular dystrophy, spinal muskular atrofi, sindrom Guillain Barre, dan chronic inflamatory demyelinating polyneuropathy.

scholarly journals Effect of nusinersen on respiratory function in paediatric spinal muscular atrophy types 1–3

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2020-216564
Author(s):  
Archana Chacko ◽  
Peter D Sly ◽  
Robert S Ware ◽  
Nelufa Begum ◽  
Sean Deegan ◽  
...  
Keyword(s):  
Lung Function ◽  
Spinal Muscular Atrophy ◽  
Muscle Function ◽  
Respiratory Function ◽  
Muscular Atrophy ◽  
First Year ◽  
Peripheral Muscle ◽  
Rate Of Decline

IntroductionNusinersen is used in spinal muscular atrophy (SMA) to improve peripheral muscle function; however, respiratory effects are largely unknown.AimTo assess the effects of nusinersen on respiratory function in paediatric SMA during first year of treatment.MethodsA prospective observational study in paediatric patients with SMA who began receiving nusinersen in Queensland, Australia, from June 2018 to December 2019. Outcomes assessed were the age-appropriate respiratory investigations: spirometry, oscillometry, sniff nasal inspiratory pressure, mean inspiratory pressure, mean expiratory pressure, lung clearance index, as well as polysomnography (PSG) and muscle function testing. Lung function was collected retrospectively for up to 2 years prior to nusinersen initiation. Change in lung function was assessed using mixed effects linear regression models, while PSG and muscle function were compared using the Wilcoxon signed-rank test.ResultsTwenty-eight patients (15 male, aged 0.08–18.58 years) were enrolled: type 1 (n=7); type 2 (n=12); type 3 (n=9). The annual rate of decline in FVC z-score prior to nusinersen initiation was −0.58 (95% CI −0.75 to −0.41), and post initiation was −0.25 (95% CI −0.46 to −0.03), with a significant difference in rate of decline (0.33 (95% CI 0.02 to 0.66) (p=0.04)). Most lung function measures were largely unchanged in the year post nusinersen initiation. The total Apnoea–Hypopnoea Index (AHI) was reduced from a median of 5.5 events/hour (IQR 2.1–10.1) at initiation to 2.7 events/hour (IQR 0.7–5.3) after 1 year (p=0.02). All SMA type 1% and 75% of SMA types 2 and 3 had pre-defined peripheral muscle response to nusinersen.ConclusionThe first year of nusinersen treatment saw reduced lung function decline (especially in type 2) and improvement in AHI.

scholarly journals Persistent neuromuscular junction transmission defects in adults with spinal muscular atrophy treated with nusinersen

2021 ◽  
Vol 3 (2) ◽  
pp. e000164
Author(s):  
W David Arnold ◽  
Steven Severyn ◽  
Songzhu Zhao ◽  
David Kline ◽  
Matthew Linsenmayer ◽  
...  
Keyword(s):  
Neuromuscular Junction ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Compound Muscle Action Potential ◽  
T Test ◽  
Survival Motor Neuron ◽  
Repetitive Nerve Stimulation ◽  
Maximum Voluntary Isometric Contraction ◽  
Smn Protein

ObjectiveSpinal muscular atrophy (SMA) is a motor neuron disease caused by low levels of survival motor neuron (SMN) protein. Prior work in models and patients has demonstrated electrophysiological and morphological defects at the neuromuscular junction (NMJ). Therapeutic development has resulted in clinically available therapies to increase SMN protein levels in patients and improve muscle function. Here we aimed to investigate the effect of SMN restoration (via nusinersen) on NMJ transmission in adults with SMA.MethodsParticipants undergoing nusinersen treatment underwent 3 Hz repetitive nerve stimulation (RNS) of the spinal accessory nerve to assess compound muscle action potential amplitude decrement. Maximum voluntary isometric contraction (MVICT), Revised Upper Limb Module (RULM), and 6 min walk test (6MWT) were assessed for correlations with decrement.ResultsData from 13 ambulatory (7 men/6 women, mean age 40±11 years) and 11 non-ambulatory (3 men/8 women, mean age 38±12 years) participants were analysed. Cross-sectional analyses of RNS decrement were similar at 14 months of nusinersen (−14.2%±11.5%, n=17) vs baseline (−11.9%±8.3%, n=15) (unpaired t-test, p=0.5202). Longitudinal comparison of decrement in eight participants showed no change at 14 months (−13.9%±6.7%) vs baseline (−16.9%±13.4%) (paired t-test, p=0.5863). Decrement showed strong correlations with measures of MVICT, RULM and 6MWT but not age or disease duration.ConclusionAdults with SMA had significant NMJ transmission defects that were not corrected with 14 months of nusinersen treatment. NMJ defects were negatively associated with physical function, and thus may represent a promising target for additive or combinatorial treatments.

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.

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