Children and young adults with spinal muscular atrophy treated with nusinersen

Osredkar, Damjan; Jílková, Markéta; Butenko, Tita; Loboda, Tanja; Golli, Tanja; Fuchsová, Petra; Rohlenová, Marie; Haberlová, Jana

doi:10.1016/j.ejpn.2020.11.004

Cited by 35 publications

(43 citation statements)

References 15 publications

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“…An autopsy analysis showed the uptake of nusinersen into motor neurons throughout the spinal cord and into neurons in the brainstem [18]. Increased motor function was manifested as an increased ability to sit or walk independently [19][20][21], increased bite force [22], and increased hand strength [23]. Although nusinersen is administered intrathecally, which requires a lot of expertise, it has been shown that such application is well tolerated and safe [24].…”

Section: Introductionmentioning

confidence: 99%

Spinal Muscular Atrophy after Nusinersen Therapy: Improved Physiology in Pediatric Patients with No Significant Change in Urine, Serum, and Liquor 1H-NMR Metabolomes in Comparison to an Age-Matched, Healthy Cohort

et al. 2021

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Spinal muscular atrophy (SMA) is a genetically heterogeneous group of rare neuromuscular diseases and was until recently the most common genetic cause of death in children. The effects of 2-month nusinersen therapy on urine, serum, and liquor 1H-NMR metabolomes in SMA males and females were not explored yet, especially not in comparison to the urine 1H-NMR metabolomes of matching male and female cohorts. In this prospective, single-centered study, urine, serum, and liquor samples were collected from 25 male and female pediatric patients with SMA before and after 2 months of nusinersen therapy and urine samples from a matching healthy cohort (n = 125). Nusinersen intrathecal application was the first therapy for the treatment of SMA by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Metabolomes were analyzed using targeted metabolomics utilizing 600 MHz 1H-NMR, parametric and nonparametric multivariate statistical analyses, machine learning, and modeling. Medical assessment before and after nusinersen therapy showed significant improvements of movement, posture, and strength according to various medical tests. No significant differences were found in metabolomes before and after nusinersen therapy in urine, serum, and liquor samples using an ensemble of statistical and machine learning approaches. In comparison to a healthy cohort, 1H-NMR metabolomes of SMA patients contained a reduced number and concentration of urine metabolites and differed significantly between males and females as well. Significantly larger data scatter was observed for SMA patients in comparison to matched healthy controls. Machine learning confirmed urinary creatinine as the most significant, distinguishing SMA patients from the healthy cohort. The positive effects of nusinersen therapy clearly preceded or took place devoid of significant rearrangements in the 1H-NMR metabolomic makeup of serum, urine, and liquor. Urine creatinine was successful at distinguishing SMA patients from the matched healthy cohort, which is a simple systemic novelty linking creatinine and SMA to the physiology of inactivity and diabetes, and it facilitates the monitoring of SMA disease in pediatric patients through non-invasive urine collection.

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Section: Introductionmentioning

confidence: 99%

Spinal Muscular Atrophy after Nusinersen Therapy: Improved Physiology in Pediatric Patients with No Significant Change in Urine, Serum, and Liquor 1H-NMR Metabolomes in Comparison to an Age-Matched, Healthy Cohort

et al. 2021

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“…While the early real‐world data have mainly focused on type I patients, 8 , 9 , 10 , 11 and more recent studies have reported data in adults, 12 , 13 , 14 , 15 , 16 , 17 , 18 less has been reported in pediatric patients or, more generally, to cover the spectrum of treated younger and older type III patients who were also not included in the pivotal trials. 19 Furthermore, as there is reported evidence of the variability of the progression of type III in relation to a number of variables, such as age and functional status, 20 , 21 , 22 the interpretation of the limited real‐world data available is also affected by the lack of comparison with reference data from untreated patients.…”

Section: Introductionmentioning

confidence: 99%

Nusinersen in pediatric and adult patients with type III spinal muscular atrophy

Pera

Coratti

Bovis

et al. 2021

Ann Clin Transl Neurol

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Objective We report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort. Methods Patients were assessed using Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6‐Minute Walk Test (6MWT) with a mean follow‐up of 1.83 years after nusinersen treatment. Results Over 75% of the 144 patients had a 12‐month follow‐up. There was an increase in the mean scores from baseline to 12 months on both HFMSE (1.18 points, p = 0.004) and RULM scores (0.58 points, p = 0.014) but not on the 6MWT (mean difference = 6.65 m, p = 0.33). When the 12‐month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7 years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT. Interpretation Our results expand the available data on the effect of Nusinersen on type III patients, so far mostly limited to data from adult type III patients.

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“…This model only differs from Calucho's correlations in type III patients, since it establishes the expected SMN2_CN to be 4 instead of 3 and 4 indistinctly [9]. In the recent literature, the correlation described by Calucho et al (2018) is mainly maintained [28][29][30][31][32], although some exceptions can be found. Interestingly, the proportion of type I patients with 3 SMN2 genes was increased in some cohorts, reaching 57% among SMA I patients, while Calucho's compilation reported only 23% [33,34].…”

Section: The Known Validated Genotypesmentioning

confidence: 67%

The Importance of Digging into the Genetics of SMN Genes in the Therapeutic Scenario of Spinal Muscular Atrophy

Costa-Roger

Blasco-Pérez

Cuscò

et al. 2021

IJMS

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After 26 years of discovery of the determinant survival motor neuron 1 and the modifier survival motor neuron 2 genes (SMN1 and SMN2, respectively), three SMN-dependent specific therapies are already approved by FDA and EMA and, as a consequence, worldwide SMA patients are currently under clinical investigation and treatment. Bi-allelic pathogenic variants (mostly deletions) in SMN1 should be detected in SMA patients to confirm the disease. Determination of SMN2 copy number has been historically employed to correlate with the phenotype, predict disease evolution, stratify patients for clinical trials and to define those eligible for treatment. In view that discordant genotype-phenotype correlations are present in SMA, besides technical issues with detection of SMN2 copy number, we have hypothesized that copy number determination is only the tip of the iceberg and that more deepen studies of variants, sequencing and structures of the SMN2 genes are necessary for a better understanding of the disease as well as to investigate possible influences in treatment responses. Here, we highlight the importance of a comprehensive approach of SMN1 and SMN2 genetics with the perspective to apply for better prediction of SMA in positive neonatal screening cases and early diagnosis to start treatments.

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Children and young adults with spinal muscular atrophy treated with nusinersen

Cited by 35 publications

References 15 publications

Spinal Muscular Atrophy after Nusinersen Therapy: Improved Physiology in Pediatric Patients with No Significant Change in Urine, Serum, and Liquor 1H-NMR Metabolomes in Comparison to an Age-Matched, Healthy Cohort

Spinal Muscular Atrophy after Nusinersen Therapy: Improved Physiology in Pediatric Patients with No Significant Change in Urine, Serum, and Liquor 1H-NMR Metabolomes in Comparison to an Age-Matched, Healthy Cohort

Nusinersen in pediatric and adult patients with type III spinal muscular atrophy

The Importance of Digging into the Genetics of SMN Genes in the Therapeutic Scenario of Spinal Muscular Atrophy

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