Developmental milestones in type I spinal muscular atrophy

Sanctis, Roberto De; Coratti, Giorgia; Pasternak, Amy; Montes, Jacqueline; Pane, Marika; Mazzone, Elena; Young, Sally Dunaway; Salazar, Rachel; Quigley, Janet; Pera, Maria Carmela; Antonaci, Laura; Lapenta, Leonardo; Glanzman, Allan M.; Tiziano, Danilo; Muntoni, Francesco; Darras, Basil T.; Vivo, Darryl C. De; Finkel, Richard S.; Mercuri, Eugenio

doi:10.1016/j.nmd.2016.10.002

Cited by 108 publications

(104 citation statements)

References 13 publications

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“…The overall results in age group show a clear trend of improvement on both the CHOP INTEND and HINE-2 that is different from the negative changes observed in the untreated group in the ENDEAR study 1 and in the recent natural history studies. 15,16 An improvement was, however, also found in the infants treated between 7 and 24 months on both scales, and some improvement could also be found in the older children on the CHOP INTEND. Other factors also appeared to be important in determining the possibility of an improvement.…”

Section: Discussionmentioning

confidence: 89%

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Nusinersen in type 1 spinal muscular atrophy: Twelve‐month real‐world data

Pane

Coratti

Sansone

et al. 2019

Annals of Neurology

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Objective: The aim of the study was to report 12-month changes after treatment with nusinersen in a cohort of 85 type I spinal muscular atrophy patients of ages ranging from 2 months to 15 years and 11 months. Methods: All patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination-Section 2 (HINE-2). Results: Two of the 85 patients had 1 SMN2 copy, 61 had 2 copies, and 18 had 3 copies. In 4 patients the SMN2 copy number was not available. At baseline, the mean CHOP INTEND scores ranged between 0 and 52 (mean = 15.66, standard deviation [SD] = AE13.48), and the mean HINE-2 score was between 0 and 5 (mean = 0.69, SD = AE1.23). There was a difference between baseline and the 12-month scores on both the CHOP INTEND and the HINE-2 for the whole group (p < 0.001), the subgroups with 2 SMN2 copies (p < 0.001), and those with 3 SMN2 copies (p < 0.001). The difference was found not only in patients younger than 210 days at baseline (p < 0.001) but also in those younger than 5 years on the CHOP INTEND and younger than 2 years on the HINE-2. Interpretation: Our results, expanding the age range and the severity of type I patients treated with nusinersen over 1 year, provide additional data on the range of efficacy of the drug that will be helpful in making an informed decision on whether to start treatment in patients of different ages and severity.

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Section: Discussionmentioning

confidence: 89%

“…[13][14][15][16] In contrast, over 60% of the 84 patients improved 2 points, and over 50% improved more than 2 points. This is different from what was reported in untreated infants and children in natural history studies.…”

Section: Discussionmentioning

confidence: 90%

Nusinersen in type 1 spinal muscular atrophy: Twelve‐month real‐world data

Pane

Coratti

Sansone

et al. 2019

Annals of Neurology

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103

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“…Most infants with spinal muscular atrophy type 1 are unable to achieve or maintain most motor milestones. 6 Several of the infants in the nusinersen group achieved clinically meaningful motor milestones. The increase in the CHOP INTEND score and the CMAP amplitude among infants who received nusinersen confirms that nusinersen improves neuromuscular function.…”

Section: Discussionmentioning

confidence: 98%

“…5,6,12,15,16 Although the HINE-2 was not specifically developed to assess motor function in infants with spinal muscular atrophy, 13 it can be used to identify incremental changes in the achievement of motor milestones that are relevant among infants with spinal muscular atrophy type 1, 12 and the HINE-2 assessment can be performed reliably in a multicenter study.…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5] New developmental motor milestones are rarely achieved after diagnosis. 6 Spinal muscular atrophy is caused by a homozygous deletion or mutation in the survival motor neuron 1 (SMN1) gene, which results in decreased expression of the survival motor neuron (SMN) protein and degeneration of motor neurons in the spinal cord and brain stem. 7,8 A paralogous gene, survival motor neuron 2 (SMN2), also encodes the SMN protein; however, 90 to 95% of the translated protein is truncated and nonfunctional as a result of aberrant splicing.…”

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Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy

Finkel¹,

Mercuri²,

Darras³

et al. 2017

N Engl J Med

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BACKGROUNDSpinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. METHODSWe conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. RESULTSIn the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P = 0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P = 0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONSAmong infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074.)

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Response of plasmamicroRNAsto nusinersen treatment in patients withSMA

Zaharieva

Scoto

Aragon-Gawinska

et al. 2022

Ann Clin Transl Neurol

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Objective Spinal muscular atrophy (SMA) is a common genetic cause of infant mortality. Nusinersen treatment ameliorates the clinical outcome of SMA, however, some patients respond well, while others have limited response. We investigated microRNAs in blood samples from SMA patients and their response to nusinersen treatment evaluating the potential of circulating microRNAs as biomarkers for SMA. Methods In a discovery cohort study, microRNA next‐generation sequencing was performed in blood samples from SMA patients (SMA type 2, n = 10; SMA type 3, n = 10) and controls (n = 7). The dysregulated microRNAs were further analysed in the therapeutic response cohort comprised of SMA type 1 patients (n = 22) who had received nusinersen treatment, at three time points along the treatment course (baseline, 2 and 6 months of treatment). The levels of the studied microRNAs were correlated to the SMA clinical outcome measures. Results In the discovery cohort, 69 microRNAs were dysregulated between SMA patients and controls. In the therapeutic response cohort, the baseline plasma levels of miR‐107, miR‐142‐5p, miR‐335‐5p, miR‐423‐3p, miR‐660‐5p, miR‐378a‐3p and miR‐23a‐3p were associated with the 2 and 6 months response to nusinersen treatment. Furthermore, the levels of miR‐107, miR‐142‐5p, miR‐335‐5p, miR‐423‐3p, miR‐660‐5p and miR‐378‐3p at 2 months of treatment were associated with the response after 6 months of nusinersen treatment. Interpretation Blood microRNAs could be used as biomarkers to indicate SMA patients’ response to nusinersen and to monitor the efficacy of the therapeutic intervention. In addition, some of these microRNAs provide insight into processes involved in SMA that could be exploited as novel therapeutic targets.

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Developmental milestones in type I spinal muscular atrophy

Abstract: HighlightsThis paper reports patterns of natural progression in type I SMA.The HINE is used to capture motor developmental milestones in SMA.Motor developmental milestones are rarely acquired in type I SMA infants.

Cited by 108 publications

References 13 publications

Nusinersen in type 1 spinal muscular atrophy: Twelve‐month real‐world data

Nusinersen in type 1 spinal muscular atrophy: Twelve‐month real‐world data

Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy

Response of plasmamicroRNAsto nusinersen treatment in patients withSMA

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