Clinical Variability in Spinal Muscular Atrophy Type <scp>III</scp>

Coratti, Giorgia; Messina, Sonia; Lucibello, Simona; Pera, Maria Carmela; Montes, Jacqueline; Pasternak, Amy; Bovis, Francesca; Expósito‐Escudero, Jessica; Mazzone, Elena; Mayhew, Anna; Glanzman, Allan M.; Young, Sally Dunaway; Salazar, Rachel; Duong, Tina; Lofra, Robert Muni; Sanctis, Roberto De; Carnicella, Sara; Milev, Evelin; Civitello, Matthew; Pane, Marika; Scoto, Mariacristina; Bettolo, C. Marini; Antonaci, Laura; Frongia, A.; Sframeli, Maria; Vita, Gianluca; D’Amico, Adele; Hauwe, M. van den; Albamonte, Emilio; Goemans, Nathalie; Darras, Basil T.; Bertini, E.; Sansone, Valeria; Day, John W.; Osorio, A. Nascimento; Bruno, Claudio; Muntoni, Francesco; Vivo, Darryl C. De; Finkel, Richard S.; Mercuri, Eugenio

doi:10.1002/ana.25900

Cited by 44 publications

(57 citation statements)

References 33 publications

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“…Studies with a larger sample size and further analyses are needed to confirm whether this demonstrates a peak in grip strength as shown in previous findings, where upper limb strength (expressed in absolute values) increased before the age of 14 and decreased after 21 . Similarly, a recent, retrospective study in patients with Type 3 SMA demonstrated increased motor function, as measured by the HFMSE, up to the age of 7 and a decrease beyond this age 35 . A similar time course in motor function has been observed in DMD, where the distance covered in a 6MWT continuously increased before the age of 7 and decreased thereafter 37 .…”

Section: Discussionsupporting

confidence: 59%

“…Current clinical measures have a low sensitivity to change over 12 months: the SRM of the RULM over 12 months is 0.14 33 and the mean change in the 6MWT over 12 months is low (−7.8 m/year) and age dependent 34 . A recent study has also illustrated that the SRM of HFMSE in patients with Type 3 SMA is low and very variable according to age and ambulant status 35 . In this study, we aim to identify additional ways to detect a change in SMA severity over shorter periods.…”

Section: Discussionmentioning

confidence: 99%

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Natural history of Type 2 and 3 spinal muscular atrophy: 2‐year NatHis‐SMA study

Annoussamy

Seferian

Daron

et al. 2020

Ann Clin Transl Neurol

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Objective To characterize the natural history of spinal muscular atrophy (SMA) over 24 months using innovative measures such as wearable devices, and to provide evidence for the sensitivity of these measures to determine their suitability as endpoints in clinical trials. Methods Patients with Type 2 and 3 SMA (N = 81) with varied functional abilities (sitters, nonsitters, nonambulant, and ambulant) who were not receiving disease‐modifying treatment were assessed over 24 months: motor function (Motor Function Measure [MFM]), upper limb strength (MyoGrip, MyoPinch), upper limb activity (ActiMyo®), quantitative magnetic resonance imaging (fat fraction [FFT2] mapping and contractile cross‐sectional area [C‐CSA]), pulmonary function (forced vital capacity [FVC], peak cough flow, maximum expiratory pressure, maximum inspiratory pressure, and sniff nasal inspiratory pressure), and survival of motor neuron (SMN) protein levels. Results MFM32 scores declined significantly over 24 months, but not 12 months. Changes in upper limb activity could be detected over 6 months and continued to decrease significantly over 12 months, but not 24 months. Upper limb strength decreased significantly over 12 and 24 months. FVC declined significantly over 12 months, but not 24 months. FFT2 increased over 12 and 24 months, although not with statistical significance. A significant increase in C‐CSA was observed at 12 but not 24 months. Blood SMN protein levels were stable over 12 and 24 months. Interpretation These data demonstrate that the MFM32, MyoGrip, MyoPinch, and ActiMyo® enable the detection of a significant decline in patients with Type 2 and 3 SMA over 12 or 24 months.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Natural history of Type 2 and 3 spinal muscular atrophy: 2‐year NatHis‐SMA study

Annoussamy

Seferian

Daron

et al. 2020

Ann Clin Transl Neurol

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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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“…While any improvement in a neurodegenerative disease could be regarded as a treatment effect, previous natural history studies have shown that individual improvements in some motor scales in a timeframe less of that two years are not infrequent in the adult population. 18, [28][29][30][31] Moreover, in the last years, treatments such as salbutamol or pyridostigmine are frequently used off-label for the treatment of SMA patients and could have a positive effect in motor scales, 32 erroneously attributed to nusinersen. Accordingly, a recent systematic review highlighted that the scarcity of data, the phenotypic variability, slow disease progression and the limited sensitivity of available outcome measures difficult to draw definitive conclusions about the natural history of the disease in short timeframes.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, our and previous natural history studies show that a non-negligible proportion of "untreated" adult patients experience improvements that could be considered clinically meaningful, when followed for less than two years. 18, [28][29][30][31] These unexpected improvements could be due to three facts: test-retest inaccuracies in the scales; functional fluctuations, which are frequently reported by patients (e.g. depending on the season of the year); or to the fact that some "untreated" patients have actually started other treatments (e.g.…”

Section: Discussionmentioning

confidence: 99%

Nusinersen in adult patients with 5q spinal muscular atrophy: a multicenter observational cohorts’ study

Povedano

et al. 2021

Preprint

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Objective To assess safety and efficacy of nusinersen in adult 5q spinal muscular atrophy (SMA) patients. Methods Patients older than 15 years and followed at least for 6 months with one motor scale (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb module, RULM) in five referral centers were included. Clinical and patients global impression of change (CGI-C and PGI-C) were recorded in treated patients at the last visit. Functional scales (Egen Klassification, EK2; Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, ALSFRS-R) and the percent-predicted forced vital capacity were collected when available. Results Seventy-nine SMA patients (39 treated with nusinersen) were included. Compared with untreated patients, treated patients showed a significant improvement of 2 points (±0.46) in RULM (p<0.001) after six months. After a mean follow-up of 16 months, nusinersen treatment was associated with a significant improvement in HFMSE (OR=1.15, p=0.006), 6MWT (OR=1.07, p<0.001), and EK2 (OR=0.81, p=0.001). Compared with untreated patients, more treated patients experienced clinically meaningful improvements in all scales, but these differences were statistically significant only for RULM (p=0.033), ALSFRS-R (p=0.005), and EK2 (p<0.001). According to the CGI-C and PGI-C, 64.1% and 61.5% of treated patients improved with treatment. Being non-sitter was associated with less response to treatment, while longer time of treatment was associated with better response. Most treated patients (77%) presented at least one adverse event, mostly mild. Conclusions Nusinersen treatment associates to some improvements in adult SMA patients. Most severely affected patients with complex spines are probably those with the most unfavorable risk-benefit ratio.

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Clinical Variability in Spinal Muscular Atrophy Type III

Cited by 44 publications

References 33 publications

Natural history of Type 2 and 3 spinal muscular atrophy: 2‐year NatHis‐SMA study

Natural history of Type 2 and 3 spinal muscular atrophy: 2‐year NatHis‐SMA study

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

Nusinersen in adult patients with 5q spinal muscular atrophy: a multicenter observational cohorts’ study

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