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1. Gain and loss of upper limb abilities in Duchenne muscular dystrophy patients: A 24-month study

Author

Coratti, Giorgia, Pane, Marika, Brogna, Claudia, D'Amico, A., Pegoraro, E., Bello, L., Sansone, V. A., Albamonte, E., Ferraroli, Elisabetta, Mazzone, Elena Stacy, Fanelli, L., Messina, S., Sframeli, M., Catteruccia, M., Cicala, G., Capasso, Anna, Ricci, M., Frosini, S., De Luca, G., Rolle, E., De Sanctis, Roberto, Forcina, N., Norcia, G., Passamano, L., Scutifero, M., Gardani, A., Pini, A., Monaco, G., D'Angelo Bozzi, Michele Giovanni, Leone, D., Zanin, Renata, Vita, G. L., Panicucci, C., Bruno, C., Mongini, T., Ricci, F., Berardinelli, A., Battini, Roberta, Masson, R., Baranello, Giovanni, Dosi, C., Bertini, Enrico Silvio, Nigro, V., Politano, L., Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Pane M. (ORCID:0000-0002-4851-6124), Brogna C., Ferraroli E., Mazzone E. S., Capasso A., De Sanctis R., D'Angelo M. G., Zanin R., Battini R., Baranello G., Bertini E., Mercuri E. (ORCID:0000-0002-9851-5365), Coratti, Giorgia, Pane, Marika, Brogna, Claudia, D'Amico, A., Pegoraro, E., Bello, L., Sansone, V. A., Albamonte, E., Ferraroli, Elisabetta, Mazzone, Elena Stacy, Fanelli, L., Messina, S., Sframeli, M., Catteruccia, M., Cicala, G., Capasso, Anna, Ricci, M., Frosini, S., De Luca, G., Rolle, E., De Sanctis, Roberto, Forcina, N., Norcia, G., Passamano, L., Scutifero, M., Gardani, A., Pini, A., Monaco, G., D'Angelo Bozzi, Michele Giovanni, Leone, D., Zanin, Renata, Vita, G. L., Panicucci, C., Bruno, C., Mongini, T., Ricci, F., Berardinelli, A., Battini, Roberta, Masson, R., Baranello, Giovanni, Dosi, C., Bertini, Enrico Silvio, Nigro, V., Politano, L., Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Pane M. (ORCID:0000-0002-4851-6124), Brogna C., Ferraroli E., Mazzone E. S., Capasso A., De Sanctis R., D'Angelo M. G., Zanin R., Battini R., Baranello G., Bertini E., and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Duchenne muscular dystrophy (DMD) is a neuromuscular condition characterized by muscle weakness. The Performance of upper limb (PUL) test is designed to evaluate upper limb function in DMD patients across three domains. The aim of this study is to identify frequently lost or gained PUL 2.0 abilities at distinct functional stages in DMD patients. This retrospective study analyzed prospectively collected data on 24-month PUL 2.0 changes related to ambulatory function. Ambulant patients were categorized based on initial 6MWT distance, non-ambulant patients by time since ambulation loss. Each PUL 2.0 item was classified as shift up, no change, or shift down. The study's cohort incuded 274 patients, with 626 paired evaluations at the 24-month mark. Among these, 55.1 % had activity loss, while 29.1 % had gains. Ambulant patients showed the lowest loss rates, mainly in the shoulder domain. The highest loss rate was in the shoulder domain in the transitioning subgroup and in elbow and distal domains in the non-ambulant patients. Younger ambulant patients demonstrated multiple gains, whereas in the other functional subgroups there were fewer gains, mostly tied to singular activities. Our findings highlight divergent upper limb domain progression, partly linked to functional status and baseline function.

Published
2024

2. Onasemnogene abeparvovec in spinal muscular atrophy: predictors of efficacy and safety in naïve patients with spinal muscular atrophy and following switch from other therapies

Author

Pane, Marika, Berti, B., Capasso, Anna, Coratti, Giorgia, Varone, A., D'Amico, A., Messina, S., Masson, R., Sansone, V. A., Donati, M. A., Agosto, C., Bruno, C., Ricci, F., Pini, A., Gagliardi, D., Filosto, M., Corti, S., Leone, D., Palermo, C., Onesimo, Roberta, De Sanctis, Roberto, Ricci, Martina, Bitetti, I., Sframeli, M., Dosi, C., Albamonte, E., Ticci, C., Brolatti, N., Bertini, Enrico Silvio, Finkel, R., Mercuri, Eugenio Maria, Pera, Maria Carmela, Bravetti, C., Piastra, Marco, Genovese, Orazio, Cicala, Gianpaolo, Forcina, N., Carnicella, S., Stanca, G., Sacchini, M., Catteruccia, M., Tosi, M., Cutrera, Renato, Chierchi, C., Chiarini, M. B., Salmin, F., Pedemonte, M., Govoni, A., Mizzoni, I., Morando, S., Zanin, R., Rolle, E., Salomon, E., Giannotta, M., Scarpini, G., Toscano, A., Gitto, E., Materia, R., D'Alessandro, R., Pane M. (ORCID:0000-0002-4851-6124), Capasso A., Coratti G. (ORCID:0000-0001-6666-5628), Onesimo R., De Sanctis R., Ricci M., Bertini E., Mercuri E. (ORCID:0000-0002-9851-5365), Pera M. C. (ORCID:0000-0001-6777-1721), Piastra M. (ORCID:0000-0002-3144-8970), Genovese O., Cicala G., Cutrera R., Pane, Marika, Berti, B., Capasso, Anna, Coratti, Giorgia, Varone, A., D'Amico, A., Messina, S., Masson, R., Sansone, V. A., Donati, M. A., Agosto, C., Bruno, C., Ricci, F., Pini, A., Gagliardi, D., Filosto, M., Corti, S., Leone, D., Palermo, C., Onesimo, Roberta, De Sanctis, Roberto, Ricci, Martina, Bitetti, I., Sframeli, M., Dosi, C., Albamonte, E., Ticci, C., Brolatti, N., Bertini, Enrico Silvio, Finkel, R., Mercuri, Eugenio Maria, Pera, Maria Carmela, Bravetti, C., Piastra, Marco, Genovese, Orazio, Cicala, Gianpaolo, Forcina, N., Carnicella, S., Stanca, G., Sacchini, M., Catteruccia, M., Tosi, M., Cutrera, Renato, Chierchi, C., Chiarini, M. B., Salmin, F., Pedemonte, M., Govoni, A., Mizzoni, I., Morando, S., Zanin, R., Rolle, E., Salomon, E., Giannotta, M., Scarpini, G., Toscano, A., Gitto, E., Materia, R., D'Alessandro, R., Pane M. (ORCID:0000-0002-4851-6124), Capasso A., Coratti G. (ORCID:0000-0001-6666-5628), Onesimo R., De Sanctis R., Ricci M., Bertini E., Mercuri E. (ORCID:0000-0002-9851-5365), Pera M. C. (ORCID:0000-0001-6777-1721), Piastra M. (ORCID:0000-0002-3144-8970), Genovese O., Cicala G., and Cutrera R.

Abstract

Background: Efficacy and safety of onasemnogene abeparvovec (OA) for Spinal Muscular Atrophy infants under 7 months and <8.5 kg has been reported in clinical trials. This study examines efficacy and safety predictors in a wide age (22 days–72 months) and weight (3.2–17 kg) range, also including patients previously treated with other drugs. Methods: 46 patients were treated for 12 months between January 2020 and March 2022. Safety profile was also available for another 21 patients with at least 6 month follow-up after OA infusion. 19/67 were treatment naïve when treated with OA. Motor function was measured with the CHOP-INTEND. Findings: CHOP-INTEND changes varied among age groups. Baseline score and age at OA treatment best predicted changes. A mixed model post-hoc analysis showed that in patients treated before the age of 24 months the CHOP-INTEND changes were already significant 3 months after OA while in those treated after the age of 24 months the difference was only significant 12 months after OA. Adverse events occurred in 51/67. The risk for elevated transaminases serum levels was higher in older patients. This was also true for weight and for pre-treatment with nusinersen when analysed individually. A binomial negative regression analysis showed that only age at OA treatment had a significant effect on the risk of elevated transaminases. Interpretation: Our paper describes OA 12-month follow-up showing efficacy across various age and weight groups not targeted by clinical trials. The study identifies prognostic factors for safety and efficacy in treatment selection. Funding: None.

Published
2023

3. Upper Limb Changes in DMD Patients Amenable to Skipping Exons 44, 45, 51 and 53: A 24-Month Study

Author

Brogna, Claudia, Pane, Marika, Coratti, Giorgia, D’Amico, A., Pegoraro, E., Bello, L., Sansone, V. A. M., Albamonte, E., Messina, S., Pini, A., D’Angelo, M. G., Bruno, C., Mongini, T., Ricci, F. S., Berardinelli, A., Battini, Roberta, Masson, R., Bertini, Enrico Silvio, Politano, L., Mercuri, Eugenio Maria, Brogna C., Pane M. (ORCID:0000-0002-4851-6124), Coratti G. (ORCID:0000-0001-6666-5628), Battini R., Bertini E. S., Mercuri E. (ORCID:0000-0002-9851-5365), Brogna, Claudia, Pane, Marika, Coratti, Giorgia, D’Amico, A., Pegoraro, E., Bello, L., Sansone, V. A. M., Albamonte, E., Messina, S., Pini, A., D’Angelo, M. G., Bruno, C., Mongini, T., Ricci, F. S., Berardinelli, A., Battini, Roberta, Masson, R., Bertini, Enrico Silvio, Politano, L., Mercuri, Eugenio Maria, Brogna C., Pane M. (ORCID:0000-0002-4851-6124), Coratti G. (ORCID:0000-0001-6666-5628), Battini R., Bertini E. S., and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Introduction: The Performance of Upper Limb version 2.0 (PUL 2.0) is increasingly used in Duchenne Muscular Dystrophy (DMD) to study longitudinal functional changes of motor upper limb function in ambulant and non-ambulant patients. The aim of this study was to evaluate changes in upper limb functions in patients carrying mutations amenable to skipping exons 44, 45, 51 and 53. Methods: All DMD patients were assessed using the PUL 2.0 for at least 2 years, focusing on 24-month paired visits in those with mutations eligible for skipping exons 44, 45, 51 and 53. Results: 285 paired assessments were available. The mean total PUL 2.0 12-month change was -0.67 (2.80), -1.15 (3.98), -1.46 (3.37) and -1.95 (4.04) in patients carrying mutations amenable to skipping exon 44, 45, 51 and 53, respectively. The mean total PUL 2.0 24-month change was -1.47 (3.73), -2.78 (5.86), -2.95 (4.56) and -4.53 (6.13) in patients amenable to skipping exon 44, 45, 51 and 53, respectively. The difference in PUL 2.0 mean changes among the type of exon skip class for the total score was not significant at 12 months but was significant at 24 months for the total score (p < 0.001), the shoulder (p = 0.01) and the elbow domain (p < 0.001), with patients amenable to skipping exon 44 having smaller changes compared to those amenable to skipping exon 53. There was no difference within ambulant or non-ambulant cohorts when subdivided by exon skip class for the total and subdomains score (p > 0.05). Conclusions: Our results expand the information on upper limb function changes detected by the PUL 2.0 in a relatively large group of DMD patients with distinct exon-skipping classes. This information can be of help when designing clinical trials or in the interpretation of the real world data including non-ambulant patients.

Published
2023

4. Caregivers’ Expectations on Possible Functional Changes following Disease-Modifying Treatment in Type II and III Spinal Muscular Atrophy: A Comparative Study

Author

Pera, Maria Carmela, Coratti, Giorgia, Casiraghi, Jacopo Luca, Bravetti, Chiara, Fedeli, A., Strika, M., Albamonte, E., Antonaci, Laura, Rossi, Dario, Pane, Marika, Sansone, V. A., Mercuri, Eugenio Maria, Pera M. C. (ORCID:0000-0001-6777-1721), Coratti G. (ORCID:0000-0001-6666-5628), Casiraghi J., Bravetti C., Antonaci L., Rossi D., Pane M. (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Pera, Maria Carmela, Coratti, Giorgia, Casiraghi, Jacopo Luca, Bravetti, Chiara, Fedeli, A., Strika, M., Albamonte, E., Antonaci, Laura, Rossi, Dario, Pane, Marika, Sansone, V. A., Mercuri, Eugenio Maria, Pera M. C. (ORCID:0000-0001-6777-1721), Coratti G. (ORCID:0000-0001-6666-5628), Casiraghi J., Bravetti C., Antonaci L., Rossi D., Pane M. (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Background: The primary aim of this study was to explore current caregivers’ expectations on possible functional changes following treatment in comparison to data obtained in the pre-pharmacological era. Methods: A questionnaire, previously used in 2016, was administered to caregivers of type II and III SMA patients of age between 3 and 71 years, and to patients over the age of 13 years. The questionnaire focuses on (1) caregivers and patients expectations, (2) meaningfulness of the changes observed on the functional motor scales, and (3) their willingness to be enrolled in a clinical trial. A comparative study was performed with data obtained using the same questionnaire soon before the advent of disease-modifying therapies. Results: We administered the questionnaire to 150 caregivers. When comparing current caregiver data to those obtained in 2016, the most obvious differences were related to disease perception over the last year (stability: 16.5% in 2016 vs. 43.6% in 2022; deterioration 70.5% vs. 12.8%, and improvement: 12.9% vs. 43.6%) and expectations from clinical trials with higher expectations in 2022 compared to 2016 (p < 0.001). Forty-five of the 150 in the current study were caregivers of patients above the age of 13. In these 45 the questionnaire was also administered to the patient. No difference was found in responses between patients and their caregivers. Conclusions: Both carers and patients reported that even small changes on functional scales, similar to those reported by clinical studies and real-world data, are perceived as meaningful. Comparing the recent responses to those obtained in 2016, before pharmacological treatment was available, we found significant changes in caregivers’ perception with increased expectations. These findings will provide a better understanding of the patients’ expectations and facilitate discussion with regulators.

Published
2023

5. Patient reported outcome measure for upper limb in Duchenne muscular dystrophy: correlation with PUL2.0

Author

Cicala, G., Pane, Marika, Coratti, Giorgia, Brogna, Claudia, Fanelli, L., Norcia, G., Forcina, N., Mazzone, Elena Stacy, Stanca, G., Ferrante, Angela Maria Rosaria, Vento, A., Ferraroli, Elisabetta, Ricci, M., Capasso, Anna, Leone, D., Palermo, Francesco Cesare, Berti, B., Cutrona, Costanza, Mahyew, A., Duong, T., Goemans, N., Vroom, E., Mercuri, Eugenio Maria, Pane M. (ORCID:0000-0002-4851-6124), Coratti G. (ORCID:0000-0001-6666-5628), Brogna C., Mazzone E., Ferrante R. (ORCID:0000-0002-5653-6934), Ferraroli E., Capasso A., Palermo C., Cutrona C., Mercuri E. (ORCID:0000-0002-9851-5365), Cicala, G., Pane, Marika, Coratti, Giorgia, Brogna, Claudia, Fanelli, L., Norcia, G., Forcina, N., Mazzone, Elena Stacy, Stanca, G., Ferrante, Angela Maria Rosaria, Vento, A., Ferraroli, Elisabetta, Ricci, M., Capasso, Anna, Leone, D., Palermo, Francesco Cesare, Berti, B., Cutrona, Costanza, Mahyew, A., Duong, T., Goemans, N., Vroom, E., Mercuri, Eugenio Maria, Pane M. (ORCID:0000-0002-4851-6124), Coratti G. (ORCID:0000-0001-6666-5628), Brogna C., Mazzone E., Ferrante R. (ORCID:0000-0002-5653-6934), Ferraroli E., Capasso A., Palermo C., Cutrona C., and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

The increasing pressure to include non ambulant Duchenne muscular dystrophy (DMD) boys in clinical trials has highlighted the need for outcome measures that could address the impact of upper limb function on activities of daily living. The aim of the present study was to establish the correlation between the recently developed Patient Reported Outcome Measure for the upper limb (PROM UL) and the observer rated functional scale Performance of Upper Limb (PUL 2.0) in a large cohort of DMD boys and young adults. As part of a larger natural history study, non ambulant DMD patients were assessed using PUL2.0 and PROM UL. One hundred and twenty-five concurrent PUL 2.0 and PROM UL evaluations from 60 non ambulant DMD boys were taken into consideration. The total PROM UL scores showed a strong correlation with both PUL 2.0 total scores and with PUL 2.0 entry item score. The strong correlation between the two tools confirms the clinical meaningfulness of the PUL2.0 and that the PROM UL can help to detect the gradient of progression of upper limb involvement.

Published
2023

6. Early treatment of type II SMA slows rate of progression of scoliosis

Author

Coratti, Giorgia, Lenkowicz, Jacopo, Pera, Maria Carmela, D'Amico, A., Bruno, C., Gulli, C., Brolatti, N., Pedemonte, M., Antonaci, Laura, Ricci, M., Capasso, Anna, Cicala, G., Cutrona, Costanza, De Sanctis, Roberto, Carnicella, S., Forcina, N., Cateruccia, M., Damasio, M. B., Labianca, Luca, Manfroni, F., Leone, A., Bertini, Enrico Silvio, Pane, Marika, Patarnello, S., Valentini, V., Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Lenkowicz J., Pera M. C. (ORCID:0000-0001-6777-1721), Antonaci L., Capasso A., Cutrona C., De Sanctis R., Labianca L., Bertini E., Pane M. (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Coratti, Giorgia, Lenkowicz, Jacopo, Pera, Maria Carmela, D'Amico, A., Bruno, C., Gulli, C., Brolatti, N., Pedemonte, M., Antonaci, Laura, Ricci, M., Capasso, Anna, Cicala, G., Cutrona, Costanza, De Sanctis, Roberto, Carnicella, S., Forcina, N., Cateruccia, M., Damasio, M. B., Labianca, Luca, Manfroni, F., Leone, A., Bertini, Enrico Silvio, Pane, Marika, Patarnello, S., Valentini, V., Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Lenkowicz J., Pera M. C. (ORCID:0000-0001-6777-1721), Antonaci L., Capasso A., Cutrona C., De Sanctis R., Labianca L., Bertini E., Pane M. (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Background: Type II spinal muscular atrophy (SMA) often leads to scoliosis in up to 90% of cases. While pharmacological treatments have shown improvements in motor function, their impact on scoliosis progression remains unclear. This study aims to evaluate potential differences in scoliosis progression between treated and untreated SMA II patients. Methods: Treatment effect on Cobb's angle annual changes and on reaching a 50° Cobb angle was analysed in treated and untreated type II SMA patients with a minimum 1.5-year follow-up. A sliding cut-off approach identified the optimal treatment subpopulation based on age, Cobb angle and Hammersmith Functional Motor Scale Expanded at the initial visit. Mann-Whitney U-test assessed statistical significance. Results: There were no significant differences in baseline characteristics between the untreated (n=46) and treated (n=39) populations. The mean Cobb angle variation did not significantly differ between the two groups (p=0.4). Optimal cut-off values for a better outcome were found to be having a Cobb angle <26° or an age <4.5 years. When using optimal cut-off, the treated group showed a lower mean Cobb variation compared with the untreated group (5.61 (SD 4.72) degrees/year vs 10.05 (SD 6.38) degrees/year; p=0.01). Cox-regression analysis indicated a protective treatment effect in reaching a 50° Cobb angle, significant in patients <4.5 years old (p=0.016). Conclusion: This study highlights that pharmacological treatment, if initiated early, may slow down the progression of scoliosis in type II SMA patients. Larger studies are warranted to further investigate the effectiveness of individual pharmacological treatment on scoliosis progression in this patient population.

Published
2023

7. Profile of cognitive abilities in spinal muscular atrophy type II and III: what is the role of motor impairment?

Author

Buchignani, B., Cicala, G., Moriconi, Federica, Ricci, M., Capasso, Anna, Coratti, Giorgia, Casiraghi, Jacopo Luca, Albamonte, E., Cristofani, P., Cutrona, Costanza, Pera, Maria Carmela, Antonaci, Laura, Roncoroni, C., Chieffo, Daniela Pia Rosaria, Sansone, V. A., Battini, Roberta, Pane, Marika, Mercuri, Eugenio Maria, Moriconi F., Capasso A., Coratti G. (ORCID:0000-0001-6666-5628), Casiraghi J., Cutrona C., Pera M. C. (ORCID:0000-0001-6777-1721), Antonaci L., Chieffo D., Battini R., Pane M. (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Buchignani, B., Cicala, G., Moriconi, Federica, Ricci, M., Capasso, Anna, Coratti, Giorgia, Casiraghi, Jacopo Luca, Albamonte, E., Cristofani, P., Cutrona, Costanza, Pera, Maria Carmela, Antonaci, Laura, Roncoroni, C., Chieffo, Daniela Pia Rosaria, Sansone, V. A., Battini, Roberta, Pane, Marika, Mercuri, Eugenio Maria, Moriconi F., Capasso A., Coratti G. (ORCID:0000-0001-6666-5628), Casiraghi J., Cutrona C., Pera M. C. (ORCID:0000-0001-6777-1721), Antonaci L., Chieffo D., Battini R., Pane M. (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

There has recently been some concern on possible cognitive impairment in patients with Spinal Muscular Atrophy (SMA). The aim of this study was to assess cognitive profiles in type II and III SMA with a focus on individual indexes and possible correlations with motor function. 57 type II and III individuals, aged 3.5–17 years, were consecutively enrolled in a prospective, multicentric study. Cognitive function was assessed using age-appropriate Weschler Scales. Motor function was concomitantly assessed using disease-specific functional scales. Only 2 individuals (3%) had a intellectual disability of mild degree while the others were within normal range, with no significant difference in relation to SMA type, gender or functional status. While the overall quotients were mostly within normal range, some indexes showed wider variability. A significant positive medium correlation was found between Processing Speed Index and motor functional scores. Working memory had lower scores in type III patients compared to type II. Intellectual disability is uncommon in type II and III SMA. Motor functional abilities may play a role in some of the items contributing to the overall cognitive profile.

Published
2023

8. Correction to: Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study (Neurology and Therapy, (2023), 12, 2, (543-557), 10.1007/s40120-023-00444-1)

Author

Chiriboga, C. A., Bruno, C., Duong, T., Fischer, D., Mercuri, Eugenio Maria, Kirschner, J., Kostera-Pruszczyk, A., Jaber, B., Gorni, K., Kletzl, H., Carruthers, I., Martin, Craig, Warren, F., Scalco, R. S., Wagner, K. R., Muntoni, F., Deconinck, N., Balikova, I., Joniau, I., Tahon, V., Wittevrongel, S., Goemans, N., Cassiman, C., Prove, L., Vancampenhout, L., van den Hauwe, M., Van Impe, A., Cances, C., Soler, V., De La Morandais, L. M., Vovan, D., Cintas, P., Auriol, F., Mus, M., Alphonsa, G., Bellio, V., Gil Mato, O., Flamein, F., Evrard, C., Ziouche, A., Bouacha-Allou, I., Debruyne, P., Derlyn, G., Defoort, S., Leroy, F., Danjoux, L., Desguerre, I., Bremond-Gignac, D., Rateuax, M., Deladriere, E., Vuillerot, C., Veillerot, Q., Sibille-Dabadi, B., Barriere, A., Tinat, M., Saidi, M., Fontaine, S., De Montferrand, C., Le-Goff, L., Portefaix, A., Louvier, U. W., Duval, P. -A., Caradec, P., Touati, S., Herranz, A. Z., Bollig, J., Molnar, F., Vogt, S., Pechmann, A., Schorling, D., Wider, S., Kolbel, H., Schara, U., Braun, F., Gangfuss, A., Hagenacker, T., Eckstein, A., Dekowski, D., Oeverhaus, M., Stoehr, M., Andres, B., Smuda, K., Bertini, Enrico Silvio, D'Amico, A., Petroni, S., Valente, Paola, Bonetti, A. M., Carlesi, A., Mizzoni, I., Pedemonte, M., Brolatti, N., Priolo, E., Rao, G., Sposetti, L., Morando, S., Comi, G., Osnaghi, S., Minorini, V., Abbati, F., Fassini, F., Foa, M., Lopopolo, M. A., Magri, F., Govoni, A., Meneri, M., Parente, V., Antonaci, Laura, Pera, Maria Carmela, Pane, Marika, Amorelli, Giulia Maria, Barresi, C., D'Amico, Guglielmo, Orazi, Lorenzo, Coratti, Giorgia, De Sanctis, Roberto, Vita, G., Sframeli, M., Vita, G. L., Aragona, P., Inferrera, L., Postorino, E. I., Montanini, D., Di Bella, V., Donato, C., Cala, E., Van der Pol, L., Aalbers, J., de Boer, J., Imhof, S., Cooijmans, P., Ruyten, T., Van Der Woude, D., Klimaszewska, B., Romanczak, D., Gierlak-Wojcicka, Z., Kepa, M., Sikorski, A., Sobieraj, M., Lusakowska, A., Kierdaszuk, B., Czeczko, K., Henzi, B., Gugleta, K., Kusnyerik, A., Siems, P., Akos, S., Frei, N., Seppi, C., Haschke, C. W., Guglieri, M., Straub, V., Bell, R., Nassar, M., Page, S., Clarke, M. P., Regan, A., Mayhew, A., Lofra, R. M., Parasuraman, D., Bruschi, Sara, Ghauri, A. -J., Castle, A., Naqvi, S., Patt, N., Scoto, M., Trucco, F., Henderson, R. H., Kukadia, R., Moore, W., Milev, E., Rye, C., Selby, V., Wolfe, A., Darras, B., Baglieri, A. M., Fulton, A., Lucken, C., Maczek, E., Pasternak, A., Kane, S., Bautista, M. E. M., Frommer, E., Pensec, N., Salazar, R., Yochai, C., Rodrigues-Torres, R., Chawla, M., Day, J., Beres, S., Gee, R., Young, S. D., Finkel, R., Nazario, A. N., Fasiuddin, A., Wells, J. A., Wilson, J., Berry, D., Rizzo, V., Duke, J., Monduy, M., Collado, J., Mercuri E. (ORCID:0000-0002-9851-5365), Martin C., Bertini E., Valente P., Antonaci L., Pera M. C. (ORCID:0000-0001-6777-1721), Pane M. (ORCID:0000-0002-4851-6124), Amorelli G. M., D'Amico G., Orazi L., Coratti G. (ORCID:0000-0001-6666-5628), De Sanctis R., Bruschi S., Chiriboga, C. A., Bruno, C., Duong, T., Fischer, D., Mercuri, Eugenio Maria, Kirschner, J., Kostera-Pruszczyk, A., Jaber, B., Gorni, K., Kletzl, H., Carruthers, I., Martin, Craig, Warren, F., Scalco, R. S., Wagner, K. R., Muntoni, F., Deconinck, N., Balikova, I., Joniau, I., Tahon, V., Wittevrongel, S., Goemans, N., Cassiman, C., Prove, L., Vancampenhout, L., van den Hauwe, M., Van Impe, A., Cances, C., Soler, V., De La Morandais, L. M., Vovan, D., Cintas, P., Auriol, F., Mus, M., Alphonsa, G., Bellio, V., Gil Mato, O., Flamein, F., Evrard, C., Ziouche, A., Bouacha-Allou, I., Debruyne, P., Derlyn, G., Defoort, S., Leroy, F., Danjoux, L., Desguerre, I., Bremond-Gignac, D., Rateuax, M., Deladriere, E., Vuillerot, C., Veillerot, Q., Sibille-Dabadi, B., Barriere, A., Tinat, M., Saidi, M., Fontaine, S., De Montferrand, C., Le-Goff, L., Portefaix, A., Louvier, U. W., Duval, P. -A., Caradec, P., Touati, S., Herranz, A. Z., Bollig, J., Molnar, F., Vogt, S., Pechmann, A., Schorling, D., Wider, S., Kolbel, H., Schara, U., Braun, F., Gangfuss, A., Hagenacker, T., Eckstein, A., Dekowski, D., Oeverhaus, M., Stoehr, M., Andres, B., Smuda, K., Bertini, Enrico Silvio, D'Amico, A., Petroni, S., Valente, Paola, Bonetti, A. M., Carlesi, A., Mizzoni, I., Pedemonte, M., Brolatti, N., Priolo, E., Rao, G., Sposetti, L., Morando, S., Comi, G., Osnaghi, S., Minorini, V., Abbati, F., Fassini, F., Foa, M., Lopopolo, M. A., Magri, F., Govoni, A., Meneri, M., Parente, V., Antonaci, Laura, Pera, Maria Carmela, Pane, Marika, Amorelli, Giulia Maria, Barresi, C., D'Amico, Guglielmo, Orazi, Lorenzo, Coratti, Giorgia, De Sanctis, Roberto, Vita, G., Sframeli, M., Vita, G. L., Aragona, P., Inferrera, L., Postorino, E. I., Montanini, D., Di Bella, V., Donato, C., Cala, E., Van der Pol, L., Aalbers, J., de Boer, J., Imhof, S., Cooijmans, P., Ruyten, T., Van Der Woude, D., Klimaszewska, B., Romanczak, D., Gierlak-Wojcicka, Z., Kepa, M., Sikorski, A., Sobieraj, M., Lusakowska, A., Kierdaszuk, B., Czeczko, K., Henzi, B., Gugleta, K., Kusnyerik, A., Siems, P., Akos, S., Frei, N., Seppi, C., Haschke, C. W., Guglieri, M., Straub, V., Bell, R., Nassar, M., Page, S., Clarke, M. P., Regan, A., Mayhew, A., Lofra, R. M., Parasuraman, D., Bruschi, Sara, Ghauri, A. -J., Castle, A., Naqvi, S., Patt, N., Scoto, M., Trucco, F., Henderson, R. H., Kukadia, R., Moore, W., Milev, E., Rye, C., Selby, V., Wolfe, A., Darras, B., Baglieri, A. M., Fulton, A., Lucken, C., Maczek, E., Pasternak, A., Kane, S., Bautista, M. E. M., Frommer, E., Pensec, N., Salazar, R., Yochai, C., Rodrigues-Torres, R., Chawla, M., Day, J., Beres, S., Gee, R., Young, S. D., Finkel, R., Nazario, A. N., Fasiuddin, A., Wells, J. A., Wilson, J., Berry, D., Rizzo, V., Duke, J., Monduy, M., Collado, J., Mercuri E. (ORCID:0000-0002-9851-5365), Martin C., Bertini E., Valente P., Antonaci L., Pera M. C. (ORCID:0000-0001-6777-1721), Pane M. (ORCID:0000-0002-4851-6124), Amorelli G. M., D'Amico G., Orazi L., Coratti G. (ORCID:0000-0001-6666-5628), De Sanctis R., and Bruschi S.

Abstract

In this article the JEWELFISH Study Group members were missing in the Acknowledgements. The collaborator names are corrected in the supplementary material and the complete list is given below. In Table 1, footnote symbol ‘g’ was incorrectly written as ‘f’ in the entries Non-sitters—2 (14)g and Sitters-12 (86)g under column Onasemnogene abeparvovec of section Motor function, n (%)f. The original article has been corrected.

Published
2023

9. Clinical Phenotype of Pediatric and Adult Patients With Spinal Muscular Atrophy With Four SMN2 Copies: Are They Really All Stable?

Author

Ricci, M., Cicala, G., Capasso, Anna, Coratti, Giorgia, Fiori, Simona, Cutrona, Costanza, D'Amico, A., Sansone, V. A., Bruno, C., Messina, S., Mongini, T., Coccia, M., Siciliano, Giovanni, Pegoraro, E., Masson, R., Filosto, M., Comi, G. P., Corti, Serafino, Ronchi, D., Maggi, L., D'Angelo Bozzi, Michele Giovanni, Vacchiano, V., Ticci, C., Ruggiero, L., Verriello, L., Ricci, F. S., Berardinelli, A. L., Maioli, M. A., Garibaldi, Ida Marina Elisabetta, Nigro, V., Previtali, S. C., Pera, Maria Carmela, Tizzano, E., Pane, Marika, Tiziano, Francesco Danilo, Mercuri, Eugenio Maria, Capasso A., Coratti G. (ORCID:0000-0001-6666-5628), Fiori S., Cutrona C., Siciliano G., Corti S., D'Angelo M. G., Garibaldi M., Pera M. C. (ORCID:0000-0001-6777-1721), Pane M. (ORCID:0000-0002-4851-6124), Tiziano F. D. (ORCID:0000-0002-5545-6158), Mercuri E. (ORCID:0000-0002-9851-5365), Ricci, M., Cicala, G., Capasso, Anna, Coratti, Giorgia, Fiori, Simona, Cutrona, Costanza, D'Amico, A., Sansone, V. A., Bruno, C., Messina, S., Mongini, T., Coccia, M., Siciliano, Giovanni, Pegoraro, E., Masson, R., Filosto, M., Comi, G. P., Corti, Serafino, Ronchi, D., Maggi, L., D'Angelo Bozzi, Michele Giovanni, Vacchiano, V., Ticci, C., Ruggiero, L., Verriello, L., Ricci, F. S., Berardinelli, A. L., Maioli, M. A., Garibaldi, Ida Marina Elisabetta, Nigro, V., Previtali, S. C., Pera, Maria Carmela, Tizzano, E., Pane, Marika, Tiziano, Francesco Danilo, Mercuri, Eugenio Maria, Capasso A., Coratti G. (ORCID:0000-0001-6666-5628), Fiori S., Cutrona C., Siciliano G., Corti S., D'Angelo M. G., Garibaldi M., Pera M. C. (ORCID:0000-0001-6777-1721), Pane M. (ORCID:0000-0002-4851-6124), Tiziano F. D. (ORCID:0000-0002-5545-6158), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Objective: The aim of this study was to provide an overview of the clinical phenotypes associated with 4 SMN2 copies. Methods: Clinical phenotypes were analyzed in all the patients with 4 SMN2 copies as part of a nationwide effort including all the Italian pediatric and adult reference centers for spinal muscular atrophy (SMA). Results: The cohort includes 169 patients (102 men and 67 women) with confirmed 4 SMN2 copies (mean age at last follow-up = 36.9 ± 19 years). Six of the 169 patients were presymptomatic, 8 were classified as type II, 145 as type III (38 type IIIA and 107 type IIIB), and 8 as type IV. The remaining 2 patients were asymptomatic adults identified because of a familial case. The cross-sectional functional data showed a reduction of scores with increasing age. Over 35% of the type III and 25% of the type IV lost ambulation (mean age = 26.8 years ± 16.3 SD). The risk of loss of ambulation was significantly associated with SMA type (p < 0.0001), with patients with IIIB and IV less likely to lose ambulation compared to type IIIA. There was an overall gender effect with a smaller number of women and a lower risk for women to lose ambulation. This was significant in the adult (p = 0.009) but not in the pediatric cohort (p = 0.43). Interpretation: Our results expand the existing literature on natural history of 4 SMN2 copies confirming the variability of phenotypes in untreated patients, ranging from type II to type IV and an overall reduction of functional scores with increasing age. ANN NEUROL 2023;94:1126–1135.

Published
2023

10. Language Development in Preschool Duchenne Muscular Dystrophy Boys

Author

Chieffo, Daniela Pia Rosaria, Moriconi, F., Mastrilli, L., Lino, F., Brogna, Claudia, Coratti, Giorgia, Altobelli, M., Massaroni, V., Norcia, G., Ferraroli, Elisabetta, Lucibello, Simona, Pane, Marika, Mercuri, Eugenio Maria, Chieffo D. P. R., Brogna C., Coratti G. (ORCID:0000-0001-6666-5628), Ferraroli E., Lucibello S., Pane M. (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Chieffo, Daniela Pia Rosaria, Moriconi, F., Mastrilli, L., Lino, F., Brogna, Claudia, Coratti, Giorgia, Altobelli, M., Massaroni, V., Norcia, G., Ferraroli, Elisabetta, Lucibello, Simona, Pane, Marika, Mercuri, Eugenio Maria, Chieffo D. P. R., Brogna C., Coratti G. (ORCID:0000-0001-6666-5628), Ferraroli E., Lucibello S., Pane M. (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Background: the present study aims to assess language in preschool-aged Duchenne muscular dystrophy (DMD) boys with normal cognitive quotients, and to establish whether language difficulties are related to attentional aspects or to the involvement of brain dystrophin isoforms. Methods: 20 children aged between 48 and 72 months were assessed with language and attention assessments for preschool children. Nine had a mutation upstream of exon 44, five between 44 and 51, four between 51 and 63, and two after exon 63. A control group comprising 20 age-matched boys with a speech language disorder and normal IQ were also used. Results: lexical and syntactic comprehension and denomination were normal in 90% of the boys with Duchenne, while the articulation and repetition of long words, and sentence repetition frequently showed abnormal results (80%). Abnormal results were also found in tests assessing selective and sustained auditory attention. Language difficulties were less frequent in patients with mutations not involving isoforms Dp140 and Dp71. The profile in Duchenne boys was different form the one observed in SLI with no cognitive impairment. Conclusion: The results of our observational cross-sectional study suggest that early language abilities are frequently abnormal in preschool Duchenne boys and should be assessed regardless of their global neurodevelopmental quotient.

Published
2022

11. Assessing floppy infants: a new module

Author

Cutrona, Costanza, Pede, Elisa, De Sanctis, Roberto, Coratti, Giorgia, Tiberi, Eloisa, Luciano, Rita Paola Maria, Pera, Maria Carmela, Velli, Chiara, Capasso, Anna, Vento, Giovanni, Romeo, Domenico Marco, Pane, Marika, Mercuri, Eugenio Maria, Cutrona C., Pede E., De Sanctis R., Coratti G. (ORCID:0000-0001-6666-5628), Tiberi E., Luciano R. (ORCID:0000-0003-4358-0757), Pera M. C. (ORCID:0000-0001-6777-1721), Velli C., Capasso A., Vento G. (ORCID:0000-0002-8132-5127), Romeo D. M. (ORCID:0000-0002-6229-1208), Pane M. (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Cutrona, Costanza, Pede, Elisa, De Sanctis, Roberto, Coratti, Giorgia, Tiberi, Eloisa, Luciano, Rita Paola Maria, Pera, Maria Carmela, Velli, Chiara, Capasso, Anna, Vento, Giovanni, Romeo, Domenico Marco, Pane, Marika, Mercuri, Eugenio Maria, Cutrona C., Pede E., De Sanctis R., Coratti G. (ORCID:0000-0001-6666-5628), Tiberi E., Luciano R. (ORCID:0000-0003-4358-0757), Pera M. C. (ORCID:0000-0001-6777-1721), Velli C., Capasso A., Vento G. (ORCID:0000-0002-8132-5127), Romeo D. M. (ORCID:0000-0002-6229-1208), Pane M. (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Our aim was to develop a new module for assessing the floppy infant, to describe the application of the module in a cohort of low-risk newborns and piloting the module in a cohort of floppy infants. The module was applied to a cohort of 143 low-risk newborns and piloted in in a cohort of 24 floppy infants. The new add-on module includes a neurological section and provides a section for recording information obtained by physical examination and antenatal history. For each item, column 1 reports abnormal findings, column 3 normal findings, and column 2 intermediate signs to be followed. Consistent with previous studies, in low-risk infants, none had definitely abnormal or mildly abnormal signs, with the exception of tendon reflexes that were not easily elicitable in 17.14% of term-born infants. Conclusion: Our study suggest that the module can be easily used in a clinical setting as an add-on to the regular neonatal neurological examination in newborns identified as hypotonic on routine examination. Larger cohorts are needed to establish the accuracy of the prognostic value of the module in the differential diagnosis of floppy infant.What is Known:• Hypotonia is one of the key signs in newborns with neuromuscular disorders and can be associated with a wide range of other conditions (central nervous system involvement, genetic and metabolic diseases).• Weakness or/and contractures can identify infants with a neuromuscular disorder and help in the differential diagnosis of floppy infants.What is New:• To date, this is the first attempt to develop and apply a specific neurological module for the assessment of the floppy infant.• The module can be used in a routine clinical setting as an add-on to the regular neurological examination and has potential to differentiate the floppy infants from the low-risk infants.

Published
2022

12. Neurological assessment of newborns with spinal muscular atrophy identified through neonatal screening

Author

Pane, Marika, Donati, M. A., Cutrona, Costanza, De Sanctis, Roberto, Pirinu, M., Coratti, Giorgia, Ricci, Martina, Palermo, C., Berti, B., Leone, D., Ticci, C., Sacchini, M., Cerboneschi, M., Capasso, Anna, Cicala, Gianpaolo, Pera, Maria Carmela, Bravetti, C., Abiusi, Emanuela, Vaisfeld, Alessandro, Vento, Giovanni, Tiziano, Francesco Danilo, Mercuri, Eugenio Maria, Pane M. (ORCID:0000-0002-4851-6124), Cutrona C., De Sanctis R., Coratti G. (ORCID:0000-0001-6666-5628), Ricci M., Capasso A., Cicala G., Pera M. C. (ORCID:0000-0001-6777-1721), Abiusi E. (ORCID:0000-0001-9028-012X), Vaisfeld A., Vento G. (ORCID:0000-0002-8132-5127), Tiziano F. D. (ORCID:0000-0002-5545-6158), Mercuri E. (ORCID:0000-0002-9851-5365), Pane, Marika, Donati, M. A., Cutrona, Costanza, De Sanctis, Roberto, Pirinu, M., Coratti, Giorgia, Ricci, Martina, Palermo, C., Berti, B., Leone, D., Ticci, C., Sacchini, M., Cerboneschi, M., Capasso, Anna, Cicala, Gianpaolo, Pera, Maria Carmela, Bravetti, C., Abiusi, Emanuela, Vaisfeld, Alessandro, Vento, Giovanni, Tiziano, Francesco Danilo, Mercuri, Eugenio Maria, Pane M. (ORCID:0000-0002-4851-6124), Cutrona C., De Sanctis R., Coratti G. (ORCID:0000-0001-6666-5628), Ricci M., Capasso A., Cicala G., Pera M. C. (ORCID:0000-0001-6777-1721), Abiusi E. (ORCID:0000-0001-9028-012X), Vaisfeld A., Vento G. (ORCID:0000-0002-8132-5127), Tiziano F. D. (ORCID:0000-0002-5545-6158), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

The possibility to identify patients with spinal muscular atrophy through neonatal screenings has highlighted the need for clinical assessments that may systematically evaluate the possible presence of early neurological signs. The aim of this study was to use the Hammersmith Neonatal Neurological Examination (HNNE) and a module specifically designed for floppy infants to assess the possible variability of neurological findings in infants identified through neonatal screening. The infants included in this study were identified as part of a pilot study exploring neonatal screening in two Italian regions. A neurological examination was performed using the HNNE and an additional module developed for the assessment of floppy infants. Seventeen infants were identified through the screening. One patient had 1 SMN2 copy, 9 had 2 copies, 3 had 3, and 4 had more than 3 copies. Nine of the 17 infants (53%) had completely normal results on both scales, 3 had minimal signs, and the other 5 had more obvious clinical signs. The number of SMN2 copies was related to the presence of abnormal neurological signs (p = 0.036) but two SMN2 copies were associated with variable clinical signs as they were found in some infants with respectively normal examination or obvious severe early signs. Conclusions: Our results suggest that the combination of both scales increases the possibility to detect neonatal neurological signs and to define different early patterns of involvement also identifying paucisymptomatic patients.What is Known:• The use of new therapeutic options in presymptomatic SMA patients leads to a dramatic reduction of the onset and severity of the diesease.• The already existing tools commonly used in Type I SMA (HINE and CHOP-intend) may not be suitable to identify minor neurological signs in the neonatal period.What is New:• Combining the HNNE and the floppy infant module, we were able to identify early neurological signs in SMA infants identified through newborn screening&

Published
2022

13. Predictive models in SMA II natural history trajectories using machine learning: A proof of concept study

Author

Coratti, Giorgia, Lenkowicz, Jacopo, Patarnello, S., Gulli, C., Pera, Maria Carmela, Masciocchi, Carlotta, Rinaldi, Riccardo, Lovato, V., Leone, Antonio, Cesario, Alfredo, Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Lenkowicz J., Pera M. C. (ORCID:0000-0001-6777-1721), Masciocchi C., Rinaldi R., Leone A. (ORCID:0000-0003-3669-6321), Cesario A. (ORCID:0000-0003-4687-0709), Mercuri E. (ORCID:0000-0002-9851-5365), Coratti, Giorgia, Lenkowicz, Jacopo, Patarnello, S., Gulli, C., Pera, Maria Carmela, Masciocchi, Carlotta, Rinaldi, Riccardo, Lovato, V., Leone, Antonio, Cesario, Alfredo, Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Lenkowicz J., Pera M. C. (ORCID:0000-0001-6777-1721), Masciocchi C., Rinaldi R., Leone A. (ORCID:0000-0003-3669-6321), Cesario A. (ORCID:0000-0003-4687-0709), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

It is known from previous literature that type II Spinal Muscular Atrophy (SMA) patients generally, after the age of 5 years, presents a steep deterioration until puberty followed by a relative stability, as most abilities have been lost. Although it is possible to identify points of slope indicating early improvement, steep decline and relative stabilizations, there is still a lot of variability within each age group and it’s not always possible to predict individual trajectories of progression from age only. The aim of the study was to develop a predictive model based on machine learning using an XGBoost algorithm for regression and report, explore and quantify, in a single centre longitudinal natural history study, the influence of clinical variables on the 6/12-months Hammersmith Motor Functional Scale Expanded score prediction (HFMSE). This study represents the first approach to artificial intelligence and trained models for the prediction of individualized trajectories of HFMSE disease progression using individual characteristics of the patient. The application of this method to larger cohorts may allow to identify different classes of progression, a crucial information at the time of the new commercially available therapies.

Published
2022

14. Hammersmith Infant Neurological Examination in low-risk infants born very preterm: a longitudinal prospective study

Author

Romeo, Domenico Marco, Apicella, Massimo, Velli, Chiara, Brogna, Claudia, Ricci, Daniela, Pede, Elisa, Sini, F., Coratti, Giorgia, Gallini, Francesca, Cota, Francesco, Bovis, F., Vento, Giovanni, Mercuri, Eugenio Maria, Romeo D. M. (ORCID:0000-0002-6229-1208), Apicella M., Velli C., Brogna C., Ricci D., Pede E., Coratti G. (ORCID:0000-0001-6666-5628), Gallini F. (ORCID:0000-0002-9510-8481), Cota F. (ORCID:0000-0002-9009-3997), Vento G. (ORCID:0000-0002-8132-5127), Mercuri E. (ORCID:0000-0002-9851-5365), Romeo, Domenico Marco, Apicella, Massimo, Velli, Chiara, Brogna, Claudia, Ricci, Daniela, Pede, Elisa, Sini, F., Coratti, Giorgia, Gallini, Francesca, Cota, Francesco, Bovis, F., Vento, Giovanni, Mercuri, Eugenio Maria, Romeo D. M. (ORCID:0000-0002-6229-1208), Apicella M., Velli C., Brogna C., Ricci D., Pede E., Coratti G. (ORCID:0000-0001-6666-5628), Gallini F. (ORCID:0000-0002-9510-8481), Cota F. (ORCID:0000-0002-9009-3997), Vento G. (ORCID:0000-0002-8132-5127), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Aim: To describe the profile of global and single items of the Hammersmith Infant Neurological Examination (HINE) in a population of low-risk infants born very preterm during the first year of life. Method: The HINE was performed at 3, 6, 9, and 12 months’ corrected age in a population of low-risk infants born preterm with a gestational age of fewer than 32 weeks and with normal or minimal changes on neuroimaging. Results: A total of 174 infants born preterm (96 males, 78 females; mean gestational age = 27 weeks [SD = 1.8], range 23–31 weeks) fulfilled the inclusion criteria. The 10th centile cut-off score with median and range was reported for the HINE global and subsection scores. A progressive increase in global HINE scores was observed. Most of the single items, especially those related to tone, posture, and reflexes, showed progressive maturation. Interpretation: Our results, which provide longitudinal data for single-item and global scores in a population of low-risk infants born very preterm, can be used as a reference in both clinical and research settings to monitor early neurological signs in these infants. These data could be used as normative data when examining low-risk infants born preterm.

Published
2022

15. Body mass index in type 2 spinal muscular atrophy: a longitudinal study

Author

Ferrantini, Gloria, Coratti, Giorgia, Onesimo, Roberta, Lucibello, Simona, Bompard, S., Turrini, Ida, Cicala, Gianpaolo, Caprarelli, Michela, Pera, Maria Carmela, Bravetti, C., Berti, B., Giorgio, Valentina, Bruno, C., Brolatti, N., Panicucci, C., D'Amico, Adele, Longo, A., Leoni, Chiara, Sansone, V. A., Albamonte, E., Messina, S., Sframeli, M., Bertini, E., Pane, Marika, Mercuri, Eugenio Maria, Ferrantini G., Coratti G. (ORCID:0000-0001-6666-5628), Onesimo R., Lucibello S., Turrini I., Cicala G., Caprarelli M., Pera M. C. (ORCID:0000-0001-6777-1721), Giorgio V., D'Amico A., Leoni C., Pane M. (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Ferrantini, Gloria, Coratti, Giorgia, Onesimo, Roberta, Lucibello, Simona, Bompard, S., Turrini, Ida, Cicala, Gianpaolo, Caprarelli, Michela, Pera, Maria Carmela, Bravetti, C., Berti, B., Giorgio, Valentina, Bruno, C., Brolatti, N., Panicucci, C., D'Amico, Adele, Longo, A., Leoni, Chiara, Sansone, V. A., Albamonte, E., Messina, S., Sframeli, M., Bertini, E., Pane, Marika, Mercuri, Eugenio Maria, Ferrantini G., Coratti G. (ORCID:0000-0001-6666-5628), Onesimo R., Lucibello S., Turrini I., Cicala G., Caprarelli M., Pera M. C. (ORCID:0000-0001-6777-1721), Giorgio V., D'Amico A., Leoni C., Pane M. (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

The aim of this retrospective study was to review body mass index (BMI) in a large cohort of Italian pediatric type 2 spinal muscular atrophy (SMA) patients, aged between 0 and 20 years and to establish possible differences in relation to a number of variables such as ventilation, motor function, and survival motor neuron 2 gene copies. Cross-sectional data were collected from 102 patients for a total of 344 visits. Standard growth charts for height and weight were used as reference, with age adjusted BMI calculated using the Center for Disease and Prevention Children’s BMI Tool. In the 344 visits, weight ranged between 3.90 and 83 kg, and the BMI between 8.4 and 31.6 with a BMI/age z-scores < − 2SD present in 28% and BMI/age z-scores > + 2SD in 9% of the measurements. The BMI/age z-scores were relatively stable < 5 years of age with an increasing number of patients < − 2SD after the age of 5, and a wider range of BMI/age z-scores after the age of 13. A difference on the BMI/age z-scores was found among the different age subgroups (< 5, 5–12, ≥ 13 years). A multivariate analysis in 58 patients with longitudinal assessments showed that baseline BMI/age z-scores and gender were significantly contributing to the changes while other variables were not. Conclusion: Our results confirm that careful surveillance of weight and BMI/age z-scores is needed in type 2 SMA. Further studies, including assessments of chewing and swallowing and of lean/fat body mass, will help to better understand the possible mechanisms underlying weight issues.What is Known:• Feeding difficulties have been reported in a few studies and were invariably found in patients with type 1 SMA.• Type 2 SMA patients often have low BMI with a relevant number of patients requiring tube feeding.What is New:• Reduction in BMI/age z-score overtime appeared to depend on baseline BMI/age z-score and gender.• Patients with a low BMI/age z-score were at higher risk of developing fu

Published
2022

16. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial

Author

Mercuri, Eugenio Maria, Deconinck, N., Mazzone, Elena Stacy, Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, Giovanni, Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Gerber, M., Gorni, K., Khwaja, O., Kletzl, H., Scalco, R. S., Staunton, H., Yeung, W. Y., Martin, Craig, Fontoura, P., Day, J. W., Volpe, J. J., Posner, J., Kellner, U., Quinlivan, R., Fuerst-Recktenwald, S., Marquet, A., Mulhardt, N., Trundell, D., Daron, A., Delstanche, S., Romain, B., Dal Farra, F., Schneider, O., Balikova, I., Delbeke, P., Joniau, I., Tahon, V., Wittevrongel, S., De Vos, E., Casteels, I., De Waele, L., Cassiman, C., Prove, L., Kinoo, D., Vancampenhout, L., Van Den Hauwe, M., Van Impe, A., Prufer de Queiroz Campos Araujo, A., Chacon Pereira, A., Nardes, F., Haefeli, L., Rossetto, J., Almeida Pereira, J., Ferreira Rebel, M., Campbell, C., Sharan, S., Mcdonald, W., Scholtes, C., Mah, J., Sframeli, M., Chiu, A., Hagel, J., Beneish, R., Pham, C., Toffoli, D., Arpin, S., Turgeon Desilets, S., Wang, Y., Hu, C., Huang, J., Qian, C., Shen, L., Xiao, Y., Zhou, Z., Li, H., Wang, S., Xiong, H., Chang, X., Dong, H., Liu, Y., Sang, T., Wei, C., Wen, J., Cao, Y., Lv, X., Zhao, J., Li, W., Qin, L., Barisic, N., Galiot Delic, M., Ivkic, P. K., Vukojevic, N., Kern, I., Najdanovic, B., Skugor, M., Gidaro, T., Seferian, A., De Lucia, Sara Sofia, Barreau, E., Mnafek, N., Momtchilova, M. M., Peche, H., Valherie, C., Grange, A., Lilien, C., Milascevic, D., Tachibana, S., Ravelli, C., Cardas, R., Vanden Brande, L., Davion, J. -B., Coopman, S., Bouacha, I., Debruyne, P., Defoort, S., Derlyn, G., Leroy, F., Danjoux, L., Guilbaud, J., Desguerre, I., Barnerias, C., Semeraro, M., Bremond-Gignac, D., Bruere, L., Rateaux, M., Deladriere, E., Germa, V., Pereon, Y., Magot, A., Mercie, S., Billaud, F., Le Goff, L., Letellier, G., Portefaix, A., Fontaine, S., De-Montferrand, C., Le-Goff, L., Saidi, M., Bouzid, N., Barriere, A., Tinat, M., Dreesbach, M., Lagreze, W., Michaelis, B., Molnar, F., Seger, D., Vogt, S., Bertini, Enrico Silvio, D'Amico, Adele, Petroni, S., Bonetti, A. M., Carlesi, A., Mizzoni, I., Bruno, C., Priolo, E., Rao, G., Morando, S., Tacchetti, P., Zuffi, A., Comi, G. P., Brusa, R., Corti, Serafino, Daniele, V., Govoni, A., Magri, F., Minorini, V., Osnaghi, S. G., Abbati, F., Fassini, F., Foa, M., Lopopolo, A., Meneri, M., Zoppas, F., Parente, V., Masson, R., Bianchi Marzoli, Stefania, Santarsiero, Rocco Domenico, Garcia Sierra, M., Tremolada, G., Arnoldi, M. T., Vigano, M., Zanin, Renata, Amorelli, Giulia Maria, Barresi, C., D'Amico, Guglielmo, Orazi, Lorenzo, Coratti, Giorgia, Haginoya, K., Kato, A., Morishita, Y., Kira, R., Akiyama, K., Goto, M., Mori, Y., Okamoto, M., Tsutsui, S., Takatsuji, Y., Tanaka, A., Komaki, H., Suzuki, I., Takeuchi, M., Todoroki, D., Watanabe, S., Omori, M., Matsubayashi, T., Inakazu, E., Nagura, H., Suzuki, A., Osaka, H., Ohashi, M., Ishikawa, N., Harada, Y., Fudeyasu, K., Hirata, K., Michiue, K., Ueda, K., Yashiro, S., Seki, M., Sano, N., Uemura, A., Fukuyama, K., Matsumoto, Y., Miyazaki, H., Shibata, M., Kobayashi, K., Nakamura, Y., Takeshima, Y., Kuma, M., Fraczek, A., Jedrzejowska, M., Lusakowska, A., Czeszyk-Piotrowicz, A., Hautz, W., Rakusiewicz, K., Burlewicz, M., Gierlak-Wojcicka, Z., Kepa, M., Sikorski, A., Sobieraj, M., Mazurkiewicz-Beldzinska, M., Lemska, A., Modrzejewska, S., Koberda, M., Stodolska-Koberda, U., Waskowska, A., Kolendo, J., Sobierajska-Rek, A., Steinborn, B., Dalz, M., Grabowska, J., Hajduk, W., Janasiewicz-Karachitos, J., Klimas, M., Stopa, M., Gajewska, E., Pusz, B., Vlodavets, D., Melnik, E., Leppenen, N., Yupatova, N., Monakhova, A., Papina, Y., Shidlovsckaia, O., Milic Rasic, V., Brankovic, V., Kosac, A., Djokic, O., Jaksic, V., Pepic, A., Martinovic, J., Munell Casadesus, F., Tizzano, E., Martin Begue, N., Wolley Dod, C., Subira, O., Planas Pascual, B., Toro Tamargo, E., Madruga Garrido, M., Medina Romero, J. D., Salinas, M. P., Nascimento Osorio, A., Diaz Cortes, A., Jimenez Ganan, E., Suh, S. D., Medina Cantillo, J., Moya, O., Padros, N., Roca Urraca, S., Gonzalez Valdivia, H., Pascual Pascual, S., de Manuel, S., Noval Martin, S., Burnham, P., Espinosa Garcia, S., Martinez Moreno, M., Topaloglu, H., Oncel, I., Eroglu Ertugrul, N., Konuskan, B., Eldem, B., Kadayifcilar, S., Alemdaroglu, I., Ayse Karaduman, A., Tunca Yilmaz, O., Bilgin, N., Sari, S., Chiriboga, C., Kane, S., Lee, J., Rome-Martin, D., Beres, S., Duong, T., Gee, R., Dunaway Young, S., Mercuri E. (ORCID:0000-0002-9851-5365), Mazzone E. S., Baranello G., Martin C., De Lucia S., Bertini E., D'Amico A., Corti S., Bianchi Marzoli S., Santarsiero D., Zanin R., Amorelli G. M., D'Amico G., Orazi L., Coratti G. (ORCID:0000-0001-6666-5628), Mercuri, Eugenio Maria, Deconinck, N., Mazzone, Elena Stacy, Nascimento, A., Oskoui, M., Saito, K., Vuillerot, C., Baranello, Giovanni, Boespflug-Tanguy, O., Goemans, N., Kirschner, J., Kostera-Pruszczyk, A., Servais, L., Gerber, M., Gorni, K., Khwaja, O., Kletzl, H., Scalco, R. S., Staunton, H., Yeung, W. Y., Martin, Craig, Fontoura, P., Day, J. W., Volpe, J. J., Posner, J., Kellner, U., Quinlivan, R., Fuerst-Recktenwald, S., Marquet, A., Mulhardt, N., Trundell, D., Daron, A., Delstanche, S., Romain, B., Dal Farra, F., Schneider, O., Balikova, I., Delbeke, P., Joniau, I., Tahon, V., Wittevrongel, S., De Vos, E., Casteels, I., De Waele, L., Cassiman, C., Prove, L., Kinoo, D., Vancampenhout, L., Van Den Hauwe, M., Van Impe, A., Prufer de Queiroz Campos Araujo, A., Chacon Pereira, A., Nardes, F., Haefeli, L., Rossetto, J., Almeida Pereira, J., Ferreira Rebel, M., Campbell, C., Sharan, S., Mcdonald, W., Scholtes, C., Mah, J., Sframeli, M., Chiu, A., Hagel, J., Beneish, R., Pham, C., Toffoli, D., Arpin, S., Turgeon Desilets, S., Wang, Y., Hu, C., Huang, J., Qian, C., Shen, L., Xiao, Y., Zhou, Z., Li, H., Wang, S., Xiong, H., Chang, X., Dong, H., Liu, Y., Sang, T., Wei, C., Wen, J., Cao, Y., Lv, X., Zhao, J., Li, W., Qin, L., Barisic, N., Galiot Delic, M., Ivkic, P. K., Vukojevic, N., Kern, I., Najdanovic, B., Skugor, M., Gidaro, T., Seferian, A., De Lucia, Sara Sofia, Barreau, E., Mnafek, N., Momtchilova, M. M., Peche, H., Valherie, C., Grange, A., Lilien, C., Milascevic, D., Tachibana, S., Ravelli, C., Cardas, R., Vanden Brande, L., Davion, J. -B., Coopman, S., Bouacha, I., Debruyne, P., Defoort, S., Derlyn, G., Leroy, F., Danjoux, L., Guilbaud, J., Desguerre, I., Barnerias, C., Semeraro, M., Bremond-Gignac, D., Bruere, L., Rateaux, M., Deladriere, E., Germa, V., Pereon, Y., Magot, A., Mercie, S., Billaud, F., Le Goff, L., Letellier, G., Portefaix, A., Fontaine, S., De-Montferrand, C., Le-Goff, L., Saidi, M., Bouzid, N., Barriere, A., Tinat, M., Dreesbach, M., Lagreze, W., Michaelis, B., Molnar, F., Seger, D., Vogt, S., Bertini, Enrico Silvio, D'Amico, Adele, Petroni, S., Bonetti, A. M., Carlesi, A., Mizzoni, I., Bruno, C., Priolo, E., Rao, G., Morando, S., Tacchetti, P., Zuffi, A., Comi, G. P., Brusa, R., Corti, Serafino, Daniele, V., Govoni, A., Magri, F., Minorini, V., Osnaghi, S. G., Abbati, F., Fassini, F., Foa, M., Lopopolo, A., Meneri, M., Zoppas, F., Parente, V., Masson, R., Bianchi Marzoli, Stefania, Santarsiero, Rocco Domenico, Garcia Sierra, M., Tremolada, G., Arnoldi, M. T., Vigano, M., Zanin, Renata, Amorelli, Giulia Maria, Barresi, C., D'Amico, Guglielmo, Orazi, Lorenzo, Coratti, Giorgia, Haginoya, K., Kato, A., Morishita, Y., Kira, R., Akiyama, K., Goto, M., Mori, Y., Okamoto, M., Tsutsui, S., Takatsuji, Y., Tanaka, A., Komaki, H., Suzuki, I., Takeuchi, M., Todoroki, D., Watanabe, S., Omori, M., Matsubayashi, T., Inakazu, E., Nagura, H., Suzuki, A., Osaka, H., Ohashi, M., Ishikawa, N., Harada, Y., Fudeyasu, K., Hirata, K., Michiue, K., Ueda, K., Yashiro, S., Seki, M., Sano, N., Uemura, A., Fukuyama, K., Matsumoto, Y., Miyazaki, H., Shibata, M., Kobayashi, K., Nakamura, Y., Takeshima, Y., Kuma, M., Fraczek, A., Jedrzejowska, M., Lusakowska, A., Czeszyk-Piotrowicz, A., Hautz, W., Rakusiewicz, K., Burlewicz, M., Gierlak-Wojcicka, Z., Kepa, M., Sikorski, A., Sobieraj, M., Mazurkiewicz-Beldzinska, M., Lemska, A., Modrzejewska, S., Koberda, M., Stodolska-Koberda, U., Waskowska, A., Kolendo, J., Sobierajska-Rek, A., Steinborn, B., Dalz, M., Grabowska, J., Hajduk, W., Janasiewicz-Karachitos, J., Klimas, M., Stopa, M., Gajewska, E., Pusz, B., Vlodavets, D., Melnik, E., Leppenen, N., Yupatova, N., Monakhova, A., Papina, Y., Shidlovsckaia, O., Milic Rasic, V., Brankovic, V., Kosac, A., Djokic, O., Jaksic, V., Pepic, A., Martinovic, J., Munell Casadesus, F., Tizzano, E., Martin Begue, N., Wolley Dod, C., Subira, O., Planas Pascual, B., Toro Tamargo, E., Madruga Garrido, M., Medina Romero, J. D., Salinas, M. P., Nascimento Osorio, A., Diaz Cortes, A., Jimenez Ganan, E., Suh, S. D., Medina Cantillo, J., Moya, O., Padros, N., Roca Urraca, S., Gonzalez Valdivia, H., Pascual Pascual, S., de Manuel, S., Noval Martin, S., Burnham, P., Espinosa Garcia, S., Martinez Moreno, M., Topaloglu, H., Oncel, I., Eroglu Ertugrul, N., Konuskan, B., Eldem, B., Kadayifcilar, S., Alemdaroglu, I., Ayse Karaduman, A., Tunca Yilmaz, O., Bilgin, N., Sari, S., Chiriboga, C., Kane, S., Lee, J., Rome-Martin, D., Beres, S., Duong, T., Gee, R., Dunaway Young, S., Mercuri E. (ORCID:0000-0002-9851-5365), Mazzone E. S., Baranello G., Martin C., De Lucia S., Bertini E., D'Amico A., Corti S., Bianchi Marzoli S., Santarsiero D., Zanin R., Amorelli G. M., D'Amico G., Orazi L., and Coratti G. (ORCID:0000-0001-6666-5628)

Abstract

Background: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy. Methods: In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2–25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing ≥20 kg) or 0·25 mg/kg (for individuals weighing <20 kg), or daily oral placebo (matched to risdiplam in colour and taste). Randomisation was conducted by permutated block randomisation with a computerised system run by an external party. Patients, investigators, and all individuals in direct contact with patients were masked to treatment assignment. The primary endpoint was the change from baseline in the 32-item Motor Function Measure total score at month 12. All individuals who were randomly assigned to risdiplam or placebo, and who did not meet the prespecified missing item criteria for exclusion, were included in the primary efficacy analysis. Individuals who received at least one dose of risdiplam or placebo were included in the safety analysis. SUNFISH is registered with ClinicalTrials.gov, NCT02908685. Recruitment is closed; the study is ongoing. Findings: Between Oct 9, 2017, and Sept 4, 2018, 180 patients were rand

Published
2022

17. Revised upper limb module in type II and III spinal muscular atrophy: 24-month changes

Author

Coratti, Giorgia, Carmela Pera, M., Montes, J., Scoto, M., Pasternak, A., Bovis, F., Sframeli, M., D'Amico, Adele, Pane, Marika, Albamonte, E., Antonaci, Laura, Lia Frongia, A., Mizzoni, I., Sansone, V. A., Russo, M., Bruno, C., Baranello, Giovanni, Messina, S., Dunaway Young, S., Glanzman, A. M., Duong, T., De Sanctis, Roberto, Stacy Mazzone, E., Milev, E., Rohwer, A., Civitello, M., Darras, B. T., Bertini, Enrico Silvio, Day, J., Muntoni, F., De Vivo, D. C., Finkel, R. S., Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), D'Amico A., Pane M. (ORCID:0000-0002-4851-6124), Antonaci L., Baranello G., de Sanctis R., Bertini E., Mercuri E. (ORCID:0000-0002-9851-5365), Coratti, Giorgia, Carmela Pera, M., Montes, J., Scoto, M., Pasternak, A., Bovis, F., Sframeli, M., D'Amico, Adele, Pane, Marika, Albamonte, E., Antonaci, Laura, Lia Frongia, A., Mizzoni, I., Sansone, V. A., Russo, M., Bruno, C., Baranello, Giovanni, Messina, S., Dunaway Young, S., Glanzman, A. M., Duong, T., De Sanctis, Roberto, Stacy Mazzone, E., Milev, E., Rohwer, A., Civitello, M., Darras, B. T., Bertini, Enrico Silvio, Day, J., Muntoni, F., De Vivo, D. C., Finkel, R. S., Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), D'Amico A., Pane M. (ORCID:0000-0002-4851-6124), Antonaci L., Baranello G., de Sanctis R., Bertini E., and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

The aim of the study was to establish 24-month changes in a large cohort of type II and III spinal muscular atrophy (SMA) patients assessed with the Revised Upper Limb Module (RULM), a tool specifically developed to assess upper limb function in SMA. We included 107 patients (54 type II and 53 type III) with at least 24-months follow up. The overall RULM 24-month changes showed a mean decline of -0.79 points. The difference between baseline and 24 months was significant in type II but not in type III patients. There was also a difference among functional subgroups but not in relation to age. Most patients had 24-month mean changes within 2 points, with 23% decreasing more than 2 points and 7% improving by >2 points. Our results suggest an overall progressive decline in upper limb function over 24 months. The negative changes were most notable in type II, in non-ambulant type III and with a different pattern of progression, also in non-sitter type II. In contrast, ambulant type III showed relative stability within the 24-month follow up. These findings will help in the interpretation of the real world data collected following the availability of new therapeutic approaches.

Published
2022

18. Revised upper limb module in type II and III spinal muscular atrophy: 24-month changes

Author

Coratti, Giorgia, Carmela Pera, M., Montes, J., Scoto, M., Pasternak, A., Bovis, F., Sframeli, M., D'Amico, Adele, Pane, Marika, Albamonte, E., Antonaci, Laura, Lia Frongia, A., Mizzoni, I., Sansone, V. A., Russo, M., Bruno, C., Baranello, Giovanni, Messina, S., Dunaway Young, S., Glanzman, A. M., Duong, T., De Sanctis, Roberto, Stacy Mazzone, E., Milev, E., Rohwer, A., Civitello, M., Darras, B. T., Bertini, Enrico Silvio, Day, J., Muntoni, F., De Vivo, D. C., Finkel, R. S., Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), D'Amico A., Pane M. (ORCID:0000-0002-4851-6124), Antonaci L., Baranello G., de Sanctis R., Bertini E., Mercuri E. (ORCID:0000-0002-9851-5365), Coratti, Giorgia, Carmela Pera, M., Montes, J., Scoto, M., Pasternak, A., Bovis, F., Sframeli, M., D'Amico, Adele, Pane, Marika, Albamonte, E., Antonaci, Laura, Lia Frongia, A., Mizzoni, I., Sansone, V. A., Russo, M., Bruno, C., Baranello, Giovanni, Messina, S., Dunaway Young, S., Glanzman, A. M., Duong, T., De Sanctis, Roberto, Stacy Mazzone, E., Milev, E., Rohwer, A., Civitello, M., Darras, B. T., Bertini, Enrico Silvio, Day, J., Muntoni, F., De Vivo, D. C., Finkel, R. S., Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), D'Amico A., Pane M. (ORCID:0000-0002-4851-6124), Antonaci L., Baranello G., de Sanctis R., Bertini E., and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

The aim of the study was to establish 24-month changes in a large cohort of type II and III spinal muscular atrophy (SMA) patients assessed with the Revised Upper Limb Module (RULM), a tool specifically developed to assess upper limb function in SMA. We included 107 patients (54 type II and 53 type III) with at least 24-months follow up. The overall RULM 24-month changes showed a mean decline of -0.79 points. The difference between baseline and 24 months was significant in type II but not in type III patients. There was also a difference among functional subgroups but not in relation to age. Most patients had 24-month mean changes within 2 points, with 23% decreasing more than 2 points and 7% improving by >2 points. Our results suggest an overall progressive decline in upper limb function over 24 months. The negative changes were most notable in type II, in non-ambulant type III and with a different pattern of progression, also in non-sitter type II. In contrast, ambulant type III showed relative stability within the 24-month follow up. These findings will help in the interpretation of the real world data collected following the availability of new therapeutic approaches.

Published
2022

19. Longitudinal Motor Functional Outcomes and Magnetic Resonance Imaging Patterns of Muscle Involvement in Upper Limbs in Duchenne Muscular Dystrophy.

Author

Brogna, C, Cristiano, L, Verdolotti, T, Norcia, G, Ficociello, L, Ruiz, R, Coratti, G, Fanelli, L, Forcina, N, Petracca, G, Chieppa, F, Tartaglione, T, Colosimo, C, Pane, M, Mercuri, E., Brogna C, Cristiano L, Verdolotti T, Ficociello L, Ruiz R, Coratti G (ORCID:0000-0001-6666-5628), Fanelli L, Petracca G, Chieppa F, Tartaglione T (ORCID:0000-0003-3896-4078), Colosimo C (ORCID:0000-0003-3800-3648), Pane M (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Brogna, C, Cristiano, L, Verdolotti, T, Norcia, G, Ficociello, L, Ruiz, R, Coratti, G, Fanelli, L, Forcina, N, Petracca, G, Chieppa, F, Tartaglione, T, Colosimo, C, Pane, M, Mercuri, E., Brogna C, Cristiano L, Verdolotti T, Ficociello L, Ruiz R, Coratti G (ORCID:0000-0001-6666-5628), Fanelli L, Petracca G, Chieppa F, Tartaglione T (ORCID:0000-0003-3896-4078), Colosimo C (ORCID:0000-0003-3800-3648), Pane M (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Background and Objectives: The aim of this study was to evaluate longitudinal changes using both upper limb muscle Magnetic Resonance Imaging (MRI) at shoulder, arm and forearm levels and Performance of upper limb (PUL) in ambulant and non-ambulant Duchenne Muscular Dystrophy (DMD) patients. We also wished to define whether baseline muscle MRI could help to predict functional changes after one year. Materials and Methods: Twenty-seven patients had both baseline and 12month muscle MRI and PUL assessments one year later. Results: Ten were ambulant (age range 5-16 years), and 17 non ambulant (age range 10-30 years). Increased abnormalities equal or more than 1.5 point on muscle MRI at follow up were found on all domains: at shoulder level 12/27 patients (44%), at arm level 4/27 (15%) and at forearm level 6/27 (22%). Lower follow up PUL score were found in 8/27 patients (30%) at shoulder level, in 9/27 patients (33%) at mid-level whereas no functional changes were found at distal level. There was no constant association between baseline MRI scores and follow up PUL scores at arm and forearm levels but at shoulder level patients with moderate impairment on the baseline MRI scores between 16 and 34 had the highest risk of decreased function on PUL over a year. Conclusions: Our results confirmed that the integrated use of functional scales and imaging can help to monitor functional and MRI changes over time.

Published
2021

20. Sometimes they come back: New and old spinal muscular atrophy adults in the era of nusinersen

Author

Sansone, V A, Coratti, Giorgia, Pera, Maria Carmela, Pane, Marika, Messina, S, Salmin, F, Albamonte, E, De Sanctis, Roberto, Sframeli, M, Di Bella, V, Morando, S, D'Amico, Adele, Frongia, Anna Lia, Antonaci, Laura, Pirola, A, Pedemonte, M, Bertini, Enrico Silvio, Bruno, C, Mercuri, Eugenio Maria, Italian ISMAC, Group., Coratti, G (ORCID:0000-0001-6666-5628), Pera, M C (ORCID:0000-0001-6777-1721), Pane, M (ORCID:0000-0002-4851-6124), De Sanctis, R, d'Amico, A, Frongia, A L, Antonaci, L, Bertini, E, Mercuri, E (ORCID:0000-0002-9851-5365), Sansone, V A, Coratti, Giorgia, Pera, Maria Carmela, Pane, Marika, Messina, S, Salmin, F, Albamonte, E, De Sanctis, Roberto, Sframeli, M, Di Bella, V, Morando, S, D'Amico, Adele, Frongia, Anna Lia, Antonaci, Laura, Pirola, A, Pedemonte, M, Bertini, Enrico Silvio, Bruno, C, Mercuri, Eugenio Maria, Italian ISMAC, Group., Coratti, G (ORCID:0000-0001-6666-5628), Pera, M C (ORCID:0000-0001-6777-1721), Pane, M (ORCID:0000-0002-4851-6124), De Sanctis, R, d'Amico, A, Frongia, A L, Antonaci, L, Bertini, E, and Mercuri, E (ORCID:0000-0002-9851-5365)

Abstract

Background and purpose Following the commercial availability of nusinersen, there have been a number of new referrals of adults with spinal muscular atrophy (SMA) not regularly followed in tertiary-care centers or enrolled in any disease registry.Methods We compared demographics and disease characteristics, including assessment of motor and respiratory function, in regularly followed patients and newcomers subdivided according to the SMA type.Results The cohort included 166 adult patients (mean age: 37.09 years): one type I, 65 type II, 99 type III, and one type IV. Of these 166, there were 67 newcomers. There was no significant difference between newcomers and regularly followed patients in relation to age and disease duration. The Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module scores were higher in the regularly followed patients compared to newcomers in the whole cohort and in both SMA II and II. A difference was also found on ventilatory status (p = 0.013) and Cobb's angle >50 degrees (p = 0.039) between the two subgroups. No difference was found in scoliosis surgery prevalence (p > 0.05).Conclusions Our results showed differences between the two subgroups, even if less marked in the type III patients. In the type II patients, there was a higher proportion of newcomers who were in the severe end of the spectrum. Of the newcomers, only approximately a third initiated treatment, as opposed to the 51% in the regularly followed patients. The identification of patients who were not part of the registries will help to redefine the overall prevalence of SMA and the occurrence of different phenotypes.

Published
2021

21. Motor function in type 2 and 3 SMA patients treated with Nusinersen: a critical review and meta-analysis

Author

Coratti, Giorgia, Cutrona, Costanza, Pera, Maria Carmela, Bovis, F., Ponzano, M., Chieppa, Fabrizia, Antonaci, Laura, Sansone, V., Finkel, R., Pane, Marika, Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Cutrona C., Pera M. C. (ORCID:0000-0001-6777-1721), Chieppa F., Antonaci L., Pane M. (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Coratti, Giorgia, Cutrona, Costanza, Pera, Maria Carmela, Bovis, F., Ponzano, M., Chieppa, Fabrizia, Antonaci, Laura, Sansone, V., Finkel, R., Pane, Marika, Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Cutrona C., Pera M. C. (ORCID:0000-0001-6777-1721), Chieppa F., Antonaci L., Pane M. (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Background: There is an increasing number of papers reporting the real world use of Nusinersen in different cohorts of SMA patients. Main body: The aim of this paper was to critically review the literature reporting real world data on motor function in type 2 and 3 patients treated with Nusinersen, subdividing the results according to SMA type, age and type of assessment and performing a meta-analysis of the available results. We also report the available data collected in untreated patients using the same measures. Of the 400 papers identified searching for Nusinersen and spinal muscular atrophy, 19 reported motor function in types 2 and 3: 13 in adults, 4 in children and 2 included both. Twelve papers reported untreated patients’ data. All studies reported positive changes on at least one of the functional measures and at every time point while all-untreated cohorts showed negative changes. Conclusion: Our review suggests that Nusinersen provides a favorable benefit in motor function across a wide range of SMA type 2 and 3 patients over a 10–14 month observation period. Although a direct comparison with studies reporting data from untreated patients cannot be made, the longitudinal changes in the treated cohorts (consistently positive) are divergent from those observed in the untreated cohorts (consistently negative). The difference could be observed both in the global cohorts and in smaller groups subdivided according to age, type or functional status.

Published
2021

22. SMA-miRs (MiR-181a- 5p, -324-5p, and -451a) are overexpressed in spinal muscular atrophy skeletal muscle and serum samples

Author

Abiusi, E., Infante, P., Cagnoli, C., Severini, L. L., Pane, M., Coratti, G., Pera, M. C., D'amico, A., Diano, F., Novelli, A., Spartano, S., Fiori, S., Baranello, G., Moroni, I., Mora, M., Pasanisi, M. B., Pocino, K., Le Pera, L., D'Amico, D., Travaglini, L., Ria, F., Bruno, C., Locatelli, D., Bertini, E. S., Morandi, L. O., Mercuri, E., Di Marcotullio, L., Tiziano, F. D., Abiusi E. (ORCID:0000-0001-9028-012X), Pane M. (ORCID:0000-0002-4851-6124), Coratti G. (ORCID:0000-0001-6666-5628), Pera M. C. (ORCID:0000-0001-6777-1721), D'amico A., Diano F., Novelli A., Spartano S., Fiori S., Baranello G., Pocino K. (ORCID:0000-0003-2456-5308), Ria F. (ORCID:0000-0002-8444-0307), Bertini E. S., Mercuri E. (ORCID:0000-0002-9851-5365), Tiziano F. D. (ORCID:0000-0002-5545-6158), Abiusi, E., Infante, P., Cagnoli, C., Severini, L. L., Pane, M., Coratti, G., Pera, M. C., D'amico, A., Diano, F., Novelli, A., Spartano, S., Fiori, S., Baranello, G., Moroni, I., Mora, M., Pasanisi, M. B., Pocino, K., Le Pera, L., D'Amico, D., Travaglini, L., Ria, F., Bruno, C., Locatelli, D., Bertini, E. S., Morandi, L. O., Mercuri, E., Di Marcotullio, L., Tiziano, F. D., Abiusi E. (ORCID:0000-0001-9028-012X), Pane M. (ORCID:0000-0002-4851-6124), Coratti G. (ORCID:0000-0001-6666-5628), Pera M. C. (ORCID:0000-0001-6777-1721), D'amico A., Diano F., Novelli A., Spartano S., Fiori S., Baranello G., Pocino K. (ORCID:0000-0003-2456-5308), Ria F. (ORCID:0000-0002-8444-0307), Bertini E. S., Mercuri E. (ORCID:0000-0002-9851-5365), and Tiziano F. D. (ORCID:0000-0002-5545-6158)

Abstract

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by the degeneration of the second motor neuron. The phenotype ranges from very severe to very mild forms. All patients have the homozygous loss of the SMN1 gene and a variable number of SMN2 (generally 2–4 copies), inversely related to the severity. The amazing results of the available treatments have made compelling the need of prognostic biomarkers to predict the progression trajectories of patients. Besides the SMN2 products, few other biomarkers have been evaluated so far, including some miRs. Methods: We performed whole miRNome analysis of muscle samples of patients and controls (14 biopsies and 9 cultures). The levels of muscle differentially expressed miRs were evaluated in serum samples (51 patients and 37 controls) and integrated with SMN2 copies, SMN2 full-length transcript levels in blood and age (SMA-score). Results: Over 100 miRs were differentially expressed in SMA muscle; 3 of them (hsa-miR-181a-5p, -324-5p, -451a; SMA-miRs) were significantly upregulated in the serum of patients. The severity predicted by the SMA-score was related to that of the clinical classification at a correlation coefficient of 0.87 (p<10-5). Conclusions: MiRNome analyses suggest the primary involvement of skeletal muscle in SMA pathogenesis. The SMA-miRs are likely actively released in the blood flow; their function and target cells require to be elucidated. The accuracy of the SMA-score needs to be verified in replicative studies: If confirmed, its use could be crucial for the routine prognostic assessment, also in presymptomatic patients.

Published
2021

23. Longitudinal motor functional outcomes and magnetic resonance imaging patterns of muscle involvement in upper limbs in duchenne muscular dystrophy

Author

Brogna, Claudia, Cristiano, Lara, Verdolotti, Tommaso, Norcia, G., Ficociello, Luana, Ruiz, Roberta Giusy, Coratti, Giorgia, Fanelli, Lavinia, Forcina, N., Petracca, Giorgia, Chieppa, Fabrizia, Tartaglione, Tommaso, Colosimo, Cesare, Pane, Marika, Mercuri, Eugenio Maria, Brogna C., Cristiano L., Verdolotti T., Ficociello L., Ruiz R., Coratti G. (ORCID:0000-0001-6666-5628), Fanelli L., Petracca G., Chieppa F., Tartaglione T. (ORCID:0000-0003-3896-4078), Colosimo C. (ORCID:0000-0003-3800-3648), Pane M. (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Brogna, Claudia, Cristiano, Lara, Verdolotti, Tommaso, Norcia, G., Ficociello, Luana, Ruiz, Roberta Giusy, Coratti, Giorgia, Fanelli, Lavinia, Forcina, N., Petracca, Giorgia, Chieppa, Fabrizia, Tartaglione, Tommaso, Colosimo, Cesare, Pane, Marika, Mercuri, Eugenio Maria, Brogna C., Cristiano L., Verdolotti T., Ficociello L., Ruiz R., Coratti G. (ORCID:0000-0001-6666-5628), Fanelli L., Petracca G., Chieppa F., Tartaglione T. (ORCID:0000-0003-3896-4078), Colosimo C. (ORCID:0000-0003-3800-3648), Pane M. (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Background and Objectives: The aim of this study was to evaluate longitudinal changes using both upper limb muscle Magnetic Resonance Imaging (MRI) at shoulder, arm and forearm levels and Performance of upper limb (PUL) in ambulant and non-ambulant Duchenne Muscular Dystrophy (DMD) patients. We also wished to define whether baseline muscle MRI could help to predict functional changes after one year. Materials and Methods: Twenty-seven patients had both baseline and 12month muscle MRI and PUL assessments one year later. Results: Ten were ambulant (age range 5–16 years), and 17 non ambulant (age range 10–30 years). Increased abnormalities equal or more than 1.5 point on muscle MRI at follow up were found on all domains: at shoulder level 12/27 patients (44%), at arm level 4/27 (15%) and at forearm level 6/27 (22%). Lower follow up PUL score were found in 8/27 patients (30%) at shoulder level, in 9/27 patients (33%) at mid-level whereas no functional changes were found at distal level. There was no constant association between baseline MRI scores and follow up PUL scores at arm and forearm levels but at shoulder level patients with moderate impairment on the baseline MRI scores between 16 and 34 had the highest risk of decreased function on PUL over a year. Conclusions: Our results confirmed that the integrated use of functional scales and imaging can help to monitor functional and MRI changes over time.

Published
2021

24. Motor function in type 2 and 3 SMA patients treated with Nusinersen: a critical review and meta-analysis

Author

Coratti, Giorgia, Cutrona, Costanza, Pera, Maria Carmela, Bovis, F., Ponzano, M., Chieppa, Fabrizia, Antonaci, Laura, Sansone, V., Finkel, R., Pane, Marika, Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Cutrona C., Pera M. C. (ORCID:0000-0001-6777-1721), Chieppa F., Antonaci L., Pane M. (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Coratti, Giorgia, Cutrona, Costanza, Pera, Maria Carmela, Bovis, F., Ponzano, M., Chieppa, Fabrizia, Antonaci, Laura, Sansone, V., Finkel, R., Pane, Marika, Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Cutrona C., Pera M. C. (ORCID:0000-0001-6777-1721), Chieppa F., Antonaci L., Pane M. (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Background: There is an increasing number of papers reporting the real world use of Nusinersen in different cohorts of SMA patients. Main body: The aim of this paper was to critically review the literature reporting real world data on motor function in type 2 and 3 patients treated with Nusinersen, subdividing the results according to SMA type, age and type of assessment and performing a meta-analysis of the available results. We also report the available data collected in untreated patients using the same measures. Of the 400 papers identified searching for Nusinersen and spinal muscular atrophy, 19 reported motor function in types 2 and 3: 13 in adults, 4 in children and 2 included both. Twelve papers reported untreated patients’ data. All studies reported positive changes on at least one of the functional measures and at every time point while all-untreated cohorts showed negative changes. Conclusion: Our review suggests that Nusinersen provides a favorable benefit in motor function across a wide range of SMA type 2 and 3 patients over a 10–14 month observation period. Although a direct comparison with studies reporting data from untreated patients cannot be made, the longitudinal changes in the treated cohorts (consistently positive) are divergent from those observed in the untreated cohorts (consistently negative). The difference could be observed both in the global cohorts and in smaller groups subdivided according to age, type or functional status.

Published
2021

25. SMA-miRs (MiR-181a- 5p, -324-5p, and -451a) are overexpressed in spinal muscular atrophy skeletal muscle and serum samples

Author

Abiusi, Emanuela, Infante, P., Cagnoli, C., Severini, L. L., Pane, Marika, Coratti, Giorgia, Pera, Maria Carmela, D'Amico, Adele, Diano, Federica, Novelli, Agnese, Spartano, Serena, Fiori, Simona, Baranello, Giovanni, Moroni, I., Mora, M., Pasanisi, M. B., Pocino, Krizia, Le Pera, L., D'Amico, D., Travaglini, L., Ria, Francesco, Bruno, C., Locatelli, D., Bertini, Enrico Silvio, Morandi, L. O., Mercuri, Eugenio Maria, Di Marcotullio, L., Tiziano, Francesco Danilo, Abiusi E. (ORCID:0000-0001-9028-012X), Pane M. (ORCID:0000-0002-4851-6124), Coratti G. (ORCID:0000-0001-6666-5628), Pera M. C. (ORCID:0000-0001-6777-1721), D'amico A., Diano F., Novelli A., Spartano S., Fiori S., Baranello G., Pocino K. (ORCID:0000-0003-2456-5308), Ria F. (ORCID:0000-0002-8444-0307), Bertini E. S., Mercuri E. (ORCID:0000-0002-9851-5365), Tiziano F. D. (ORCID:0000-0002-5545-6158), Abiusi, Emanuela, Infante, P., Cagnoli, C., Severini, L. L., Pane, Marika, Coratti, Giorgia, Pera, Maria Carmela, D'Amico, Adele, Diano, Federica, Novelli, Agnese, Spartano, Serena, Fiori, Simona, Baranello, Giovanni, Moroni, I., Mora, M., Pasanisi, M. B., Pocino, Krizia, Le Pera, L., D'Amico, D., Travaglini, L., Ria, Francesco, Bruno, C., Locatelli, D., Bertini, Enrico Silvio, Morandi, L. O., Mercuri, Eugenio Maria, Di Marcotullio, L., Tiziano, Francesco Danilo, Abiusi E. (ORCID:0000-0001-9028-012X), Pane M. (ORCID:0000-0002-4851-6124), Coratti G. (ORCID:0000-0001-6666-5628), Pera M. C. (ORCID:0000-0001-6777-1721), D'amico A., Diano F., Novelli A., Spartano S., Fiori S., Baranello G., Pocino K. (ORCID:0000-0003-2456-5308), Ria F. (ORCID:0000-0002-8444-0307), Bertini E. S., Mercuri E. (ORCID:0000-0002-9851-5365), and Tiziano F. D. (ORCID:0000-0002-5545-6158)

Abstract

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by the degeneration of the second motor neuron. The phenotype ranges from very severe to very mild forms. All patients have the homozygous loss of the SMN1 gene and a variable number of SMN2 (generally 2–4 copies), inversely related to the severity. The amazing results of the available treatments have made compelling the need of prognostic biomarkers to predict the progression trajectories of patients. Besides the SMN2 products, few other biomarkers have been evaluated so far, including some miRs. Methods: We performed whole miRNome analysis of muscle samples of patients and controls (14 biopsies and 9 cultures). The levels of muscle differentially expressed miRs were evaluated in serum samples (51 patients and 37 controls) and integrated with SMN2 copies, SMN2 full-length transcript levels in blood and age (SMA-score). Results: Over 100 miRs were differentially expressed in SMA muscle; 3 of them (hsa-miR-181a-5p, -324-5p, -451a; SMA-miRs) were significantly upregulated in the serum of patients. The severity predicted by the SMA-score was related to that of the clinical classification at a correlation coefficient of 0.87 (p<10-5). Conclusions: MiRNome analyses suggest the primary involvement of skeletal muscle in SMA pathogenesis. The SMA-miRs are likely actively released in the blood flow; their function and target cells require to be elucidated. The accuracy of the SMA-score needs to be verified in replicative studies: If confirmed, its use could be crucial for the routine prognostic assessment, also in presymptomatic patients.

Published
2021

26. Early Gross Motor Milestones in Duchenne Muscular Dystrophy

Author

Norcia, G., Lucibello, Simona, Coratti, Giorgia, Onesimo, Roberta, Pede, Elisa, Ferrantini, Gloria, Brogna, Claudia, Cicala, Graziamaria, Carnicella, S., Forcina, N., Fanelli, L., Pane, Marika, Mercuri, Eugenio Maria, Lucibello S., Coratti G. (ORCID:0000-0001-6666-5628), Onesimo R., Pede E., Ferrantini G., Brogna C., Cicala G., Pane M. (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Norcia, G., Lucibello, Simona, Coratti, Giorgia, Onesimo, Roberta, Pede, Elisa, Ferrantini, Gloria, Brogna, Claudia, Cicala, Graziamaria, Carnicella, S., Forcina, N., Fanelli, L., Pane, Marika, Mercuri, Eugenio Maria, Lucibello S., Coratti G. (ORCID:0000-0001-6666-5628), Onesimo R., Pede E., Ferrantini G., Brogna C., Cicala G., Pane M. (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Background: Over the last few years there has been increasing attention to detect early signs of impairment in young Duchenne muscular dystrophy boys but less has been reported on whether the delay may also affect the very early aspects of motor development, such as gross motor milestones. Objective: The aim of this study was to retrospectively assess the age when early motor milestones were achieved in Duchenne muscular dystrophy. Methods: The study is a retrospective analysis of data collected as part of a larger natural history project. Information on past medical history, collected at the time the boys were seen for the first time, were recorded and re available on clinical notes and on electronic CRF. Results: Data were collected in 134 DMD boys. Sitting was achieved at 7.04 months. The % of DMD boys not achieving sitting by 9.4 months was 10%, ranging from 2% in the boys with mutations before exon 44 to 33% in those beyond exon 63. Walking was achieved at a mean age of 16.35 months. The % of DMD boys not achieving independent walking by 18 months was 17%, ranging from 9% in the boys with mutations between 44 and 51 to 42% in those beyond exon 63. Conclusions: Our results showed that the risk of a delay in sitting and walking was increasingly high in patients with mutations predictive of the involvement of different brain dystrophin isoforms.

Published
2021

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

Author

Pera, Maria Carmela, Coratti, Giorgia, Bovis, F., Pane, Marika, Pasternak, A., Montes, J., Sansone, V. A., Dunaway Young, S., Duong, T., Messina, S., Mizzoni, I., D'Amico, A., Civitello, M., Glanzman, A. M., Bruno, C., Salmin, F., Morando, S., De Sanctis, Roberto, Sframeli, M., Antonaci, Laura, Frongia, Anna Lia, Rohwer, A., Scoto, M., De Vivo, D. C., Darras, B. T., Day, J., Martens, W., Patanella, K. A., Bertini, E., Muntoni, F., Finkel, R., Mercuri, Eugenio Maria, Pera M. C. (ORCID:0000-0001-6777-1721), Coratti G. (ORCID:0000-0001-6666-5628), Pane M. (ORCID:0000-0002-4851-6124), De Sanctis R., Antonaci L., Frongia A. L., Mercuri E. (ORCID:0000-0002-9851-5365), Pera, Maria Carmela, Coratti, Giorgia, Bovis, F., Pane, Marika, Pasternak, A., Montes, J., Sansone, V. A., Dunaway Young, S., Duong, T., Messina, S., Mizzoni, I., D'Amico, A., Civitello, M., Glanzman, A. M., Bruno, C., Salmin, F., Morando, S., De Sanctis, Roberto, Sframeli, M., Antonaci, Laura, Frongia, Anna Lia, Rohwer, A., Scoto, M., De Vivo, D. C., Darras, B. T., Day, J., Martens, W., Patanella, K. A., Bertini, E., Muntoni, F., Finkel, R., Mercuri, Eugenio Maria, Pera M. C. (ORCID:0000-0001-6777-1721), Coratti G. (ORCID:0000-0001-6666-5628), Pane M. (ORCID:0000-0002-4851-6124), De Sanctis R., Antonaci L., Frongia A. L., and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

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.

Published
2021

28. Oral and Swallowing Abilities Tool (OrSAT) for Type 1 SMA Patients: Development of a New Module

Author

Berti, B., Fanelli, L., De Sanctis, R., Onesimo, R., Palermo, C., Leone, D., Carnicella, S., Norcia, G., Forcina, N., Coratti, G., Giorgio, V., Cerchiari, A., Lucibello, S., Finkel, R., Pane, M., Mercuri, E., De Sanctis R., Onesimo R., Coratti G. (ORCID:0000-0001-6666-5628), Giorgio V., Lucibello S., Pane M. (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Berti, B., Fanelli, L., De Sanctis, R., Onesimo, R., Palermo, C., Leone, D., Carnicella, S., Norcia, G., Forcina, N., Coratti, G., Giorgio, V., Cerchiari, A., Lucibello, S., Finkel, R., Pane, M., Mercuri, E., De Sanctis R., Onesimo R., Coratti G. (ORCID:0000-0001-6666-5628), Giorgio V., Lucibello S., Pane M. (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

We describe the development of a new tool specifically designed to record oral abilities, swallowing and, more generally, feeding in young type 1 SMA patients, to be used during the first 24 months of life. The tool is composed by a checklist and a separate section summarizing the functional abilities into levels of feeding/swallowing impairment. The checklist includes 12 questions assessing aspects thought to be clinically meaningful for a type 1 SMA population and developmentally appropriate for infants during the first months of life. Each item is graded with a score of 0 or 1, depending on the child's ability to perform the activity. As some items are age-dependent, the number of items to be used, and therefore the maximum score, changes with increasing age. The levels of feeding/swallowing impairment include four levels that can be identified using easily identifiable clinical criteria. In an attempt to validate the tool in an untreated population we applied it to 24 type 1 SMA patients (age range: 2.3-24.1 months, mean: 10.8) in whom the same information collected by the new tool had been previously recorded using a less-structured format. When patients were classified in three groups according to the Dubowitz decimal classification, there was a significant difference both at baseline and at follow-up (p<0.001). The items assessing fatigue during the nursing sessions were the most frequently impaired even in infants who did not have any other obvious clinical sign of swallowing difficulties.

Published
2021

29. Age related treatment effect in type II Spinal Muscular Atrophy pediatric patients treated with nusinersen

Author

Coratti, G., Pane, M., Lucibello, S., Pera, M. C., Pasternak, A., Montes, J., Sansone, V. A., Duong, T., Dunaway Young, S., Messina, S., D'Amico, A., Civitello, M., Glanzman, A. M., Bruno, C., Salmin, F., Tacchetti, P., Carnicella, S., Sframeli, M., Antonaci, L., Frongia, A. L., De Vivo, D. C., Darras, B. T., Day, J., Bertini, E., Muntoni, F., Finkel, R., Mercuri, E., Coratti G. (ORCID:0000-0001-6666-5628), Pane M. (ORCID:0000-0002-4851-6124), Lucibello S., Pera M. C. (ORCID:0000-0001-6777-1721), Antonaci L., Frongia A. L., Mercuri E. (ORCID:0000-0002-9851-5365), Coratti, G., Pane, M., Lucibello, S., Pera, M. C., Pasternak, A., Montes, J., Sansone, V. A., Duong, T., Dunaway Young, S., Messina, S., D'Amico, A., Civitello, M., Glanzman, A. M., Bruno, C., Salmin, F., Tacchetti, P., Carnicella, S., Sframeli, M., Antonaci, L., Frongia, A. L., De Vivo, D. C., Darras, B. T., Day, J., Bertini, E., Muntoni, F., Finkel, R., Mercuri, E., Coratti G. (ORCID:0000-0001-6666-5628), Pane M. (ORCID:0000-0002-4851-6124), Lucibello S., Pera M. C. (ORCID:0000-0001-6777-1721), Antonaci L., Frongia A. L., and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Previous natural history studies suggest that type II SMA patients remain stable over one year but show some progression over two years. Since nusinersen approval, there has been increasing attention to identify more specific age-related changes. The aim of the study was to establish 12-month changes in a cohort of pediatric type II SMA treated with nusinersen and to establish possible patterns of treatment effect in relation to different variables such as age, baseline value and SMN2 copy number. The Hammersmith Functional Motor Scale Expanded and the Revised Upper Limb Module were performed at T0 and 12 months after treatment (T12). Data in treated patients were compared to available data in untreated patients collected by the same evaluators.Seventy-seven patients of age between 2.64 and 17.88 years (mean:7.47, SD:3.79) were included. On t-test there was an improvement, with increased mean scores between T0 and T12 on both scales (p < 0.001). Using multivariate linear regression analysis, age and baseline scores were predictive of changes on both scales (p < 0.05) while SMN2 copy number was not. Differences were also found between study cohort and untreated data on both scales (p < 0.001). At 12 months, an increase in scores was observed in all the age subgroups at variance with natural history data. Our real-world data confirm the treatment effect of nusinersen in pediatric type II SMA patients and that the data interpretation should take into account different variables. These data confirm and expand the ones already reported in the Cherish study.

Published
2021

30. The Spinal Muscular Atrophy Health Index: Italian validation of a disease-specific outcome measure

Author

Sansone, V. A., Pirola, A., Lizio, A., Greco, L. C., Coratti, G., Casiraghi, J., Pane, M., Pera, M. C., Italiano, C., Messina, S., Pozzi, S., Sframeli, M., D'Amico, A., Bertini, E., Bruno, C., Mauro, L., Salmin, F., Stancanelli, C., Pedemonte, M., Albamonte, E., Zizzi, C., Heatwole, C., Mercuri, E., Coratti G. (ORCID:0000-0001-6666-5628), Pane M. (ORCID:0000-0002-4851-6124), Pera M. C. (ORCID:0000-0001-6777-1721), Mercuri E. (ORCID:0000-0002-9851-5365), Sansone, V. A., Pirola, A., Lizio, A., Greco, L. C., Coratti, G., Casiraghi, J., Pane, M., Pera, M. C., Italiano, C., Messina, S., Pozzi, S., Sframeli, M., D'Amico, A., Bertini, E., Bruno, C., Mauro, L., Salmin, F., Stancanelli, C., Pedemonte, M., Albamonte, E., Zizzi, C., Heatwole, C., Mercuri, E., Coratti G. (ORCID:0000-0001-6666-5628), Pane M. (ORCID:0000-0002-4851-6124), Pera M. C. (ORCID:0000-0001-6777-1721), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Patient report outcome measures in Spinal Muscular Atrophy (SMA) represent a potential complement to observer rated scales which can be used to better understand treatment response. We developed, translated and validated an Italian version of the Spinal Muscular Atrophy Health Index (SMAHI), a disease-specific, patient reported outcome measure questionnaire, designed to estimate the patients’ perception of disease burden. Test-retest reliability was assessed in 37 patients (16 children aged 12–17 and 21 adults) and was excellent in both cohorts. Internal consistency in an additional 98 patients (24 children, 74 adults) was also excellent (Cronbach's alpha = 0.93 and 0.91 respectively). In children the highest level of disease burden was generated from lower limb dysfunction and fatigue as well as their perception of decreased performance in social situations. Most patients in the adult cohort were sitters and complained of problems with upper limb functions as well as of fatigue. The SMAHI-IT was also able to differentiate between SMA types according to diseases severity. The results of our study demonstrate that the SMAHI can be considered a marker of disease-specific burden in patients with SMA with a high test-retest reliability and internal validity in Italian patients aged 12 and older.

Published
2021

31. Respiratory Trajectories in Type 2 and 3 Spinal Muscular Atrophy in the iSMAC Cohort Study

Author

Trucco, F., Ridout, D., Scoto, M., Coratti, Giorgia, Main, M. L., Muni Lofra, R., Mayhew, A. G., Montes, J., Pane, Marika, Sansone, V., Albamonte, E., D'Amico, Adele, Bertini, Enrico Silvio, Messina, S., Bruno, C., Parasuraman, D., Childs, A. -M., Gowda, V., Willis, T., Ong, M., Marini-Bettolo, C., De Vivo, D. C., Darras, B. T., Day, J., Kichula, E. A., Mayer, O. H., Navas Nazario, A. A., Finkel, R. S., Mercuri, Eugenio Maria, Muntoni, F., Coratti G. (ORCID:0000-0001-6666-5628), Pane M. (ORCID:0000-0002-4851-6124), D'Amico A., Bertini E., Mercuri E. (ORCID:0000-0002-9851-5365), Trucco, F., Ridout, D., Scoto, M., Coratti, Giorgia, Main, M. L., Muni Lofra, R., Mayhew, A. G., Montes, J., Pane, Marika, Sansone, V., Albamonte, E., D'Amico, Adele, Bertini, Enrico Silvio, Messina, S., Bruno, C., Parasuraman, D., Childs, A. -M., Gowda, V., Willis, T., Ong, M., Marini-Bettolo, C., De Vivo, D. C., Darras, B. T., Day, J., Kichula, E. A., Mayer, O. H., Navas Nazario, A. A., Finkel, R. S., Mercuri, Eugenio Maria, Muntoni, F., Coratti G. (ORCID:0000-0001-6666-5628), Pane M. (ORCID:0000-0002-4851-6124), D'Amico A., Bertini E., and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

OBJECTIVE: To describe the respiratory trajectories and their correlation with motor function in an international pediatric cohort of patients with type 2 and nonambulant type 3 spinal muscular atrophy (SMA). METHODS: This was an 8-year retrospective observational study of patients in the International SMA Consortium (iSMAc) natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC percent predicted (FVC%P), and noninvasive ventilation (NIV) requirement. Hammersmith Functional Motor Scale (HFMS) and revised Performance of Upper Limb (RULM) scores were correlated with respiratory function. We excluded patients in interventional clinical trials and on nusinersen commercial therapy. RESULTS: There were 437 patients with SMA: 348 with type 2 and 89 with nonambulant type 3. Mean age at first visit was 6.9 (±4.4) and 11.1 (±4) years. In SMA type 2, FVC%P declined by 4.2%/y from 5 to 13 years, followed by a slower decline (1.0%/y). In type 3, FVC%P declined by 6.3%/y between 8 and 13 years, followed by a slower decline (0.9%/y). Thirty-nine percent with SMA type 2% and 9% with type 3 required NIV at a median age 5.0 (1.8-16.6) and 15.1 (13.8-16.3) years. Eighty-four percent with SMA type 2% and 80% with type 3 had scoliosis; 54% and 46% required surgery, which did not significantly affect respiratory decline. FVC%P positively correlated with HFMS and RULM scores in both subtypes. CONCLUSIONS: In SMA type 2 and nonambulant type 3, lung function declines differently, with a common leveling after age 13 years. Lung and motor function correlated in both subtypes. Our data further define the milder SMA phenotypes and provide information to benchmark the long-term efficacy of new treatments for SMA.

Published
2021

32. The nonsense mutation stop+4 model correlates with motor changes in Duchenne muscular dystrophy

Author

Brogna, Claudia, Coratti, Giorgia, Rossi, R., Neri, M., Messina, S., Amico, A. D., Bruno, C., Lucibello, Simona, Vita, G., Berardinelli, A., Magri, F., Ricci, F., Pedemonte, M., Mongini, T., Battini, Roberta, Bello, L., Pegoraro, E., Baranello, Giovanni, Politano, L., Comi, G. P., Sansone, V. A., Albamonte, E., Donati, A., Bertini, Enrico Silvio, Goemans, N., Previtali, S., Bovis, F., Pane, Marika, Ferlini, A., Mercuri, Eugenio Maria, Brogna C., Coratti G. (ORCID:0000-0001-6666-5628), Lucibello S., Battini R., Baranello G., Bertini E., Pane M. (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Brogna, Claudia, Coratti, Giorgia, Rossi, R., Neri, M., Messina, S., Amico, A. D., Bruno, C., Lucibello, Simona, Vita, G., Berardinelli, A., Magri, F., Ricci, F., Pedemonte, M., Mongini, T., Battini, Roberta, Bello, L., Pegoraro, E., Baranello, Giovanni, Politano, L., Comi, G. P., Sansone, V. A., Albamonte, E., Donati, A., Bertini, Enrico Silvio, Goemans, N., Previtali, S., Bovis, F., Pane, Marika, Ferlini, A., Mercuri, Eugenio Maria, Brogna C., Coratti G. (ORCID:0000-0001-6666-5628), Lucibello S., Battini R., Baranello G., Bertini E., Pane M. (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

The aim was to assess 3-year longitudinal data using 6MWT in 26 ambulant boys affected by DMD carrying nonsense mutations and to compare their results to other small mutations. We also wished to establish, within the nonsense mutations group, patterns of change according to several variables. Patients with nonsense mutations were categorized according to the stop codon type newly created by the mutation and also including the adjacent 5′ (upstream) and 3′ (downstream) nucleotides. No significant difference was found between nonsense mutations and other small mutations (p > 0.05) on the 6MWT. Within the nonsense mutations group, there was no difference in 6MWT when the patients were subdivided according to: Type of stop codon, frame status of exons involved, protein domain affected. In contrast, there was a difference when the stop codon together with the 3′ adjacent nucleotide (“stop+4 model”) was considered (p < 0.05) with patients with stop codon TGA and 3′ adjacent nucleotide G (TGAG) having a more rapid decline. Our finding suggest that the stop+4 model may help in predicting functional changes. This data will be useful at the time of interpreting the long term follow up of patients treated with Ataluren that are becoming increasingly available.

Published
2021

33. Sometimes they come back: New and old spinal muscular atrophy adults in the era of nusinersen

Author

Sansone, V. A., Coratti, Giorgia, Pera, Maria Carmela, Pane, Marika, Messina, S., Salmin, F., Albamonte, E., De Sanctis, Roberto, Sframeli, M., Di Bella, V., Morando, S., D'Amico, Adele, Frongia, Anna Lia, Antonaci, Laura, Pirola, A., Pedemonte, M., Bertini, Enrico Silvio, Bruno, C., Mercuri, Eugenio Maria, Di Bari, A., Signorino, A., Longo, A., Tacchetti, P., Brolatti, N., Rossi, Dario, Bravetti, C., Lucibello, Simona, Fanelli, Luca, Forcina, N., Norcia, G., Carnicella, S., Patanella, K. A., Leone, D., Palermo, C., Berti, B., Catania, Francesca, Colombo, A., Bozzardi, A., Ferrantini, Gloria, Vita, G., Coratti G. (ORCID:0000-0001-6666-5628), Pera M. C. (ORCID:0000-0001-6777-1721), Pane M. (ORCID:0000-0002-4851-6124), De Sanctis R., d'Amico A., Frongia A. L., Antonaci L., Bertini E., Mercuri E. (ORCID:0000-0002-9851-5365), Rossi D., Lucibello S., Fanelli L., Catania F., Ferrantini G., Sansone, V. A., Coratti, Giorgia, Pera, Maria Carmela, Pane, Marika, Messina, S., Salmin, F., Albamonte, E., De Sanctis, Roberto, Sframeli, M., Di Bella, V., Morando, S., D'Amico, Adele, Frongia, Anna Lia, Antonaci, Laura, Pirola, A., Pedemonte, M., Bertini, Enrico Silvio, Bruno, C., Mercuri, Eugenio Maria, Di Bari, A., Signorino, A., Longo, A., Tacchetti, P., Brolatti, N., Rossi, Dario, Bravetti, C., Lucibello, Simona, Fanelli, Luca, Forcina, N., Norcia, G., Carnicella, S., Patanella, K. A., Leone, D., Palermo, C., Berti, B., Catania, Francesca, Colombo, A., Bozzardi, A., Ferrantini, Gloria, Vita, G., Coratti G. (ORCID:0000-0001-6666-5628), Pera M. C. (ORCID:0000-0001-6777-1721), Pane M. (ORCID:0000-0002-4851-6124), De Sanctis R., d'Amico A., Frongia A. L., Antonaci L., Bertini E., Mercuri E. (ORCID:0000-0002-9851-5365), Rossi D., Lucibello S., Fanelli L., Catania F., and Ferrantini G.

Abstract

Background and purpose: Following the commercial availability of nusinersen, there have been a number of new referrals of adults with spinal muscular atrophy (SMA) not regularly followed in tertiary-care centers or enrolled in any disease registry. Methods: We compared demographics and disease characteristics, including assessment of motor and respiratory function, in regularly followed patients and newcomers subdivided according to the SMA type. Results: The cohort included 166 adult patients (mean age: 37.09 years): one type I, 65 type II, 99 type III, and one type IV. Of these 166, there were 67 newcomers. There was no significant difference between newcomers and regularly followed patients in relation to age and disease duration. The Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module scores were higher in the regularly followed patients compared to newcomers in the whole cohort and in both SMA II and II. A difference was also found on ventilatory status (p = 0.013) and Cobb’s angle >50° (p = 0.039) between the two subgroups. No difference was found in scoliosis surgery prevalence (p > 0.05). Conclusions: Our results showed differences between the two subgroups, even if less marked in the type III patients. In the type II patients, there was a higher proportion of newcomers who were in the severe end of the spectrum. Of the newcomers, only approximately a third initiated treatment, as opposed to the 51% in the regularly followed patients. The identification of patients who were not part of the registries will help to redefine the overall prevalence of SMA and the occurrence of different phenotypes.

Published
2021

34. North Star Ambulatory Assessment changes in ambulant Duchenne boys amenable to skip exons 44, 45, 51, and 53: A 3 year follow up

Author

Coratti, Giorgia, Pane, Marika, Brogna, Claudia, Ricotti, V., Messina, S., D'Amico, A., Bruno, C., Vita, G., Berardinelli, A., Mazzone, Elena Stacy, Magri, F., Ricci, F., Mongini, T., Battini, R., Bello, L., Pegoraro, E., Baranello, G., Previtali, S. C., Politano, L., Comi, G. P., Sansone, V. A., Donati, A., Hogrel, J. Y., Straub, V., De Lucia, S., Niks, E., Servais, L., De Groot, I., Chesshyre, M., Bertini, E., Goemans, N., Muntoni, F., Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Pane M. (ORCID:0000-0002-4851-6124), Brogna C., Mazzone E., Mercuri E. (ORCID:0000-0002-9851-5365), Coratti, Giorgia, Pane, Marika, Brogna, Claudia, Ricotti, V., Messina, S., D'Amico, A., Bruno, C., Vita, G., Berardinelli, A., Mazzone, Elena Stacy, Magri, F., Ricci, F., Mongini, T., Battini, R., Bello, L., Pegoraro, E., Baranello, G., Previtali, S. C., Politano, L., Comi, G. P., Sansone, V. A., Donati, A., Hogrel, J. Y., Straub, V., De Lucia, S., Niks, E., Servais, L., De Groot, I., Chesshyre, M., Bertini, E., Goemans, N., Muntoni, F., Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Pane M. (ORCID:0000-0002-4851-6124), Brogna C., Mazzone E., and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Introduction The aim of this study was to report 36-month longitudinal changes using the North Star Ambulatory Assessment (NSAA) in ambulant patients affected by Duchenne muscular dystrophy amenable to skip exons 44, 45, 51 or 53. Materials and methods We included 101 patients, 34 had deletions amenable to skip exon 44, 25 exon 45, 19 exon 51, and 28 exon 53, not recruited in any ongoing clinical trials. Five patients were counted to skip exon 51 and 53 since they had a single deletion of exon 52. Results The difference between subgroups (skip 44, 45, 51 and 53) was significant at 12 (p = 0.043), 24 (p = 0.005) and 36 months (p≤0.001). Discussion Mutations amenable to skip exons 53 and 51 had lower baseline values and more negative changes than the other subgroups while those amenable to skip exon 44 had higher scores both at baseline and at follow up. Conclusion Our results confirm different progression of disease in subgroups of patients with deletions amenable to skip different exons. This information is relevant as current long term clinical trials are using the NSAA in these subgroups of mutations.

Published
2021

35. Different trajectories in upper limb and gross motor function in spinal muscular atrophy

Author

Coratti, Giorgia, Pera, Maria Carmela, Montes, J., Pasternak, A., Scoto, M., Baranello, Giovanni, Messina, S., Dunaway Young, S., Glanzman, A. M., Duong, T., De Sanctis, Roberto, Mazzone, Elena Stacy, Milev, E., Rohwer, A., Civitello, M., Pane, Marika, Antonaci, Laura, Frongia, Anna Lia, Sframeli, M., Vita, G. L., D'Amico, Adele, Mizzoni, I., Albamonte, E., Darras, B. T., Bertini, Enrico Silvio, Sansone, V. A., Bovis, F., Day, J., Bruno, C., Muntoni, F., De Vivo, D. C., Finkel, R., Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Pera M. C. (ORCID:0000-0001-6777-1721), Baranello G., De Sanctis R., Mazzone E. S., Pane M. (ORCID:0000-0002-4851-6124), Antonaci L., Frongia A. L., D'Amico A., Bertini E., Mercuri E. (ORCID:0000-0002-9851-5365), Coratti, Giorgia, Pera, Maria Carmela, Montes, J., Pasternak, A., Scoto, M., Baranello, Giovanni, Messina, S., Dunaway Young, S., Glanzman, A. M., Duong, T., De Sanctis, Roberto, Mazzone, Elena Stacy, Milev, E., Rohwer, A., Civitello, M., Pane, Marika, Antonaci, Laura, Frongia, Anna Lia, Sframeli, M., Vita, G. L., D'Amico, Adele, Mizzoni, I., Albamonte, E., Darras, B. T., Bertini, Enrico Silvio, Sansone, V. A., Bovis, F., Day, J., Bruno, C., Muntoni, F., De Vivo, D. C., Finkel, R., Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Pera M. C. (ORCID:0000-0001-6777-1721), Baranello G., De Sanctis R., Mazzone E. S., Pane M. (ORCID:0000-0002-4851-6124), Antonaci L., Frongia A. L., D'Amico A., Bertini E., and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Introduction: The Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM) have been widely used in natural history studies and clinical trials. Our aim was to establish how the scales relate to each other at different age points in spinal muscular atrophy (SMA) type 2 and 3, and to describe their coherence over 12 mo. Methods: The study was performed by cross-sectional and longitudinal reanalysis of previously published natural history data. The longitudinal analysis of the 12-mo changes also included the analysis of concordance between scales with changes grouped as stable (±2 points), improved (>+2) or declined (>−2). Results: Three hundred sixty-four patients were included in the cross-sectional analysis, showing different trends in score and point of slope change for the two scales. For type 2, the point of slope change was 4.1 y for the HFMSE and 5.8 for the RULM, while for type 3, it was 6 y for the HFMSE and 7.3 for the RULM. One-hundred-twenty-one patients had at least two assessments at 12 mo. Full concordance was found in 57.3% of the assessments, and in 40.4% one scale remained stable and the other changed. Each scale appeared to be more sensitive to specific age or functional subgroups. Discussion: The two scales, when used in combination, may increase the sensitivity to detect clinically meaningful changes in motor function in patients with SMA types 2 and 3.

Published
2021

36. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial

Author

Mercuri, Eugenio Maria, Muntoni, F., Baranello, Giovanni, Masson, R., Boespflug-Tanguy, O., Bruno, C., Corti, S., Daron, A., Deconinck, N., Servais, L., Straub, V., Ouyang, H., Chand, D., Tauscher-Wisniewski, S., Mendonca, N., Lavrov, A., Seferian, A., De Lucia, S., Tachibana, S., Jollet, A., Mouffak, S., Pedemonte, M., Brolatti, N., Morando, S., Vanlander, A., De Vos, E., Tahon, V., Govoni, A., Magri, F., Comi, G., Foa, M., Parente, V., Buscemi, L., Dal Farra, F., Schneider, O., Jonas, A., Defeldre, A. C., Pagliano, E., Zanin, R., Arnoldi, M. T., Schembri, V., Del Sole, M., Mandelli, A., Pera, Maria Carmela, Antonaci, Laura, Coratti, Giorgia, De Sanctis, Roberto, Pane, Marika, Scoto, M., Groves, K., Edel, L., Abel, F., Van Ruiten, H., Lofra, R. M., Thompson, E., Mercuri E. (ORCID:0000-0002-9851-5365), Baranello G., Pera M. C. (ORCID:0000-0001-6777-1721), Antonaci L., Coratti G. (ORCID:0000-0001-6666-5628), de Sanctis R., Pane M. (ORCID:0000-0002-4851-6124), Mercuri, Eugenio Maria, Muntoni, F., Baranello, Giovanni, Masson, R., Boespflug-Tanguy, O., Bruno, C., Corti, S., Daron, A., Deconinck, N., Servais, L., Straub, V., Ouyang, H., Chand, D., Tauscher-Wisniewski, S., Mendonca, N., Lavrov, A., Seferian, A., De Lucia, S., Tachibana, S., Jollet, A., Mouffak, S., Pedemonte, M., Brolatti, N., Morando, S., Vanlander, A., De Vos, E., Tahon, V., Govoni, A., Magri, F., Comi, G., Foa, M., Parente, V., Buscemi, L., Dal Farra, F., Schneider, O., Jonas, A., Defeldre, A. C., Pagliano, E., Zanin, R., Arnoldi, M. T., Schembri, V., Del Sole, M., Mandelli, A., Pera, Maria Carmela, Antonaci, Laura, Coratti, Giorgia, De Sanctis, Roberto, Pane, Marika, Scoto, M., Groves, K., Edel, L., Abel, F., Van Ruiten, H., Lofra, R. M., Thompson, E., Mercuri E. (ORCID:0000-0002-9851-5365), Baranello G., Pera M. C. (ORCID:0000-0001-6777-1721), Antonaci L., Coratti G. (ORCID:0000-0001-6666-5628), de Sanctis R., and Pane M. (ORCID:0000-0002-4851-6124)

Abstract

Background: Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US. Methods: STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes [vg]/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov, NCT03461289 (completed). Findings: From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of function

Published
2021

37. Type I SMA “new natural history”: long-term data in nusinersen-treated patients

Author

Pane, Marika, Coratti, Giorgia, Sansone, V. A., Messina, S., Catteruccia, M., Bruno, C., Sframeli, M., Albamonte, E., Pedemonte, M., D'Amico, Adele, Bravetti, C., Berti, B., Palermo, C., Leone, D., Brigati, G., Tacchetti, P., Salmin, F., De Sanctis, Roberto, Lucibello, Simona, Pera, Maria Carmela, Piastra, Marco, Genovese, Orazio, Bertini, Enrico Silvio, Vita, G., Tiziano, Francesco Danilo, Mercuri, Eugenio Maria, Pane M. (ORCID:0000-0002-4851-6124), Coratti G. (ORCID:0000-0001-6666-5628), D'Amico A., De Sanctis R., Lucibello S., Pera M. C. (ORCID:0000-0001-6777-1721), Piastra M. (ORCID:0000-0002-3144-8970), Genovese O., Bertini E., Tiziano F. D. (ORCID:0000-0002-5545-6158), Mercuri E. (ORCID:0000-0002-9851-5365), Pane, Marika, Coratti, Giorgia, Sansone, V. A., Messina, S., Catteruccia, M., Bruno, C., Sframeli, M., Albamonte, E., Pedemonte, M., D'Amico, Adele, Bravetti, C., Berti, B., Palermo, C., Leone, D., Brigati, G., Tacchetti, P., Salmin, F., De Sanctis, Roberto, Lucibello, Simona, Pera, Maria Carmela, Piastra, Marco, Genovese, Orazio, Bertini, Enrico Silvio, Vita, G., Tiziano, Francesco Danilo, Mercuri, Eugenio Maria, Pane M. (ORCID:0000-0002-4851-6124), Coratti G. (ORCID:0000-0001-6666-5628), D'Amico A., De Sanctis R., Lucibello S., Pera M. C. (ORCID:0000-0001-6777-1721), Piastra M. (ORCID:0000-0002-3144-8970), Genovese O., Bertini E., Tiziano F. D. (ORCID:0000-0002-5545-6158), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Objective: The aim of this paper was to report the 2-year follow-up in type I patients treated with Nusinersen and to assess whether possible changes in motor function are related to the subtype, age, or SMN2 copy number. Methods: Sixty-eight patients, with ages ranging from 0.20 to 15.92 years (mean: 3.96; standard deviation: +3.90) were enrolled in the study. All patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the developmental section of the Hammersmith Infant Neurological Examination (HINE-2) at the time they started treatment and 12 and 24 months after that. Results: For both CHOP and HINE-2 repeated measures analysis of variance showed a significant difference (P < 0.001) between baseline and 12 months, 12 months and 24 months, and baseline and 24-month scores for the whole group. When age subgroups (<210 days, <2 years, 2–4 years, 5–11 years, 12–18 years) were considered, on the CHOP INTEND the difference was significant between baseline and 24 months in all age subgroups. On the HINE-2, the difference between baseline and 24 months was significant in all the subgroups before the age of 4 years. Age was predictive of changes on both scales (P < 0.05), whereas SMN2 copy number and decimal classification were not. Interpretation: Our results suggest that some improvement of motor function can be observed even after the first year of treatment. This is more obvious in the infants treated in the first 2 years but some improvement can also be found in older children.

Published
2021

38. Gain and loss of abilities in type II SMA: A 12-month natural history study

Author

Coratti, Giorgia, Lucibello, Simona, Pera, Maria Carmela, Duong, T., Muni Lofra, R., Civitello, M., D'Amico, Adele, Goemans, N., Darras, B. T., Bruno, C., Sansone, V. A., Day, J., Nascimento Osorio, A., Muntoni, F., Montes, J., Sframeli, M., Finkel, R., Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Lucibello S., Pera M. C. (ORCID:0000-0001-6777-1721), D'Amico A., Mercuri E. (ORCID:0000-0002-9851-5365), Coratti, Giorgia, Lucibello, Simona, Pera, Maria Carmela, Duong, T., Muni Lofra, R., Civitello, M., D'Amico, Adele, Goemans, N., Darras, B. T., Bruno, C., Sansone, V. A., Day, J., Nascimento Osorio, A., Muntoni, F., Montes, J., Sframeli, M., Finkel, R., Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Lucibello S., Pera M. C. (ORCID:0000-0001-6777-1721), D'Amico A., and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

The advent of clinical trials in spinal muscular atrophy (SMA) has highlighted the need to define patterns of progression using functional scales. It has recently been suggested that the analysis of abilities gained or lost applied to functional scales better reflects meaningful changes. We defined as “gain” a positive change between scores from 0 to either 1 or 2 and as “loss” a negative change from either 2 or 1 to 0. The aim of this study was to describe, over 12 months, which abilities on the Hammersmith Functional Motor Scale Expanded (HFMSE) were more frequently lost or gained in patients with SMA II. The cohort included 614 12-month assessments from 243 patients (age range: 30 months - 63 years; mean 9.94, SD ±7.91). The peak of abilities gained occurred before the age of 5 years while the highest number of lost abilities was found in the group 5–13 years. A correlation between the HFMSE baseline score and the ordinal number of the items was found for both lost (p<0.001) or gained (p<0.001) activities. No correlation was found with SMN2 copy number. These findings will have implications for clinical trial design and for the interpretation of real-world data using new therapeutic approaches.

Published
2020

39. Respiratory function and therapeutic expectations in DMD: Families experience and perspective

Author

Brogna, Claudia, Lucibello, Simona, Coratti, Giorgia, Vita, G., Sansone, V. A., Messina, S., Albamonte, E., Salmin, F., Ferrantini, Gloria, Pede, Elisa, Consulo, C., Fanelli, L., Forcina, N., Norcia, G., Pane, Marika, Mercuri, Eugenio Maria, Brogna C., Lucibello S., Coratti G. (ORCID:0000-0001-6666-5628), Ferrantini G., Pede E., Pane M. (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Brogna, Claudia, Lucibello, Simona, Coratti, Giorgia, Vita, G., Sansone, V. A., Messina, S., Albamonte, E., Salmin, F., Ferrantini, Gloria, Pede, Elisa, Consulo, C., Fanelli, L., Forcina, N., Norcia, G., Pane, Marika, Mercuri, Eugenio Maria, Brogna C., Lucibello S., Coratti G. (ORCID:0000-0001-6666-5628), Ferrantini G., Pede E., Pane M. (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Objective. The aim of this study was to use a structured questionnaire in a large cohort of Duchenne Muscular Dystrophy (DMD) patients to assess caregivers and patients views on respiratory function and to establish if their responses were related to the patients' age or level of functional impairment. Methods. Questionnaires were administered to caregivers in 205 DMD patients of age between 3 and 36 years (115 ambulant, 90 non-ambulant), and to 64 DMD patients (3 ambulant, 61 non-ambulant) older than 18 years, subdivided into groups according to age, FVC, ambulatory and ventilatory status. Results. Some differences were found in relation to FVC % values (p = 0.014), ambulatory (p = 0.043) and ventilatory status (p = 0.014). Nearly half of the caregivers expected deterioration over the next years, with the perspective of deterioration more often reported by caregivers of non-ambulant (p = 0.018) and ventilated patients (p = 0.004). Caregivers appeared to be aware of the relevance of respiratory function on quality of life (84%) showing willingness to enter possible clinical trials if these were aiming to stabilize the progression of respiratory function with a very high number of positive responses across the spectrum of age, FVC, ambulatory and ventilatory status. The boys older than 18 years showed similar results. Conclusions. Our study showed that the concern for respiratory function increases with age and with the reduction of FVC or the need for ventilation, but the need for intervention was acknowledged across the whole spectrum of age and functional status.

Published
2020

40. Performance of Upper Limb module for Duchenne muscular dystrophy

Author

Mayhew, A. G., Coratti, G., Mazzone, E. S., Klingels, K., James, M., Pane, M., Straub, V., Goemans, N., Mercuri, E., Ricotti, V., Muntoni, F., Ridout, D., Selby, V., Coratti G. (ORCID:0000-0001-6666-5628), Mazzone E. S., Pane M. (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Mayhew, A. G., Coratti, G., Mazzone, E. S., Klingels, K., James, M., Pane, M., Straub, V., Goemans, N., Mercuri, E., Ricotti, V., Muntoni, F., Ridout, D., Selby, V., Coratti G. (ORCID:0000-0001-6666-5628), Mazzone E. S., Pane M. (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Aim: To report the differences between Performance of Upper Limb (PUL) versions 1.2 and 2.0, compare the measurement ability of the two versions, and compare their longitudinal performance in Duchenne muscular dystrophy. Method: Rasch analysis was performed on the dual data from three centres to confirm whether the two scales measure the same construct. Change scores in natural history for the different domains were compared for the two versions. Results: Rasch analysis demonstrated that both versions measure the same construct and that the PUL 2.0 was a better fit to the construct of motor performance and better able to detect change at 12 months in all levels of ability than the PUL 1.2. This was also true when change scores were reviewed over 2 years. Interpretation: Our results confirm that the PUL 1.2 and 2.0 versions detect change in all domains over 2 years. They also demonstrate that simplifying the original scoring of the PUL 1.2 for the revised PUL 2.0 maintains the validity of the construct and enhances the scale measurement qualities. What this paper adds: The original and revised Performance of Upper Limb (PUL) scales measure the same construct. Both scales detected change in all domains over 2 years. The PUL 2.0 enhances the measurement qualities of the scale.

Published
2020

41. Longitudinal natural history of type I spinal muscular atrophy: A critical review

Author

Mercuri, Eugenio Maria, Lucibello, Simona, Perulli, Marco, Coratti, Giorgia, De Sanctis, Roberto, Pera, Maria Carmela, Pane, Marika, Montes, J., De Vivo, D. C., Darras, B. T., Kolb, S. J., Finkel, R. S., Mercuri E. (ORCID:0000-0002-9851-5365), Lucibello S., Perulli M., Coratti G. (ORCID:0000-0001-6666-5628), De Sanctis R., Pera M. C. (ORCID:0000-0001-6777-1721), Pane M. (ORCID:0000-0002-4851-6124), Mercuri, Eugenio Maria, Lucibello, Simona, Perulli, Marco, Coratti, Giorgia, De Sanctis, Roberto, Pera, Maria Carmela, Pane, Marika, Montes, J., De Vivo, D. C., Darras, B. T., Kolb, S. J., Finkel, R. S., Mercuri E. (ORCID:0000-0002-9851-5365), Lucibello S., Perulli M., Coratti G. (ORCID:0000-0001-6666-5628), De Sanctis R., Pera M. C. (ORCID:0000-0001-6777-1721), and Pane M. (ORCID:0000-0002-4851-6124)

Abstract

Background: The advent of new therapies in spinal muscular atrophy (SMA) has highlighted the need to have natural history data for comparison. Natural history studies using structured assessments in type I however are very limited. We identified and reviewed all the existing longitudinal history data in infants with type I SMA first assessed before the age of 7 months with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Main text: Three longitudinal natural history studies, two performed in the United States and one in Italy, were identified. The different study design of these three studies made it possible for the cumulative dataset to include the full spectrum of severity; from infants with neonatal onset to those with a milder phenotype that were not always included in the individual natural history studies. The cumulative analysis confirmed that, even in a larger cohort, there was never an improvement on the CHOP INTEND over time. This was true for all the infants, irrespective of their age or baseline CHOP INTEND scores. Infants with neonatal onset had low CHOP INTEND scores and a fast decline. The relatively large number of patients allowed us to calculate the rate of progression in subgroups identified according to SMN2 copy number and baseline CHOP INTEND scores. Conclusion: A detailed understanding of the existing data is important, as it will be difficult to acquire new systematic longitudinal history data because of the availability of disease modifying therapies. The cumulative findings in this review help to better understand the variability of natural history data in untreated patients and will be of use for comparison to the real world patients treated with the recently approved therapies that have shown encouraging results in clinical trials.

Published
2020

42. Age and baseline values predict 12 and 24-month functional changes in type 2 SMA

Author

Coratti, Giorgia, Pera, Maria Carmela, Lucibello, Simona, Montes, J., Pasternak, A., Mayhew, A., Glanzman, A. M., Young, S. D., Pane, Marika, Scoto, M., Messina, S., Goemans, N., Osorio, A. N., Pedemonte, M., Sansone, V., Bertini, E., De Vivo, D. C., Finkel, R., Muntoni, F., Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Pera M. C. (ORCID:0000-0001-6777-1721), Lucibello S., Pane M. (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Coratti, Giorgia, Pera, Maria Carmela, Lucibello, Simona, Montes, J., Pasternak, A., Mayhew, A., Glanzman, A. M., Young, S. D., Pane, Marika, Scoto, M., Messina, S., Goemans, N., Osorio, A. N., Pedemonte, M., Sansone, V., Bertini, E., De Vivo, D. C., Finkel, R., Muntoni, F., Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Pera M. C. (ORCID:0000-0001-6777-1721), Lucibello S., Pane M. (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

The aim of this retrospective study was to establish the range of functional changes at 12 and 24-month in 267 type 2 Spinal Muscular Atrophy (SMA) patients with multiple assessments. We included 652 Hammersmith Functional Motor Scale Expanded (HFMSE) assessments at 12 month- and 305 at 24 month- intervals. The cohort was subdivided by functional level, Survival of Motor Neuron copy number and age. Stable scores (± 2 points) were found in 68% at 12 months and in 55% at 24 months. A decrease ≥2 points was found in 21% at 12 months and in 35% at 24 months. An increase ≥2 points was found in 11% at 12 months and 9.5% at 24 months. The risk of losing ≥2 points increased with age and HFMSE score at baseline both at 12 and 24-month. For each additional HFMSE point at baseline, the relative risk of a >2 point decline at 12 months increases by 5% before age 5 years (p = 0.023), by 8% between 5 and 13 (p<0.001) and by 26% after 13 years (p = 0.003). The combination of age and HFMSE scores at baseline increased the ability to predict progression in type 2 SMA.

Published
2020

43. Patient and parent oriented tools to assess health-related quality of life, activity of daily living and caregiver burden in SMA. Rome, 13 July 2019

Author

Mercuri, Eugenio Maria, Messina, S., Montes, J., Muntoni, F., Sansone, V. A., Antonaci, Laura, Civitello, M., Coratti, Giorgia, Lemus, M. D., Sanctis, R. D., Avexis, M. D., Duong, T., Finkel, R., Frongia, Anna Lia, Roche, K. G., Heatwole, C., Gusset, N., Henricson, E., Mayhew, A., Marchesi, C., Pasternak, A., Pechmann, A., Pera, Maria Carmela, Rubino, I., Sansone, V., Schroth, M., Trundell, D., Straub, V., Mercuri E. (ORCID:0000-0002-9851-5365), Antonaci L., Coratti G. (ORCID:0000-0001-6666-5628), Frongia A. L., Pera M. C. (ORCID:0000-0001-6777-1721), Mercuri, Eugenio Maria, Messina, S., Montes, J., Muntoni, F., Sansone, V. A., Antonaci, Laura, Civitello, M., Coratti, Giorgia, Lemus, M. D., Sanctis, R. D., Avexis, M. D., Duong, T., Finkel, R., Frongia, Anna Lia, Roche, K. G., Heatwole, C., Gusset, N., Henricson, E., Mayhew, A., Marchesi, C., Pasternak, A., Pechmann, A., Pera, Maria Carmela, Rubino, I., Sansone, V., Schroth, M., Trundell, D., Straub, V., Mercuri E. (ORCID:0000-0002-9851-5365), Antonaci L., Coratti G. (ORCID:0000-0001-6666-5628), Frongia A. L., and Pera M. C. (ORCID:0000-0001-6777-1721)

Abstract

n/a

Published
2020

44. Respiratory Needs in Patients with Type 1 Spinal Muscular Atrophy Treated with Nusinersen

Author

Sansone, V. A., Pirola, A., Albamonte, E., Pane, M., Lizio, A., D'Amico, A., Catteruccia, M., Cutrera, R., Bruno, C., Pedemonte, M., Messina, S., Rao, F., Roma, E., Salmin, F., Coratti, Giorgia, Di Bari, A., De Sanctis, R., Pera, C. M., Sframeli, M., Piastra, Marco, Macagno, F., Vita, G., Bertini, E., Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Piastra M. (ORCID:0000-0002-3144-8970), Mercuri E. (ORCID:0000-0002-9851-5365), Sansone, V. A., Pirola, A., Albamonte, E., Pane, M., Lizio, A., D'Amico, A., Catteruccia, M., Cutrera, R., Bruno, C., Pedemonte, M., Messina, S., Rao, F., Roma, E., Salmin, F., Coratti, Giorgia, Di Bari, A., De Sanctis, R., Pera, C. M., Sframeli, M., Piastra, Marco, Macagno, F., Vita, G., Bertini, E., Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Piastra M. (ORCID:0000-0002-3144-8970), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

Objective: To evaluate the effects of nusinersen on respiratory function of patients with type 1 spinal muscular atrophy. Study design: Observational, longitudinal cohort study. We collected respiratory data from 118 children with type 1 spinal muscular atrophy and differing pulmonary requirements and conducted a semistructured qualitative interview among a subsample of caregivers at baseline, 6 months, and 10 months after the first nusinersen treatment. Patients were stratified according to ventilation modalities and age at study entry. Results: Most patients in our cohort remained stable (84/109 = 77%). More than 80% of the children treated before age 2 years survived, in contrast to the lower survival reported in natural history studies, and did so without tracheostomy or noninvasive ventilation (NIV) ≥16 hours. In those less than 2 years old, only 3 patients shifted from NIV ≤10 hours to NIV >10 hours, and the other 3 reduced the hours of NIV required. Most of the older patients remained stable; this included not only those on tracheostomy or NIV >10 hours but also 75% of those on NIV ≤10 hours. Conclusions: Our results suggest that nusinersen may produce some improvement in the progression of respiratory impairment, both in terms of survival and need for respiratory support ≥16 hours, especially before the age of 2 years.

Published
2020

45. Early Childhood Attention Battery: Italian adaptation and new expanded normative data.

Author

Coratti, Giorgia, Mallardi, Maria, Coppola, C, Tinelli, F, Bartoli, M, Laganà, V, Lucibello, Simona, Sivo, Serena, Gallini, Francesca, Romeo, Domenico Marco, Atkinson, J, Braddick, O, Mercuri, Eugenio Maria, Ricci, Daniela, Coratti G (ORCID:0000-0001-6666-5628), Mallardi M, Lucibello S, Sivo S, Gallini F (ORCID:0000-0002-9510-8481), Romeo DM (ORCID:0000-0002-6229-1208), Mercuri E (ORCID:0000-0002-9851-5365), Ricci D., Coratti, Giorgia, Mallardi, Maria, Coppola, C, Tinelli, F, Bartoli, M, Laganà, V, Lucibello, Simona, Sivo, Serena, Gallini, Francesca, Romeo, Domenico Marco, Atkinson, J, Braddick, O, Mercuri, Eugenio Maria, Ricci, Daniela, Coratti G (ORCID:0000-0001-6666-5628), Mallardi M, Lucibello S, Sivo S, Gallini F (ORCID:0000-0002-9510-8481), Romeo DM (ORCID:0000-0002-6229-1208), Mercuri E (ORCID:0000-0002-9851-5365), and Ricci D.

Abstract

BACKGROUND: The Early Childhood Attention Battery (ECAB) has been used to assess three different components of attention in preschool children, namely, selective, sustained and attentional control. AIM: The aim of the study was: I) to adapt the ECAB to the Italian language; II) to collect Italian reference data using the translated version and III) to expand the available reference data using 6-month age intervals. STUDY DESIGN: The adaptation of the ECAB to Italian language and the collection of Italian reference data was performed in four phases: translation and identification of the manual and subtests that needed adaptation; interobserver reliability and feasibility of the Italian version; application of the Italian ECAB; statistical analysis. SUBJECTS: The ECAB was performed on a low risk population between 3 and 5 years, 11 months. RESULTS: Statistical analysis was conducted subdividing the cohort in 6-month age groups. The final cohort included 300 low-risk typically developing children. The assessment was well accepted and enjoyed by most of the children except for some in the youngest group who refused to complete all of the tests. Our data showed a progressive improvement in attention across age in seven of the eight subtests of the ECAB. CONCLUSION: The ECAB is a feasible battery in Italian as in the English version, for the assessment of early attention in preschool children, allowing the assessment of the different components of attention and a specific maturation follow up with increasing age.

Published
2020

46. Longitudinal natural history in young boys with Duchenne muscular dystrophy

Author

Coratti, Giorgia, Brogna, Claudia, Norcia, G., Ricotti, V., Abbott, L., D'Amico, Adele, Berardinelli, A., Vita, G. L., Lucibello, Simona, Messina, S., Sansone, V., Albamonte, E., Colia, G., Salmin, F., Gardani, A., Manzur, A., Main, M., Baranello, Giovanni, Arnoldi, M. T., Parsons, J., Carry, T., Connolly, A. M., Bertini, Enrico Silvio, Muntoni, F., Pane, Marika, Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Brogna C., D'Amico A., Lucibello S., Baranello G., Bertini E., Pane M. (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Coratti, Giorgia, Brogna, Claudia, Norcia, G., Ricotti, V., Abbott, L., D'Amico, Adele, Berardinelli, A., Vita, G. L., Lucibello, Simona, Messina, S., Sansone, V., Albamonte, E., Colia, G., Salmin, F., Gardani, A., Manzur, A., Main, M., Baranello, Giovanni, Arnoldi, M. T., Parsons, J., Carry, T., Connolly, A. M., Bertini, Enrico Silvio, Muntoni, F., Pane, Marika, Mercuri, Eugenio Maria, Coratti G. (ORCID:0000-0001-6666-5628), Brogna C., D'Amico A., Lucibello S., Baranello G., Bertini E., Pane M. (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

The aim of this prospective multicentric study was to document disease progression in young boys affected by Duchenne muscular dystrophy (DMD) between age 3 and 6 years (±3 months) using the North Star Ambulatory Assessment scale. One hundred fifty-three DMD boys (573 assessments) younger than 6 years (mean: 4.68, SD: 0.84) with a genetically proven DMD diagnoses were included. Our results showed North Star Ambulatory Assessment scores progressively increased with age. The largest increase was observed between age 3 and 4 years but further increase was steadily observed until age of 6 years. Using a multiple linear regression analysis, we found that both the use of corticosteroids and the site of mutation significantly contributed to the North Star Ambulatory Assessment changes (p < 0.001). At each age point, boys on corticosteroid treatment had higher scores than corticosteroid naïve ones (p < 0.001). Similarly, patients with mutations downstream exon 44, had lower baseline scores and lower magnitude of changes compared to those with mutations located at the 5′ end of the gene (p < 0,001). Very few boys achieved the age appropriate maximum score. These results provide useful information for the assessment and counselling of young DMD boys and for the design of clinical trials in this age group.

Published
2019

47. A critical review of patient and parent caregiver oriented tools to assess health-related quality of life, activity of daily living and caregiver burden in spinal muscular atrophy

Author

Messina, S., Frongia, Anna Lia, Antonaci, Laura, Pera, Maria Carmela, Coratti, Giorgia, Pane, Marika, Pasternak, A., Civitello, M., Montes, J., Mayhew, A., Finkel, R., Muntoni, F., Mercuri, Eugenio Maria, Frongia A. L., Antonaci L., Pera M. C. (ORCID:0000-0001-6777-1721), Coratti G. (ORCID:0000-0001-6666-5628), Pane M. (ORCID:0000-0002-4851-6124), Mercuri E. (ORCID:0000-0002-9851-5365), Messina, S., Frongia, Anna Lia, Antonaci, Laura, Pera, Maria Carmela, Coratti, Giorgia, Pane, Marika, Pasternak, A., Civitello, M., Montes, J., Mayhew, A., Finkel, R., Muntoni, F., Mercuri, Eugenio Maria, Frongia A. L., Antonaci L., Pera M. C. (ORCID:0000-0001-6777-1721), Coratti G. (ORCID:0000-0001-6666-5628), Pane M. (ORCID:0000-0002-4851-6124), and Mercuri E. (ORCID:0000-0002-9851-5365)

Abstract

The positive outcome of different therapeutic approaches for spinal muscular atrophy (SMA) in clinical trials and in clinical practice have highlighted the need to establish if functional changes are associated with possible changes of patient health-related quality of life or have an effect on activities of daily living and caregiver burden. The aim of this paper is to provide a critical review of the tools previously or currently used to measure quality of life, activity of daily living, and caregiver burden in SMA. We identified 36 measures. Only 6 tools were specifically developed for SMA while the others had been used and at least partially validated in wider groups of neuromuscular disorders including SMA. Twelve of the 36 focused on health-related quality of life, 5 on activities of daily living and 9 on caregiver burden. Ten included a combination of items. The review provides a roadmap of the different tools indicating their suitability for different SMA types or age groups. Scales assessing activities of daily living and care burden can provide patients and carers perspective on functional changes over time that should be added to the observer rated scales used in clinic.

Published
2019

48. Development of an academic disease registry for spinal muscular atrophy

Author

Mercuri, Eugenio Maria, Finkel, R., Scoto, M., Hall, S., Eaton, S., Rashid, A., Balashkina, J., Coratti, Giorgia, Pera, Maria Carmela, Samsuddin, S., Civitello, M., Muntoni, F., De Vivo, D. C., Darras, B. T., Day, J., Montes, J., Glanzmann, A., Pasternack, A., Salazar, R., Dunaway Young, S., Duong, T., Pane, Marika, Berti, B., Palermo, C., Leone, D., Frongia, Anna Lia, Antonaci, Laura, De Sanctis, Roberto, Messina, S., Bertini, Enrico Silvio, Vita, G., Bruno, C., Sframeli, M., Sansone, V. A., Albamonte, E., D'Amico, Adele, Mercuri E. (ORCID:0000-0002-9851-5365), Coratti G. (ORCID:0000-0001-6666-5628), Pera M. C. (ORCID:0000-0001-6777-1721), Pane M. (ORCID:0000-0002-4851-6124), Frongia A., Antonaci L., De Sanctis R., Bertini E., D'Amico A., Mercuri, Eugenio Maria, Finkel, R., Scoto, M., Hall, S., Eaton, S., Rashid, A., Balashkina, J., Coratti, Giorgia, Pera, Maria Carmela, Samsuddin, S., Civitello, M., Muntoni, F., De Vivo, D. C., Darras, B. T., Day, J., Montes, J., Glanzmann, A., Pasternack, A., Salazar, R., Dunaway Young, S., Duong, T., Pane, Marika, Berti, B., Palermo, C., Leone, D., Frongia, Anna Lia, Antonaci, Laura, De Sanctis, Roberto, Messina, S., Bertini, Enrico Silvio, Vita, G., Bruno, C., Sframeli, M., Sansone, V. A., Albamonte, E., D'Amico, Adele, Mercuri E. (ORCID:0000-0002-9851-5365), Coratti G. (ORCID:0000-0001-6666-5628), Pera M. C. (ORCID:0000-0001-6777-1721), Pane M. (ORCID:0000-0002-4851-6124), Frongia A., Antonaci L., De Sanctis R., Bertini E., and D'Amico A.

Abstract

We report the development of a new disease registry on SMA as the result of a collaboration among three national networks in United States, Italy, and United Kingdom in partnership with a biotechnology company and with the support of advocacy groups. The aim of establishing a large collaborative registry within academic centers was to establish a structured but flexible system for collection of prospective, highly curated data that will deeply phenotype all patients with SMA and follow them longitudinally over several years. This paper describes the process leading to the development of the registry including the identification of the relevant data elements, the design of an electronic CRF with a shared data dictionary, the piloting of the first version and the definition of the final version. The registry will provide a central structure for conducting academic studies based on a much larger cohort of patients than those available in the individual networks. Due to the quality control of the data collected the registry can also be used for postmarketing purposes, allowing to share, in a transparent and controlled way, real-world data with pharmaceutical partners, drug regulatory agencies, and advocacy groups for better understanding of safety and effectiveness of new treatments.

Published
2019

49. Long-term progression in type II spinal muscular atrophy: A retrospective observational study

Author

Mercuri, E., Lucibello, S., Pera, M. C., Carnicella, S., Coratti, G., De Sanctis, R., Messina, S., Mazzone, E., Forcina, N., Fanelli, L., Norcia, G., Antonaci, L., Frongia, A. L., Pane, M., Mercuri E. (ORCID:0000-0002-9851-5365), Lucibello S., Pera M. C. (ORCID:0000-0001-6777-1721), Coratti G. (ORCID:0000-0001-6666-5628), Antonaci L., Frongia A. L., Pane M. (ORCID:0000-0002-4851-6124), Mercuri, E., Lucibello, S., Pera, M. C., Carnicella, S., Coratti, G., De Sanctis, R., Messina, S., Mazzone, E., Forcina, N., Fanelli, L., Norcia, G., Antonaci, L., Frongia, A. L., Pane, M., Mercuri E. (ORCID:0000-0002-9851-5365), Lucibello S., Pera M. C. (ORCID:0000-0001-6777-1721), Coratti G. (ORCID:0000-0001-6666-5628), Antonaci L., Frongia A. L., and Pane M. (ORCID:0000-0002-4851-6124)

Abstract

ObjectiveTo report the long-term progression in a cohort of patients with type II spinal muscular atrophy (SMA) assessed with the Hammersmith Functional Motor Scale-Expanded.MethodsSeventy-three patients (age 2.6-25 years) were included in the study. Twenty-eight of the 73 were first assessed before the age of 5 years and had been followed up for ≈5 years or longer. We observed an overall progression that was not linear. A piecewise regression analysis showed an improvement of scores in the younger patients with a point of slope change at ≈5 years of age, a decline between 5 and 13 years of age, and stability/slower decline after that.ResultsPatients with the lowest scores at baseline had the earliest onset of scoliosis and a higher need for noninvasive ventilation compared to those with higher scores. Our results confirm that on the long-term follow-up all patients with type II SMA show a clear and progressive decline.ConclusionThe severity of functional impairment at baseline can help to predict the magnitude of changes over time and the overall progression, including onset of scoliosis and need for noninvasive ventilation.

Published
2019

50. Long-term progression in type II spinal muscular atrophy: A retrospective observational study

Author

Mercuri, Eugenio Maria, Lucibello, Simona, Pera, Maria Carmela, Carnicella, S., Coratti, Giorgia, De Sanctis, Roberto, Messina, S., Mazzone, E., Forcina, N., Fanelli, L., Norcia, G., Antonaci, Laura, Frongia, Anna Lia, Pane, Marika, Mercuri E. (ORCID:0000-0002-9851-5365), Lucibello S., Pera M. C. (ORCID:0000-0001-6777-1721), Coratti G. (ORCID:0000-0001-6666-5628), De Sanctis R., Antonaci L., Frongia A. L., Pane M. (ORCID:0000-0002-4851-6124), Mercuri, Eugenio Maria, Lucibello, Simona, Pera, Maria Carmela, Carnicella, S., Coratti, Giorgia, De Sanctis, Roberto, Messina, S., Mazzone, E., Forcina, N., Fanelli, L., Norcia, G., Antonaci, Laura, Frongia, Anna Lia, Pane, Marika, Mercuri E. (ORCID:0000-0002-9851-5365), Lucibello S., Pera M. C. (ORCID:0000-0001-6777-1721), Coratti G. (ORCID:0000-0001-6666-5628), De Sanctis R., Antonaci L., Frongia A. L., and Pane M. (ORCID:0000-0002-4851-6124)

Abstract

ObjectiveTo report the long-term progression in a cohort of patients with type II spinal muscular atrophy (SMA) assessed with the Hammersmith Functional Motor Scale-Expanded.MethodsSeventy-three patients (age 2.6-25 years) were included in the study. Twenty-eight of the 73 were first assessed before the age of 5 years and had been followed up for ≈5 years or longer. We observed an overall progression that was not linear. A piecewise regression analysis showed an improvement of scores in the younger patients with a point of slope change at ≈5 years of age, a decline between 5 and 13 years of age, and stability/slower decline after that.ResultsPatients with the lowest scores at baseline had the earliest onset of scoliosis and a higher need for noninvasive ventilation compared to those with higher scores. Our results confirm that on the long-term follow-up all patients with type II SMA show a clear and progressive decline.ConclusionThe severity of functional impairment at baseline can help to predict the magnitude of changes over time and the overall progression, including onset of scoliosis and need for noninvasive ventilation.

Published
2019

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