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.
Percentages of regularly followed patients and newcomers.
Over the past few years, the field of medicine has witnessed significant advances in the treatment of Spinal Muscular Atrophy (SMA) with the approval of three disease-modifying drugs worldwide. ...However, little is known about the role that various clinical variables could play in contributing to the overall phenotype. To explore this possibility, we will employ a novel machine learning-based approach, which involves the development of a predictive algorithm using retrospective data from treated SMA patients. The study underway aims to gather data from patients with SMA, including those afflicted with SMA I, II, III, and pre-symptomatic cases, whether or not they have already received treatment. The inclusion of data from a broad range of SMA patients will provide researchers with a more comprehensive understanding of the disease and increase the potential of the machine learning algorithm to predict therapeutic response. The ultimate goals are to identify novel biomarkers associated with the disease, to develop personalized treatments and to improve the management of patients with SMA. The data collected will consist of clinical, biological, and Patient Reported Outcome Measures (PROMs) data. The clinical data will include information about patients' demographics, medical history, neurological assessment, motor function measures and laboratory results. PROMs will be collected using standardized questionnaires to assess patient-reported outcomes, such as the PEDI-CAT, SMA-HI and other. Additionally, the RNA molecular signature profiling will be carried out using Next-Generation Sequencing (NGS) to identify possible novel biomarkers. Machine learning algorithms are proving to be useful tools in predicting individual responses to treatments and interpreting outcomes. By leveraging the power of machine learning, researchers hope to identify patterns and associations within the large amounts of data being collected, leading to new potential treatment approaches. The machine learning algorithm can perform clinical predictions and provide an insight into the biological mechanisms behind the disease progression. The use of machine learning algorithms in SMA research represents a significant shift towards personalized medicine. The ability to predict individual responses to treatments can lead to the development of tailored treatments that cater to the specific needs of each patient. This, in turn, could improve the quality of life for SMA patients, enhance the efficiency of clinical trials, already-approved treatments, and reduce healthcare costs. In conclusion, the study underway seeks to collect data from SMA patients to investigate the potential use of machine learning algorithms in predicting individual responses to treatments, identifying novel biomarkers, and molecular signatures associated with the disease. This novel approach has the potential to offer a better understanding of the disease and support the development of personalized treatments for individual patients. Ultimately, the use of machine learning algorithms in SMA research could lead to better outcomes for patients and enable more efficient use of healthcare resources.
8-year-old girl referred for hyperckaemia and early onset scoliosis. No family history of neuromuscular disorders, uneventful pregnancy, normal motor development, and no previous concerns. When seen ...at the age of 8 years, the family reported difficulties in climbing stairs in the previous 12 months. On clinical assessment, there was proximal muscle weakness in the lower and upper limbs (hamstring, iliopsoas, glutei, deltoid 4/5) and axial weakness (neck flexors 3/5, paraspinal, abdominal muscles 4/5) with no facial involvement. Distal laxity, scapular winging, scoliosis (Cobb 20°), and mild hyperlordosis were also noted. Muscle MRI revealed hypotrophy and fatty infiltration (grade 1-3) in the gluteus maximus and minimal signs of edema in the medius gluteus. Disease course was slowly progressive. Next-generation sequencing did not reveal any genetic defect related to phenotype. EMG (biceps brachii and quadriceps) identified a myogenic pattern with abundant spontaneous activity, fibrillation potentials, and complex repetitive discharges suggestive of muscle inflammation/necrosis. The discrepancy between weakness severity and the fatty substitution in T1, and the EMG pattern, led to consider an inflammatory myopathy. The autoimmune serologic screening revealed anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies. The patient was treated with IVIg monotherapy (2 g/kg monthly). After ten months was shifted to SC injection every four days (0,2 mg/kg). We report the clinical case of a paediatric patient with a delayed diagnosis of anti-HMGCR myopathy in whom CK levels, clinical and MRI signs were initially thought to be consistent with LGMD. Monotherapy treatment with Ig was safe and showed the first clinical improvement after two months of the first Ig infusion. Muscle strength and functional tests completely normalized after one year of treatment. CK levels persist slightly high. Due to its similarity with LGMD, anti-HMGCR myopathy in paediatric patients may be under-recognized and treatment delayed. We suggest considering serologic screening for HMGCR Ab in the differential diagnosis of unresolved LGMD-like phenotypes. The minority of side effects compared with long-term corticosteroids treatment lead to consider IVIg as first-line treatment in those cases with subtle onset and slow progression. Home maintenance with SC Ig seems to be effective in controlling relapses and well tolerated by the patient and her family.
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.
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).
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 functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p<0·0001). 31 (97%, 95% CI 91–100) of 32 patients in the ITT population survived free from permanent ventilatory support at 14 months compared with six (26%, 8–44) of 23 patients in the PNCR natural history cohort (p<0·0001). 32 (97%) of 33 patients had at least one adverse event and six (18%) had adverse events that were considered serious and related to onasemnogene abeparvovec. The most common adverse events were pyrexia (22 67% of 33), upper respiratory infection (11 33%), and increased alanine aminotransferase (nine 27%). One death, unrelated to the study drug, occurred from hypoxic-ischaemic brain damage because of a respiratory tract infection during the study.
STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline.
Novartis Gene Therapies.
Spinal Muscular Atrophy (SMA) is a debilitating disease that affects patients worldwide. While pharmacological therapies have shown to be effective in enhancing motor function in SMA patients, ...scoliosis management remains a significant challenge. The impact of these therapies on scoliosis is still uncertain, and it can have a negative impact on patient health outcomes. Therefore, it is important to conduct research to assess the effectiveness of pharmacological therapies in scoliosis management. This study aims to examine the effectiveness of these treatments in altering scoliosis progression in individuals diagnosed with SMA II. The Italian ISMAC centers conducted a retrospective analysis of prospective data on patients with SMA types II from January 2013 to September 2023, with patients being analysed in either treated or untreated subgroups for a minimum of 1.5 years. Patients' motor function level, age, and sex details, along with X-rays while sitting were included, and Cobb angle differences were computed by dividing the total change over the follow-up time. Comparing the two arms of the study, scoliosis progression showed no significant differences in the overall population. Differences were observed when analyzing patients treated <4.5 years old (p=0.01) or with a Cobb angle of <26 degrees (p=0.01). In this specific cohort, the Kaplan-Meier curve also demonstrated significant differences in patients reaching 40° or 50° of Cobb Angle over time. These findings suggest that early treatment with pharmacological therapies can not only improve motor function in SMA patients, but it can also modify scoliosis progression. This highlights the importance of initiating prompt and timely pharmacological treatment for SMA patients to improve outcomes. In conclusion, early treatment can optimize outcomes and modify scoliosis progression, emphasizing the critical role of timely action in managing SMA. Future research should aim to replicate these findings in larger samples and across different populations to improve the generalizability of the results. Overall, this study makes a significant contribution to the understanding of the effectiveness of pharmacological therapies in scoliosis management in SMA patients.
Drugs injected intradermally spread slowly into the underlying tissues and produce a drug-saving effect. The Italian society of mesotherapy suggested that intradermal therapy obtains analgesic effect ...on localized pain, with a lower risk of systemic drug interactions. We report a case of post-herpetic pain successfully treated by this technique. This case confirms that the intradermal administration technique (mesotherapy), which is based on the pathophysiology of the disorder, according to the recommendations, can contribute to the management of patients who do not tolerate standard therapies.
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