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Introduction: Schizophrenia (SCZ) and autism spectrum disorder (ASD) are neurodevelopmental diseases characterized by different psychopathological manifestations and divergent clinical trajectories. Various alterations at glutamatergic synapses have been reported in both disorders, including abnormal NMDA and metabotropic receptor signaling. Methods: We conducted a bicentric study to assess the blood serum levels of NMDA receptors-related glutamatergic amino acids and their precursors, including L-glutamate, L-glutamine, D-aspartate, L-aspartate, L-asparagine, D-serine, L-serine and glycine, in ASD, SCZ patients and their respective control subjects. Specifically, the SCZ patients were subdivided into treatment-resistant and non-treatment-resistant SCZ patients, based on their responsivity to conventional antipsychotics. Results: D-serine and D-aspartate serum reductions were found in SCZ patients compared to controls. Conversely, no significant differences between cases and controls were found in amino acid concentrations in the two ASD cohorts analyzed. Discussion: This result further encourages future research to evaluate the predictive role of selected D-amino acids as peripheral markers for SCZ pathophysiology and diagnosis.
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Several studies have shown the efficacy of new disease-modifying therapies in slowing down type II SMA progression using the Hammersmith Functional Motor Scale Expanded (HFMSE). This research aims to enhance understanding of activity changes across age groups post-nusinersen treatment using shift analysis, compared with untreated individuals. Retrospective data from the, international SMA consortium (iSMAc) dataset were analyzed, assessing individual item changes over 12 months. Shift analysis was used to determine the gain or loss of abilities, defining "gain" as a positive change between scores from 0 to either 1 or 2 and "loss" as a negative change from either 2 or 1 to 0. The cohort included 130 SMA II patients who underwent 12-month assessments from their first nusinersen dose, with age range between 0.6 and 49.6 years. One-third of the entire cohort experienced at least a loss in one activity, while 60% experienced a gain, particularly notable in children aged 2.5 to 5 years and 5 to 13 years. Overall, the study demonstrates a positive impact of nusinersen treatment on SMA II patients, showing a trend of increased activity gains and decreased probability of ability loss across different age groups.
Subject(s)
Oligonucleotides , Spinal Muscular Atrophies of Childhood , Humans , Oligonucleotides/therapeutic use , Oligonucleotides/pharmacology , Child , Child, Preschool , Male , Female , Adolescent , Adult , Retrospective Studies , Infant , Middle Aged , Young Adult , Spinal Muscular Atrophies of Childhood/drug therapy , Treatment Outcome , Disease ProgressionABSTRACT
Background and Objectives: Nusinersen has shown significant functional motor benefit in the milder types of spinal muscular atrophy (SMA). Less is known on the respiratory outcomes in patients with nusinersen-treated SMA. The aim of this study was to describe changes in respiratory function in pediatric patients with SMA type 2 and 3 on regular treatment with nusinersen within the iSMAc international cohort and to compare their trajectory with the natural history (NH) data published by the consortium in 2020. Methods: This is a 5-year retrospective observational study of pediatric SMA type 2 and nonambulant type 3 (age ≤18 years) treated with nusinersen. The primary objective was to compare the slopes of decline in forced vital capacity % predicted (FVC% pred.), FVC, and age when FVC dropped below 60% between the treated patients and a control group from the natural history cohort. Data on peak cough flow and the use of noninvasive ventilation (NIV) and cough assist were collected. Results: Data were available for 69 treated patients, 53 were SMA type 2 and 16 type 3. The mean (SD) age at first injection was 8.5 (3.2) and 9.7 (3.7) years, respectively. The median (interquartile range) treatment duration was 1 (0.7; 1.9) and 1.2 (0.9; 1.9) years, respectively. At the time of the first nusinersen injection, 24 of 52 (46%) patients with SMA type 2 and 2 of 16 (13%) patients with SMA type 3 were on NIV. Forty-three of 53 (81%) and 4 of 16 (25%) patients used cough device. FVC% pred. in treated patients with SMA type 2 declined annually by 2.3% vs 3.9% in NH (p = 0.08) and in treated patients with type 3 by 2.6% vs 3.4% NH (p = 0.59). Patients treated reached FVC <60% later than untreated (12.1 vs 10 years, p = 0.05). A higher percentage of treated vs untreated patients maintained FVC% pred. equal/above their baseline after 12 (65% vs 36%) and 24 (50% vs 24%) months, respectively. NIV use among treated did not significantly change throughout 1-year follow-up. Discussion: This study included the largest real-world cohort of pediatric patients with milder SMA types. The results suggest a positive role of nusinersen in delaying the respiratory decline in patients treated longer than 1 year when compared with natural history. Larger cohorts and longer observation are planned. Classification of Evidence: This study provided Class III evidence that nusinersen slows progression for patients with SMA types 2 and 3 compared with a natural history cohort.
ABSTRACT
Risdiplam is a once-daily oral, survival of motor neuron 2 (SMN2) splicing modifier approved for the treatment of spinal muscular atrophy (SMA). JEWELFISH (NCT03032172) investigated the safety, tolerability, pharmacokinetics (PK), and PK/pharmacodynamic (PD) relationship of risdiplam in non-treatment-naïve patients with SMA. JEWELFISH enrolled adult and pediatric patients (N = 174) with confirmed diagnosis of 5q-autosomal recessive SMA who had previously received treatment with nusinersen (n = 76), onasemnogene abeparvovec (n = 14), olesoxime (n = 71), or were enrolled in the MOONFISH study (NCT02240355) of the splicing modifier RG7800 (n = 13). JEWELFISH was an open-label study with all participants scheduled to receive risdiplam. The most common adverse event (AE) was pyrexia (42 patients, 24%) and the most common serious AE (SAE) was pneumonia (5 patients, 3%). The rate of AEs and SAEs decreased by > 50% from the first to the second year of treatment, and there were no treatment-related AEs that led to withdrawal from treatment. An increase in SMN protein in blood was observed following risdiplam treatment and sustained over 24 months of treatment irrespective of previous treatment. Exploratory efficacy assessments of motor function showed an overall stabilization in mean total scores as assessed by the 32-item Motor Function Measure, Hammersmith Functional Motor Scale-Expanded, and Revised Upper Limb Module. The safety profile of risdiplam in JEWELFISH was consistent with previous clinical trials of risdiplam in treatment-naïve patients. Exploratory efficacy outcomes are reported but it should be noted that the main aim of JEWELFISH was to assess safety and PK/PD, and the study was not designed for efficacy analysis. TRIAL REGISTRATION: The study was registered (NCT03032172) on ClinicalTrials.gov on January 24, 2017; First patient enrolled: March 3, 2017.
Subject(s)
Pyrimidines , Humans , Male , Female , Adult , Child , Adolescent , Young Adult , Middle Aged , Child, Preschool , Pyrimidines/pharmacokinetics , Pyrimidines/adverse effects , Pyrimidines/administration & dosage , Muscular Atrophy, Spinal/drug therapy , Treatment Outcome , Heterocyclic Compounds, 4 or More Rings/adverse effects , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/administration & dosage , Azo CompoundsABSTRACT
BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is a rare and progressive neuromuscular disorder with varying severity levels. The aim of the study was to calculate minimal clinically important difference (MCID), minimal detectable change (MDC), and values for the Hammersmith Functional Motor Scale Expanded (HFMSE) in an untreated international SMA cohort. METHODS: The study employed two distinct methods. MDC was calculated using distribution-based approaches to consider standard error of measurement and effect size change in a population of 321 patients (176 SMA II and 145 SMA III), allowing for stratification based on age and function. MCID was assessed using anchor-based methods (receiver operating characteristic [ROC] curve analysis and standard error) on 76 patients (52 SMA II and 24 SMA III) for whom the 12-month HFMSE could be anchored to a caregiver-reported clinical perception questionnaire. RESULTS: With both approaches, SMA type II and type III patients had different profiles. The MCID, using ROC analysis, identified optimal cutoff points of -2 for type II and -4 for type III patients, whereas using the standard error we found the optimal cutoff points to be 1.5 for improvement and -3.2 for deterioration. Furthermore, distribution-based methods uncovered varying values across age and functional status subgroups within each SMA type. CONCLUSIONS: These results emphasize that the interpretation of a single MCID or MDC value obtained in large cohorts with different functional status needs to be made with caution, especially when these may be used to assess possible responses to new therapies.
Subject(s)
Minimal Clinically Important Difference , Muscular Atrophy, Spinal , Humans , Male , Female , Child , Adolescent , Muscular Atrophy, Spinal/physiopathology , Muscular Atrophy, Spinal/diagnosis , Child, Preschool , Adult , Young Adult , Severity of Illness Index , Cohort Studies , Spinal Muscular Atrophies of Childhood/physiopathology , Spinal Muscular Atrophies of Childhood/diagnosis , Infant , Disability EvaluationABSTRACT
Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterised by progressive motor function decline. Motor function is assessed using several functional outcome measures including the Revised Hammersmith Scale (RHS). Objective: In this study, we present longitudinal trajectories for the RHS in an international cohort of 149 untreated paediatric SMA 2 and 3 patients (across 531 assessments collected between March 2015 and July 2019). Methods: We contextualise these trajectories using both the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). At baseline, this cohort included 50% females and 15% of patients had undergone spinal fusion surgery. Patient trajectories were modelled using a natural cubic spline with age, sex, and random effects for each patient. Results: RHS and HFMSE scores show similar trends over time in this cohort not receiving disease modifying therapies. The results confirm the strong correlation between the RHS and RULM previously observed in SMA types 2 and 3a. Scoliosis surgery is associated with a reduction of 3 points in the RHS, 4.5 points in the HFMSE for the SMA 2 population, and a reduction of 11.8 points in the RHS, and 13.4 points in the HFMSE for the SMA 3a populations. When comparing the RHS and RULM, there is a lower correlation in the type 3a's than the type 2 patients. In the SMA 2 population, there is no significant difference between the sexes in either the RHS or HFMSE trajectories. There is no significant difference in the RULM trajectory in the SMA 2 or 3a participants by sex. Conclusions: This study demonstrates that the RHS could be used in conjunction with other functional measures such as the RULM to holistically detect SMA disease progression. This will assist with fully understanding changes that occur with treatments, further defining trajectories and therapy outcomes.
Subject(s)
Spinal Muscular Atrophies of Childhood , Humans , Female , Male , Spinal Muscular Atrophies of Childhood/physiopathology , Spinal Muscular Atrophies of Childhood/therapy , Child , Child, Preschool , Adolescent , Disease Progression , Cohort Studies , Severity of Illness Index , Longitudinal Studies , Scoliosis/therapy , Scoliosis/physiopathology , Spinal Fusion , InfantABSTRACT
Background: Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes. Methods and Results: We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (-0.80%) and SF (-0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (-11.01âmL/m2, pâ=â0.03) while for dp116 were correlated with decreased EF (-4.14%, pâ=â<0.001). The rs10880 genotype in the LTBP4 gene, previously shown to prolong ambulation, was also associated with increased EF and decreased EDV (+3.29%, pâ=â0.002, and -10.62âmL/m2, pâ=â0.008) with a recessive model. Conclusions: We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4 genotype of DCM in DMD.
Subject(s)
Cardiomyopathies , Muscular Dystrophy, Duchenne , Humans , Dystrophin/genetics , Dystrophin/metabolism , Haplotypes , Retrospective Studies , Stroke Volume , Ventricular Function, Left , Muscular Dystrophy, Duchenne/genetics , Muscular Dystrophy, Duchenne/complications , Cardiomyopathies/etiology , Cardiomyopathies/genetics , Protein Isoforms/genetics , Latent TGF-beta Binding Proteins/geneticsABSTRACT
DAG1 encodes for dystroglycan, a key component of the dystrophin-glycoprotein complex (DGC) with a pivotal role in skeletal muscle function and maintenance. Biallelic loss-of-function DAG1 variants cause severe muscular dystrophy and muscle-eye-brain disease. A possible contribution of DAG1 deficiency to milder muscular phenotypes has been suggested. We investigated the genetic background of twelve subjects with persistent mild-to-severe hyperCKemia to dissect the role of DAG1 in this condition. Genetic testing was performed through exome sequencing (ES) or custom NGS panels including various genes involved in a spectrum of muscular disorders. Histopathological and Western blot analyses were performed on muscle biopsy samples obtained from three patients. We identified seven novel heterozygous truncating variants in DAG1 segregating with isolated or pauci-symptomatic hyperCKemia in all families. The variants were rare and predicted to lead to nonsense-mediated mRNA decay or the formation of a truncated transcript. In four cases, DAG1 variants were inherited from similarly affected parents. Histopathological analysis revealed a decreased expression of dystroglycan subunits and Western blot confirmed a significantly reduced expression of beta-dystroglycan in muscle samples. This study supports the pathogenic role of DAG1 haploinsufficiency in isolated or pauci-symptomatic hyperCKemia, with implications for clinical management and genetic counseling.
Subject(s)
Muscular Diseases , Muscular Dystrophies , Humans , Dystroglycans/genetics , Dystroglycans/metabolism , Haploinsufficiency , Muscular Dystrophies/genetics , Muscle, Skeletal/pathology , Muscular Diseases/pathologyABSTRACT
OBJECTIVE: The aim of this study was to assess early language acquisitions in treated individuals with spinal muscular atrophy (SMA) type 1 and in infants identified by newborn screening (NBS). METHODS: Parents of SMA individuals aged between 8 and 36 months were asked to fill in the MacArthur-Bates Communicative Development Inventory (MB-CDI) that assesses comprehension, gesture and expressive skills. A follow-up assessment was performed in 21 of the 36. RESULTS: The MB-CDI was completed by parents of 24 type 1 and 12 infants identified by NBS. Comprehension skills were preserved in 81% of the type 1 SMA and in 87% infants identified by NBS. Gesture abilities were <5th centile in 55% of the type 1 SMA and in none of those identified by NBS. Lexical expressions were <5th centile in more than 80% type 1 SMA and in 50% of infants identified by NBS. At follow-up, despite an increase in lexical expression skills, the scores remained below the fifth centile in 43% type 1 SMA and in 86% of infants identified by NBS. CONCLUSIONS: These results suggest that language and communication development may follow a similar pattern to that observed in motor function with the possibility to develop skills (eg, ability to say clear words) that are not usually present in untreated infants but with a level of performance that does not reach that of their typically developing peers.
Subject(s)
Muscular Atrophy, Spinal , Spinal Muscular Atrophies of Childhood , Infant, Newborn , Infant , Humans , Child, Preschool , Cohort Studies , Muscular Atrophy, Spinal/diagnosis , Spinal Muscular Atrophies of Childhood/diagnosis , Language Development , GesturesABSTRACT
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.
Subject(s)
Scoliosis , Spinal Muscular Atrophies of Childhood , Humans , Child, Preschool , Scoliosis/diagnostic imaging , Scoliosis/therapy , Treatment Outcome , Retrospective StudiesABSTRACT
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.
Subject(s)
Muscular Dystrophy, Duchenne , Humans , Muscular Dystrophy, Duchenne/complications , Retrospective Studies , Upper Extremity , Walking , Muscle WeaknessABSTRACT
BACKGROUND: Spinal muscular atrophy (SMA) type 1 is a severe condition leading to early respiratory failure. Treatment options have become available, yet respiratory outcome measures in SMA type 1 are limited. The aim of this study was to assess the respiratory pattern in SMA type 1 patients via structured light plethysmography (SLP). SLP measures the thoraco-abdominal movements by projecting a light grid onto the anterior thoraco-abdominal surface. METHODS: Cross-sectional study of consecutive children with SMA type 1. All children underwent motor assessment (CHOP-INTEND) and one-minute tidal breathing recording by SLP in supine position while self-ventilating in room air. The Respiratory rate, the abdominal vs. chest contribution to breath (Relative Expired Abdomen%, Relative Expired Chest%) and the severity of thoraco-abdominal paradox (Phase Angle) were acquired. RESULTS: Nineteen patients were included, median (IQR) age 2.3 years (1.4-7.9). Their respiratory pattern captured via SLP showed a raised median (IQR) respiratory rate per age of 33.5 bpm (26.6-41.7), a prevalent abdominal contribution to tidal breathing with median (IQR) Relative Expired Abdomen 77% (68-90) vs. Chest 23% (10-32). Thoracoabdominal paradox was detected (median Phase Angle 48.70°) and its severity correlated negatively with CHOP-INTEND (r -0.8, p < 0.01). CONCLUSIONS: SLP captured and quantified the respiratory features of infants and children with SMA type 1.
ABSTRACT
Duchenne muscular dystrophy (DMD) is a devastating X-linked muscular disease, caused by mutations in the DMD gene encoding Dystrophin and affecting 1:5000 boys worldwide. Lack of Dystrophin leads to progressive muscle wasting and degeneration resulting in cardiorespiratory failure. Despite the absence of a definitive cure, innovative therapeutic avenues are emerging. Myopathologic studies are important to further understand the biological mechanisms of the disease and to identify histopathologic benchmarks for clinical evaluations. We conducted a myopathologic analysis on twenty-four muscle biopsies from DMD patients, with particular emphasis on regeneration, fibro-adipogenic progenitors and muscle stem cells behavior. We describe an increase in content of fibro-adipogenic progenitors, central orchestrators of fibrotic progression and lipid deposition, concurrently with a decline in muscle regenerative capacity. This regenerative impairment strongly correlates with compromised activation and expansion of muscle stem cells. Furthermore, our study uncovers an early acquisition of a senescence phenotype by DMD-afflicted muscle stem cells. Here we describe the myopathologic trajectory intrinsic to DMD and establish muscle stem cell senescence as a pivotal readout for future therapeutic interventions.
Subject(s)
Muscular Dystrophy, Duchenne , Satellite Cells, Skeletal Muscle , Humans , Male , Dystrophin/genetics , Fibrosis , Muscle, Skeletal/pathology , Muscular Dystrophy, Duchenne/pathology , Regeneration/genetics , Cellular Senescence/geneticsABSTRACT
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.
Subject(s)
Muscular Atrophy, Spinal , Male , Adult , Child , Humans , Female , Adolescent , Young Adult , Middle Aged , Cross-Sectional Studies , Muscular Atrophy, Spinal/diagnosis , Muscular Atrophy, Spinal/genetics , Phenotype , Walking , Survival of Motor Neuron 1 Protein/genetics , Survival of Motor Neuron 2 Protein/geneticsABSTRACT
BACKGROUND: The development of e-health technologies for teleconsultation and exchange of knowledge is one of the core purposes of European Reference Networks (ERNs), including the ERN EURO-NMD for rare neuromuscular diseases. Within ERNs, the Clinical Patient Management System (CPMS) is a web-based platform that seeks to boost active collaboration within and across the network, implementing data sharing. Through CPMS, it is possible to both discuss patient cases and to make patients' data available for registries and databases in a secure way. In this view, CPMS may be considered a sort of a temporary storage for patients' data and an effective tool for data sharing; it facilitates specialists' consultation since rare diseases (RDs) require multidisciplinary skills, specific, and outstanding clinical experience. Following European Union (EU) recommendation, and to promote the use of CPMS platform among EURO-NMD members, a twelve-month pilot project was set up to train the 15 Italian Health Care Providers (HCPs). In this paper, we report the structure, methods, and results of the teaching course, showing that tailored, ERN-oriented, training can significantly enhance the profitable use of the CPMS. RESULTS: Throughout the training course, 45 professionals learned how to use the many features of the CPMS, eventually opening 98 panels of discussion-amounting to 82% of the total panels included in the EURO-NMD. Since clinical, genetic, diagnostic, and therapeutic data of patients can be securely stored within the platform, we also highlight the importance of this platform as an effective tool to discuss and share clinical cases, in order to ease both case solving and data storing. CONCLUSIONS: In this paper, we discuss how similar course could help implementing the use of the platform, highlighting strengths and weaknesses of e-health for ERNs. The expected result is the creation of a "map" of neuromuscular patients across Europe that might be improved by a wider use of CPMS.
Subject(s)
Information Dissemination , Rare Diseases , Humans , Pilot Projects , Europe , European UnionABSTRACT
Emery-Dreifuss muscular dystrophy (EDMD) is a rare disease characterized by early contractures, progressive muscle weakness, and cardiac abnormalities. Different subtypes of EDMD have been described, with the two most common forms represented by the X-linked EDMD1, caused by mutations in the EMD gene encoding emerin, and the autosomal EDMD2, due to mutations in the LMNA gene encoding lamin A/C. A clear definition of the magnetic resonance imaging (MRI) pattern in the two forms, and especially in the rarer EDMD1, is still lacking, although a preferential involvement of the medial head of the gastrocnemius has been suggested in EDMD2. We report a 13-year-old boy with mild limb girdle muscle weakness, elbow and ankle contractures, with absence of emerin at muscle biopsy, carrying a hemizygous frameshift mutation on the EMD gene (c.153dupC/p.Ser52Glufs*9) of maternal inheritance. Minor cardiac rhythm abnormalities were detected at 24-hour Holter electrocardiogram and required ß-blocker therapy. MRI scan of the thighs showed a mild diffuse involvement, while tibialis anterior, extensor digitorum longus, peroneus longus, and medial gastrocnemius were the most affected muscles in the leg. We also provide a review of the muscular MRI data in EDMD patients and highlight the relative heterogeneity of the MRI patterns found in EDMDs, suggesting that muscle MRI should be studied in larger EDMD cohorts to better define disease patterns and to cover the wide disease spectrum.
Subject(s)
Contracture , Muscular Dystrophy, Emery-Dreifuss , X-Linked Emery-Dreifuss Muscular Dystrophy , Male , Humans , Child , Adolescent , Muscle, Skeletal/diagnostic imaging , Muscle, Skeletal/pathology , Muscular Dystrophy, Emery-Dreifuss/diagnostic imaging , Muscular Dystrophy, Emery-Dreifuss/genetics , Muscular Dystrophy, Emery-Dreifuss/pathology , Mutation , Muscle Weakness , Magnetic Resonance ImagingABSTRACT
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.
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.
ABSTRACT
BACKGROUND: The performance of upper limb 2.0 (PUL) is widely used to assess upper limb function in DMD patients. The aim of the study was to assess 24 month PUL changes in a large cohort of DMD patients and to establish whether domains changes occur more frequently in specific functional subgroups. METHODS: The PUL was performed in 311 patients who had at least one pair of assessments at 24 months, for a total of 808 paired assessments. Ambulant patients were subdivided according to the ability to walk: >350, 250-350, ≤250 meters. Non ambulant patients were subdivided according to the time since they lost ambulation: <1, 1-2, 2-5 or >5 years. RESULTS: At 12 months, the mean PUL 2.0 change on all the paired assessments was -1.30 (-1.51--1.05) for the total score, -0.5 (-0.66--0.39) for the shoulder domain, -0.6 (-0.74--0.5) for the elbow domain and -0.1 (-0.20--0.06) for the distal domain.At 24 months, the mean PUL 2.0 change on all the paired assessments was -2.9 (-3.29--2.60) for the total score, -1.30 (-1.47--1.09) for the shoulder domain, -1.30 (-1.45--1.11) for the elbow domain and -0.4 (-1.48--1.29) for the distal domain.Changes at 12 and 24 months were statistically significant between subgroups with different functional abilities for the total score and each domain (pâ<â0.001). CONCLUSION: There were different patterns of changes among the functional subgroups in the individual domains. The time of transition, including the year before and after loss of ambulation, show the peak of negative changes in PUL total scores that reflect not only loss of shoulder but also of elbow activities. These results suggest that patterns of changes should be considered at the time of designing clinical trials.