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Using Cluster Analysis to Overcome the Limits of Traditional Phenotype-Genotype Correlations: The Example of RYR1-Related Myopathies.
Dosi, C, Rubegni, A, Baldacci, J, Galatolo, D, Doccini, S, Astrea, G, Berardinelli, A, Bruno, C, Bruno, G, Comi, GP, et al
Genes. 2023;(2)
Abstract
Thanks to advances in gene sequencing, RYR1-related myopathy (RYR1-RM) is now known to manifest itself in vastly heterogeneous forms, whose clinical interpretation is, therefore, highly challenging. We set out to develop a novel unsupervised cluster analysis method in a large patient population. The objective was to analyze the main RYR1-related characteristics to identify distinctive features of RYR1-RM and, thus, offer more precise genotype-phenotype correlations in a group of potentially life-threatening disorders. We studied 600 patients presenting with a suspicion of inherited myopathy, who were investigated using next-generation sequencing. Among them, 73 index cases harbored variants in RYR1. In an attempt to group genetic variants and fully exploit information derived from genetic, morphological, and clinical datasets, we performed unsupervised cluster analysis in 64 probands carrying monoallelic variants. Most of the 73 patients with positive molecular diagnoses were clinically asymptomatic or pauci-symptomatic. Multimodal integration of clinical and histological data, performed using a non-metric multi-dimensional scaling analysis with k-means clustering, grouped the 64 patients into 4 clusters with distinctive patterns of clinical and morphological findings. In addressing the need for more specific genotype-phenotype correlations, we found clustering to overcome the limits of the "single-dimension" paradigm traditionally used to describe genotype-phenotype relationships.
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INOVATYON/ ENGOT-ov5 study: Randomized phase III international study comparing trabectedin/pegylated liposomal doxorubicin (PLD) followed by platinum at progression vs carboplatin/PLD in patients with recurrent ovarian cancer progressing within 6-12 months after last platinum line.
Colombo, N, Gadducci, A, Sehouli, J, Rulli, E, Mäenpää, J, Sessa, C, Montes, A, Ottevanger, NB, Berger, R, Vergote, I, et al
British journal of cancer. 2023;(8):1503-1513
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Abstract
BACKGROUND This trial investigated the hypothesis that the treatment with trabectedin/PLD (TP) to extend the platinum-free interval (TFIp) can improve overall survival (OS) in patients with recurrent ovarian cancer (OC). METHODS Patients with OC (up to two previous platinum-based lines), with a TFIp of 6-12 months, were randomised to receive carboplatin/PLD (CP) or TP followed by platinum therapy at relapse. The primary endpoint was OS (HR: 0.75). RESULTS The study enrolled 617 patients. The median TFIp was 8.3 months and 30.3% of patients had received two previous platinum lines. 74% and 73.9% of patients, respectively, received a subsequent therapy (ST) in the CP and TP arm; in the latter TP arm 87.2% of ST was platinum-based, as per protocol. The median OS was 21.4 for CP and 21.9 months for TP (HR 1.13; 95% CI: 0.94-1.35; p = 0.197). Grade 3-5 adverse reactions occurred in 37.1% of patients in the CP arm and 69.7% of patients in the TP arm, and the most frequent were neutropenia (22.8% CP, 39.5% TP), gastrointestinal (7.1% CP, 17.4% TP), hepatic (0.7% CP, 19.1% TP). CONCLUSIONS This study did not meet the primary endpoint. CP combination remains the standard for patients with recurrent OC and a 6-12 months TFIp; TP is an effective treatment in patients suffering from persistent platinum toxicities. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, number NCT01379989.
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Clinical Classification of Variants in the Valosin-Containing Protein Gene Associated With Multisystem Proteinopathy.
Schiava, M, Ikenaga, C, Topf, A, Caballero-Ávila, M, Chou, TF, Li, S, Wang, F, Daw, J, Stojkovic, T, Villar-Quiles, R, et al
Neurology. Genetics. 2023;(5):e200093
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Abstract
BACKGROUND AND OBJECTIVES Pathogenic variants in the valosin-containing protein (VCP) gene cause a phenotypically heterogeneous disorder that includes myopathy, motor neuron disease, Paget disease of the bone, frontotemporal dementia, and parkinsonism termed multisystem proteinopathy. This hallmark pleiotropy makes the classification of novel VCP variants challenging. This retrospective study describes and assesses the effect of 19 novel or nonpreviously clinically characterized VCP variants identified in 28 patients (26 unrelated families) in the retrospective VCP International Multicenter Study. METHODS A 6-item clinical score was developed to evaluate the phenotypic level of evidence to support the pathogenicity of the novel variants. Each item is allocated a value, a score ranging from 0.5 to 5.5 points. A receiver-operating characteristic curve was used to identify a cutoff value of 3 to consider a variant as high likelihood disease associated. The scoring system results were confronted with results of in vitro ATPase activity assays and with in silico analysis. RESULTS All variants were missense, except for one small deletion-insertion, 18 led to amino acid changes within the N and D1 domains, and 13 increased the enzymatic activity. The clinical score coincided with the functional studies in 17 of 19 variants and with the in silico analysis in 12 of 19. For 12 variants, the 3 predictive tools agreed, and for 7 variants, the predictive tools disagreed. The pooled data supported the pathogenicity of 13 of 19 novel VCP variants identified in the study. DISCUSSION This study provides data to support pathogenicity of 14 of 19 novel VCP variants and provides guidance for clinicians in the evaluation of novel variants in the VCP gene.
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Expanding the clinical-pathological and genetic spectrum of RYR1-related congenital myopathies with cores and minicores: an Italian population study.
Fusto, A, Cassandrini, D, Fiorillo, C, Codemo, V, Astrea, G, D'Amico, A, Maggi, L, Magri, F, Pane, M, Tasca, G, et al
Acta neuropathologica communications. 2022;(1):54
Abstract
Mutations in the RYR1 gene, encoding ryanodine receptor 1 (RyR1), are a well-known cause of Central Core Disease (CCD) and Multi-minicore Disease (MmD). We screened a cohort of 153 patients carrying an histopathological diagnosis of core myopathy (cores and minicores) for RYR1 mutation. At least one RYR1 mutation was identified in 69 of them and these patients were further studied. Clinical and histopathological features were collected. Clinical phenotype was highly heterogeneous ranging from asymptomatic or paucisymptomatic hyperCKemia to severe muscle weakness and skeletal deformity with loss of ambulation. Sixty-eight RYR1 mutations, generally missense, were identified, of which 16 were novel. The combined analysis of the clinical presentation, disease progression and the structural bioinformatic analyses of RYR1 allowed to associate some phenotypes to mutations in specific domains. In addition, this study highlighted the structural bioinformatics potential in the prediction of the pathogenicity of RYR1 mutations. Further improvement in the comprehension of genotype-phenotype relationship of core myopathies can be expected in the next future: the actual lack of the human RyR1 crystal structure paired with the presence of large intrinsically disordered regions in RyR1, and the frequent presence of more than one RYR1 mutation in core myopathy patients, require designing novel investigation strategies to completely address RyR1 mutation effect.
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Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients.
Maggi, L, Brugnoni, R, Canioni, E, Tonin, P, Saletti, V, Sola, P, Piccinelli, SC, Colleoni, L, Ferrigno, P, Pini, A, et al
Frontiers in neurology. 2020;:646
Abstract
Background: Four main clinical phenotypes have been traditionally described in patients mutated in SCN4A, including sodium-channel myotonia (SCM), paramyotonia congenita (PMC), Hypokaliemic type II (HypoPP2), and Hyperkaliemic/Normokaliemic periodic paralysis (HyperPP/NormoPP); in addition, rare phenotypes associated with mutations in SCN4A are congenital myasthenic syndrome and congenital myopathy. However, only scarce data have been reported in literature on large patient cohorts including phenotypes characterized by myotonia and episodes of paralysis. Methods: We retrospectively investigated clinical and molecular features of 80 patients fulfilling the following criteria: (1) clinical and neurophysiological diagnosis of myotonia, or clinical diagnosis of PP, and (2) presence of a pathogenic SCN4A gene variant. Patients presenting at birth with episodic laryngospasm or congenital myopathy-like phenotype with later onset of myotonia were considered as neonatal SCN4A. Results: PMC was observed in 36 (45%) patients, SCM in 30 (37.5%), Hyper/NormoPP in 7 (8.7%), HypoPP2 in 3 (3.7%), and neonatal SCN4A in 4 (5%). The median age at onset was significantly earlier in PMC than in SCM (p < 0.01) and in Hyper/NormoPP than in HypoPP2 (p = 0.02). Cold-induced myotonia was more frequently observed in PMC (n = 34) than in SCM (n = 23) (p = 0.04). No significant difference was found in age at onset of episodes of paralysis among PMC and PP or in frequency of permanent weakness between PP (n = 4), SCM (n = 5), and PMC (n = 10). PP was more frequently associated with mutations in the S4 region of the NaV1.4 channel protein compared to SCM and PMC (p < 0.01); mutations causing PMC were concentrated in the C-terminal region of the protein, while SCM-associated mutations were detected in all the protein domains. Conclusions: Our data suggest that skeletal muscle channelopathies associated with mutations in SCN4A represent a continuum in the clinical spectrum.
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Effects of aquatic exercise on mental health, functional autonomy and oxidative stress in depressed elderly individuals: A randomized clinical trial.
Silva, LAD, Tortelli, L, Motta, J, Menguer, L, Mariano, S, Tasca, G, Silveira, GB, Pinho, RA, Silveira, PCL
Clinics (Sao Paulo, Brazil). 2019;74:e322
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Decreased physical activity can contribute significantly to increased levels of depression. Whereas, regular physical activity positively alters the symptoms of depression thereby promoting mental health. The aim of this study was to investigate the effects of aquatic exercise on mental health, functional autonomy and oxidative stress parameters in depressed elderly individuals. The study is a longitudinal clinical study, conducted over a period of 12 weeks. Forty participants were recruited: 20 elderly individuals (men n = 9 men) with depression formed the depression group and another 20 (n = 13 men) individuals without depression formed the non-depression group. Both groups were subjected to the same aquatic physical training program. Results showed that a low-intensity aerobic training program in the aquatic environment can contribute to the treatment of depression by reducing anxiety and depression scores, improving functional autonomy and decreasing oxidative stress. Authors conclude that an intermittent aquatic physical exercise program improves the functional capacity of depressed elderly individuals.
Abstract
OBJECTIVES The aim of this study was to investigate the effects of aquatic exercise on mental health, functional autonomy and oxidative stress parameters in depressed elderly individuals. METHODS Initially, ninety-two elderly individuals were included in the study and were allocated into the depression group (n=16) and nondepression group (n=14). Both groups engaged in the aquatic exercise program for 12 weeks, including two weekly sessions (45 min/session) at a low intensity (between 50% and 60% of maximal heart rate or Borg scale scores of 13 to 14) throughout the intervention. All outcomes were evaluated at baseline and 12 weeks later. RESULTS The patients were 63.5±8.8 years old. The following scores were decreased after training in the depressed group: depression (53%), anxiety (48%), and Timed Up & Go (33%). The following scores increased: Berg Balance Scale (9%) and flexibility (44%). Regarding the blood-based parameters, there were decreases in protein carbonylation (46%) and nitric oxide (60%) and increases in glutathione (170%) and superoxide dismutase (160%) in the depression group (p<0.005). CONCLUSIONS The aquatic exercise program reduces depression and anxiety, improves functional autonomy and decreases oxidative stress in depressed elderly individuals.
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The italian limb girdle muscular dystrophy registry: Relative frequency, clinical features, and differential diagnosis.
Magri, F, Nigro, V, Angelini, C, Mongini, T, Mora, M, Moroni, I, Toscano, A, D'angelo, MG, Tomelleri, G, Siciliano, G, et al
Muscle & nerve. 2017;(1):55-68
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INTRODUCTION Limb girdle muscular dystrophies (LGMDs) are characterized by high molecular heterogeneity, clinical overlap, and a paucity of specific biomarkers. Their molecular definition is fundamental for prognostic and therapeutic purposes. METHODS We created an Italian LGMD registry that included 370 molecularly defined patients. We reviewed detailed retrospective and prospective data and compared each LGMD subtype for differential diagnosis purposes. RESULTS LGMD types 2A and 2B are the most frequent forms in Italy. The ages at disease onset, clinical progression, and cardiac and respiratory involvement can vary greatly between each LGMD subtype. In a set of extensively studied patients, targeted next-generation sequencing (NGS) identified mutations in 36.5% of cases. CONCLUSION Detailed clinical characterization combined with muscle tissue analysis is fundamental to guide differential diagnosis and to address molecular tests. NGS is useful for diagnosing forms without specific biomarkers, although, at least in our study cohort, several LGMD disease mechanisms remain to be identified. Muscle Nerve 55: 55-68, 2017.