Whole-exome sequencing in patients with protein aggregate myopathies reveals causative mutations associated with novel atypical phenotypes

BACKGROUND: Myofibrillar myopathies (MFM) are a subgroup of protein aggregate myopathies (PAM) characterized by a common histological picture of myofibrillar dissolution, Z-disk disintegration, and accumulation of degradation products into inclusions. Mutations in genes encoding components of the Z-disk or Z-disk-associated proteins occur in some patients whereas in most of the cases, the causative gene defect is still unknown. We aimed to search for pathogenic mutations in genes not previously associated with MFM phenotype.METHODS: We performed whole-exome sequencing in four patients from three unrelated families who were diagnosed with PAM without aberrations in causative genes for MFM.RESULTS: In the first patient and her affected daughter, we identified a heterozygous p.(Arg89Cys) missense mutation in LMNA gene which has not been linked with PAM pathology before. In the second patient, a heterozygous p.(Asn4807Phe) mutation in RYR1 not previously described in PAM represents a novel, candidate gene with a possible causative role in the disease. Finally, in the third patient and his symptomatic daughter, we found a previously reported heterozygous p.(Cys30071Arg) mutation in TTN gene that was clinically associated with cardiac involvement.CONCLUSIONS: Our study identifies a new genetic background in PAM pathology and expands the clinical phenotype of known pathogenic mutations

Prevalence of Spinal Muscular Atrophy in the Era of Disease-Modifying Therapies: An Italian Nationwide Survey

Objective: Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in the SMN1 gene. The aim of this study was to assess the prevalence of SMA and treatment prescription in Italy. Methods: An online survey was distributed to 36 centers identified by the Italian government as referral centers for SMA. Data on the number of patients with SMA subdivided according to age, type, SMN2 copy number, and treatment were collected. Results: One thousand two hundred fifty-five patients with SMA are currently followed in the Italian centers with an estimated prevalence of 2.12/100,000. Of the 1,255, 284 were type I, 470 type II, 467 type III, and 15 type IV with estimated prevalence of 0.48, 0.79, 0.79 and 0.02/100,000, respectively. Three patients with SMA 0 and 16 presymptomatic patients were also included. Approximately 85% were receiving one of the available treatments. The percentage of treated patients decreased with decreasing severity (SMA I: 95.77%, SMA II: 85.11%, SMA III: 79.01%). Discussion: The results provide for the first time an estimate of the prevalence of SMA at the national level and the current distribution of patients treated with the available therapeutical options. These data provide a baseline to assess future changes in relation to the evolving therapeutical scenario

Evaluating the SERCA2 and VEGF mRNAs as Potential Molecular Biomarkers of the Onset and Progression in Huntington's Disease

Abnormalities of intracellular Ca2+ homeostasis and signalling as well as the down-regulation of neurotrophic factors in several areas of the central nervous system and in peripheral tissues are hallmarks of Huntington\u2019s disease (HD). As there is no therapy for this hereditary, neurodegenerative fatal disease, further effort should be made to slow the progression of neurodegeneration in patients through the definition of early therapeutic interventions. For this purpose, molecular biomarker(s) for monitoring disease onset and/or progression and response to treatment need to be identified. In the attempt to contribute to the research of peripheral candidate biomarkers in HD, we adopted a multiplex real-time PCR approach to analyse the mRNA level of targeted genes involved in the control of cellular calcium homeostasis and in neuroprotection. For this purpose we recruited a total of 110 subjects possessing the HD mutation at different clinical stages of the disease and 54 sex- and agematched controls. This study provides evidence of reduced transcript levels of sarco-endoplasmic reticulum-associated ATP2A2 calcium pump (SERCA2) and vascular endothelial growth factor (VEGF) in peripheral blood mononuclear cells (PBMCs) of manifest and premanifest HD subjects. Our results provide a potentially new candidate molecular biomarker for monitoring the progression of this disease and contribute to understanding some early events that might have a role in triggering cellular dysfunctions in HD

Formal semantics in the neurology clinic: Atypical understanding of aspectual coercion in ALS patients

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with subtle adverse effects on cognition. It is still unclear whether ALS also affects language and semantics, and if so, what aspects and processes exactly. We investigated how ALS patients understand verb phrases modified by temporal preposition phrases, e.g., “To watch TV for half an hour.” Interpretation here requires operations such as aspectual coercion that add or delete elements from event structures, depending on temporal modifiers, and constraints on coercion, which make combinations with certain modifiers not viable. Using a theoretically-motivated experimental design, we observed that acceptance rates for aspectual coercion were abnormally high in ALS patients. The effect was largest for the more complex cases of coercion: not those that involve enrichment of event structures (“To switch on the TV in half an hour,” where a number of failed attempts must be included in the interpretation) but those that, if applied, would result in deletion of event structure elements (“To repair the TV for half an hour”). Our experimental results are consistent with a deficit of constraints on coercion, and not with impaired semantic processes or representations, in line with recent studies suggesting that verb semantics is largely spared in ALS

Formal semantics in the neurology clinic: Atypical understanding of aspectual coercion in ALS patients

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with subtle adverse effects on cognition. It is still unclear whether ALS also affects language and semantics, and if so, what aspects and processes exactly. We investigated how ALS patients understand verb phrases modified by temporal preposition phrases, e.g., ‘To watch TV for half an hour’. Interpretation here requires operations such as aspectual coercion that add or delete elements from event structures, depending on temporal modifiers, and constraints on coercion, which make combinations with certain modifiers not viable. Using a theoretically-motivated experimental design, we observed that acceptance rates for aspectual coercion were abnormally high in ALS patients. The effect was largest for the more complex cases of coercion: not those that involve enrichment of event structures (‘To switch on the TV in half an hour’, where a number of failed attempts must be included in the interpretation) but those that, if applied, would result in deletion of event structure elements (‘To repair the TV for half an hour’). Our experimental results are consistent with a deficit of constraints on coercion, and not with impaired semantic processes or representations, in line with recent studies suggesting that verb semantics is largely spared in ALS

Interpreting signals from the peripheral nerve in amyloidosis: a call for action

Systemic amyloidosis includes a group of disorders, characterized by deposition of insoluble aggregates of amyloid fibrils in various tissues that lead to disruption of normal tissue structure and impaired function. They are currently categorized as hereditary and secondary. Peripheral neuropathy is a frequent complication of systemic amyloidosis. The most common phenotype is a length-dependent sensorimotor polyneuropathy with autonomic dysfunction, but there are many atypical presentations that often lead to delayed diagnosis. In this review, we emphasize the neurological clinical aspects that induce a suspicion of amyloidosis, the possible differential diagnosis and the diagnostic pitfalls. An early diagnosis of the disease is crucial for rapid initiation of appropriate treatment that may change the course and the progression of the disease

Hemispheric Asymmetry of the Hand Motor Representations in Patients with Highly Malignant Brain Tumors: Implications for Surgery and Clinical Practice

We addressed both brain pre-surgical functional and neurophysiological aspects of the hand representation in 18 right-handed patients harboring a highly malignant brain tumor in the sensorimotor (SM) cortex (10 in the left hemisphere, LH, and 8 in the right hemisphere, RH) and 10 healthy controls, who performed an fMRI hand-clenching task with both hands alternatively. We extracted the main ROI in the SM cortex and compared ROI values and volumes between hemispheres and groups, in addition to their motor neurophysiological measures. Hemispheric asymmetry in the fMRI signal was observed for healthy controls, namely higher signal for the left-hand movements, but not for either patients’ groups. ROI values, although altered in patients vs. controls, did not differ significantly between groups. ROI volumes associated with right-hand movement were lower for both patients’ groups vs. controls, and those associated with left-hand movement were lower in the RH group vs. all groups. These results are relevant to interpret potential preoperative plasticity and make inferences about postoperative plasticity and can be integrated in the surgical planning to increase surgery success and postoperative prognosis and quality of life

Insights into neurological dysfunction of critically ill COVID-19 patients

Novel coronavirus spread rapidly around the world infecting millions of people. It was thus declared a pandemic. This new virus damages the lungs. In the most severe cases, it leads to acute respiratory failure that requires intensive care treatment. However, many clinical reports have listed different neurological symptoms, leading to increased interest in the neurological involvement of COVID-19.Various pathophysiological mechanisms have been proposed to explain these neurological aspects. Direct viral invasion of the nervous system, systemic cytokine storm and severe hypoxemia are key factors in the development of symptoms.Critically ill patients present several additional risk factors for nervous system damage. Reasons for these include deep sedation and extended muscular paralysis, bed rest for several days, and the inability to receive proper physical rehabilitation.After ICU treatment, COVID-19 patients generally require an extensive rehabilitation program. However, distancing restrictions mean that in many cases physiotherapists are unable to enter ICUs, delaying the process of rehabilitation. The role of telemedicine should be considered as an adjunctive tool in the rehabilitation of critically ill COVID-19 patients. (C) 2020 Elsevier Ltd. All rights reserved

The use of antidepressant medication before and after the diagnosis of amyotrophic lateral sclerosis: A population-based cohort study

Background: The prevalent use of antidepressants (ATDs) in patients with Amyotrophic Lateral Sclerosis (ALS) varies across cross-sectional and clinic-based published studies. This population-based cohort study assesses the real-world prevalence of the use of ATDs, its trajectory and the association of incident use with clinical characteristics. Methods: All patients with incident ALS in the Friuli Venezia Giulia region, Italy, from 2002 to 2009, were identified through multiple sources including health databases. Diagnosis was validated through clinical documentation review. ATDs prescriptions from 2000 to 2011 were obtained from regional database. The trajectory was estimated through generalized estimating equations for repeated measures logistic regression and the Hazard ratio (HR) of initiating ATDs through multivariate proportional hazard Cox regression. Results: In this cohort of 261 ALS cases, age-, sex-adjusted prevalence of the use of ATDs was 37.3%, higher than in general population. The trajectory increased by 16% in 1-year period across diagnosis. Age 6467 years at diagnosis (HR 1.28, 95% CI 0.84-1.95) and bulbar onset (1.43, 95% CI 0.90-2.26) were positively associated with initiating ATDs after diagnosis. Conclusions: More than one-third of patients used ATDs. Depression may occur more frequently than previously reported. Depression may precede motor alterations and be related to both ALS diagnosis and progressio