Atrofia Muscolare Spinale: presentazione clinica, quadri radiologici, nuovi trattamenti e biomarcatori

Spinal Muscular Atrophy is an autosomal recessive disorder affecting 1:100,000 live births, in which survival motor neuron (SMN) protein deficiency leads to motor neuron degeneration and progressive muscle atrophy, weakness,and early mortality. Most of SMA patients harbor homozygous SMN1 deletions while SMN2 copy number predicts the clinical subtype (SMA-I, -II, -III-IV). Few (3-5%) SMA patients display small mutations point mutations on the second allele. The behavior of point mutations in SMN1/SMN2 is heterogenous and requires proper validation. In recent years the discovery of effective therapies has marked the history of Spinal Muscular Atrophy(SMA). The only currently approved drug is Nusinersen, which is an antisense oligonucleotide that binds to the SMN2 pre-mRNA downstream of exon 7,leading to the translation of a fully functional SMN protein. The treatment has opened up a new scenario with the creation of a new phenotypic spectrum. We have studied prospectively patients treated with nusinersen, by planning serial evaluations : neurological exam, muscle strength (MRC), motor functional scales, timed tests, muscle MRI, CMAP and MUNE. Monitoring long-term outcome measures will allow us to characterize the new phenotypes of the disease and to define the efficacy spectrum of Nusinersen in patients with different ages and degrees of motor impairment. Neurofilament chains (Nf) are sensitive, liquor-based marker that can identify patients with neurodegenerative diseases, aid in the prediction of their long-term outcomes, and be used for assessing effects of treatment. At present, little is known about serum Nf levels in patients with SMA. To that purpose, we have measured the levels of Nf during the treatment with Nusinersen

Atrofia Muscolare Spinale: presentazione clinica, quadri radiologici, nuovi trattamenti e biomarcatori

Spinal Muscular Atrophy is an autosomal recessive disorder affecting 1:100,000 live births, in which survival motor neuron (SMN) protein deficiency leads to motor neuron degeneration and progressive muscle atrophy, weakness,and early mortality. Most of SMA patients harbor homozygous SMN1 deletions while SMN2 copy number predicts the clinical subtype (SMA-I, -II, -III-IV). Few (3-5%) SMA patients display small mutations point mutations on the second allele. The behavior of point mutations in SMN1/SMN2 is heterogenous and requires proper validation. In recent years the discovery of effective therapies has marked the history of Spinal Muscular Atrophy(SMA). The only currently approved drug is Nusinersen, which is an antisense oligonucleotide that binds to the SMN2 pre-mRNA downstream of exon 7,leading to the translation of a fully functional SMN protein. The treatment has opened up a new scenario with the creation of a new phenotypic spectrum. We have studied prospectively patients treated with nusinersen, by planning serial evaluations : neurological exam, muscle strength (MRC), motor functional scales, timed tests, muscle MRI, CMAP and MUNE. Monitoring long-term outcome measures will allow us to characterize the new phenotypes of the disease and to define the efficacy spectrum of Nusinersen in patients with different ages and degrees of motor impairment. Neurofilament chains (Nf) are sensitive, liquor-based marker that can identify patients with neurodegenerative diseases, aid in the prediction of their long-term outcomes, and be used for assessing effects of treatment. At present, little is known about serum Nf levels in patients with SMA. To that purpose, we have measured the levels of Nf during the treatment with Nusinersen

Case Report: Rare Homozygous RNASEH1 Mutations Associated With Adult-Onset Mitochondrial Encephalomyopathy and Multiple Mitochondrial DNA Deletions

Mitochondrial DNA (mtDNA) maintenance disorders embrace a broad range of clinical syndromes distinguished by the evidence of mtDNA depletion and/or deletions in affected tissues. Among the nuclear genes associated with mtDNA maintenance disorders, RNASEH1 mutations produce a homogeneous phenotype, with progressive external ophthalmoplegia (PEO), ptosis, limb weakness, cerebellar ataxia, and dysphagia. The encoded enzyme, ribonuclease H1, is involved in mtDNA replication, whose impairment leads to an increase in replication intermediates resulting from mtDNA replication slowdown. Here, we describe two unrelated Italian probands (Patient 1 and Patient 2) affected by chronic PEO, ptosis, and muscle weakness. Cerebellar features and severe dysphagia requiring enteral feeding were observed in one patient. In both cases, muscle biopsy revealed diffuse mitochondrial abnormalities and multiple mtDNA deletions. A targeted next-generation sequencing analysis revealed the homozygous RNASEH1 mutations c.129-3C>G and c.424G>A in patients 1 and 2, respectively. The c.129-3C>G substitution has never been described as disease-related and resulted in the loss of exon 2 in Patient 1 muscle RNASEH1 transcript. Overall, we recommend implementing the use of high-throughput sequencing approaches in the clinical setting to reach genetic diagnosis in case of suspected presentations with impaired mtDNA homeostasis

The impact of upper motor neuron involvement on clinical features, disease progression and prognosis in amyotrophic lateral sclerosis

ObjectivesIn amyotrophic lateral sclerosis (ALS) both upper (UMNs) and lower motor neurons (LMNs) are involved in the process of neurodegeneration, accounting for the great disease heterogeneity. We evaluated the associations of the burden of UMN impairment, assessed through the Penn Upper Motor Neuron Score (PUMNS), with demographic and clinical features of ALS patients to define the independent role of UMN involvement in generating disease heterogeneity, predicting disease progression and prognosis.MethodsWe collected the following clinical parameters on a cohort of 875 ALS patients: age and site of onset, survival, MRC scale, lower motor neuron score (LMNS), PUMNS, ALSFRS-R, change in ALSFRS-R over time (DFS), MITOS and King’s staging systems (KSS). Transcranial magnetic stimulation was performed on a subgroup of patients and central motor conduction time (CMCT) and cortical silent period (CSP) were calculated.ResultsWe observed that patients with an earlier age at onset and bulbar onset had higher PUMNS values. Higher values were also associated to lower ALSFRS-R and to higher DFS scores, as well as to higher MITOS and KSS, indicating that a greater UMN burden correlates with disease severity. Conversely, we did not appreciate any association between UMN involvement and survival or markers of LMN impairment. Moreover, PUMNS values showed a positive association with CMCT and a negative one with CSP values.InterpretationOur results suggest that the burden of UMN pathology, assessed through PUMNS, has an important independent role in defining clinical characteristics, functional disability, disease progression and prognosis in ALS patients. We also support the role of TMS in defining severity of UMN involvement

Primary mitochondrial myopathy: Clinical features and outcome measures in 118 cases from Italy

Objective: To determine whether a set of functional tests, clinical scales, patient-reported questionnaires, and specific biomarkers can be considered reliable outcome measures in patients with primary mitochondrial myopathy (PMM), we analyzed a cohort of Italian patients. Methods: Baseline data were collected from 118 patients with PMM, followed by centers of the Italian network for mitochondrial diseases. We used the 6-Minute Walk Test (6MWT), Timed Up-and-Go Test (x3) (3TUG), Five-Times Sit-To-Stand Test (5XSST), Timed Water Swallow Test (TWST), and Test of Masticating and Swallowing Solids (TOMASS) as functional outcome measures; the Fatigue Severity Scale and West Haven-Yale Multidimensional Pain Inventory as patient-reported outcome measures; and FGF21, GDF15, lactate, and creatine kinase (CK) as biomarkers. Results: A total of 118 PMM cases were included. Functional outcome measures (6MWT, 3TUG, 5XSST, TWST, and TOMASS) and biomarkers significantly differed from healthy reference values and controls. Moreover, functional measures correlated with patients' perceived fatigue and pain severity. Patients with either mitochondrial or nuclear DNA point mutations performed worse in functional measures than patients harboring single deletion, even if the latter had an earlier age at onset but similar disease duration. Both the biomarkers FGF21 and GDF15 were significantly higher in the patients compared with a matched control population; however, there was no relation with severity of disease. Conclusions: We characterized a large cohort of PMM by evaluating baseline mitochondrial biomarkers and functional scales that represent potential outcome measures to monitor the efficacy of treatment in clinical trials; these outcome measures will be further reinvestigated longitudinally to define the natural history of PMM

Atrofia Muscolare Spinale: presentazione clinica, quadri radiologici, nuovi trattamenti e biomarcatori

Spinal Muscular Atrophy is an autosomal recessive disorder affecting 1:100,000 live births, in which survival motor neuron (SMN) protein deficiency leads to motor neuron degeneration and progressive muscle atrophy, weakness,and early mortality. Most of SMA patients harbor homozygous SMN1 deletions while SMN2 copy number predicts the clinical subtype (SMA-I, -II, -III-IV). Few (3-5%) SMA patients display small mutations point mutations on the second allele. The behavior of point mutations in SMN1/SMN2 is heterogenous and requires proper validation. In recent years the discovery of effective therapies has marked the history of Spinal Muscular Atrophy(SMA). The only currently approved drug is Nusinersen, which is an antisense oligonucleotide that binds to the SMN2 pre-mRNA downstream of exon 7,leading to the translation of a fully functional SMN protein. The treatment has opened up a new scenario with the creation of a new phenotypic spectrum. We have studied prospectively patients treated with nusinersen, by planning serial evaluations : neurological exam, muscle strength (MRC), motor functional scales, timed tests, muscle MRI, CMAP and MUNE. Monitoring long-term outcome measures will allow us to characterize the new phenotypes of the disease and to define the efficacy spectrum of Nusinersen in patients with different ages and degrees of motor impairment. Neurofilament chains (Nf) are sensitive, liquor-based marker that can identify patients with neurodegenerative diseases, aid in the prediction of their long-term outcomes, and be used for assessing effects of treatment. At present, little is known about serum Nf levels in patients with SMA. To that purpose, we have measured the levels of Nf during the treatment with Nusinersen

Advancing Stroke Research on Cerebral Thrombi with Omic Technologies

Cerebrovascular diseases represent a leading cause of disability, morbidity, and death worldwide. In the last decade, the advances in endovascular procedures have not only improved acute ischemic stroke care but also conceded a thorough analysis of patients’ thrombi. Although early anatomopathological and immunohistochemical analyses have provided valuable insights into thrombus composition and its correlation with radiological features, response to reperfusion therapies, and stroke etiology, these results have been inconclusive so far. Recent studies applied single- or multi-omic approaches—such as proteomics, metabolomics, transcriptomics, or a combination of these—to investigate clot composition and stroke mechanisms, showing high predictive power. Particularly, one pilot studies showed that combined deep phenotyping of stroke thrombi may be superior to classic clinical predictors in defining stroke mechanisms. Small sample sizes, varying methodologies, and lack of adjustments for potential confounders still represent roadblocks to generalizing these findings. However, these techniques hold the potential to better investigate stroke-related thrombogenesis and select secondary prevention strategies, and to prompt the discovery of novel biomarkers and therapeutic targets. In this review, we summarize the most recent findings, overview current strengths and limitations, and present future perspectives in the field

New Insights into Cerebral Vessel Disease Landscapes at Single-Cell Resolution: Pathogenetic and Therapeutic Perspectives

Cerebrovascular diseases are a leading cause of death and disability globally. The development of new therapeutic targets for cerebrovascular diseases (e.g., ischemic, and hemorrhagic stroke, vascular dementia) is limited by a lack of knowledge of the cellular and molecular biology of health and disease conditions and the factors that cause injury to cerebrovascular structures. Here, we describe the role of advances in omics technology, particularly RNA sequencing, in studying high-dimensional, multifaceted profiles of thousands of individual blood and vessel cells at single-cell resolution. This analysis enables the dissection of the heterogeneity of diseased cerebral vessels and their atherosclerotic plaques, including the microenvironment, cell evolutionary trajectory, and immune response pathway. In animal models, RNA sequencing permits the tracking of individual cells (including immunological, endothelial, and vascular smooth muscle cells) that compose atherosclerotic plaques and their alteration under experimental settings such as phenotypic transition. We describe how single-cell RNA transcriptomics in humans allows mapping to the molecular and cellular levels of atherosclerotic plaques in cerebral arteries, tracking individual lymphocytes and macrophages, and how these data can aid in identifying novel immune mechanisms that could be exploited as therapeutic targets for cerebrovascular diseases. Single-cell multi-omics approaches will likely provide the unprecedented resolution and depth of data needed to generate clinically relevant cellular and molecular signatures for the precise treatment of cerebrovascular diseases