Statins are drugs widely prescribed in high-risk patients for cerebrovascular or cardiovascular diseases and are, usually, safe and well tolerated. However, these drugs sometimes may cause ...neuromuscular side effects that represent about two-third of all adverse events. Muscle-related adverse events include cramps, myalgia, weakness, immune-mediated necrotizing myopathy and, more rarely, rhabdomyolysis. Moreover, they may lead to peripheral neuropathy and induce or unmask a preexisting neuromuscular junction dysfunction. A clinical follow up of patients assuming statins could reveal early side effects that may cause neuromuscular damage and suggest how to better modulate their use. In fact, statin dechallenge or cessation, or the alternative use of other lipid-lowering agents, can avoid adverse events. This review summarizes the current knowledge on statin-associated neuromuscular adverse effects, diagnosis, and management. It is conceivable that the incidence of neuromuscular complications will increase because, nowadays, use of statins is even more diffused than in the past. On this purpose, it is expected that pharmacogenomic and environmental studies will help to timely predict neuromuscular complications due to statin exposure, leading to a more personalized therapeutic approach.
Charcot-Marie-Tooth disease type 2A (CMT2A) is a rare inherited axonal neuropathy caused by mutations in MFN2 gene, which encodes Mitofusin 2, a transmembrane protein of the outer mitochondrial ...membrane. We performed a cross-sectional analysis on thirteen patients carrying mutations in MFN2, from ten families, describing their clinical and genetic characteristics. Evaluated patients presented a variable age of onset and a wide phenotypic spectrum, with most patients presenting a severe phenotype. A novel heterozygous missense variant was detected, p.K357E. It is located at a highly conserved position and predicted as pathogenic by in silico tools. At a clinical level, the p.K357E carrier shows a severe sensorimotor axonal neuropathy. In conclusion, our work expands the genetic spectrum of CMT2A, disclosing a novel mutation and its related clinical effect, and provides a detailed description of the clinical features of a cohort of patients with MFN2 mutations. Obtaining a precise genetic diagnosis in affected families is crucial both for family planning and prenatal diagnosis, and in a therapeutic perspective, as we are entering the era of personalized therapy for genetic diseases.
Mutual interactions between the diaphragm and lung transplantation (LTx) are known to exist. Before LTx, many factors can exert notable impact on the diaphragmatic function, such as the underlying ...respiratory disease, the comorbidities, and the chronic treatments of the patient. In the post-LTx setting, even the surgical procedure itself can cause a stressful trauma to the diaphragm, potentially leading to morphological and functional alterations. Conversely, the diaphragm can significantly influence various aspects of the LTx process, ranging from graft-to-chest cavity size matching to the long-term postoperative respiratory performance of the recipient. Despite this, there are still no standard criteria for evaluating, defining, and managing diaphragmatic dysfunction in the context of LTx to date. This deficiency hampers the accurate assessment of those factors which affect the diaphragm and its reciprocal influence on LTx outcomes. The objective of this narrative review is to delve into the complex role the diaphragm plays in the different stages of LTx and into the modifications of this muscle following surgery.
Author Affiliation: (1) Neurorehabilitation Unit, NeMO Clinical Center, University of Milano, Piazza Ospedale Maggiore 3, 20162, Milano, Italy (2) Neuromuscular and Rare Diseases Unit, Department of ...Neuroscience, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milano, Italy (3) NeMO LAB S.r.l., Piazza Ospedale Maggiore 3, 20162, Milano, Italy (a) andrea.barp1985@libero.it Article History: Registration Date: 02/22/2021 Received Date: 01/03/2021 Accepted Date: 02/22/2021 Online Date: 03/01/2021 Byline:
The antisense oligonucleotide Nusinersen has been recently licensed to treat spinal muscular atrophy (SMA). Since SMA type 3 is characterized by variable phenotype and milder progression, biomarkers ...of early treatment response are urgently needed. We investigated the cerebrospinal fluid (CSF) concentration of neurofilaments in SMA type 3 patients treated with Nusinersen as a potential biomarker of treatment efficacy. The concentration of phosphorylated neurofilaments heavy chain (pNfH) and light chain (NfL) in the CSF of SMA type 3 patients was evaluated before and after six months since the first Nusinersen administration, performed with commercially available enzyme‐linked immunosorbent assay (ELISA) kits. Clinical evaluation of SMA patients was performed with standardized motor function scales. Baseline neurofilament levels in patients were comparable to controls, but significantly decreased after six months of treatment, while motor functions were only marginally ameliorated. No significant correlation was observed between the change in motor functions and that of neurofilaments over time. The reduction of neurofilament levels suggests a possible early biochemical effect of treatment on axonal degeneration, which may precede changes in motor performance. Our study mandates further investigations to assess neurofilaments as a marker of treatment response.
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a maternally inherited genetic mitochondrial disease with a typical onset in the first two decades of ...life and a major involvement of central nervous system (CNS). We present the case of a man affected with an oligosymptomatic, genetically determined MELAS syndrome, whose clinical picture dramatically and irreversibly worsened following a mild head injury. We hypothesize that the CNS metabolic stress induced by the brain injury activated an irreversible cascade of events leading to progressive neurodegeneration because damaged mitochondria were unable to restore the balance between energy requirements and availability.
Exercise-induced muscle stiffness is the hallmark of Brody disease, an autosomal recessive myopathy due to biallelic pathogenic variants in
, encoding the sarcoplasmic/endoplasmic reticulum Ca
ATPase ...SERCA1. About 40 patients have been reported so far. Our knowledge about the natural history of this disorder, genotype-phenotype correlations and the effect of symptomatic treatment is partial. This results in incomplete recognition and underdiagnosis of the disease. Here, we report the clinical, instrumental, and molecular features of two siblings presenting childhood-onset exercise-induced muscle stiffness without pain. Both the probands display difficulty in climbing stairs and running, frequent falls, delayed muscle relaxation after exertion. Cold temperatures worsen these symptoms. No myotonic discharges were observed at electromyography. Whole Exome Sequencing analysis in the probands revealed the presence of two
variants: the previously reported frameshift microdeletion c.2464delC and the likely pathogenic novel splice-site variant c.324 + 1G > A, whose detrimental effect was demonstrated in
transcript analysis. The bi-allelic inheritance was verified by Sanger sequencing in the unaffected parents. This study expands the molecular defects associated with Brody myopathy.
Collagen VI is a heterotrimeric protein expressed in several tissues and involved in the maintenance of cell integrity. It localizes at the cell surface, creating a microfilamentous network that ...links the cytoskeleton to the extracellular matrix. The heterotrimer consists of three chains encoded by
,
and
genes. Recessive and dominant molecular defects cause two main disorders, the severe Ullrich congenital muscular dystrophy and the relatively mild and slowly progressive Bethlem myopathy. We analyzed the clinical aspects, pathological features and mutational spectrum of 15 COL6-mutated patients belonging to our cohort of muscular dystrophy probands. Patients presented a heterogeneous phenotype ranging from severe forms to mild adult-onset presentations. Molecular analysis by NGS detected 14 different pathogenic variants, three of them so far unreported. Two changes, localized in the triple-helical domain of COL6A1, were associated with a more severe phenotype. Histological, immunological and ultrastructural techniques were employed for the validation of the genetic variants; they documented the high variability in COL6 distribution and the extracellular matrix disorganization, highlighting the clinical heterogeneity of our cohort. The combined use of these different technologies is pivotal in the diagnosis of COL6 patients.
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