Non-hematologic toxicity of bortezomib in multiple myeloma: the neuromuscular and cardiovascular adverse effects

The overall approach to the treatment of multiple myeloma (MM) has undergone several changes during the past decade. and proteasome inhibitors (PIs) including bortezomib, carfilzomib, and ixazomib have considerably improved the outcomes in affected patients. The first-in-class selective PI bortezomib has been initially approved for the refractory forms of the disease but has now become, in combination with other drugs, the backbone of the frontline therapy for newly diagnosed MM patients, as well as in the maintenance therapy and relapsed/refractory setting. Despite being among the most widely used and highly effective agents for MM, bortezomib can induce adverse events that potentially lead to early discontinuation of the therapy with negative effects on the quality of life and outcome of the patients. Although peripheral neuropathy and myelosuppression have been recognized as the most relevant bortezomib-related adverse effects, cardiac and skeletal muscle toxicities are relatively common in MM treated patients, but they have received much less attention. Here we review the neuromuscular and cardiovascular side effects of bortezomib. focusing on the molecular mechanisms underlying its toxicity. We also discuss our preliminary data on the effects of bortezomib on skeletal muscle tissue in mice receiving the drug

A novel in-frame deletion in MYOT causes an early adult onset distal myopathy

Missense mutations in MYOT encoding the sarcomeric Z-disk protein myotilin cause three main myopathic phenotypes including proximal limb-girdle muscular dystrophy, spheroid body myopathy, and late-onset distal myopathy. We describe a family carrying a heterozygous MYOT deletion (Tyr4_His9del) that clinically was characterized by an early-adult onset distal muscle weakness and pathologically by a myofibrillar myopathy (MFM). Molecular modeling of the full-length myotilin protein revealed that the 4-YERPKH-9 amino acids are involved in local interactions within the N-terminal portion of myotilin. Injection of in vitro synthetized mutated human MYOT RNA or of plasmid carrying its cDNA sequence in zebrafish embryos led to muscle defects characterized by sarcomeric disorganization of muscle fibers and widening of the I-band, and severe motor impairments. We identify MYOT novel Tyr4_His9 deletion as the cause of an early-onset MFM with a distal myopathy phenotype and provide data supporting the importance of the amino acid sequence for the structural role of myotilin in the sarcomeric organization of myofibers

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

Acetylcholine receptor-antibody-positive myasthenia gravis presenting with early atrophy and nonfluctuating weakness of proximal limb muscles

[no abstract available

Early secondary prevention after initially ineffective revascularization treatments for acute ischemic stroke due to tandem occlusion

The most effective treatment of patients with stroke due to tandem occlusion is still unclear. We report the case of a man with stroke due to tandem internal carotid artery/middle cerebral artery occlusion, who underwent initially ineffective intravenous thrombolysis (IVT) and endovascular treatment. Early anticoagulation with apixaban was started after 48 h of IVT, given a newly diagnosed nonvalvular atrial fibrillation. Spontaneous partial recanalization of the cervical internal carotid artery was noted, and carotid endarterectomy was performed 72 h after IVT and 8 h after the last dose of apixaban. Surgery was conducted without any complication and the patient was discharged 7 days after onset with a residual mild hemiparesis. This is the first report of urgent carotid endarterectomy in an anticoagulated patient receiving a direct oral anticoagulant. This case highlights the importance of an early multidisciplinary approach to achieve a successful treatment of stroke due to tandem occlusion. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved

Response to Nagai et\ua0al.

Refers to: Nagai M, Dote K, Kato M, Sasaki S, Oda N. The insular cortex and QTc interval: Was there the effect of hemispheric lateralization? Eur J Neurol 2017; 24: e45. - Referred to: Turri G, Calabrese M, Pancheri E, Monaco S, Gajofatto A, Marafioti V. QTc interval in patients with multiple sclerosis: an infer- ence from the insula of Reil? Eur J Neurol 2017; 24: 491 \u2013 496

QTc interval in patients with multiple sclerosis: an inference from the insula of Reil?

BACKGROUND AND PURPOSE: The aim of this study was to investigate the correlation between the duration of the QTc interval and the brain lesion load at the level of the structures involved in superior autonomic control (insula, cingulate cortex and amygdala-hippocampus) in multiple sclerosis (MS) patients. METHODS: Thirty-one consecutive patients with relapsing-remitting MS were recruited. The QT interval was measured manually in all 12 leads by a single blinded observer, with the longest QT value adjusted for heart rate by using the Bazett's formula. All patients performed a brain magnetic resonance imaging (MRI) scan including three-dimensional double inversion recovery and three volumetric fast-field echo sequences. The following MRI measures were obtained: (i) global and regional cortical thickness (CTh); (ii) white matter lesion load volume; (iii) cortical damage blindly assessed by a trained observer who assigned, on the basis of the number of cortical lesions, a score from 0 to 5 for each of the brain areas analysed. RESULTS: In all, 16% of the patients had an increased QTc interval. The QTc interval was correlated with disease duration, cortical insular lesion volume and grey matter lesion volume in the three examined areas and inversely correlated with global and insular CTh. CONCLUSIONS: An increased QTc interval in patients with MS may have a cerebral origin possibly driven by involvement of the insular cortex. With the recent introduction in clinical practice of treatments with potential cardiac effects such as fingolimod, the recognition of a long QTc interval could be clinically crucial and should encourage appropriate electrocardiographic monitoring in order to prevent the risk of malignant ventricular pro-arrhythmia and iatrogenic sudden death

Amyloid myopathy: an intriguing diagnosis

[no abstract available

A novel emerin gene mutation in Emery Dreifuss muscular dystrophy patient with spontaneous chordae tendinae rupture

Emery Dreifuss muscular dystrophy (EDMD) is an inherited myopathy characterized by early contractures, slow progressive muscle weakness and cardiac involvement. To date at least seven genes have been associated to EDMD with different inheritance patterns, being emerin gene responsible for the X-linked form of the disease. We report a 40-year-old man who was referred for severe gait difficulty. At age 6 years the patient presented with a waddling gate, lumbar lordosis and heel contractures. Both electrophysiology and muscle biopsy were consistent with a neurogenic disorder and he received a diagnosis of spinal muscular atrophy type 3. At the age of 30 the patient developed heart involvement with junctional escape rhythm and, eight years later, had a spontaneous chordae tendinae rupture. A new clinical examination showed severe muscular weakness and atrophy in scapulohumeroperoneal pattern with significant involvement of the lower facial and intrinsic hand muscles and on a second muscle biopsy emerin was absent by immunohistochemistry and by immunoblot analysis. Sequence analysis of EMD gene revealed the presence of a novel mutation represented by an out-of-frame deletion spanning from the beginning of exon 1 to the half of intron 2 (p.Asp6Glyfs*27). Our study expands the clinical and molecular spectrum of X-linked EDMD