45 research outputs found
Recessive myosin myopathy with external ophthalmoplegia associated with MYH2 mutations
No full textMyosin myopathies comprise a group of inherited diseases caused by mutations in myosin heavy chain (MyHC) genes. Homozygous or compound heterozygous truncating MYH2 mutations have been demonstrated to cause recessive myopathy with ophthalmoplegia, mild-to-moderate muscle weakness and complete lack of type 2A muscle fibers. In this study, we describe for the first time the clinical and morphological characteristics of recessive myosin IIa myopathy associated with MYH2 missense mutations. Seven patients of five different families with a myopathy characterized by ophthalmoplegia and mild-to-moderate muscle weakness were investigated. Muscle biopsy was performed to study morphological changes and MyHC isoform expression. Five of the patients were homozygous for MYH2 missense mutations, one patient was compound heterozygous for a missense and a nonsense mutation and one patient was homozygous for a frame-shift MYH2 mutation. Muscle biopsy demonstrated small or absent type 2A muscle fibers and reduced or absent expression of the corresponding MyHC IIa transcript and protein. We conclude that mild muscle weakness and ophthalmoplegia in combination with muscle biopsy demonstrating small or absent type 2A muscle fibers are the hallmark of recessive myopathy associated with MYH2 mutations.</p
Late-onset myopathy responsive to immunomodulatory treatment: sporadic late-onset nemaline myopathy without nemaline rods?
No full textBackground Late-onset sporadic nemaline myopathy (SLONM) is a rare, treatable or potentially life-threatening muscle disorder that typically manifests late in life and is characterised by the presence of nemaline rods within muscle fibres, serving as the hallmark of the disease and the key to diagnosis.Methods We report a case of an elderly patient with subacute onset of severe weakness affecting the upper and lower limbs, neck extensors and abdominal muscles. A comprehensive laboratory workup was performed.Results Muscle biopsies showed nonspecific myopathic changes without inflammation, and electron microscopy did not reveal rods or aggregates. The laboratory workup was unremarkable except for the detection of monoclonal gammopathy of undetermined significance. Steroid treatment was ineffective; however, there was a notable positive response to intravenous immunoglobulins. The neurological findings, subacute course, normal creatine kinase levels, presence of monoclonal gammopathy of unknown significance and responsiveness to immunoglobulin treatment but not to steroids align with the characteristics of SLONM.Conclusion We propose that the diagnosis of SLONM should be considered even in the absence of nemaline rods in muscle biopsy, and this should not impede the consideration of immunomodulatory treatment. Future progress in understanding the pathogenetic basis of SLONM may reduce reliance on pathological findings in muscle biopsies for establishing the diagnosis
Variable Myopathic Presentation in a Single Family with Novel Skeletal RYR1 Mutation
No full textWe describe an autosomal recessive heterogeneous congenital myopathy in a large consanguineous family. The disease is characterized by variable severity, progressive course in 3 of 4 patients, myopathic face without ophthalmoplegia and proximal muscle weakness. Absence of cores was noted in all patients. Genome wide linkage analysis revealed a single locus on chromosome 19q13 with Zmax = 3.86 at theta = 0.0 and homozygosity of the polymorphic markers at this locus in patients. Direct sequencing of the main candidate gene within the candidate region, RYR1, was performed. A novel homozygous A to G nucleotide substitution (p.Y3016C) within exon 60 of the RYR1 gene was found in patients. ARMS PCR was used to screen for the mutation in all available family members and in an additional 150 healthy individuals. This procedure confirmed sequence analysis and did not reveal the A to G mutation (p.Y3016C) in 300 chromosomes from healthy individuals. Functional analysis on EBV immortalized cell lines showed no effect of the mutation on RyR1 pharmacological activation or the content of intracellular Ca(2+) stores. Western blot analysis demonstrated a significant reduction of the RyR1 protein in the patient's muscle concomitant with a reduction of the DHPRalpha1.1 protein. This novel mutation resulting in RyR1 protein decrease causes heterogeneous clinical presentation, including slow progression course and absence of centrally localized cores on muscle biopsy. We suggest that RYR1 related myopathy should be considered in a wide variety of clinical and pathological presentation in childhood myopathies
Deep brain stimulation and bowstringing: Case report and pathological correlation
No full textDeep Brain Stimulation (DBS) is an established surgical therapy for movement disorders, epilepsy and more recently certain psychiatric disorders. The procedure is safe and complications fortunately few. Bowstringing as a complication has not been well documented and is most probably underreported. Bowstringing describes an entity where the subcutaneous electrode extensions running from head to chest cause a sensation of unpleasant tension, pulling and tightness. Patients may even complain of difficulty with turning their head to the contralateral side. This unpleasant feeling may continue to occur even after the removal of DBS extension leads as the cord like scar still remains. The underlying pathological process and why this occurs in a subset of patients is poorly understood. As such, to date in the literature, there are but a few proposed methods to manage bowstringing in DBS patients and certainly no consensus. We present an illustrative case report with histopathological correlation and suggestions for how this complication might be prevented and managed. Keywords: Deep brain stimulation, Bowstringing, Complication, Pseudocapsul
Liposomal Bupivacaine (Bupigel) Demonstrates Minimal Local Nerve Toxicity in a Rabbit Functional Model
No full textWe previously reported the development of a novel formulation of an ultra-long-acting local anesthetic based on bupivacaine encapsulated in large multivesicular liposomes (Bupisomes) embedded in hydrogel. This formulation (Bupigel) prolonged bupivacaine release from the formulation in dissolution-like studies in vitro and analgesia in vivo in mouse, rat, and pig models. In this study we assessed Bupigel neurotoxicity on rabbit sciatic nerve using histopathology and electrophysiologic testing. Sciatic nerves of both hind limbs were injected dropwise with different formulations. Nerve conduction studies and needle electromyography two weeks after perineural administration showed signs of neural damage after injection of free lidocaine and bupivacaine, while there was no sign of neural damage after injection with saline, demonstrating the validity of the method. This test also did not show evidence of motor or sensory nerve damage after injection with liposomal bupivacaine at a dose 10-times higher than free bupivacaine. Histologically, signs of neural damage could be observed with lidocaine. Nerves injected with Bupigel showed mild signs of inflammation and small residues of hydrogel in granulomas, indicating a long residence time of the hydrogel at the site of injection, but no histopathological signs of nerve damage. This demonstrated that early signs of neural damage were detected electrophysiologically, showing the usefulness and sensitivity of electrodiagnostic testing in detection of neural damage from new formulations
MYH2 mutation in recessive myopathy with external ophthalmoplegia linked to chromosome 17p13.1-p12
No full textIntradural Extramedullary Hemangiopericytoma of the Thoracic Spine Infiltrating a Nerve Root
No full textSingle Exon Skipping Can Address a Multi-Exon Duplication in the Dystrophin Gene
No full textDuchenne muscular dystrophy (DMD) is a severe muscle wasting disease typically caused by protein-truncating mutations that preclude synthesis of a functional dystrophin. Exonic deletions are the most common type of DMD lesion, however, whole exon duplications account for between 10–15% of all reported mutations. Here, we describe in vitro evaluation of antisense oligonucleotide-induced splice switching strategies to re-frame the transcript disrupted by a multi-exon duplication within the DMD gene. Phosphorodiamidate morpholino oligomers and phosphorodiamidate morpholino oligomers coupled to a cell penetrating peptide were evaluated in a Duchenne muscular dystrophy patient cell strain carrying an exon 14–17 duplication. Two strategies were employed; the conventional approach was to remove both copies of exon 17 in addition to exon 18, and the second strategy was to remove only the first copy of exon 17. Both approaches result in a larger than normal but in-frame DMD transcript, but surprisingly, the removal of only the first exon 17 appeared to be more efficient in restoring dystrophin, as determined using western blotting. The emergence of a normal sized DMD mRNA transcript that was not apparent in untreated samples may have arisen from back splicing and could also account for some of the dystrophin protein being produced
The oncofetal H19 RNA connection: Hypoxia, p53 and cancer
No full textAbstractExpression of the imprinted H19 gene is remarkably elevated in a large number of human cancers. Recently, we reported that H19 RNA is up-regulated in hypoxic stress and furthermore, it possesses oncogenic properties. However, the underlying mechanism(s) of these phenomena remain(s) unknown. Here we demonstrate a tight correlation between H19 RNA elevation by hypoxia and the status of the p53 tumor suppressor. Wild type p53 (p53wt) prevents the induction of H19 upon hypoxia, and upon its reconstitution in p53null cells. The last case is accompanied by a decrease in cell viability. The p53 effect is nuclear and seems independent of its tetramerization. Furthermore, using knockdown and over-expression approaches we identified HIF1-α as a critical factor that is responsible for H19 induction upon hypoxia. Knocking down HIF1-α abolishes H19 RNA induction, while its over-expression significantly enhances the H19 elevation in p53null hypoxic cells. In p53wt hypoxic cells simultaneous suppression of p53 and over-expression of HIF1-α are needed to induce H19 significantly, while each treatment separately resulting in a mild induction, indicating that the molecular mechanism of p53 suppression effect on H19 may at least in part involve interfering with HIF1-α activity. In vivo a significant increase in H19 expression occurred in tumors derived from p53null cells but not in p53wt cells. Taken together, our results indicate that a functional link exists between p53, HIF1-α and H19 that determines H19 elevation in hypoxic cancer cells. We suggest that this linkage plays a role in tumor development
