To explore phenotypic differences between individuals with sporadic inclusion body myositis (sIBM) who are seropositive for the NT5c1A antibody compared with those who are seronegative.
...Cross-sectional clinical, serological and functional analysis in 25 consecutive participants with sIBM.
All participants met criteria for clinically defined or probable sIBM. 18 of 25 participants with sIBM (72%) were seropositive for the NT5c1A antibody. No differences between median age and duration of illness between the two groups were seen. Females have higher odds of being seropositive (OR=2.30). Participants with seropositive sIBM took significantly longer to get up and stand (p=0.012). There were no significant differences between the two groups in terms of distance covered on a 6 min walk. Seropositive participants were more likely to require assistive devices such as a walker or wheelchair for mobility (OR=23.00; p=0.007). A number of secondary (exploratory) outcomes were assessed. NT5c1A seropositive sIBM cases had lower total Medical Research Council (MRC) sum score and MRC sum score on the right (p=0.03 and 0.02, respectively). Participants with the NT5c1A antibody were significantly more likely to have symptoms of dysphagia (OR=10.67; p=0.03) and reduced forced vital capacity (p=0.005). Facial weakness occurred in 50% of seropositive participants while it was only seen in 14% of seronegative participants.
Even though the small sample size limits definite conclusions, our cross-sectional study showed seropositivity to the NT5c1A antibody is associated with greater motor and functional disability in sIBM. The study also suggests more prominent bulbar, facial and respiratory involvement in individuals positive for NT5c1A antibodies.
It is now difficult to classify acquired immune and inflammatory myopathies (IIMs) into traditional groups: dermatomyositis, polymyositis, and inclusion body myositis (IBM). Myopathologic ...classification of IIM provides more specific and inclusive diagnostic information. Pathologic features used to define IIM subtypes include: Muscle fiber changes; Immune abnormalities (cellular, humoral); and Tissue types involved (connective tissue, vessels, muscle fibers). Some features, like B-cell foci and alkaline phosphatase positive vessels or perimysium, occur more generally with treatable IIM. Myopathologic subtypes of IIM include: (1) Immune myopathies with perimysial pathology (IMPP) have perimysial connective tissue with fragmentation and histiocytic cellularity. Jo-1 antibody associated IIM often have IMPP pathology; (2) Myovasculopathies have damaged perimysial or endomysial vessels. Muscle damage may be due to ischemia rather than direct immune attack. Childhood dermatomyositis syndromes are often myovasculopathies. (3). Immune polymyopathies are active myopathies with necrosis but little inflammation. Serum CK is very high. Myopathies with signal recognition particle antibodies are an example. (4) Immune myopathies with endomysial pathology (IM-EP) often have C5b-9 complement deposition on endomysial connective tissue, and mononuclear cell foci. Brachio-cervical inflammatory myopathies illustrate IM-EP. (5) Histiocytic inflammatory myopathies have granulomas and focal invasion of muscle fibers by mononuclear cells. They include sarcoid myopathy. (6) Inflammatory myopathies with vacuoles, aggregates and mitochondrial pathology (IM-VAMP) in myofibers can also have diffusely upregulated myofiber MHC I, CD4 and CD8 cell foci and NT5C1A antibodies. IBM is a subgroup. IM-VAMP are poorly treatable. Myopathologic classification of IIM adds diagnostic and prognostic accuracy, and focuses testing, treatment, and pathogenic investigations.
To study the clinical and pathological correlations of neuromuscular patients with a high aldolase and normal creatine kinase (CK) in serum at presentation or during a symptomatic exacerbation.
...Records and muscle biopsies were retrospectively reviewed in a consecutive series of 12 patients. Pathological results were compared to 75 abnormal muscle biopsies associated with acquired immune or inflammatory myopathy syndromes and 14 muscle biopsies from patients with myopathies associated with serum anti-Jo-1 antibodies.
All patients with selectively elevated serum aldolase had muscle discomfort (92%), weakness (proximal and distal) (50%), or both. Frequent systemic features included joint pain (75%), skin disorders (75%) and pulmonary involvement (50%). Electromyography patterns included normal (36%), non-irritable myopathy (45%) and irritable myopathy (18%). Jo-1 antibodies were not found in the five patients tested. The distinctive feature of muscle biopsies was perimysial pathology (92%), including acid phosphatase positive cellularity (83%) and fragmented connective tissue (75%).
Selectively elevated serum aldolase is associated with syndromes including myopathies with discomfort and weakness, systemic disorders and myopathology in perimysial connective tissue. The myopathy with perimysial pathology and the associated clinical syndromes seen in our patients are similar to disorders associated with antisynthetase antibodies. In patients with muscle discomfort or mild weakness and a normal CK, measurement of serum aldolase can be useful in the evaluation of possible myopathies.
TAR DNA binding protein-43 (TDP-43) is found in ubiquitinated inclusions (UBIs) in some frontotemporal dementias (FTD-U). One form of FTD-U, due to mutations in the valosin containing protein (VCP) ...gene, occurs with an inclusion body myopathy (IBMPFD). Since IBMPFD brain has TDP-43 in UBIs, we looked for TDP-43 inclusions in IBMPFD muscle. In normal muscle, TDP-43 is present in nuclei. In IBMPFD muscle, TDP-43 is additionally present as large inclusions within UBIs in muscle cytoplasm. TDP-43 inclusions were also found in 78% of sporadic inclusion body myositis (sIBM) muscles. In IBMPFD and sIBM muscle, TDP-43 migrated with an additional band on immunoblot similar to that reported in FTD-U brains. This study adds sIBM and hereditary inclusion body myopathies to the growing list of TDP-43 positive inclusion diseases.
To identify the gene responsible for 14q32-linked dominant spinal muscular atrophy with lower extremity predominance (SMA-LED, OMIM 158600).
Target exon capture and next generation sequencing was ...used to analyze the 73 genes in the 14q32 linkage interval in 3 SMA-LED family members. Candidate gene sequencing in additional dominant SMA families used PCR and pooled target capture methods. Patient fibroblasts were biochemically analyzed.
Regional exome sequencing of all candidate genes in the 14q32 interval in the original SMA-LED family identified only one missense mutation that segregated with disease state-a mutation in the tail domain of DYNC1H1 (I584L). Sequencing of DYNC1H1 in 32 additional probands with lower extremity predominant SMA found 2 additional heterozygous tail domain mutations (K671E and Y970C), confirming that multiple different mutations in the same domain can cause a similar phenotype. Biochemical analysis of dynein purified from patient-derived fibroblasts demonstrated that the I584L mutation dominantly disrupted dynein complex stability and function.
We demonstrate that mutations in the tail domain of the heavy chain of cytoplasmic dynein (DYNC1H1) cause spinal muscular atrophy and provide experimental evidence that a human DYNC1H1 mutation disrupts dynein complex assembly and function. DYNC1H1 mutations were recently found in a family with Charcot-Marie-Tooth disease (type 2O) and in a child with mental retardation. Both of these phenotypes show partial overlap with the spinal muscular atrophy patients described here, indicating that dynein dysfunction is associated with a range of phenotypes in humans involving neuronal development and maintenance.
Objectives: Polyneuropathies with associated serum IgM antibodies are often difficult to treat. Rituximab is a monoclonal antibody directed against the B cell surface membrane marker CD20. Rituximab ...eliminates B cells from the circulation, and, over time, could reduce cells producing autoantibodies. This study tested the ability of rituximab to produce changes in serum antibody titres, and improvement in strength, in patients with neuromuscular disorders and IgM autoantibodies. Methods: Over a period of two years, the authors evaluated changes in strength, measured by quantitative dynamometry, and concentrations of several types of serum antibodies in patients with polyneuropathies and serum IgM autoantibodies. Twenty one patients treated with rituximab were compared with 13 untreated controls. Results: Treatment with rituximab was followed by improved strength (an increase of mean (SEM) 23% (2%)of normal levels of strength), a reduction in serum IgM autoantibodies (to 43% (4%) of initial values), and a reduction in total levels of IgM (to 55% (4%) of initial values). There was no change in levels of serum IgG antibodies. There were no major side effects, even though B cells were virtually eliminated from the circulation for periods up to two years. Conclusions: In patients with IgM autoantibody associated peripheral neuropathies, rituximab treatment is followed by reduced serum concentrations of IgM, but not IgG, antibodies, and by improvement in strength. Additional studies, with placebo controls and blinded outcome measures, are warranted to further test the efficacy of rituximab treatment of IgM associated polyneuropathies.
To perform a double-blind, randomized study comparing efficacy and safety of daily and weekend prednisone in boys with Duchenne muscular dystrophy (DMD).
A total of 64 boys with DMD who were between ...4 and 10 years of age were randomized at 1 of 12 centers of the Cooperative International Neuromuscular Research Group. Efficacy and safety of 2 prednisone schedules (daily 0.75 mg/kg/day and weekend 10 mg/kg/wk) were evaluated over 12 months.
Equivalence was met for weekend and daily dosing of prednisone for the primary outcomes of quantitative muscle testing (QMT) arm score and QMT leg score. Secondary strength scores for QMT elbow flexors also showed equivalence between the 2 treatment groups. Overall side effect profiles of height and weight, bone density, cataract formation, blood pressure, and behavior, analyzed at 12 months, did not differ between weekend and daily dosing of prednisone.
Weekend dosing of prednisone is equally beneficial to the standard daily dosing of prednisone. Analysis of side effect profiles demonstrated overall tolerability of both dosing regimens.
This study provides Class I evidence that weekend prednisone dosing is as safe and effective as daily prednisone in preserving muscle strength and preventing body mass index increases in boys with DMD over a 12-month period.
An open-label dose-escalation trial was performed to assess the safety and tolerability of high doses of coenzyme Q10 (CoQ10) in ALS. CoQ10, a cofactor in mitochondrial electron transfer, may improve ...the mitochondrial dysfunction in ALS. In this study, CoQ10 was safe and well tolerated in 31 subjects treated with doses as high as 3,000 mg/day for 8 months.
Objectives: To study myopathies with serum antibodies to the signal recognition particle (SRP), an unusual, myositis specific antibody associated syndrome that has not been well characterised ...pathologically. Methods: Clinical, laboratory, and myopathological features were evaluated in seven consecutive patients with a myopathy and serum anti-SRP antibodies, identified over three years. The anti-SRP myopathy was compared with myopathology in other types of inflammatory and immune myopathies. Results: The patients with anti-SRP antibodies developed weakness at ages ranging from 32 to 70 years. Onset was seasonal (August to January). Weakness became severe and disability developed rapidly over a period of months. Muscle pain and fatigue were present in some patients. No patient had a dermatomyositis-like rash. Serum creatine kinase was very high (3000 to 25 000 IU/l). Muscle biopsies showed an active myopathy, including muscle fibre necrosis and regeneration. There was prominent endomysial fibrosis, but little or no inflammation. Endomysial capillaries were enlarged, reduced in number, and associated with deposits of the terminal components of complement (C5b-9, membrane attack complex). Strength improved in several patients after corticosteroid treatment. Conclusions: Myopathies associated with anti-SRP antibodies may produce severe and rapidly progressive weakness and disability. Muscle biopsies show active myopathy with pathological changes in endomysial capillaries but little inflammation. Corticosteroid treatment early in the course of the illness is often followed by improvement in strength. In patients with rapidly progressive myopathies and a high serum creatine kinase but little inflammation on muscle biopsy, measurement of anti-SRP antibodies and pathological examination of muscle, including evaluation of endomysial capillaries, may provide useful information on diagnosis and treatment.
OBJECTIVE To evaluate muscle pathology and clinical characteristics in patients with a myopathy and serum antibodies to the Jo-1 antigen (histidyl t-RNA synthetase). BACKGROUND Anti-Jo-1 antibodies ...occur in syndromes that may include muscle weakness and pain, Raynaud's phenomenon, interstitial lung disease, arthritis, and a skin rash different from that seen in dermatomyositis. The muscle pathology is not well defined. METHODS Case series. Review of charts, muscle biopsies, and laboratory records. Features of myopathology in 11 patients with anti-Jo-1 antibody associated myopathies were compared with other types of inflammatory myopathies. RESULTS Myopathology in patients with anti-Jo-1 antibodies consistently included fragmentation of, and macrophage predominant inflammation in, perimysial connective tissue. Perifascicular myopathic changes, including atrophy, regenerating muscle fibres, and some muscle fibre necrosis, were most common in regions near the connective tissue pathology and were most prominent in patients with more severe weakness. Unlike many other inflammatory myopathies, inflammation in endomysial and perivascular regions was uncommon. By contrast with dermatomyositis, capillary density was normal. CONCLUSIONS Myopathological changes in the anti-Jo-1 antibody syndrome include perimysial connective tissue fragmentation and inflammation, with muscle fibre pathology in neighbouring perifascicular regions. Myositis with anti-Jo-1 antibodies may result from an immune mediated disorder of connective tissue.
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