Olavo M. Vasconcelos

Missense mutations in desmin associated with familial cardiac and skeletal myopathy.

Desmin-related myopathy (OMIM 601419) is a familial disorder characterized by skeletal muscle weakness associated with cardiac conduction blocks, arrhythmias and restrictive heart failure, and by intracytoplasmic accumulation of desmin-reactive deposits in cardiac and skeletal muscle cells. The underlying molecular mechanisms are unknown. Involvement of the desmin gene (DES) has been excluded in three families diagnosed with desmin-related myopathy. We report two new families with desmin-related cardioskeletal myopathy associated with mutations in the highly conserved carboxy-terminal end of the desmin rod domain. A heterozygous A337P mutation was identified in a family with an adult-onset skeletal myopathy and mild cardiac involvement. Compound heterozygosity for two other mutations, A360P and N393I, was detected in a second family characterized by childhood-onset aggressive course of cardiac and skeletal myopathy.

Dermatomyositis‐like syndrome and HMG‐CoA reductase inhibitor (statin) intake

A patient developed an adult‐onset dermatomyositis‐like syndrome characterized by skin rash and progressive proximal muscle weakness concurrent with the intake of simvastatin. Despite discontinuation of the statin, symptoms progressed and required conventional steroid therapy for remission. The association between statins and the development of a musculocutaneous syndrome closely resembling dermatomyositis in susceptible subjects is poorly understood and has been reported rarely. The purpose of this report is to provide additional support for this pathological association. Since the population receiving statins is large and rapidly growing, caregivers are urged to be alert regarding the early recognition and proper care of the spectrum of neuromuscular complications linked to statin intake. Muscle Nerve, 2004

Expression of IFN-γ-inducible chemokines in inclusion body myositis

Abstract Because IFN-γ-inducible chemokines, Mig (CXCL9), IP-10 (CXCL10), I-TAC (CXCL11) and their receptor, CXCR3, are critical molecules in T cell trafficking and generation of effector T cells, we examined their expression in the muscle biopsies of patients with sporadic inclusion body myositis (s-IBM) and disease controls. The functional role of these molecules was also studied by examining the effect and time kinetics of IFN-γ in inducing Mig and IP-10 expression in human myotubes in vitro. We found significantly high levels of Mig and IP-10 mRNA expression in s-IBM muscles compared to controls. IFN-γ upregulated the mRNA expression of Mig and IP-10 by human myotubes in a dose-dependent manner. By double-label immunohistochemistry, Mig was expressed on a subset of CD8+ cells and the areas of the muscle fiber in contact or contiguous to the T cells; CXCR3 was expressed only on a subset of the autoinvasive CD8+ T cells but not the myofibers. IP-10 and I-TAC were not detected by immunocytochemistry. The findings indicate that in s-IBM, IFN-γ is involved in the upregulation and in situ production of proinflammatory chemokines, which, in turn, participate in the recruitment of activated T cells and contribute to the self-sustaining nature of endomysial inflammation.

Progressive skeletal myopathy, a phenotypic variant of desmin myopathy associated with desmin mutations

Desmin myopathy is a familial or sporadic disorder characterized by the presence of desmin mutations that cause skeletal muscle weakness associated with cardiac conduction block, arrhythmia and heart failure. Distinctive histopathologic features include intracytoplasmic accumulation of desmin-reactive deposits and electron-dense granular aggregates in skeletal and cardiac muscle cells. We describe two families with features of adult-onset slowly progressive skeletal myopathy without cardiomyopathy. N342D point mutation was present in the desmin helical rod domain in patients of family 1, and I451M mutation was found in the non-helical tail domain in patients of family 2. Of interest, the same I451M mutation has previously been reported in patients with cardiomyopathy and no signs of skeletal myopathy. Some carriers of the I451M mutation did not develop any disease, suggesting incomplete penetrance. Expression studies demonstrated inability of the N342D mutant desmin to form cellular filamentous network, confirming the pathogenic role of this mutation, but the network was not affected by the tail-domain I451M mutation. Progressive skeletal myopathy is a rare phenotypic variant of desmin myopathy allelic to the more frequent cardio-skeletal form.

Potential Outcome Factors in Subacute Combined Degeneration: Review of Observational Studies

BACKGROUND: Subacute combined degeneration is an acquired myelopathy caused by vitamin B12 deficiency. Therapy with B12 leads to improvement in most but to complete recovery in only a few patients. Prognostic indicators in subacute combined degeneration are unknown; therefore, predicting complete recovery of neurologic deficits is challenging.PURPOSE: To identify potential correlates of outcome and to generate hypotheses concerning predictors of complete resolution of neurologic deficits in subacute combined degeneration.DATA SOURCE: We searched EMBASE (1974 to October 2005), MEDLINE (1968 to October 2005), and references from identified reports.REPORTS SELECTION: Reports of patients with subacute combined degeneration containing results of magnetic resonance imaging (MRI) and description of outcome and 1 patient treated by the authors.DATA EXTRACTION, SYNTHESIS: We extracted data from 45 reports and 57 patients (36 males, 21 females: age range: 10 to 81) with a diagnosis of subacute combined degeneration, and estimated the strength of association between clinical, laboratory, and radiological factors and complete resolution of signs and symptoms.RESULTS: Eight patients (14%) achieved clinical resolution and 49 (86%) improved with B12 therapy. The absence of sensory dermatomal deficit, Romberg, and Babinski signs were associated with a higher complete resolution rate. Patients with MRI lesions in ≤7 segments and age less than 50 also appear to have higher rates of complete resolution.CONCLUSIONS: B12 therapy is reported to stop progression and improve neurologic deficits in most patients with subacute combined degeneration. However, complete resolution only occurs in a small percentage of patients and appears to be associated with factors suggestive of less severe disease at the time of diagnosis.

GNE mutations in an American family with quadriceps-sparing IBM and lack of mutations in s-IBM

Analysis for GNE mutations was performed in an American, non-Iranian Jewish, family with quadriceps-sparing inclusion body myopathy (QS-IBM) and in 11 patients with sporadic IBM (s-IBM). Two novel nonallosteric site missense mutations were found in the QS-IBM kinship. No mutations were identified in s-IBM patients. After 8 years of follow-up and severe disease progression, the quadriceps muscle in the QS-IBM patient remains strong despite subclinical involvement documented with repeat MRI and muscle biopsy.

Light therapy and supplementary Riboflavin in the SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis (FALS).

Familial amyotrophic lateral sclerosis (FALS) is a neurodegenerative disease characterized by progressive loss of motor neurons and death. Mitochondrial dysfunction and oxidative stress play an important role in motor neuron loss in ALS. Light therapy (LT) has biomodulatory effects on mitochondria. Riboflavin improves energy efficiency in mitochondria and reduces oxidative injury. The purpose of this study was to examine the synergistic effect of LT and riboflavin on the survival of motor neurons in a mouse model of FALS.

MODAFINIL FOR TREATMENT OF FATIGUE IN POST-POLIO SYNDROME: A RANDOMIZED CONTROLLED TRIAL

Objective: To determine if modafinil can improve fatigue in patients with post-polio syndrome. Methods: We used a randomized, placebo-controlled crossover trial. Intervention with modafinil (400 mg/day) and placebo occurred over 6-week periods. Primary endpoint (fatigue) was assessed using the Fatigue Severity Scale as the main outcome measure. Other measures included the Visual Analog Scale for Fatigue and the Fatigue Impact Scale. Secondary endpoint (health-related quality of life) was assessed using the 36-Item Short-Form. Analysis of variance for repeated measures was applied to assess treatment, period, and carryover effects. Results: Thirty-six patients were randomized, 33 of whom (mean age: 61 years) completed required interventions. Treatment with modafinil was safe and well-tolerated. After adjusting for periods and order effects, no difference was observed between treatments. Conclusion: Based on the utilized measures of outcome modafinil was not superior to placebo in alleviating fatigue or improving quality of life in the studied post-polio syndrome population.

Effect of 810 nm light on nerve regeneration after autograft repair of severely injured rat median nerve.

Destruction of large segments of peripheral nerves results in chronic loss of sensation and paralysis. For this type of severe injury, the defect can be bridged by nerve grafts. However, even with state‐of‐the‐art microsurgical techniques, there is minimal recovery of sensation and motor function. Light therapy (LT) has been shown to improve functional outcome after surgical intervention to repair injured nerves using different techniques. Our objective was to investigate the effect of LT on peripheral nerve regeneration and function after severe median nerve injury and microsurgical autologous nerve graft repair using fibrin glue.

Late‐onset muscle weakness in partial phosphofructokinase deficiency A unique myopathy with vacuoles, abnormal mitochondria, and absence of the common exon 5/intron 5 junction point mutation

Three patients (ages 51, 59, and 79) from two generations of an Ashkenazi Jewish family had partial (33% activity) phosphofructokinase (PFK) deficiency that presented with fixed muscle weakness after the age of 50 years. MR spectroscopy revealed accumulation of phosphomonoesters during exercise. Muscle biopsy showed a vacuolar myopathy with increased autophagic activity and several ragged-red and cytochrome c oxidase-negative fibers. The older patient, age 79 at biopsy, had several necrotic fibers. Electron microscopy revealed subsarcolemmal and intermyofibrillar glycogen accumulation and proliferation of mitochondria with paracrystalline inclusions, probably related to reduced availability of energy due to impaired glycolysis. The common point mutation of exon 5/intron 5 junction seen in Jewish Ashkenazi patients with PFK deficiency was excluded. We conclude that late-onset fixed muscle weakness occurs in partial PFK deficiency and it may represent the end result of continuing episodes of muscle fiber destruction. Partial enzyme deficiency in two successive generations suggests a unique molecular mechanism.