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Biomedical subjects

Marinos C Dalakas

Publications and source records attributed to Marinos C Dalakas.

At least 19 recordsLinked to original sources
PubMed2007

Absence of upregulated genes associated with protein accumulations in desmin myopathy.

In desmin myopathy but not hereditary inclusion-body myopathy (hIBM), there is accumulation of myofibrillar proteins including desmin, myotilin, dystrophin, gelsolin, actin, and CDC kinase. To assess the cause of protein excess, we studied the genes coding the accumulated proteins in desmin myopathy, hIBM, and controls. No differences were found among them. In desmin myopathy, protein accumulation is not due to upregulation of genes triggered by mutant desmin, but rather to posttranslational disassembly of intermediate filaments.

Actins↗
PubMed2007

Drug Insight: the use of intravenous immunoglobulin in neurology--therapeutic considerations and practical issues.

Over the past few years, we have achieved increasing success in the treatment of a number of autoimmune-mediated disorders affecting nerves and muscles. This success is partly attributable to the use of high-dose polyclonal intravenous immunoglobulin (IVIg), which has dramatically changed our treatment options. On the basis of results from controlled, but non-FDA-approved, clinical trials, IVIg is now the treatment of choice for Guillain-Barré syndrome, chronic idiopathic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy; IVIg offers rescue therapy for patients with rapidly worsening myasthenia gravis, and is a second-line therapy for dermatomyositis, stiff-person syndrome, and pregnancy-associated or postpartum multiple sclerosis attacks. The ability of IVIg to treat such immunologically diverse disorders effectively, coupled with its excellent safety profile, has led clinicians to use the drug more liberally, even in diseases for which the data are weak and not evidence-based and in patients with coexisting conditions. Use of IVIg for such indications can increase the risk of complications while raising the cost of the drug. Practical issues regarding dosing and frequency of infusions generate dilemmas in clinical practice. In this article, we review the current indications for IVIg treatment, address practical issues related to the use and costs of the drug, and summarize its mechanisms of action.

Autoimmune Diseases↗
PubMed2006

The challenge of diagnosing ALS in patients with prior poliomyelitis.

Four patients with postpolio syndrome (PPS) developed ALS. Weakness and atrophy started from previously unaffected extremities but, contrary to PPS, spread to all muscles leading to death within 0.4 to 8 (mean 3.9) years. Upper motor neuron signs were absent in the atrophic limbs. Abundant spontaneous activity and group atrophy in newly affected muscles were prominent. ALS can rarely occur in the postpolio population starting de novo rather than as evolution of PPS.

Aged↗
PubMed2006

Stiff person syndrome with cerebellar disease and high-titer anti-GAD antibodies.

We report five of 38 patients with stiff person syndrome (SPS), who also had cerebellar disease, gait ataxia, dysarthria, and oculomotor dysfunction (SPS-Cer). Cerebellar manifestations either preceded SPS or occurred concurrently. Brain MRI was normal. The intrathecal production of glutamic acid decarboxylase antibodies was elevated. Gamma-aminobutyric acid-enhancing drugs and immunotherapies improved only the stiffness. SPS-Cer is a distinct subset of SPS causing a more severe and complex clinical phenotype.

Adult↗
PubMed2006

Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome.

Stiff-person syndrome (SPS) is an autoimmune neurological disorder characterized by autoantibodies to glutamic acid decarboxylase (GAD), the enzyme responsible for the synthesis of inhibitory neurotransmitter GABA. To search for biomarkers that distinguish SPS from other neurological disorders (OND), we used surface enhanced laser desorption/ionization-time of flight (SELDI-TOF) mass spectrometry to obtain proteomic profile of sera from 25 GAD-positive SPS patients and 25 controls. A significant decrease was found in the level of a protein corresponding to GABA(A)-receptor-associated protein (GABARAP), which is responsible for the stability and surface expression of the GABA(A)-receptor. Up to 70% of the SPS sera examined, compared with 10% of the controls, immunoprecipitated GABARAP protein. Antibodies raised against GABARAP immunostained neuronal cell bodies as well as axonal and dendritic processes, as visualized by confocal microscopy. In vitro experiments demonstrated that the IgG from GABARAP antibody-positive patients, but not control IgG, significantly inhibited the surface expression of GABA(A)-receptor. We conclude that GABARAP is a new autoantigen in SPS. Because the patients' IgG inhibits the expression of GABA(A)-receptors, the circulating antibodies could impair GABAergic pathways and play a role in the clinical symptomatology of SPS patients.

Adaptor Proteins, Signal Transducing↗
PubMed2006

B cells in the pathophysiology of autoimmune neurological disorders: a credible therapeutic target.

There is evidence that B cells are involved in the pathophysiology of many neurological diseases, either in a causative or contributory role, via production of autoantibodies, cytokine secretion, or by acting as antigen-presenting cells leading to T cell activation. Clonal expansion of B cells either in situ or intrathecally and circulating autoantibodies are critical elements in multiple sclerosis (MS), Devic's disease, paraneoplastic central nervous system disorders, stiff-person syndrome, myasthenia gravis, autoimmune demyelinating neuropathies and dermatomyositis. The pathogenic role of B cells and autoantibodies in central and peripheral nervous system disorders, as reviewed here, provides a rationale for investigating whether depletion of B cells with new agents can improve clinical symptomatology and, potentially, restore immune function. Preliminary results from several clinical studies and case reports suggest that B cell depletion may become a viable alternative approach to the treatment of autoimmune neurological disorders.

Animals↗
PubMed2006

Inflammatory, immune, and viral aspects of inclusion-body myositis.

Muscle biopsies from patients with sporadic inclusion-body myositis (sIBM) consistently demonstrate that the inflammatory T cells almost invariably invade intact (not vacuolated) fibers, whereas the vacuolated fibers are rarely invaded by T cells. This indicates two concurrently ongoing processes, an autoimmune mediated by cytotoxic T cells and a degenerative manifested by the vacuolated muscle fibers and deposits of amyloid-related proteins. The autoimmune features of IBM are highlighted by the strong association of the disease with: a) HLA I, II antigens, in frequency identical to classic autoimmune diseases; b) other autoimmune disorders in up to 32% of the patients, autoantibodies, paraproteinemias, or immunodeficiency; c) HIV and HTLV-I infection with increasingly recognized frequency (up to 13 known cases); and d) antigen-specific, cytotoxic, and clonally expanded CD8+ autoinvasive T cells with rearranged T-cell receptor genes that persist over time, even in different muscles, and invade muscle fibers expressing MHC-I antigen and costimulatory molecules. In contrast to IBM, in various dystrophies the inflammatory cells are clonally diverse and the muscle fibers do not express MHC-I or costimulatory molecules in the pattern seen in IBM. Like other chronic autoimmune conditions with coexisting inflammatory and degenerative features (i.e., primary progressive MS), IBM is resistant to conventional immunotherapies. Recent data suggest that strong anti-T cell therapies can be promising and they are the focus of ongoing research.

Aged↗
PubMed2006

Variable pathogenic potentials of mutations located in the desmin alpha-helical domain.

Mutations in the desmin gene have been recognized as a cause of desminopathy, a familial or sporadic disorder characterized by skeletal muscle weakness, often associated with cardiomyopathy or respiratory insufficiency. Distinctive histopathologic features include aberrant intracytoplasmic accumulation of desmin (DES). We present here comparative phenotypic, molecular, and functional characteristics of four novel and three previously reported, but not fully characterized, desmin mutations localized in desmin alpha-helical domain. The results indicate that the c.638C>T (p.A213V), c.1178A>T (p.N393I), and to some extent the c.1078G>C (p.A360P) mutations exhibit pathogenic potentials only if combined with other mutations in desmin or other genes and should therefore be considered conditionally pathogenic. The c.1009G>C (p.A337P), c.1013T>G (p.L338R), c.1195G>T (p.D399Y), and c.1201G>A (p.E401K) mutations make desmin filaments dysfunctional and are capable of causing disease. The pathogenic potentials of desmin mutations correlate with the type and location of the disease-associated mutations in the relatively large and structurally and functionally complex desmin molecule. Mutations within the highly conserved alpha-helical structures are especially damaging since the integrity of the alpha-helix is critical for desmin filament assembly and stability.

Adult↗
PubMed2006

Role of IVIg in autoimmune, neuroinflammatory and neurodegenerative disorders of the central nervous system: present and future prospects.

INTRODUCTION: Although IVIg is highly effective in several autoimmune neuromuscular disorders (neuropathies, myopathies and neuromuscular junction disorders), its effectiveness in autoimmune or neuroinflammatory CNS diseases, with the exception of multiple sclerosis, has not been explored. Emerging data suggest that IVIg may have a role not only in certain antibody-mediated CNS diseases but also in some neurodegenerative disorders associated with "neuroinflammation" mediated by proinflammatory cytokines. METHODS: Data from a previously reported controlled study conducted in patients with stiff person syndrome (SPS) are presented as a paradigm of a CNS disorder associated with specific autoantibodies responding to IVIg. Emerging data using IVIg in various neuroinflammatory and neurodegenerative conditions such as Alzheimers disease, postpolio syndrome (PPS), fibrotic disorders, chronic painful conditions and narcoplepsy are summarized. RESULTS: On the basis of a double-blind placebo-controlled trial conducted in SPS patients with high anti-GAD antibodies, IVIg was shown to be effective resulting in improvement of stiffness and heightened sensitivity scores and increasing the patients' ability to carry out daily activities. In SPS, IVIg also suppressed the anti-GAD antibodies titers probably via an anti-idiotypic effect. A controlled study in patients with PPS, showed reduction in cytokines in serum and CSF with concomitant improvement in the patients' strength and ability to carry out their daily activities. The effect of IVIg in a small number of patients with Alzheimer's disease was promising by reducing the ADAS-cog scores, suggesting a reversal of disease progression. IVIg has been shown to have an effect on tissue fibrosis and in certain subacute painful conditions by suppressing cytokines that mediate fibrosis or pain. In another uncontrolled study, IVIg reduced the number of cataplectic attacks in narcolepsy patients. CONCLUSIONS: IVIg is effective in anti-GAD-positive patients with SPS. Whether it is also effective in other GAD-positive CNS disorders such as epilepsies, cerebellar degenerations or Batten's disease need to be studied in control trials. Emerging data suggest that IVIg, by suppressing proinflammatory cytokines, may exert a beneficial effect in patients with Alzheimer's disease, postpolio syndrome, chronic pain syndromes, fibrotic disorders and narcolepsy. Controlled studies are being planned or conducted to substantiate the benefit of IVIg in neurodegenerative disorders.

Autoimmune Diseases of the Nervous System↗
PubMed2006

A comparison of fatigue scales in postpoliomyelitis syndrome.

OBJECTIVE: To examine the applicability and validity of traditional fatigue questionnaires in postpoliomyelitis syndrome (PPS) patients with disabling fatigue. DESIGN: Cross-sectional study. PPS and disabling fatigue were ascertained according to published criteria. Descriptiveness was determined using the McNemar test, and interscale z-score agreement was estimated with Pearson's coefficients. SETTING: PPS clinic. PARTICIPANTS: Fifty-six survivors of poliomyelitis: 39 met criteria for PPS, 25 of whom met criteria for disabling fatigue. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The Fatigue Severity Scale (FSS), visual analog scale (VAS) for fatigue, and Fatigue Impact Scale (FIS). RESULTS: Twenty-four patients scored 50% or higher on the scale range for FSS, compared with 19 patients for VAS for fatigue (P=.042), and 7 patients for FIS (P<.001). Scores for patients with disabling fatigue averaged 81.5%, 62%, and 40.9% of the scale range for FSS, VAS for fatigue, and FIS, respectively. Agreement was moderate between the FSS and VAS for fatigue (r=.45, P=.02), but low between FSS and FIS (r=.29, P=.15), and FIS and VAS for fatigue (r=.20, P=.33). Two sample t tests showed significant differences between those with disabling fatigue and those without, based on FSS scores (t=3.8, P<.001), but not for VAS for fatigue or FIS scores. CONCLUSIONS: FSS was the most descriptive of the instruments tested. Scores generated by the scales were not interchangeable. Of the 3 scales, FFS seemed to be the most informative for the clinical assessment of fatigue in patients with PPS.

Adult↗
PubMed2006

Sporadic inclusion body myositis--diagnosis, pathogenesis and therapeutic strategies.

Sporadic inclusion body myositis (sIBM) presents with a characteristic clinical phenotype of slow-onset weakness and atrophy, affecting proximal and distal limb muscles and facial and pharyngeal muscles. Histologically, sIBM is characterized by chronic myopathic features, lymphocytic infiltrates invading non-vacuolated fibers, vacuolar degeneration, and accumulation of amyloid-related proteins. The cause of sIBM is unclear, but two processes-one autoimmune and the other degenerative-appear to occur in parallel. In contrast to dystrophies, in sIBM the autoinvasive CD8(+) T cells are cytotoxic and antigen-driven, invading muscle fibers expressing major histocompatibility complex class I antigen and costimulatory molecules. The concurrent degenerative features include vacuolization, filamentous inclusions and intracellular accumulations of amyloid-beta-related molecules. Although viruses have not been amplified from the muscle fibers, at least 12 cases of sIBM have been seen in association with retroviral infections, indicating that a chronic persistent viral infection might be a potential triggering factor. Emerging data imply that continuous upregulation of cytokines and major histocompatibility complex class I on the muscle fibers causes an endoplasmic reticulum stress response, resulting in intracellular accumulation of misfolded glycoproteins and activation of the transcription factor NFkappaB, leading to further cytokine activation. In spite of the brisk, antigen-driven T-cell infiltrates, sIBM does not respond to immunotherapies. New therapies using monoclonal antibodies against lymphocyte signaling pathways might prove helpful in arresting disease progression.

Diagnosis, Differential↗
PubMed2006

Mechanisms of disease: signaling pathways and immunobiology of inflammatory myopathies.

The signaling pathways involved in the immunobiology of polymyositis, dermatomyositis, and inclusion-body myositis are outlined in this Review, which is based on research performed during the past 10 years. In dermatomyositis, the complement cascade is activated and the expression of cytokines and chemokines is upregulated. In polymyositis and inclusion-body myositis, autoinvasive CD8+ T cells are clonally expanded. This T-cell subset possesses conserved amino-acid sequences in complementarity-determining region 3 of the T-cell receptor and, via the perforin pathway, exerts a myotoxic effect on muscle fibers that express major histocompatibility complex (MHC) class I molecules. In all inflammatory myopathies, molecules associated with T-cell transmigration and cytokine signaling, as well as chemokines and their receptors, are strongly expressed by endothelial and inflammatory cells. Early in the pathogenesis of polymyositis and inclusion-body myositis, expression of MHC class I molecules on muscle fibers is upregulated, even in the absence of autoinvasive CD8+ T cells. Emerging data indicate that such continuous upregulation of the expression of MHC class I molecules on muscle fibers leads to an endoplasmic reticulum stress response, intracellular accumulation of misfolded glycoproteins, and activation of nuclear factor kappaB pathways, which can further stimulate formation of MHC class I-CD8 complexes, resulting in a self-sustaining inflammatory response. Advances in our understanding of the signaling pathways involved in the pathogenesis of these inflammatory myopathies are expected to result in the identification of novel therapeutic targets for these diseases.

Disease Progression↗
PubMed2005

The role of high-dose immune globulin intravenous in the treatment of dermatomyositis.

Dermatomyositis (DM) is a complement-mediated microangiopathy affecting skin and muscle resulting in skin abnormalities, including subcutenous calcifications, muscle weakness and disability. The disease generally responds to steroids or immunosuppressive drugs, but a number of patients are resistant or partially responsive to these therapies, prompting us to examine the efficacy of IVIg. A double-blind placebo-controlled study demonstrated that IVIg is very effective in improving both the muscle strength and the skin rash. The clinical benefit, which was impressive in patients with early disease, was associated with improvement in the muscle cytoarchitecture. Quantitative histological studies in repeated muscle biopsies showed a statistically significant increase in the size of muscle fibers and the number of capillaries with normalization of the capillary diameter. Resolution of the aberrant immunopathological parameters, including interception of complement activation products and downregulation of T cells, ICAM-I, VCAM, TGF-beta and MHC-I molecules, was also noted. Further, a number of immunoregulatory and structural genes were modified in the patients' muscle biopsies after therapy. The study concluded that IVIg is an effective second-line therapy for patients with DM incompletely responding to steroids.

Clinical Trials as Topic↗
PubMed2005

Analysis of GAD65 autoantibodies in Stiff-Person syndrome patients.

Autoantibodies to the 65-kDa isoform of glutamate decarboxylase GAD65 (GAD65Ab) are strong candidates for a pathological role in Stiff-Person syndrome (SPS). We have analyzed the binding specificity of the GAD65Ab in serum and cerebrospinal fluid (CSF) of 12 patients with SPS by competitive displacement studies with GAD65-specific rFab-derived from a number of human and mouse mAbs specific for different determinants on the Ag. We demonstrate considerable differences in the epitope specificity when comparing paired serum and CSF samples, suggesting local stimulation of B cells in the CSF compartment of these patients. Moreover, these autoantibodies strongly inhibit the enzymatic activity of GAD65, thus blocking the formation of the neurotransmitter gamma-aminobutyric acid. The capacity of the sera to inhibit the enzymatic activity of GAD65 correlated with their binding to a conformational C-terminal Ab epitope. Investigation of the inhibitory mechanism revealed that the inhibition could not be overcome by high concentrations of glutamate or the cofactor pyridoxal phosphate, suggesting a noncompetitive inhibitory mechanism. Finally, we identified a linear epitope on amino acids residues 4-22 of GAD65 that was recognized solely by autoantibodies from patients with SPS but not by serum from type 1 diabetes patients. A mAb (N-GAD65 mAb) recognizing this N-terminal epitope was successfully humanized to enhance its potential therapeutic value by reducing its overall immunogenicity.

Adult↗
PubMed2005

Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations.

We describe clinical, electrophysiological, histopathological and molecular features of a unique disease caused by mutations in the glycyl-tRNA synthetase (GARS) gene. Sixty patients from five multigenerational families have been evaluated. The disease is characterized by adolescent onset of weakness, and atrophy of thenar and first dorsal interosseus muscles progressing to involve foot and peroneal muscles in most but not all cases. Mild to moderate sensory deficits develop in a minority of patients. Neurophysiologically confirmed chronic denervation in distal muscles with reduced compound motor action potentials were features consistent with both motor neuronal and axonal pathology. Sural nerve biopsy showed mild to moderate selective loss of small- and medium-sized myelinated and small unmyelinated axons, although sensory nerve action potentials were not significantly decreased. Based on the presence or absence of sensory changes, the disease phenotype was initially defined as distal spinal muscular atrophy type V (dSMA-V) in three families, Charcot-Marie-Tooth disease type 2D (CMT2D) in a single family, and as either dSMA-V or CMT2D in patients of another large family. Linkage to chromosome 7p15 and the presence of disease-associated heterozygous GARS mutations have been identified in patients from each of the five studied families. We conclude that patients with GARS mutations present a clinical continuum of predominantly motor distal neuronopathy/axonopathy with mild to moderate sensory involvement that varies between the families and between members of the same family. Awareness of these overlapping clinical phenotypes associated with mutations in GARS will facilitate identification of this disorder in additional families and direct future research toward better understanding of its pathogenesis.

Adolescent↗
PubMed2005

Use of a cell-free system to determine UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase activities in human hereditary inclusion body myopathy.

Hereditary inclusion body myopathy (HIBM) is an autosomal recessive neuromuscular disorder associated with mutations in uridine diphosphate (UDP)-N-acetylglucosamine (GlcNAc) 2-epimerase (GNE)/N-acetylmannosamine (ManNAc) kinase (MNK), the bifunctional and rate-limiting enzyme of sialic acid biosynthesis. We developed individual GNE and MNK enzymatic assays and determined reduced activities in cultured fibroblasts of patients, with HIBM harboring missense mutations in either or both the GNE and MNK enzymatic domains. To assess the effects of individual mutations on enzyme activity, normal and mutated GNE/MNK enzymatic domains were synthesized in a cell-free in vitro transcription-translation system and subjected to the GNE and MNK enzymatic assays. This cell-free system was validated for both GNE and MNK activities, and it revealed that mutations in one enzymatic domain (in GNE, G135V, V216A, and R246W; in MNK, A631V, M712T) affected not only that domain's enzyme activity, but also the activity of the other domain. Moreover, studies of the residual enzyme activity associated with specific mutations revealed a discrepancy between the fibroblasts and the cell-free systems. Fibroblasts exhibited higher residual activities of both GNE and MNK than the cell-free system. These findings add complexity to the tightly regulated system of sialic acid biosynthesis. This cell-free approach can be applied to other glycosylation pathway enzymes that are difficult to evaluate in whole cells because their substrate specificities overlap with those of ancillary enzymes.

Adult↗
PubMed2005

A neuropsychological assessment of phobias in patients with stiff person syndrome.

A neuropsychological assessment was performed in 10 patients with stiff person syndrome (SPS) to determine whether their anxiety and phobic symptoms precede stiffness and spasms or represent a reaction to disability. No neurocognitive dysfunction was noted. Patients perceived fears and anxiety as realistic and caused by SPS rather than due to an inherent phobic neurosis.

Accidental Falls↗