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M C Dalakas

Publications and source records attributed to M C Dalakas.

At least 19 recordsLinked to original sources
PubMed2006

Update on idiopathic inflammatory myopathies.

The inflammatory myopathies are a group of acquired diseases, characterized by an inflammatory infiltrate of the skeletal muscle. On the basis of clinical, immuno-pathological and demographic features, three major diseases can be identified: dermatomyositis (DM); polymyositis (PM); and inclusion body myositis (IBM). New diagnostic criteria have recently been introduced, which are crucial for discriminating between the three different subsets of inflammatory myopathies and for excluding other disorders. DM is a complement-mediated microangiopathy affecting skin and muscle. PM and IBM are T cell-mediated disorders, where CD8-positive cytotoxic T cells invade muscle fibres expressing MHC class I antigens, thus leading to fibre necrosis. In IBM, vacuolar formation with amyloid deposits are also present. This article summarizes the main clinical, laboratory, electrophysiological, immunological and histologic features as well as the therapeutic options of the inflammatory myopathies.

Autoantibodies↗
PubMed2005

Autoimmune muscular pathologies.

The T cell-mediated mechanism responsible for Polymyositis and inclusion Body Myositis and the complement-mediated microangiopathy associated with Dermatomyositis are reviewed. The management of autoimmune myopathies with the presently available immunotherapeutic agents as well as new therapies and ongoing trials are discussed.

Antigens, CD↗
PubMed2004

Correlating phenotype and genotype in the periodic paralyses.

BACKGROUND: Periodic paralyses and paramyotonia congenita are rare disorders causing disabling weakness and myotonia. Mutations in sodium, calcium, and potassium channels have been recognized as causing disease. OBJECTIVE: To analyze the clinical phenotype of patients with and without discernible genotype and to identify other mutations in ion channel genes associated with disease. METHODS: The authors have reviewed clinical data in patients with a diagnosis of hypokalemic periodic paralysis (56 kindreds, 71 patients), hyperkalemic periodic paralysis (47 kindreds, 99 patients), and paramyotonia congenita (24 kindreds, 56 patients). For those patients without one of the classically known mutations, the authors analyzed the entire coding region of the SCN4A, KCNE3, and KCNJ2 genes and portions of the coding region of the CACNA1S gene in order to identify new mutations. RESULTS: Mutations were identified in approximately two thirds of kindreds with periodic paralysis or paramyotonia congenita. The authors found differences between the disorders and between those with and without identified mutations in terms of age at onset, frequency of attacks, duration of attacks, fixed proximal weakness, precipitants of attacks, myotonia, electrophysiologic studies, serum potassium levels, muscle biopsy, response to potassium administration, and response to treatment with acetazolamide. CONCLUSIONS: Hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and paramyotonia congenita may be distinguished based on clinical data. This series of 226 patients (127 kindreds) confirms some clinical features of this disorder with notable exceptions: In this series, patients without mutations had a less typical clinical presentation including an older age at onset, no changes in diet as a precipitant, and absence of vacuolar myopathy on muscle biopsy.

Adolescent↗
PubMed2004

Desmin myopathy.

Desmin myopathy is a recently identified disease associated with mutations in desmin or alphaB-crystallin. Typically, the illness presents with lower limb muscle weakness slowly spreading to involve truncal, neck-flexor, facial, bulbar and respiratory muscles. Skeletal myopathy is often combined with cardiomyopathy manifested by conduction blocks and arrhythmias resulting in premature sudden death. Sections of the affected skeletal and cardiac muscles show abnormal fibre areas containing amorphous eosinophilic deposits seen as granular or granulofilamentous material on electron microscopic examination. Immuno-staining for desmin is positive in each region containing abnormal structures. The inheritance pattern in familial desmin myopathy is autosomal dominant or autosomal recessive, but many cases have no family history. At least some, and probably most, non-familial desmin myopathy cases are associated with de novo desmin mutations. Age of disease onset and rate of progression may vary depending on the type of inheritance and location of the causative mutation. Multiple mutations have been identified in the desmin gene: point substitutions, insertion, small in-frame deletions and a larger exon-skipping deletion. The majority of these mutations are located in conserved alpha-helical segments of desmin. Many of the missense mutations result in changing the original amino acid into proline, which is known as a helix breaker. Studies of transfected cell cultures indicate that mutant desmin is assembly-incompetent and able to disrupt a pre-existing filamentous network in dominant-negative fashion. Disease-associated desmin mutations in humans or transgenic mice cause accumulation of chimeric intracellular aggregates containing desmin and other cytoskeletal proteins. alphaB-crystallin serves in the muscle as a chaperone preventing desmin aggregation under various forms of stress. If mutated, alphaB-crystallin may cause a myopathy similar to those resulting from desmin mutations. Routine genetic testing of patients for mutations in desmin and alphaB- crystallin genes is now available and necessary for establishing an accurate diagnosis and providing appropriate genetic counselling. Better understanding of disease pathogenesis would stimulate research focused on developing specific treatments for these conditions.

Amino Acid Sequence↗
PubMed2003

High-dose intravenous immunoglobulin in inflammatory myopathies: experience based on controlled clinical trials.

Controlled clinical trials with high-dose intravenous immunoglobulin (IVIg) have been conducted in patients with DM and IBM, but not PM. A double-blind placebo-controlled study in DM patients, resistant or partially responsive to conventional therapies, showed 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 increased 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. In IBM, IVIg showed marginal, and non statistically significant, improvements in muscle strength. Up to 20% of patients however, demonstrated clinical improvement with increased activities of daily living while certain muscle groups, such as the muscles of swallowing, showed significant improvements compared to placebo implying mild regional benefits. In PM, small uncontrolled series have shown improvements in muscle strength in up to 70% of the IVIg-treated patients. Because PM, as a stand-alone clinical entity, is a very rare disease, completion of controlled trials will be very difficult.

Dermatomyositis↗
PubMed2002

Increased brainstem excitability in stiff-person syndrome.

The recovery cycle of the R2 component of the blink reflex was studied in five patients with stiff-person syndrome (SPS) and in seven healthy control subjects. R2 recovery was enhanced in patients with SPS. This result is suggestive of hyperexcitability of brainstem interneuronal circuits in SPS. Hyperexcitability may result from abnormal input from suprasegmental structures or loss of inhibition by interneurons and is compatible with the proposal that there is a widespread dysfunction of central inhibitory mechanisms in SPS.

Adult↗
PubMed2002

Understanding the immunopathogenesis of inclusion-body myositis: present and future prospects.

Sporadic Inclusion Body Myositis (s-IBM) is the most common acquired inflammatory myopathy. It has a stereotypic clinical presentation and a predictably progressive course that leads to severe muscle weakness and permanent disability. The combination of primary endomysial inflammation with autoimmune features identical to those seen in Polymyositis, and degenerative features with vacuolization of muscle fibers and deposits of tiny speckles of amyloid, are characteristic for the disease. In this review, the immunopathology of IBM is detailed. The inflammation which is prominent even late in the disease, is characterized by activated, CD8+ cytotoxic T cells that secrete perforin and invade MHC-I-expressing muscle fibers. The autoinvasive T cells are probably antigen driven because of specific rearrangement of their T Cell Receptor profile, restriction of the CDR3 region, upregulation of co-stimulatory molecules and their ligands on the muscle fibers, and activation of various cytokines, chemokines and adhesion molecules. The disease can be seen in association with HIV and HTLV-I infection, but viruses have not been amplified from the muscle fibers and the antigen or the factors that trigger inflammation are still unknown. The disease is mysteriously resistant to conventional immunotherapies in spite of the immunopathologic similarities with PM. The cause of the vacuolar formation in IBM is also unknown and the role, that the tiny amyloid deposits play in the disease remain unclear. The treatment approaches and the prospects for future immunotherapeutic interventions are discussed.

Electromyography↗
PubMed2001

High-dose intravenous immune globulin for stiff-person syndrome.

BACKGROUND: Stiff-person syndrome is a disabling central nervous system disorder with no satisfactory treatment that is characterized by muscle rigidity, episodic muscle spasms, high titers of antibodies against glutamic acid decarboxylase (GAD65), and a frequent association with autoimmune disorders. Because stiff-person syndrome is most likely immune-mediated, we evaluated the efficacy of intravenous immune globulin. METHODS: We assigned 16 patients who had stiff-person syndrome and anti-GAD65 antibodies, in random order, to receive intravenous immune globulin or placebo for three months, followed by a one-month washout period and then by three months of therapy with the alternative agent. Efficacy was judged by improvements in scores on the distribution-of-stiffness index and heightened-sensitivity scale from base line (month 1) to the second and third month of each treatment phase. Direct and carryover effects of treatment were compared in the two groups. RESULTS: Among patients who received immune globulin first, stiffness scores decreased significantly (P=0.02) and heightened-sensitivity scores decreased substantially during immune globulin therapy but rebounded during placebo administration. In contrast, the scores in the group that received placebo first remained constant during placebo administration but dropped significantly during immune globulin therapy (P=0.01). When the data were analyzed for a direct and a first-order carryover effect, there was a significant difference in stiffness scores (P=0.01 and P<0.001, respectively) between the immune globulin and placebo groups, and immune globulin therapy had a significant direct treatment effect on sensitivity scores (P=0.03). Eleven patients who received immune globulin became able to walk more easily or without assistance, their frequency of falls decreased, and they were able to perform work-related or household tasks. The duration of the beneficial effects of immune globulin varied from six weeks to one year. Anti-GAD65 antibody titers declined after immune globulin therapy but not after placebo administration. CONCLUSIONS: Intravenous immune globulin is a well-tolerated and effective, albeit costly, therapy for patients with stiff-person syndrome and anti-GAD65 antibodies.

Adult↗
PubMed2001

Stiff person syndrome: quantification, specificity, and intrathecal synthesis of GAD65 antibodies.

OBJECTIVE: To characterize the specificity of anti-GAD(65) antibodies in patients with stiff person syndrome (SPS), quantify antibody titers, and examine antibody production within the CNS. METHODS: The authors studied 18 patients with SPS and positive serum immunoreactivity to gamma-aminobutyric acid (GABA)-ergic neurons. The reactivity of serum and CSF to purified GAD antigen was examined by Western blots, and the anti-GAD(65) antibody titers in serum and CSF were quantified by ELISA and compared with 70 disease controls (49 with other autoimmune disorders and 11 with insulin-dependent diabetes mellitus). The intrathecal synthesis of anti-GAD(65) IgG was calculated, and the functional significance of the antibodies was examined by measuring the GABA levels in the CSF. RESULTS: The serum and CSF of all selected patients with SPS had high anti-GAD(65) titers (from 7.0 to 215 microg/mL in serum and from 92 to 2500 ng/mL in CSF) and immunoreacted strongly with recombinant GAD(65) on Western blots and with GABA-ergic neurons on rat cerebellum. Among controls, only the serum of eight patients with insulin-dependent diabetes mellitus had low anti-GAD(65) antibody titers (from 200 to 1760 ng/mL) but no reactivity to recombinant GAD(65). The CSF showed oligoclonal IgG bands in 10 (67%) of 15 patients and an increased anti-GAD(65)-specific IgG index in 11 (85%) of 13. The mean level of GABA in the CSF was lower in patients with SPS than in controls. CONCLUSIONS: In patients with SPS, there is marked intrathecal antibody response against neuronal GAD(65) epitopes, indicating a clonal B cell activation in the CNS. Anti-GAD(65) antibodies at high titers, when confirmed with immunoblots, are highly specific for SPS and appear to impair GABA synthesis.

Animals↗
PubMed2001

A controlled study of intravenous immunoglobulin combined with prednisone in the treatment of IBM.

OBJECTIVE: To investigate whether the combination of intravenous immunoglobulin (IVIg) with prednisone improves muscle strength and alters endomysial inflammation in patients with sporadic inclusion body myositis (s-IBM). BACKGROUND: In a previous controlled trial in s-IBM, IVIg did not significantly improve strength in spite of modest benefits in some muscle groups. The possibility that prednisone may have a synergistic effect with IVIg prompted another controlled trial. METHODS: Thirty-six patients with biopsy-proven IBM were randomized to receive IVIg or placebo monthly for 3 months. Before infusions, all patients were started on high-dose prednisone for 3 months. Primary outcome measures were differences in the 1) Quantitative Muscle Strength (QMT) testing; and 2) modified Medical Research Council (MRC) scores, between the patients randomized to IVIg + prednisone compared with those randomized to placebo + prednisone. Repeated open muscle biopsies were performed at random in 24 patients to determine changes in the number of autoinvasive T cells and necrotic muscle fibers. RESULTS: Nineteen patients were randomized to IVIg + prednisone and 17 to placebo + prednisone. No significant change was noted in muscle strength, assessed by QMT and MRC, from baseline to the 2nd, 3rd, or 4th month after treatment between the two groups. The number of necrotic fibers was reduced in the IVIg randomized group (p < 0.01), and the mean number of CD2+ cells was significantly decreased in both groups (p < 0.0001), denoting a steroid effect. CONCLUSION: IVIg combined with prednisone for a 3-month period was not effective in IBM. Endomysial inflammation was significantly reduced after treatment, but the reduction was not of clinical significance.

Aged↗
PubMed2001

MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis.

The subthreshold, voltage-gated potassium channel of skeletal muscle is shown to contain MinK-related peptide 2 (MiRP2) and the pore-forming subunit Kv3.4. MiRP2-Kv3.4 channels differ from Kv3.4 channels in unitary conductance, voltage-dependent activation, recovery from inactivation, steady-state open probability, and block by a peptide toxin. Thus, MiRP2-Kv3.4 channels set resting membrane potential (RMP) and do not produce afterhyperpolarization or cumulative inactivation to limit action potential frequency. A missense mutation is identified in the gene for MiRP2 (KCNE3) in two families with periodic paralysis and found to segregate with the disease. Mutant MiRP2-Kv3.4 complexes exhibit reduced current density and diminished capacity to set RMP. Thus, MiRP2 operates with a classical potassium channel subunit to govern skeletal muscle function and pathophysiology.

Animals↗
PubMed2001

The molecular and cellular pathology of inflammatory muscle diseases.

The inflammatory muscle diseases dermatomyositis, polymyositis and inclusion body myositis are of unknown cause, but immune mechanisms are strongly implicated. Progress in the past two years has led to an improved understanding of the main molecular events involved in the immunological synapse between muscle and autoinvasive T cells. In particular, we now have a better understanding of TCR gene rearrangement in endomysial T cells, regulation of MHC expression, activity of co-stimulatory molecules, and the signalling cascades activated by cytokines, chemokines and metalloproteinases. Recent reports of an upregulation of strong anti-apoptotic molecules on the surface of muscle fibers identifies the end result of these disease processes, loss of muscle cells, as through necrosis, and not apoptosis. Such progress in molecular immunopathology has generated the interest to apply semispecific immunotherapies with the hope of halting disease progression or improving the strength of patients unresponsive to currently available non-specific immunotherapeutic interventions.

Animals↗
PubMed2001

Mitochondrial alterations with mitochondrial DNA depletion in the nerves of AIDS patients with peripheral neuropathy induced by 2'3'-dideoxycytidine (ddC).

The 2'3'-dideoxycytidine (ddC), a nonazylated dideoxynucleoside analog used for the treatment of AIDS, causes a dose-dependent, painful, sensorimotor axonal peripheral neuropathy in up to 30% of the patients. To investigate the cause of the neuropathy, we performed morphological and molecular studies on nerve biopsy specimens from well-selected patients with ddC-neuropathy and from control subjects with disease, including patients with AIDS-related neuropathy never treated with ddC. Because ddC, in vitro, inhibits the replication of mitochondrial DNA (mtDNA), we counted the number of normal and abnormal mitochondria in a 0.04 mm(2) cross-sectional area of the nerves and quantified the copy numbers of mtDNA by competitive PCR in all specimens. A varying degree of axonal degeneration was present in all nerves. Abnormal mitochondria with enlarged size, excessive vacuolization, electron-dense concentric inclusions and degenerative myelin structures were prominent in the ddC-neuropathy and accounted for 55% +/- 2.5% of all counted mitochondria in the axon and Schwann cells, compared with 9% +/- 0.7% of the controls (p < 0.001). Significantly (p < 0.005) reduced copy numbers, with as high as 80% depletion, of the mtDNA was demonstrated in the nerves of the ddC-treated patients compared with the controls. We conclude that ddC induces a mitochondrial neuropathy with depletion of the nerve's mtDNA. The findings are consistent with the ability of ddC to selectively inhibit the gamma-DNA polymerase in neuronal cell lines. Toxicity to mitochondria of the peripheral nerve is a new cause of acquired neuropathy induced by exogenous toxins and may be the cause of neuropathy associated with the other neurotoxic antiretroviral drugs or toxic-metabolic conditions.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Peripheral neuropathy and antiretroviral drugs.

Patients treated with nucleoside analogue reverse transcriptase inhibitors (NRTIs) develop a varying degree of myopathy or neuropathy after long-term therapy. Zidovudine (AZT) causes myopathy; zalcitabine (ddC), didanosine (ddl) and lamuvidine (3TC) cause neuropathy; stavudine (d4T) and fialuridine (FIAU) cause neuropathy or myopathy and lactic acidosis. The tissue distribution of phosphorylases responsible for phosphorylation of NRTIs relates to their selective tissue toxicity. The myopathy is characterized by muscle wasting, myalgia, fatigue, weakness and elevation of CK. The neuropathy is painful, sensory and axonal. In vitro, NRTIs inhibit the gamma-DNA polymerase, responsible for replication of mtDNA, and cause mtDNA dysfunction. In vivo, patients treated with AZT, the best studied NRTI, develop a mitochondrial myopathy with mtDNA depletion, deficiency of COX (complex IV), intracellular fat accumulation, high lactate production and marked phosphocreatine depletion, as determined with in vivo MRS spectroscopy, due to impaired oxidative phosphorylation. Animals or cultured cells treated with NRTIs develop neuropathy, myopathy, or cell destruction with similar changes in the mitochondria. There is evidence that the NRTI-related neuropathy is also due to mitochondrial toxicity. The NRTIs (AZT, ddC, ddl, d4T, 3TC) contain azido groups that compete with natural thymidine triphosphate as substrates of DNA pol-gamma and terminate mtDNA synthesis. In contrast, FIAU that contains 3'-OH groups serves as an alternate substrate for thymidine triphosphate with DNA pol-gamma and is incorporated into the DNA causing permanent mtDNA dysfunction. The NRTI-induced mitochondrial dysfunction has an influence on the clinical application of these agents, especially at high doses and when combined. They have produced in humans a new category of acquired mitochondrial toxins that cause clinical manifestations resembling the genetic mitochondrial disorders.

Acquired Immunodeficiency Syndrome↗