ABSTRACT
The p.Thr124Met mutation in the myelin protein zero (MPZ) causes the Charcot-Marie-Tooth disease type 2J, a peripheral neuropathy with additional symptoms as pupillary alterations and deafness. It was observed in several families around the world originating e. g. from Germany, Belgium, Japan, Italy and North America. Here we report Central American patients originating from a family in Costa Rica carrying this mutation. Clinical, electrophysiological and molecular analysis of patients and controls were performed, including gene and linked markers' sequencing. Carriers share almost the entire haplotype with two non related Belgian CMT patients. As a result of the haplotype analysis, based on ten markers (seven SNPs, two microsatellites and an intronic polyA stretch), the founder effect hypothesis for this allele migration is suggestive.
Subject(s)
Charcot-Marie-Tooth Disease/genetics , Hearing Loss, Sensorineural/genetics , Myelin P0 Protein/genetics , Point Mutation/genetics , Adult , Aged , Case-Control Studies , Charcot-Marie-Tooth Disease/ethnology , Costa Rica , Female , Founder Effect , Haplotypes , Hearing Loss, Sensorineural/ethnology , Humans , Male , Middle Aged , Pedigree , Young AdultABSTRACT
Intrathecal corticosteroids, initially employed in the 1950s, faced declining use due to complications like arachnoiditis and aseptic meningitis. Triamcinolone, which is nowadays used as intrathecally applied glucocorticoid formulation, has been shown to beneficially influence spasticity without demonstrable influence on disease activity or progression. We here present the case of a patient with recurrent episodes of aseptic cerebrospinal fluid (CSF) neutrophilic pleocytosis over a year following intrathecal triamcinolone treatment. CSF analyses revealed a post-injection CSF cytokine profile resembling cytokine release reaction rather than drug hypersensitivity. This case thus highlights a potential side effect of intrathecal triamcinolone injection with yet unclear clinical relevance, underscores the need for further assessment of clinical benefits of intrathecal triamcinolone, and emphasizes potential short and long-term side effects associated with extended intrathecal triamcinolone use.
ABSTRACT
Non-systemic vasculitic neuropathy (NSVN) is routinely considered in the differential diagnosis of progressive axonal neuropathies, especially those with asymmetric or multifocal features. Diagnostic criteria for vasculitic neuropathy, classification criteria for NSVN, and therapeutic approaches to NSVN are not standardized. The aim of this guideline was to derive recommendations on the classification, diagnosis, investigation, and treatment of NSVN based on the available evidence and, where evidence was not available, expert consensus. Experts on vasculitis, vasculitic neuropathy, and methodology systematically reviewed the literature for articles addressing diagnostic issues concerning vasculitic neuropathy and NSVN as well as treatment of NSVN and the small-to-medium vessel primary systemic vasculitides using MEDLINE, EMBASE, and the Cochrane Library. The selected articles were analyzed and classified. The group initially reached consensus on a classification of vasculitides associated with neuropathy. Non-diabetic radiculoplexus neuropathy was incorporated within NSVN. The consensus definition of pathologically definite vasculitic neuropathy required that vessel wall inflammation be accompanied by vascular damage. Diagnostic criteria for pathologically probable vasculitic neuropathy included five predictors of definite vasculitic neuropathy: vascular deposits of IgM, C3, or fibrinogen by direct immunofluorescence; hemosiderin deposits; asymmetric nerve fiber loss; prominent active axonal degeneration; and myofiber necrosis, regeneration, or infarcts in peroneus brevis muscle biopsy (Good Practice Points from class II/III evidence). A case definition of clinically probable vasculitic neuropathy in patients lacking biopsy proof incorporated clinical features typical of vasculitic neuropathy: sensory or sensory-motor involvement, asymmetric/multifocal pattern, lower-limb predominance, distal-predominance, pain, acute relapsing course, and non-demyelinating electrodiagnostic features (Good Practice Points from class II/III evidence). Proposed exclusionary criteria for NSVN--favoring the alternate diagnosis of systemic vasculitic neuropathy--were clinicopathologic evidence of other-organ involvement; anti-neutrophil cytoplasmic antibody (ANCAs); cryoglobulins; sedimentation rate ≥100 mm/h; and medical condition/drug predisposing to systemic vasculitis (Good Practice Points supported by class III evidence). Three class III studies on treatment of NSVN were identified, which were insufficient to permit a level C recommendation. Therefore, the group reviewed the literature on treatment of primary small-to-medium vessel systemic vasculitides prior to deriving Good Practice Points on treatment of NSVN. Principal treatment recommendations were: (1) corticosteroid (CS) monotherapy for at least 6 months is considered first-line; (2) combination therapy should be used for rapidly progressive NSVN and patients who progress on CS monotherapy; (3) immunosuppressive options include cyclophosphamide, azathioprine, and methotrexate; (4) cyclophosphamide is indicated for severe neuropathies, generally administered in IV pulses to reduce cumulative dose and side effects; (5) in patients achieving clinical remission with combination therapy, maintenance therapy should be continued for 18-24 months with azathioprine or methotrexate; and (6) clinical trials to address all aspects of treatment are needed.
Subject(s)
Immunosuppression Therapy/methods , Peripheral Nervous System Diseases , Vasculitis/diagnosis , Evidence-Based Medicine , Humans , Peripheral Nervous System Diseases/classification , Peripheral Nervous System Diseases/complications , Peripheral Nervous System Diseases/diagnosis , Peripheral Nervous System Diseases/therapy , United States , Vasculitis/classification , Vasculitis/complications , Vasculitis/therapyABSTRACT
Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous disorder. All mendelian patterns of inheritance have been described. We identified a homozygous p.A335V mutation in the MED25 gene in an extended Costa Rican family with autosomal recessively inherited Charcot-Marie-Tooth neuropathy linked to the CMT2B2 locus in chromosome 19q13.3. MED25, also known as ARC92 and ACID1, is a subunit of the human activator-recruited cofactor (ARC), a family of large transcriptional coactivator complexes related to the yeast Mediator. MED25 was identified by virtue of functional association with the activator domains of multiple cellular and viral transcriptional activators. Its exact physiological function in transcriptional regulation remains obscure. The CMT2B2-associated missense amino acid substitution p.A335V is located in a proline-rich region with high affinity for SH3 domains of the Abelson type. The mutation causes a decrease in binding specificity leading to the recognition of a broader range of SH3 domain proteins. Furthermore, Med25 is coordinately expressed with Pmp22 gene dosage and expression in transgenic mice and rats. These results suggest a potential role of this protein in the molecular etiology of CMT2B2 and suggest a potential, more general role of MED25 in gene dosage sensitive peripheral neuropathy pathogenesis.
Subject(s)
Adaptor Proteins, Signal Transducing , Amino Acid Substitution , Cell Cycle Proteins , Charcot-Marie-Tooth Disease/genetics , Mediator Complex , Myelin Proteins , Nuclear Proteins , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adult , Amino Acid Sequence , Animals , Animals, Genetically Modified , Base Sequence , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Charcot-Marie-Tooth Disease/physiopathology , Costa Rica , DNA Mutational Analysis , Disease Models, Animal , Female , Gene Dosage , Genotype , Humans , Male , Mediator Complex/chemistry , Mediator Complex/genetics , Mediator Complex/metabolism , Mice , Models, Molecular , Molecular Sequence Data , Myelin Proteins/genetics , Myelin Proteins/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Pedigree , Protein Conformation , RatsABSTRACT
The size of the neurogenic axon reflex flare (ARFS) has been proposed to serve as a non-invasive measure of C-fiber neuropathies. This idea is based on the observation that ARFS is often reduced in patients with small-fiber neuropathies. In this study, we compared ARFS and electrically evoked axon reflex sweating with intraepidermal nerve fiber density (IENF) in patients with peripheral neuropathy in order to validate these methods against an objective standard method of diagnosing small-fiber neuropathy. ARFS was significantly correlated with IENF, while axon reflex sweating was not correlated to IENF. We conclude that measurement of ARFS is a potential objective non-invasive diagnostic tool for analysis of C-fiber function in patients with small-fiber neuropathies.
Subject(s)
Axons/physiology , Epidermis/innervation , Epidermis/physiopathology , Nerve Fibers, Unmyelinated/physiology , Reflex/physiology , Sweating/physiology , Aged , Aged, 80 and over , Biopsy , Dermis/innervation , Dermis/pathology , Dermis/physiopathology , Electric Stimulation , Epidermis/pathology , Female , Humans , In Vitro Techniques , Male , Middle Aged , Peripheral Nervous System Diseases/diagnosis , Peripheral Nervous System Diseases/pathology , Peripheral Nervous System Diseases/physiopathologyABSTRACT
OBJECTIVE: To describe the clinical, electrophysiologic and morphologic features of a Costa Rican family with an autosomal dominant inherited Charcot-Marie-Tooth (CMT) neuropathy. METHODS: The field study took place in Costa Rica, Central America. Seven patients underwent neurological examinations and standard electrodiagnostic tests, and a sural nerve biopsy was taken from one patient. Fifteen family members were screened for gene defects associated with CMT disease. RESULTS: Characteristic features of this family were a late age of onset (35-56 years), positive sensory symptoms and muscle cramps. Based on electrodiagnostic and morphologic data, the patients were classified as having a CMT2 neuropathy. The CMT1A duplication/HNPP deletion and point mutations in genes PMP22, MPZ, Cx32 and EGR2 implicated in the most common types of CMT disease were excluded. Subsequently, almost all known CMT loci were excluded by linkage analysis. DISCUSSION: Features of this family were a late age of onset and positive sensory symptoms. This new autosomal dominant CMT neuropathy is associated with an unknown gene defect.
Subject(s)
Charcot-Marie-Tooth Disease/diagnosis , Charcot-Marie-Tooth Disease/genetics , Family Health , Adult , Age of Onset , Aged , Charcot-Marie-Tooth Disease/pathology , Charcot-Marie-Tooth Disease/physiopathology , Costa Rica , Female , Genes, Dominant , Humans , Male , Middle Aged , PedigreeABSTRACT
In yeast, Tom22, the central component of the TOMM (translocase of outer mitochondrial membrane) receptor complex, is responsible for the recognition and translocation of synthesized mitochondrial precursor proteins, and its protein kinase CK2-dependent phosphorylation is mandatory for TOMM complex biogenesis and proper mitochondrial protein import. In mammals, the biological function of protein kinase CSNK2/CK2 remains vastly elusive and it is unknown whether CSNK2-dependent phosphorylation of TOMM protein subunits has a similar role as that in yeast. To address this issue, we used a skeletal muscle-specific Csnk2b/Ck2ß-conditional knockout (cKO) mouse model. Phenotypically, these skeletal muscle Csnk2b cKO mice showed reduced muscle strength and abnormal metabolic activity of mainly oxidative muscle fibers, which point towards mitochondrial dysfunction. Enzymatically, active muscle lysates from skeletal muscle Csnk2b cKO mice phosphorylate murine TOMM22, the mammalian ortholog of yeast Tom22, to a lower extent than lysates prepared from controls. Mechanistically, CSNK2-mediated phosphorylation of TOMM22 changes its binding affinity for mitochondrial precursor proteins. However, in contrast to yeast, mitochondrial protein import seems not to be affected in vitro using mitochondria isolated from muscles of skeletal muscle Csnk2b cKO mice. PINK1, a mitochondrial health sensor that undergoes constitutive import under physiological conditions, accumulates within skeletal muscle Csnk2b cKO fibers and labels abnormal mitochondria for removal by mitophagy as demonstrated by the appearance of mitochondria-containing autophagosomes through electron microscopy. Mitophagy can be normalized by either introduction of a phosphomimetic TOMM22 mutant in cultured myotubes, or by in vivo electroporation of phosphomimetic Tomm22 into muscles of mice. Importantly, transfection of the phosphomimetic Tomm22 mutant in muscle cells with ablated Csnk2b restored their oxygen consumption rate comparable to wild-type levels. In sum, our data show that mammalian CSNK2-dependent phosphorylation of TOMM22 is a critical switch for mitophagy and reveal CSNK2-dependent physiological implications on metabolism, muscle integrity and behavior.
Subject(s)
Casein Kinase II/metabolism , Mitochondria, Muscle/physiology , Mitochondrial Membrane Transport Proteins/metabolism , Mitochondrial Membranes/enzymology , Mitophagy/physiology , Muscle, Skeletal/enzymology , Animals , Autophagy , Casein Kinase II/genetics , HEK293 Cells , Humans , Mice , Mice, Knockout , Mitochondrial Precursor Protein Import Complex Proteins , Mitophagy/genetics , Models, Animal , Phosphorylation , Protein Transport , Signal TransductionABSTRACT
Molecular events that result in loss of pain perception are poorly understood in diabetic neuropathy. Our results show that the receptor for advanced glycation end products (RAGE), a receptor associated with sustained NF-kappaB activation in the diabetic microenvironment, has a central role in sensory neuronal dysfunction. In sural nerve biopsies, ligands of RAGE, the receptor itself, activated NF-kappaBp65, and IL-6 colocalized in the microvasculature of patients with diabetic neuropathy. Activation of NF-kappaB and NF-kappaB-dependent gene expression was upregulated in peripheral nerves of diabetic mice, induced by advanced glycation end products, and prevented by RAGE blockade. NF-kappaB activation was blunted in RAGE-null (RAGE(-/-)) mice compared with robust enhancement in strain-matched controls, even 6 months after diabetes induction. Loss of pain perception, indicative of long-standing diabetic neuropathy, was reversed in WT mice treated with soluble RAGE. Most importantly, loss of pain perception was largely prevented in RAGE(-/-) mice, although they were not protected from diabetes-induced loss of PGP9.5-positive plantar nerve fibers. These data demonstrate, for the first time to our knowledge, that the RAGE-NF-kappaB axis operates in diabetic neuropathy, by mediating functional sensory deficits, and that its inhibition may provide new therapeutic approaches.
Subject(s)
Diabetes Mellitus/metabolism , Immunoglobulins/metabolism , Pain , Receptors, Immunologic/metabolism , Animals , Biopsy , Blood Glucose/metabolism , Diabetic Nephropathies/metabolism , Disease Models, Animal , Female , Ganglia, Spinal/cytology , Globins/metabolism , Glycation End Products, Advanced , Humans , Immunohistochemistry , Interleukin-6/metabolism , Ligands , Male , Mice , Mice, Transgenic , NF-kappa B/metabolism , Pain Threshold , Receptor for Advanced Glycation End Products , Reverse Transcriptase Polymerase Chain Reaction , Temperature , Time Factors , Transcription Factor RelA , Up-RegulationABSTRACT
OBJECTIVES: Binding of ligands to the receptor for advanced glycation end products (RAGE) results in activation of the transcription factor NF-kappaB and subsequent expression of NF-kappaB regulated cytokines and is a possible pathomechanism in diabetic and in vasculitic polyneuropathies (PNP). We wanted to investigate whether the newly discovered RAGE pathway also contributes to the pathogenesis of various other PNP. METHODS: The presence of the RAGE ligand Nepsilon-Carboxymethyllysine (CML), the receptor itself and NF-kappaBp65 was studied in sural nerve biopsies of patients with alcohol-associated PNP (n=5), PNP owing to vitamin B12 deficiency (n=5), chronic inflammatory demyelinating PNP (CIDP, n=10), Charcot-Marie-Tooth disease (CMT) I or II (n= 10), PNP caused by monoclonal gammopathy of unknown significance (MGUS) (n=5), idiopathic PNP (n=10) and five normal controls by immunohistochemistry. Biopsies of either ten patients with diabetic and vasculitic PNP served as positive controls. RESULTS: CML, RAGE and NF-kappaBp65 were found in co-localization in epineurial vessels in PNP owing to vitamin B12 deficiency, diabetes and vasculitis and in the perineurium in diabetic PNP, vasculitic PNP and in some cases in CIDP and vitamin B12 deficiency. Only diabetic subjects demonstrated co-expression of the three antigens in endoneurial vessels. Increased CML, RAGE and NF-kappaBp65 expression was detected in endoneurial and epineurial mononuclear cells in CIDP and in vasculitic PNP. Additionally, RAGE expression in Schwann cells was significantly increased in diabetic PNP. DISCUSSION: These data suggest that activation of the RAGE pathway might contribute to the pathogenesis of CIDP, PNP owing to vitamin B12 deficiency, diabetes and vasculitis, whereas it does not seem to be involved in the pathogenesis of PNP owing to alcohol, MGUS, CMT I or II and idiopathic PNP.
Subject(s)
Peripheral Nerves/metabolism , Peripheral Nerves/physiopathology , Polyneuropathies/metabolism , Polyneuropathies/physiopathology , Receptors, Immunologic/metabolism , Signal Transduction/physiology , Aged , Alcoholism/complications , Alcoholism/metabolism , Alcoholism/physiopathology , Biomarkers/analysis , Biomarkers/metabolism , Biopsy , Diabetes Complications/complications , Diabetes Complications/metabolism , Diabetes Complications/physiopathology , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/metabolism , Lysine/analogs & derivatives , Lysine/analysis , Lysine/metabolism , Middle Aged , Peripheral Nerves/blood supply , Polyneuropathies/etiology , Predictive Value of Tests , Receptor for Advanced Glycation End Products , Receptors, Immunologic/analysis , Schwann Cells/cytology , Schwann Cells/metabolism , Sural Nerve/metabolism , Transcription Factor RelA/analysis , Transcription Factor RelA/metabolism , Vasculitis/metabolism , Vasculitis/physiopathology , Vitamin B 12 Deficiency/complications , Vitamin B 12 Deficiency/metabolism , Vitamin B 12 Deficiency/physiopathologyABSTRACT
In a double-blind, placebo-controlled trial, the effect of 75 mg of a slow-release formulation of amitriptyline on the clinical severity of chronic tension-type headache and on headache-associated neurophysiological parameters (EMG activity, exteroceptive suppression of temporal muscle activity, contingent negative variation (CNV) and experimental pain sensitivity) was investigated. All of the patients treated had a history of headaches of many years' standing and many of them had failed attempts at treatment. In the amitriptyline group, a significant reduction in daily headache duration was already found in the 3rd week of treatment, while in the placebo group no significant changes in headache duration were to be seen. In week 6 the amitriptyline group had a significantly shorter daily duration of headache than did the placebo group. Treatment did not result in any significant effects on EMG recordings of pericranial muscle activity either during relaxation or contraction, on exteroceptive suppression of the temporal muscle and on CNV. The sensitivity to suprathreshold experimental pain, however, was significantly reduced. The data show a statistically relevant reduction of daily headache duration. However, they also show that amitriptyline can only partly alleviate chronic headaches but cannot cure them.
Subject(s)
Amitriptyline/therapeutic use , Muscle, Skeletal/physiopathology , Pain Measurement/drug effects , Tension-Type Headache/drug therapy , Adult , Amitriptyline/adverse effects , Chronic Disease , Contingent Negative Variation/drug effects , Double-Blind Method , Electroencephalography/drug effects , Electromyography , Female , Humans , Male , Middle Aged , Tension-Type Headache/physiopathology , Time Factors , Treatment OutcomeABSTRACT
Charcot-Marie-Tooth disease (CMT) comprises a heterogeneous group of hereditary motor and sensory peripheral neuropathies. The autosomal recessive axonal form of CMT (ARCMT2) is rare. Eight patients of a large consanguineous family of Spanish ancestry in Costa Rica were diagnosed with ARCMT2B; previous genetic studies of this family revealed linkage to chromosome 19q13.3. The clinical and electrophysiological features of these patients are reported. All patients presented with a symmetric motor and sensory neuropathy, which was more pronounced in the lower limbs. Further, distal muscle wasting and impaired deep tendon reflexes were found. Age at onset was between 26 and 42 years, and the disease duration ranged from 2 to 19 years. Electrophysiological studies revealed a primary axonal degenerative process. The clinical characteristics of this family differed in several aspects from previously reported families with ARCMT2.
Subject(s)
Charcot-Marie-Tooth Disease/genetics , Chromosomes, Human, Pair 19 , Peripheral Nerves/physiopathology , Action Potentials/physiology , Adult , Age of Onset , Atrophy/physiopathology , Charcot-Marie-Tooth Disease/physiopathology , Chromosome Mapping , Costa Rica/ethnology , Electromyography/methods , Electrophysiology/methods , Family Health , Female , Humans , Male , Middle Aged , Muscle, Skeletal/physiopathology , Neural Conduction/physiology , Pedigree , Reaction Time/physiology , Reflex, Stretch/physiologyABSTRACT
OBJECTIVES: There is evidence of impaired cardiovascular autonomic control and reduced baroreflex sensitivity in patients with amyotrophic lateral sclerosis (ALS). A compromised baroreflex-chemoreflex interaction might result in inadequate responses to chemoreflex activation with progressive hypercapnia and hypoxia and contribute to early fatalities. This study was performed to assess cardiovascular and ventilatory responses to hypercapnic and hypoxic stimulation in ALS patients with impaired baroreflex function. PATIENTS AND METHODS: In 15 ALS patients with previously demonstrated baroreflex dysfunction and in 15 age-matched controls, we compared electrocardiographic RR-interval (RRI), systolic blood pressure (SBP) and minute ventilation (VE) during normal ventilation and during selective progressive hypoxia and hypercapnia. RESULTS: Ventilatory and RRI responses to hypoxic and hypercapnic stimulation as well as SBP responses to hypercapnia did not differ between patients and controls. In contrast, hypoxia induced a significant SBP increase in patients only. CONCLUSIONS: The normal ventilatory and RRI responses to chemoreflex activation suggest intact afferent chemoreflex function. The hypertensive response to hypoxia might be due to a compromised interaction with the baroreflex. Avoiding hypoxic episodes might reduce the risk of cardiovascular crisis in ALS patients.
Subject(s)
Amyotrophic Lateral Sclerosis/physiopathology , Blood Pressure , Hypoxia/physiopathology , Adult , Baroreflex/physiology , Carbon Dioxide/blood , Cardiovascular System/physiopathology , Case-Control Studies , Female , Humans , Hypercapnia/physiopathology , Male , Middle Aged , Oxygen/blood , Pulmonary Ventilation , Respiratory Function TestsABSTRACT
Dermatomyositis and vasculitic neuropathies are disorders with immune mediated ischemic injuries. Cellular responses to hypoxia include the hypoxia-inducible factor-1 (HIF-1)-induced transcription of genes involved in angiogenesis. To study their possible roles in those disorders, the immunohistochemical expression of HIF-1alpha, HIF-1beta, HIF-2alpha, vascular endothelial growth factor (VEGF), VEGF-receptor (VEGF-R) and erythropoietin-receptor was investigated. Cases of normal nerves, diabetic neuropathy, normal muscles, polymyositis and inclusion-body-myositis served as controls. The latter were chosen because they represent comparable inflammatory disorders, however, in these ischemia/hypoxia is not supposed to play such a prominent pathogenetic role. Hypoxia-related proteins were not detected in normal controls. In polymyositis and inclusion-body-myositis, there was VEGF-R-expression in muscle fibers and HIF-2alpha reactivity in endothelial cells. In dermatomyositis, HIF-1alpha and HIF-1beta were found in endothelial cells, whereas HIF-2alpha, erythropoietin-receptor, VEGF and VEGF-R additionally were observed in muscle fibers. In vasculitic and diabetic neuropathies, a variable focal expression of hypoxia-inducible factors, VEGF, VEGF-R and erythropoietin-receptor was seen in vessels. These observations suggest that the upregulation of hypoxia-related proteins may represent an adaptation mechanism of neuromuscular tissues to immune mediated deprivation of the blood supply.
Subject(s)
Hypoxia-Inducible Factor 1/metabolism , Microvessels/metabolism , Neuromuscular Diseases/metabolism , Neuromuscular Diseases/pathology , Adult , Aged , Aged, 80 and over , Angiogenesis Inducing Agents/metabolism , Basic Helix-Loop-Helix Transcription Factors/metabolism , Ephrin-B2/metabolism , Female , HSP70 Heat-Shock Proteins , Humans , Hypoxia-Inducible Factor 1/genetics , Male , Microvessels/pathology , Middle Aged , Neovascularization, Pathologic/etiology , Neovascularization, Pathologic/metabolism , Neuromuscular Diseases/complications , Proteins/metabolism , Receptors, Erythropoietin/metabolism , Receptors, Vascular Endothelial Growth Factor/metabolism , Up-Regulation/physiology , Vascular Endothelial Growth Factor A/metabolismABSTRACT
Neuromuscular disorders (NMD) are chronic devastating diseases. The aim of this multicenter cross-sectional study was to evaluate the socioeconomic impact of three NMDs in Germany. Patients (n = 107) with amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG) or facioscapulohumeral muscular dystrophy (FSHD) were recruited consecutively in seven centers in Germany. The health-economic data were collected using a "bottom-up" approach consisting of comprehensive questionnaires and patient diaries. Costs were evaluated from the societal perspective in 2009 Euros (EUR). Total annual costs from the societal perspective were EUR 36,380 (95% CI 27,090-47,970) per patient in ALS, EUR 26,240 (95% CI 17,770-37,940) in FSHD and EUR 14,950 (95% CI 10,470-21,730) in MG. The main components of costs were the expenditures of health insurance and the loss of productivity of patients and their caregivers. The following independent cost-driving factors were identified: disease severity, assistance in activities of daily living (ADL), dementia and younger age in ALS, disease severity in FSHD and assistance in ADL, disease severity and assistance in ADL in MG. The socioeconomic burden of NMDs in Germany is considerable. Further studies evaluating both the health-economic and clinical effects of NMD treatment as well as disease management programs and benchmarking activities are necessary.
Subject(s)
Amyotrophic Lateral Sclerosis/economics , Muscular Dystrophy, Facioscapulohumeral/economics , Myasthenia Gravis/economics , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/therapy , Cross-Sectional Studies , Dementia/economics , Female , Germany , Health Care Costs , Health Expenditures , Humans , Insurance, Health , Male , Middle Aged , Muscular Dystrophy, Facioscapulohumeral/drug therapy , Muscular Dystrophy, Facioscapulohumeral/therapy , Myasthenia Gravis/drug therapy , Myasthenia Gravis/therapy , Socioeconomic Factors , Young AdultABSTRACT
Neuromuscular disorders are rare diseases with a chronic and debilitating course. Unfortunately, data on the health-related quality of life (HRQoL) in neuromuscular diseases are limited. The objective of this multicentre cross-sectional study was to compare the HRQoL in patients with amyotrophic lateral sclerosis (ALS), facioscapulohumeral muscular dystrophy (FSHD) and myasthenia gravis (MG) and to identify the determinants of the HRQoL in these diseases. We recruited 91 consecutive outpatients with ALS (n = 37), FSHD (n = 17) or MG (n = 37) in seven specialized German health centres. The HRQoL was determined using the 36-Item Short Form Health Survey (SF-36) and the EuroQol (EQ-5D). Independent predictors of the HRQoL were identified using multiple regression analysis. The HRQoL in all domains of the SF-36, except for bodily pain, was significantly reduced. The domains related to physical health (physical functioning, physical role) were most affected. The EQ-5D-index score was most reduced in ALS (0.54) and least reduced in MG (0.89). Independent predictors of a reduced HRQoL were disease severity and depression in ALS, and disease severity, depression, older age and increased body-mass index in MG. The patterns of HRQoL-impairment in neuromuscular disorders share some common features, such as a more pronounced reduction in the HRQoL related to physical health, but there are a number of disease-specific features that should be considered in outcomes of clinical trials and treatment guidelines. In addition to the treatment of motor symptoms, greater attention should be paid to the treatment of depression, which was found to be among the independent predictors of the HRQoL in ALS and MG.
Subject(s)
Amyotrophic Lateral Sclerosis/diagnosis , Health Status , Muscular Dystrophy, Facioscapulohumeral/diagnosis , Myasthenia Gravis/diagnosis , Quality of Life , Adult , Aged , Amyotrophic Lateral Sclerosis/epidemiology , Amyotrophic Lateral Sclerosis/psychology , Comorbidity , Cross-Sectional Studies , Female , Germany/epidemiology , Humans , Male , Middle Aged , Muscular Dystrophy, Facioscapulohumeral/epidemiology , Muscular Dystrophy, Facioscapulohumeral/psychology , Myasthenia Gravis/epidemiology , Myasthenia Gravis/psychology , Predictive Value of Tests , Quality of Life/psychologyABSTRACT
The p.Thr124Met mutation in the myelin protein zero (MPZ) causes the Charcot-Marie-Tooth disease type 2J, a peripheral neuropathy with additional symptoms as pupillary alterations and deafness. It was observed in several families around the world originating e. g. from Germany, Belgium, Japan, Italy and North America. Here we report Central American patients originating from a family in Costa Rica carrying this mutation. Clinical, electrophysiological and molecular analysis of patients and controls were performed, including gene and linked markers´ sequencing. Carriers share almost the entire haplotype with two non related Belgian CMT patients. As a result of the haplotype analysis, based on ten markers (seven SNPs, two microsatellites and an intronic polyA stretch), the founder effect hypothesis for this allele migration is suggestive. Rev. Biol. Trop. 62 (4): 1285-1293. Epub 2014 December 01.
La mutación p.thr124Met en la proteína mielina cero (MPZ) causa la enfermedad de Charcot-Marie-Tooth tipo 2J, una neuropatía periférica con síntomas adicionales como alteraciones pupilares y sordera. Se ha observado en varias familias alrededor del mundo, originarias de Alemania, Bélgica, Japón, Italia y Norteamérica, entre otras. Aquí reportamos a pacientes centroamericanos provenientes de Costa Rica que acarrean esta mutación. Se realizaron análisis clínico, electrofisiológico y molecular de pacientes y controles, incluyendo secuenciación del gen y de marcadores ligados a éste. Estos pacientes comparten casi por completo el haplotipo con dos pacientes belgas no emparentados. Como resultado del análisis de los haplotipos, basado en diez marcadores (siete SNPs, dos microsatélites y un elemento poli-A intrónico), se sugiere que se ha dado un efecto fundador en la migración de este alelo.
Subject(s)
Adult , Aged , Female , Humans , Male , Middle Aged , Young Adult , Charcot-Marie-Tooth Disease/genetics , Hearing Loss, Sensorineural/genetics , Myelin P0 Protein/genetics , Point Mutation/genetics , Case-Control Studies , Costa Rica , Charcot-Marie-Tooth Disease/ethnology , Founder Effect , Haplotypes , Hearing Loss, Sensorineural/ethnology , PedigreeABSTRACT
Motoneurons release the heparansulfate proteoglycan agrin and thereby activate the muscle-specific receptor tyrosine kinase (MuSK), which is the main organizer of subsynaptic specializations at the neuromuscular junction. Recently, we showed that (1) the protein kinase CK2 interacts with the intracellular region of MuSK; (2) the CK2 protein is enriched and co-localized with MuSK at postsynaptic specializations; (3) CK2-mediated phosphorylation of serine residues within a specific MuSK epitope, named the kinase insert, regulates acetylcholine receptor (AChR) clustering; (4) muscle-specific CK2beta knockout mice develop a myasthenic phenotype due to impaired muscle endplate structure and function (see Genes Dev 20(13):1800-1816, 2006). Here, we investigated for the first time if CK2 is modulated in biopsies from human patients. To this end, we measured transcript amounts of the subunits CK2alpha and CK2beta and determined holoenzyme CK2 activity in 34 muscle biopsies of human patients with different muscle pathologies.
Subject(s)
Casein Kinase II/genetics , Casein Kinase II/metabolism , Muscles/enzymology , Muscles/pathology , Muscular Diseases/enzymology , Muscular Diseases/genetics , Tissue Extracts/metabolism , Adolescent , Adult , Aged , Animals , Biopsy , Case-Control Studies , Child , Female , Gene Expression Regulation, Enzymologic , Humans , Infant , Male , Mice , Middle Aged , Protein Subunits/genetics , Protein Subunits/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
The pathogenesis of the inflammatory myopathies is still unclear, making their treatment largely empirical. Improved understanding of the molecular mechanisms of inflammatory muscle injury may, however, lead to the development of more specific immunotherapies. To elucidate a possible pathogenic contribution of calcium-binding proteins such as the annexins, we immunohistochemically investigated muscle biopsy specimens from patients with dermatomyositis (10 cases), polymyositis (9 cases), and inclusion-body myositis (4 cases), compared to control cases comprising sarcoid myopathy (3 cases), Duchenne muscular dystrophy (DMD; 4 cases), and normal muscle (3 cases). We found expression of annexins A1, A2, A4, and A6 in the vascular endothelium of all cases. Myofibers expressed annexins A5, A6, and A7 diffusely and weakly in the cytosol, whereas annexins A5 and A7 were also particularly localized to the sarcolemma. In the inflammatory myopathies, in areas of myonecrosis in DMD, and in granulomatous lesions of sarcoid myopathy, reactivity of annexins A1, A2, A4, A5, and A6 was observed in macrophages and T-lymphocytes. Whereas the latter annexins appear to be nonspecific indicators of activation, annexin A1 upregulation may represent endogenous anti-inflammatory mechanisms that merit further investigation.
Subject(s)
Annexins/metabolism , Muscle, Skeletal/metabolism , Myositis/metabolism , Adolescent , Adult , Aged , Child , Child, Preschool , Cytosol/metabolism , Endothelium, Vascular/metabolism , Female , Humans , Immunohistochemistry , Male , Middle Aged , Muscle, Skeletal/immunology , Myositis/immunologyABSTRACT
Clinically, amyotrophic lateral sclerosis (ALS) usually presents as a pure motor system disorder, whereas oculomotor and sphincter muscle control of the anus and the bladder appear to be spared. Previously, a lacking expression of calcium binding proteins (CBPs) was demonstrated in vulnerable motor neurons in contrast to spared neuronal populations, e.g., the motor neurons of the cranial nerve III (NO) and the Onufrowicz nucleus (ON), suggesting a potential role of CBPs in the selective motoneuronal vulnerability in ALS. The annexins comprise a multigene family of CBPs, constituting a significant amount of total cellular protein and presumably involved in calcium-homeostasis and intracellular calcium-regulated pathways. We immunohistochemically investigated the expression patterns of annexins A1, A2, A4, A5, A6, and A7 in spinal cord and midbrain tissues from 24 ALS patients and 5 age-matched controls to test the hypothesis that annexins also contribute to the selective vulnerability in ALS. There was no difference in the expression patterns of ALS cases and normal controls. Annexin A1 was expressed in ependymal cells and motor neurons. Annexin A2 could be detected in ependymal and endothelial cells and motor neurons. Annexins A4 and A5 were found in both ependymal and glial cells, whereas annexin A6 was strongly expressed in motor neurons. Annexin A7 was totally absent from central nervous system tissue. A contribution of annexins to the selective vulnerability in ALS could not be derived from our results.