[Show abstract][Hide abstract] ABSTRACT: The need for clinical awareness and diagnostic precision of glycogen storage disease type 2 (GSD2) has increased, as enzyme replacement therapy has become available. So far, only small series have reported the muscle pathology of late-onset GSD2. We reassessed 43 muscle biopsies of 38 GSD2 patients. In all patients the diagnosis of GSD2 has been established by biochemistry and/or mutational analysis of the GAA gene. Additionally to the expected morphological features, ultrastructural analysis revealed a high incidence of autophagic vacuoles, lipofuscin debris, structural Z-line disorganization and histological neurogenic-like pattern that were not thoroughly appreciated, previously. Comparing age at onset and morphology, excessive vacuolar and autophagic myopathy and mitochondrial disorganization of virtually all fibres is common in infants. At juvenile onset, a more moderate vacuolization without significant differences in overall morphology is notable. At late-onset, the spectrum of vacuolar myopathy is more divergent, ranging from almost normal to severe. Here pronounced secondary alterations are observed that include lipofuscin debris, autophagic vacuoles with residual lysosomal bodies and granular inclusions, structural mitochondrial and Z-line texture alterations. Moreover, there is a high incidence of subtle neurogenic-like alteration in all subtypes. Nineteen patients were genetically tested; in 15 patients the common leaky splicing mutation c.-45T>G (or IVS1-13T>G) in intron1 of the GAA gene was found on at least one allele, facilitating genetic screening. In our patients, GAA genotype appears not to be associated with secondary alterations such as autophagic vacuoles, structural alterations or neurogenic-like changes. These findings may have implications for our understanding of the pathogenesis of GSD2 and for assessing therapeutic success of enzyme replacement therapy.
No preview · Article · Nov 2007 · Neuropathology and Applied Neurobiology
[Show abstract][Hide abstract] ABSTRACT: We report on two unrelated patients clinically presenting with late-onset progressive limb girdle weakness; cardiomyopathy was seen in one patient. Muscle biopsy revealed a necrotic myopathy with numerous rimmed vacuoles, ultrastructurally typical paired-helical filaments, and reduced immunohistochemical staining for alpha-dystroglycan. Quadriceps sparing hereditary inclusion body myopathy due to mutations in GNE gene, and OPMD due to PABPN1 mutations were excluded, genetically. We detected a homozygous mutation of the FKRP gene (826C>A) in both patients. Mutations of FKRP have been reported in congenital muscular dystrophies, LGMD2I, cardiomyopathy and hyperCKemia, but not in myopathies with vacuoles and paired-helical filaments. Therefore, our findings further extend the morphological variability of muscular dystrophies due to FKRP mutations.
No preview · Article · Oct 2006 · Acta myologica: myopathies and cardiomyopathies: official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases
[Show abstract][Hide abstract] ABSTRACT: Polymyositis, dermatomyositis, and inclusion body myositis are idiopathic inflammatory myopathies of unknown etiology with autoimmune pathogenesis. For choosing an individual and efficient therapy, diagnostic assignment is an important factor. Therapeutic options in dermatomyositis and polymyositis include corticosteroids and immunosuppressives. Intravenous immunoglobulins are only needed in special cases. In inclusion body myositis, corticosteroids and immunosuppressives are not successful. At the moment intravenous immunoglobulins are the only therapeutic possibility.
Preview · Article · Oct 2006 · Journal of Neurology
[Show abstract][Hide abstract] ABSTRACT: Immunogenic inflammatory myopathies are a heterogeneous group of acquired muscle disorders. Clinical and morphological characteristics are on one side muscle weakness, on the other side inflammatory infiltrates in muscle biopsy. Three main groups of different pathogenesis and course can be subdivided: The treatment of inflammatory myopathies is predominantly based on empiric data. Baseline drugs are Corticosteroids and Immunosuppressives. High dose intravenous Immunoglobulins (IVIG) are an important additional therapeutic possibility, especially in inclusion body myositis.
No preview · Article · Mar 2006 · DMW - Deutsche Medizinische Wochenschrift
[Show abstract][Hide abstract] ABSTRACT: The distinction between multifocal motor neuropathy, treatable by intravenous immunoglobulins (IVIg), and degenerative motor neurone disorders is often difficult. To find predictive factors for the response to IVIg treatment, 40 consecutive patients with pure lower motor neurone disorders (LMND) were prospectively examined. They all received at least two times IVIg (2 g/kg bodyweight). Prior to the first and before all the following treatments a standardized evaluation was performed including clinical examination, neurophysiological and laboratory evaluation. According to changes in the neurological examination and the Neuromuscular Symptom Score, the patients were divided into responders and non-responders after the second course of treatment. In our study, no single clinical, neurophysiological, or laboratory parameter was sensitive enough to predict response. The only single parameter that highly correlated with a positive response to treatment was an elevated GM1 antibody titre. Lack of response to IVIg treatment is likely in patients with generalization of electromyographic signs of denervation beyond the clinically involved site, proximal localization of the weakness, and an elevated level of the creatinekinase. Conduction blocks do not distinguish between both groups. We propose a scoring system combining clinical, serological and neurophysiological data in order to decide which patients with LMND may receive IVIg.
No preview · Article · Mar 2006 · European Journal of Neurology
[Show abstract][Hide abstract] ABSTRACT: We monitored serum levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) before and during intravenously applied immunoglobulin (IVIG) therapy in 33 patients with chronic immune-mediated neuropathies and myopathies and 15 controls. Baseline MMP-2 and TIMP-2 serum levels were lower and MMP-9 and TIMP-1 serum levels higher in all patients compared to age-matched controls. Eight days after IVIG treatment, MMP-2, TIMP-2, and TIMP-1 serum levels increased, while MMP-9 serum levels decreased, indicating tissue repair. After 60 days, MMP-9 levels increased, MMP-2 approached normal levels, while TIMP-1 and TIMP-2 serum levels were below day 8 levels, indicating relapsing tissue damage. Comparing the MMP/TIMP results with the clinical courses, IVIG treatment tended to change MMP/TIMP levels in a way that paralleled clinical improvement and relapse. In sum, during a distinct time period, IVIG therapy seems to be able to modulate MMP-mediated tissue repair.
No preview · Article · Feb 2006 · European Neurology
[Show abstract][Hide abstract] ABSTRACT: Idiopathic CK-elevation is an exclusion diagnosis. In any case a careful investigation is necessary to diagnose an asymptomatic neuromuscular disorder which has consequences for the further life of the patient. The possibility of a susceptibility to malignant hyperthermia has to be considered.
[Show abstract][Hide abstract] ABSTRACT: A growing number of therapeutic agents and exogenous toxins are harmful to structure and function of human skeletal muscle. The clinical syndrome encompasses asymptomatic creatine kinase elevation, myalgia, exercise intolerance, muscle paresis and atrophy, and lastly acute rhabdomyolysis. Toxic myopathies are potentially reversible, hence a prompt recognition is particularly helpful for the early diagnosis and in conclusion elimination of a myopathy inducing toxin. Toxic myopathies may be classified as acute or chronic accordingly to the exposition time to a toxin. Main source of an exogenous induced toxic myopathy is chronic alcohol abuse. Alcohol excess induces acute and/or chronic neuropathy and myopathy, consequently muscle wasting and weakness occurs. Drug-induced myopathies are most frequently seen due to amplified utilization of corticosteroids or lipid lowering agents.
[Show abstract][Hide abstract] ABSTRACT: Eine zunehmende Anzahl von therapeutisch eingesetzten Substanzen und exogenen Toxinen führt zu strukturellen und funktionellen Veränderungen der Skelettmuskulatur. Das klinische Syndrom toxischer Myopathien variiert von symptomfreier Kreatinkinaseerhöhung über Muskelschmerzen mit Belastungsinsuffizienz, Schwäche und Atrophie bis hin zur akuten Rhabdomyolyse. Aufgrund der potenziellen Reversibilität einer toxischen Myopathie sollte der kausale Zusammenhang möglichst rasch erkannt werden und dann die Diagnosestellung und Elimination der Noxe erfolgen. Häufigste Ursache einer exogenen toxischen Myopathie ist die Alkoholkrankheit, die sowohl zu akuten als auch chronischen Neuropathien und Myopathien mit konsekutiver Muskelatrophie führt. Unter den medikamentös induzierten Myopathien hat neben der steroidinduzierten Myopathie zurzeit die durch Lipidsenker ausgelöste Myopathie die höchste Relevanz.
[Show abstract][Hide abstract] ABSTRACT: The myotoxicity of chloroquine and hydroxychloroquine has been known for decades. Limb-girdle weakness due to a vacuolar myopathy may occur occasionally in a dose-dependent manner during the first 24 months on chloroquine. However, we report on a case in which muscular weakness developed after a daily intake of 250 chloroquine phosphate (= 155 mg chloroquine base) for a period of 7 years. Even after long-term and apparently well-tolerated chloroquine treatment, the occurrence of severe side-effects is possible.
No preview · Article · Jun 2005 · Zeitschrift für Rheumatologie
[Show abstract][Hide abstract] ABSTRACT: Die Myotoxizitt von Chloroquin und Hydroxychloroquin ist langjhrig bekannt. blicherweise kann es dosisabhngig in den ersten 24 Monaten der Medikation zur Entwicklung einer Gliedergrtelschwche im Rahmen einer vakuolren Myopathie kommen. Wir berichten ber einen Fall mit Ausbildung einer Muskelschwche nach siebenjhriger Einnahme von tglich 250 mg Chloroquinphosphat (=155 mg Chloroquinbase). Auch nach langjhriger, scheinbar gut vertragener Chloroquinmedikation muss auf die Ausbildung relevanter Nebenwirkungen geachtet werden.The myotoxicity of chloroquine and hydroxychloroquine has been known for decades. Limb-girdle weakness due to a vacuolar myopathy may occur occasionally in a dose-dependent manner during the first 24 months on chloroquine. However, we report on a case in which muscular weakness developed after a daily intake of 250 chloroquine phosphate (= 155 mg chloroquine base) for a period of 7 years. Even after long-term and apparently well-tolerated chloroquine treatment, the occurrence of severe side-effects is possible.
No preview · Article · Apr 2005 · Zeitschrift für Rheumatologie
[Show abstract][Hide abstract] ABSTRACT: Deficiencies of different proteins involved in copper metabolism have been reported to cause human diseases. Well-known syndromes, for example, are Menkes and Wilson diseases. Here we report a patient presenting with congenital cataract, severe muscular hypotonia, developmental delay, sensorineural hearing loss and cytochrome-c oxidase deficiency with repeatedly low copper and ceruloplasmin levels. These findings were suggestive of a copper metabolism disorder. In support of this, the patient's fibroblasts showed an increased copper uptake with normal retention. Detailed follow-up examinations were performed. Immunoblotting for several proteins including ATP7A (MNK or Menkes protein), ATP7B (Wilson protein) and SOD1 showed normal results, implying a copper metabolism defect other than Wilson or Menkes disease. Sequence analysis of ATOX1 and genes coding for proteins that are known to play a role in the mitochondrial copper metabolism (COI-III, SCO1, SCO2, COX11, COX17, COX19) revealed no mutations. Additional disease genes that have been associated with cytochrome-c oxidase deficiency were negative for mutations as well. As beneficial effects of copper histidinate supplementation have been reported in selected disorders of copper metabolism presenting with low serum copper and ceruloplasmin levels, we initiated a copper histidinate supplementation. Remarkable improvement of clinical symptoms was observed, with complete restoration of cytochrome-c oxidase activity in skeletal muscle.
Full-text · Article · Feb 2005 · Journal of Inherited Metabolic Disease
[Show abstract][Hide abstract] ABSTRACT: Biopsies of skeletal muscles and nerves are important diagnostic procedures in recognising a neuromuscular disease. As biopsies are invasive procedures, they deserve special attention and should not necessarily be performed, for instance, when non-invasive procedures will yield the same diagnostic results, because these biopsies aim at purely diagnostic not curative results. This paper describes the diagnostic significance of muscle and nerve biopsies concerning different forms of neuromuscular disorders, provides advice for surgical removal and subsequent preparative methods according to modern diagnostic myopathological and neuropathological standards. It is of utmost importance that performing a biopsy and preparing the tissues is only in the hands of well-experienced physicians to guarantee optimal diagnostic benefit to the patient.
[Show abstract][Hide abstract] ABSTRACT: Myalgia is a common non specific symptom associated with a variety of neurological and other diseases. Often muscle pain is not caused by direct damage of the skeletal muscle itself, but is rather a non specific accompanying feature of different diseases. Still, disorders of the skeletal muscle must be considered to provide adequate counselling and therapy for these patients. Here we summarise myopathies and other disorders not due to primary damage of the skeletal muscle in the context of the differential diagnosis of muscle pain.
[Show abstract][Hide abstract] ABSTRACT: Localized or generalized muscle pain is a common symptom associated with a variety of neurological and other diseases. The etiologic differentiation of myalgias is based on history and clinical findings and may include further diagnostic investigations. Here we present current diagnostic possibilities including an algorithm for an efficient approach to the diagnosis of myalgias.