Adult-onset glycogen storage disease type 2: clinico-pathological phenotype revisited.

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.

Serum levels of matrix metalloproteinases-2 and -9 and their tissue inhibitors in inflammatory neuromuscular disorders.

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.

[Immunogenic myositis]. / Immunogene Myositiden.

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.

Prediction of response to IVIg treatment in patients with lower motor neurone disorders.

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.

[A randomized, double blind, placebo-controlled study of the efficacy and safety of tolperisone in spasticity following cerebral stroke].

To study the efficacy and safety of tolperisone--a centrally acting muscle relaxant with membrane stabilizing activity--in the treatment of stroke-related spasticity. This was a randomized, double-blind, placebo-controlled, multicenter study with parallel groups. Treatment lasted 12 weeks and was started with a titration period of variable length (dose range 300-900 mg tolperisone daily). The degree of spasticity determined on the Ashworth Scale in the most severely affected joint area was denned as primary target parameter. Hundred and twenty patients (43 females, 77 males) in a mean age of 63,3 +/- 10,6 years were recruited and received treatment. In the majority of patients both limbs of each side were affected by the spasticity which on average had been present for 3,3 +/- 4,4 years. A 62% of the patients were treated with a daily dose >600 mg tolperisone. Tolperisone reduced the mean Ashworth Score by a mean of 1,03 +/- 0,71 compared with a mean reduction of 0,47 +/- 0,54 in the placebo group (p<0,0001). A 78,3% of the patients on tolperisone versus 45% of the placebo patients experienced a reduction by at least 1 point on the Ashworth Scale (p<0,0001). Functional and overall assessments of efficacy confirmed superior efficacy of tolperisone. Adverse events occurred less often on active treatment (n=19) than on placebo (n=26) and were mostly of mild-to-moderate intensity. No withdrawals caused by adverse events were reported in the tolperisone group. The findings of the present study demonstrate the efficacy and excellent tolerance of tolperisone in the treatment of spastic hypertonia following cerebral stroke. Study data further suggest that an individual dose titration which may exceed the recommended maximum dose of 450 mg daily results in optimized therapeutic benefit.

Coenzyme Q10 deficiency and isolated myopathy.

Three unrelated, sporadic patients with muscle coenzyme Q10 (CoQ10) deficiency presented at 32, 29, and 6 years of age with proximal muscle weakness and elevated serum creatine kinase (CK) and lactate levels, but without myoglobinuria, ataxia, or seizures. Muscle biopsy showed lipid storage myopathy, combined deficiency of respiratory chain complexes I and III, and CoQ10 levels below 50% of normal. Oral high-dose CoQ10 supplementation improved muscle strength dramatically and normalized serum CK.

LGMD 2I due to the common mutation 826C>A in the FKRP gene presenting as myopathy with vacuoles and paired-helical filaments.

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.

[Lipid lowering drug and other toxic myopathies]. / Lipidsenker- und andere toxische Myopathien.

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.

A randomized, double-blind, placebo-controlled study of the efficacy and safety of tolperisone in spasticity following cerebral stroke.

To study the efficacy and safety of tolperisone - a centrally acting muscle relaxant with membrane stabilizing activity - in the treatment of stroke-related spasticity. This was a randomized, double-blind, placebo-controlled, multicenter study with parallel groups. Treatment lasted 12 weeks and was started with a titration period of variable length (dose range 300-900 mg tolperisone daily). The degree of spasticity determined on the Ashworth Scale in the most severely affected joint area was defined as primary target parameter. Hundred and twenty patients (43 females, 77 males) in a mean age of 63.3 +/- 10.6 years were recruited and received treatment. In the majority of patients both limbs of each side (right: n = 59; left: n = 56) were affected by the spasticity which on average had been present for 3.3 +/- 4.4 years. A 62% of the patients were treated with a daily dose >/=600 mg tolperisone. Tolperisone reduced the mean Ashworth Score by a mean of 1.03 +/- 0.71 compared with a mean reduction of 0.47 +/- 0.54 in the placebo group (P < 0.0001). A 78.3% of the patients on tolperisone versus 45% of the placebo patients experienced a reduction by at least 1 point on the Ashworth Scale (P < 0.0001). Functional and overall assessments of efficacy confirmed superior efficacy of tolperisone. Adverse events occurred less often on active treatment (n = 19) than on placebo (n = 26) and were mostly of mild-to-moderate intensity. No withdrawals caused by adverse events were reported in the tolperisone group. The findings of the present study demonstrate the efficacy and excellent tolerance of tolperisone in the treatment of spastic hypertonia following cerebral stroke. Study data further suggest that an individual dose titration which may exceed the recommended maximum dose of 450 mg daily results in optimized therapeutic benefit.

[Occurrence of chloroquine-induced myopathy after low-dose treatment of rheumatoid arthritis for seven years]. / Chloroquin-induzierte Myopathie. Folge einer siebenjährigen, niedrigdosierten Basistherapie bei primär-chronischer Polyarthritis.

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.

Congenital cataract, muscular hypotonia, developmental delay and sensorineural hearing loss associated with a defect in copper metabolism.

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.

Mutations in the acid alpha-glucosidase gene (M. Pompe) in a patient with an unusual phenotype.

Glycogenosis type II (Pompe disease) is a lysosomal storage disease caused by deficiency of acid alpha-glucosidase (acid maltase). The disease is autosomal recessive inherited and is clinically and genetically heterogenous. The authors describe a 30-year-old woman affected by late-onset Pompe disease with vascular affection resembling atherosclerotic angiopathy of the elderly. Genetic analysis revealed two novel mutations (Ala237Val and Gly293Arg) in the acid alpha-glucosidase gene in this patient.

Milling precision and fitting accuracy of Cerec Scan milled restorations.

The milling accuracy of the Cerec Scan system was examined under standard practice conditions. For this purpose, one and the same 3D design similar to an inlay was milled 30 times from Vita Mark II ceramic blocks. Cylindrical diamond burs with 1.2 or 1.6 mm diameter were used. Each individual milled body was measured exactly to 0.1 microm at five defined sections with a coordinate measuring instrument from the Zeiss company. In the statistical evaluation, both the different diamond bur diameters and the extent of material removal from the ceramic blank were taken into consideration; sections with large substance removal and sections with low substance removal were defined. The standard deviation for the 1.6-mm burs was clearly greater than that for the 1.2-mm burs for the section with large substance removal. This difference was significant according to the Levene test for variance equality. In sections with low substance removal, no difference between the use of the 1.6-mm or 1.2-mm bur was shown. The measuring results ranged between 0.053 and 0.14 mm. The spacing of the distances with large substance removal were larger than those with low substance removal. The T-test for paired random samples showed that the distance with large substance removal when using the 1.6-mm bur was significantly larger than the distance with low substance removal. The difference was not significant for the small burs. It was shown several times statistically that the use of the cylindrical diamond bur with 1.6-mm diameter led to greater inaccuracies than the use of the 1.2-mm cylindrical diamond bur, especially at sites with large material removal.

Detection of elevated N epsilon-carboxymethyllysine levels in muscular tissue and in serum of patients with fibromyalgia.

OBJECTIVES: To compare levels of the advanced glycation end product (AGE) N(epsilon)-carboxymethyllysine (CML) present in the muscle tissue and in the serum of patients with fibromyalgia (FM) vs. healthy controls. METHODS: The serum levels of CML were measured in 41 patients with FM and 81 healthy controls. The presence of CML, nuclear factor kappa B (NF-kappaB), the AGE receptor (RAGE), collagen types I, II, VI, and CD68-positive monocytes/macrophages in muscle tissue of 14 patients with FM was investigated by immunohistochemistry. RESULTS: Patients with FM showed significantly increased serum levels of CML in comparison to healthy controls. The immunohistochemical investigation revealed a stronger staining for CML and NF-kappaB and more CD68-positive monocytes/macrophages in the muscle of FM patients. The collagens and CML were co-localized, suggesting that the AGE modifications were related to collagen. RAGE was absent in controls but a faint and patchy staining was seen in FM. CONCLUSIONS: In the interstitial connective tissue of fibromyalgic muscles we found a more intensive staining of the AGE CML, activated NF-kappaB, and also higher CML levels in the serum of these patients compared to the controls. RAGE was only present in FM muscle. AGE modification of proteins causes reduced solubility and high resistance to proteolytic digestion of the altered proteins (e.g. AGE-modified collagens). AGEs can stimulate different types of cells by activation of the transcription factor NF-kappaB, mediated by specific receptors of AGEs (e.g. RAGE) on the cell surface. Both mechanisms may contribute to the development, perpetuation, and spreading of pain characteristic in FM patients.

[Polymyalgia rheumatica (arteritica)]. / Warnsignal Muskelschmerz: So grenzen Sie die Polymyalgia rheumatica ab.

Polymyalgia rheumatica occurs mainly in patients older than 60 years of age. Differential diagnostically, the condition can be identified on the basis of a number of laboratory parameters (ESR, CRP, CK, autoantibodies) and, if the findings are not unequivocal, the additional use of electromyography and muscle biopsy. Some 40-50% of the patients have concomitant giant cell arteritis. Treatment of polymyalgia rheumatica is glucocorticoids are applied, usually for a period of at least one year. The initial and the tapered dose is dependent on whether an associated arteritis is present.

Treatment of fibromyalgia with tropisetron--dose and efficacy correlations.

Previous studies evaluating the efficacy and tolerance of tropisetron for the treatment of fibromyalgia (FM) used the drug either intravenously or orally, and at different dosage levels ranging from 2 mg to 15 mg daily. The shortest treatment was a single dose and the longest treatment period covered 28 days. A significant reduction of the pain intensity was achieved by using tropisetron 5 mg per day. Apart from the fact that treatment periods were different, the efficacy of oral and intravenous administration did not differ significantly. Tropisetron was well tolerated; but in the 15 mg group in one of the studies, the decrease in pain was less than in the placebo group, however, the frequency of constipation and other gastrointestinal symptoms increased. Furthermore, it was hypothesized that due to the impacts of CYP2D6 activities, a daily dose of tropisetron 2 mg may be efficacious in slow metabolizers only. Although tropisetron proved to be efficacious in a group of fibromyalgia patients, the dose-response curves cannot yet be explained in a fully satisfactory manner, which may encourage research focusing on possible subgroups of FM.

Efficacy and tolerability of intravenous tropisetron in the treatment of fibromyalgia.

OBJECTIVE: To determine the efficacy of a serotonin receptor (5-HT(3)) antagonist in the treatment of fibromyalgia (FM) in a prospective, randomized, double-blind, placebo-controlled, multicentre trial. METHODS: Twenty-one female patients (age 21-63 years) with FM according to the American College of Rheumatology classification criteria for FM were assigned randomly to either a placebo group or to receive a daily intravenous bolus injection of 5 mg tropisetron for 5 days. RESULTS: In patients receiving tropisetron, the visual analogue scale (VAS) score for pain decreased by 28.9 compared with a decrease of 6.8 in the placebo group [probability (p)=0.063; effect size: 0.794]. Similar results were obtained using a body diagram pain score as a secondary efficacy parameter: mean pain reduction was 27.2 in the tropisetron group, versus 2.8 in the placebo group (p=0.038; effect size: 0.902). CONCLUSION: 5-HT(3) receptor antagonists provide significant pain relief for a group of FM patients.