Patient with multiple acyl-CoA dehydrogenation deficiency disease and FLAD1 mutations benefits from riboflavin therapy.

Multiple acyl-CoA dehydrogenation deficiency is genetically heterogenous metabolic disease with mutations in genes involved in electron transfer to the mitochondrial respiratory chain. Disease symptoms vary from severe neonatal form to late-onset presentation with metabolic acidosis, lethargy, vomiting, muscle pain and weakness. Riboflavin therapy has been shown to ameliorate diseases symptoms in some of these patients. Recently, mutations in FAD synthase have been described to cause multiple acyl-CoA dehydrogenation deficiency. We describe here the effect of riboflavin supplementation therapy in a previously reported adult patient with multiple acyl-CoA dehydrogenation deficiency having compound heterozygous gene variations in FLAD1 (MIM: 610595) encoding FAD synthase. We present thorough clinical history including laboratory investigations, muscle MRI, muscle biopsy and spiroergometric analyses comprising of a follow-up of 20 years. Our data suggest that patients with adult-onset multiple acyl-CoA dehydrogenation deficiency with FLAD1 gene mutations also benefit from long-term riboflavin therapy.

ATP, phosphocreatine and lactate in exercising muscle in mitochondrial disease and McArdle's disease.

We studied exercise-induced changes in the adenosine triphosphate (ATP), phosphocreatine (PCr), and lactate levels in the skeletal muscle of mitochondrial patients and patients with McArdle's disease. Needle muscle biopsy specimens for biochemical measurement were obtained before and immediately after maximal short-term bicycle exercise test from 12 patients suffering from autosomal dominant and recessive forms of progressive external ophthalmoplegia and multiple deletions of mitochondrial DNA (adPEO, arPEO, respectively), five patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) 3243 A-->G point mutation, and four patients with McArdle's disease. Muscle ATP and PCr levels at rest or after exercise did not differ significantly from those of the controls in any patient group. In patients with mitochondrial disease, muscle lactate tended to be lower at rest and increase more during exercise than in controls, the most remarkable rise being measured in patients with adPEO with generalized muscle symptoms and in patients with MELAS point mutation. In McArdle patients, the muscle lactate level decreased during exercise. No correlation was found between the muscle ATP and PCr levels and the respiratory chain enzyme activity.

Serum concentrations of collagen degrading enzymes and their inhibitors after downhill running.

In the present study the release of proteins degrading extracellular matrix compounds to circulation was measured after damaging exercise in humans. Muscle damage was induced by downhill running; furthermore, the exercise was performed at both cold temperature (5 degrees C) and room temperature (22 degrees C) to study also the possible effect of environmental temperature on serum concentrations of matrix metalloproteinases MMP-2 and MMP-9, tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2, and MMP-2/TIMP-2 complex, and muscle damage monitored by serum creatine kinase measurements. Results were compared with those obtained from patients having rhabdomyolysis, myositis and Becker muscular dystrophy. The present study demonstrates an acute increase in serum concentrations of MMP-9, TIMP-1, and MMP-2/TIMP-2 complex, but no changes in serum MMP-2 concentrations in response to eccentric exercise. Serum creatine kinase activity data suggest greater muscle damage after downhill running in a cold environment than at room temperature. The present observations about at most slight changes in serum MMP and TIMP concentrations and lack of their correlation to increased serum creatine kinase after exercise indicate that serum measurements of MMPs and TIMPs do not sensitively respond to exercise induced skeletal muscle damage and extracellular matrix regeneration. On the other hand, severe skeletal muscle damage, such as rhabdomyolysis, myositis and Becker muscular dystrophy, seemed to have an effect on serum MMP and TIMP concentrations.

Insights into muscle diseases gained by phosphorus magnetic resonance spectroscopy.

Phosphorus magnetic resonance spectroscopy (P-MRS) has now been used in the investigation of muscle energy metabolism in health and disease for over 15 years. The present review describes the basics of the metabolic observations made by P-MRS including the assumptions and problems associated with the use of this technique. Extramuscular factors, which may affect the P-MRS results, are detailed. The important P-MRS observations in patients with mitochondrial myopathies, including the monitoring of experimental therapies, are emphasized. The findings in other metabolic myopathies (those associated with glycolytic defects or endocrine disturbances) and in the destructive myopathies (the dystrophies and the inflammatory myopathies) are also described. Observations made in normal and abnormal fatigue, fibromyalgia, and malignant hyperthermia are considered. Finally, a summary of the possible diagnostic use of P-MRS in exercise intolerance is provided.

Molecular characterization of McArdle's disease in two large Finnish families.

We have studied two large unrelated Finnish families with myophosphorylase deficiency (McArdle's disease). In one, we identified a new nonsense mutation at codon 540 in exon 14 of the myophosphorylase gene, changing an encoded glutamic acid to a stop codon (E540X). The second family carried a splice-junction mutation at the 5' splice site of intron 14 (1844+G-->A), previously reported in one Caucasian patient and in a consanguineous Druze family. These data further enlarge the list of mutations associated with McArdle's disease and establish that McArdle's disease is genetically heterogeneous also within the Finnish population.

Metabolic causes of recurrent rhabdomyolysis.

OBJECTIVES: The aim of the study was to evaluate the biochemical causes of recurrent rhabdomyolysis in Finland. MATERIAL AND METHODS: We examined 22 patients with recurrent rhabdomyolysis, and 26 patients with one episode of rhabdomyolysis or other symptoms compatible with metabolic myopathy. Muscle histopathology and activities of phosphorylase (PHRL) (total and active), phosphofructokinase (PFK), carnitine palmitoyltransferase (CPT) and myoadenylate deaminase (MAD) were studied. The limit of enzyme deficiency was defined as enzyme activity less than 5% of the mean of the control subjects. RESULTS: We found 4 patients with muscle PHRL deficiency, 1 patient with PFK deficiency and 1 patient with evidence of phosphorylase kinase deficiency. One patient had Becker's muscle dystrophy, 2 patients had unspecified dystrophies, 1 patient had Miyoshi myopathy, and 1 patient had a form of mitochondrial encephalomyopathy (MELAS). CONCLUSION: Enzyme defects were found in 23% of the patients with recurrent rhabdomyolysis. Other muscle diseases, muscular dystrophies or myopathies, were detected in 18% of these patients, emphasizing the value of clinical and histopathological examination of patients with previous rhabdomyolysis.

Antimyosin scintigraphy compared with magnetic resonance imaging in inflammatory myopathies.

OBJECTIVE: To compare indium In 111 altumomab pentetate-labeled antimyosin scintigraphy with magnetic resonance imaging (MRI) in the diagnosis and follow-up of patients with myositis. DESIGN AND METHODS: Sixteen patients with polymyositis and 1 patient with dermatomyositis, all verified with biopsy samples, were examined during diagnostic evaluation with antimyosin antibody scintigraphy and low-field MRI of the thighs and calves using T1- and T2-weighted sequences. Both examinations were repeated 6 to 22 months after therapeutic intervention with antiinflammatory drugs. The performance of the 2 methods for the assessment of the severity of muscle inflammation was evaluated using comparison with clinical examination and the serum creatine kinase level. RESULTS: At diagnosis all patients had increased uptake of antimyosin antibody in the thighs and/or calves. In T2-weighted MRI images, increased signal intensity changes reflecting intramuscular edema and inflammation were seen in all patients in at least 1 muscle group in the thighs or calves. After anti-inflammatory drug therapy, the mean uptake of antibody and the mean signal intensity changes in T2-weighted MRI had decreased. However, in T1-weighted MRI the signal intensity changes reflecting intramuscular fatty degeneration were more pronounced in the follow-up study. The level of serum creatine kinase had decreased markedly by the second examination except in 1 patient who also had more accumulation of antibody in the calves after than before treatment. The clinical condition improved in 8 patients and remained unchanged in 9 patients. CONCLUSIONS: Antimyosin scintigraphy and T2-weighted MRI are feasible tools for the detection and follow-up of lesions in patients with myositis. Scintigraphy findings correlate with serum creatine kinase activity and seem to reflect disease activity better than T2-weighted MRI changes, whereas secondary degenerative intramuscular lesions are only detectable using T1-weighted MRI.

Serum gelsolin and rhabdomyolysis.

We measured the serum gelsolin, actin-modulating protein, levels in five patients after rhabdomyolysis. We observed a tendency of serum gelsolin (83 kDa) to increase during the study period of 11 days. No intracellular gelsolin (80 kDa) was found in the serum, although it is abundant in muscle, and the destruction was severe as judged by other parameters. Serum gelsolin thus behaves differently in rhabdomyolysis than after acute tissue damage in other organs, such as liver necrosis and adult respiratory distress syndrome.

Myosin heavy-chain fragments and cardiac troponins in the serum in rhabdomyolysis. Diagnostic specificity of new biochemical markers.

BACKGROUND: Myosin is the major structural protein in muscle. Antibodies to beta-type heavy meromyosin react with cardiac and slow-twitch skeletal muscle. Cardiac TnT and TnI were developed as tissue-specific indicators. OBJECTIVES: To study myosin heavy-chain fragments as a delayed marker of previous rhabdomyolysis. To examine the cardiac specificity of cardiac troponin T (TnT) and cardiac troponin I (TnI) in patients with severe skeletal muscle damage. DESIGN AND METHODS: Serum myosin heavy-chain fragments, TnT, and TnI were studied up to 12 days after diagnosis in relationship to the serum creatine kinase level in 20 patients with rhabdomyolysis. The mean peak serum creatine kinase activity was 91,300 U/L. Myosin heavy-chain fragments were measured by an immunoradiometric assay, TnT by a one-step immunoenzymometric assay, and TnI by an immunoenzymometric assay. RESULTS: Values for serum myosin heavy-chain fragments were greater than the upper limit of normal in all patients. The peak value (70 times the upper normal limit, on average) was usually achieved 4 to 7 days after the diagnosis of rhabdomyolysis, and it was increased up to 12 days. The peak level of TnT was increased in 95% of the patients, and it correlated strongly with the peak activity of serum creatine kinase. The highest TnI value was above the detection limit of myocardial infarction in 30% of the patients. Half of these patients were the only patients with ischemic changes observed on an electrocardiogram performed on admission to the hospital. CONCLUSIONS: The measurement of myosin heavy-chain fragments was useful in the diagnosis of previous rhabdomyolysis up to 12 days. The role of TnT was negligible as an indicator of cardiac muscle damage in patients with severe rhabdomyolysis. Cardiac TnI is a more tissue-specific marker for myocardial damage even with concurrent rhabdomyolysis.

Antimyosin scintigraphy in patients with acquired and hereditary muscular disorders.

Scintigraphy with indium-111 labelled antimyosin has an established role in the evaluation of cardiac muscle damage. This antibody has been shown to cross-react with myosin in skeletal muscle. We therefore studied the usefulness of this method for the detection of skeletal muscle lesions in rhabdomyolysis, myositis and hereditary muscular dystrophies. All nine patients with rhabdomyolysis had focal uptake of antimyosin antibody which correlated with the clinical findings of soft tissue damage. However, a number of symptomless lesions were also detected by immunoscintigraphy. In rhabdomyolysis the target to non-target uptake ratios varied from 1.3 to 7.6. Diffuse uptake of antibody in skeletal muscle was observed in all three patients with polymyositis-dermatomyositis and in 12 out of 13 patients with muscular dystrophies. In myositis the intensity of antibody accumulation correlated reasonably well with the magnitude of oedema detected by magnetic resonance imaging (MRI). Most patients with Becker type or non-X-chromosomal muscular dystrophies showed slight or moderate uptake of antibody, mainly in the lower extremities. In these patients more antibody accumulated in the calves than in the thighs, whereas the findings on MRI were more prominent in the thighs than in the calves, presumably because of the better preserved muscle bulk in the calves. We conclude that antimyosin scintigraphy can be used for the detection of muscle lesions not only in acquired muscle diseases but also in hereditary muscular disorders, and that immunoscintigraphy provides information on muscle disease activity not obtainable with MRI.