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Metabolic myopathies include a broad group of diseases involving inherited enzyme defects in the various metabolic pathways and skeletal musculature. They show an extensive phenotypic variability of symptoms and different ages of manifestation. Symptoms often included intolerance to duress or permanent paresis. Some forms of metabolic myopathy, in particular mitochondriopathy, are associated with multsystemic organ participation. The diagnostics must be adjusted to individual cases and carried out in stages. Primary investigations should include blood parameters (e.g. creatine kinase measurement, muscle load tests and determination of the acylcarnitine spectrum) and a second step includes muscle biopsy for histological and enzyme investigations and special molecular genetic tests although the causative enzyme defect cannot be clarified in every case. On the other hand by means of a thorough investigation it is particularly important in patients with load intolerance to differentiate between other causes, in particular psychosomatic diseases. If this is not done there is a danger of classifying the symptoms of a metabolic myopathy as a somatoform disorder. Therapy is mostly symptom-oriented as Pompe disease is the only one which can be treated with enzyme replacement therapy.

The organ most frequently affected in mitochondrial disorders is the skeletal muscle (mitochondrial myopathy). Mitochondrial myopathies may be part of syndromic as well as non-syndromic mitochondrial disorders. Involvement of the skeletal muscle may remain subclinical, may manifest as isolated elevation of the creatine-kinase, or as weakness and wasting of one or several muscle groups. The course of mitochondrial myopathies is usually slowly progressive and only rarely rapidly progressive leading to restriction of mobility and requirement of a wheel chair or even muscular respiratory insufficiency. Frequently reported symptoms of mitochondrial myopathies are permanent tiredness, easy fatigability, muscle aching at rest or already after moderate exercise, muscle cramps, muscle stiffness, fasciculations and muscle weakness. The diagnosis is based on the history, clinical neurologic examination, blood chemical investigations, lactate stress test, electromyography, magnetic resonance imaging, magnetic resonance spectroscopy, muscle biopsy, biochemical investigations of the skeletal muscles, and genetic investigations. Only symptomatic therapy is available and includes physiotherapy and orthopedic supportive devices, diet, symptomatic drug therapy (analgetics, cramp-releasing drugs, antioxidants, lactate-lowering drugs, alternative energy sources, co-factors), avoidance of mitochondrion-toxic drugs, surgery (correction of ptosis or orthopedic problems), and invasive or non-invasive mechanical ventilation. General anesthesia needs to be performed in the same way as in patients with susceptibility for malignant hyperthermia.

The term chronic progressive external ophthalmoplegia (CPEO) is not only a symptom but is also used as a syndrome within the group of mitochondrial diseases. However, the symptom CPEO might also occur in other well defined mitochondrial syndromes such as MELAS, MNGIE, SANDO. The molecular bases of the syndrome CPEO are mostly single or multiple deletions of the mtDNA, less frequently point mutations. Multiple deletions are caused by defects of nuclear encoded proteins. In this case, the mode of inheritance might be autosomal dominant or recessive. However, all these types of mtDNA mutations are not only associated with the symptom or syndrome of CPEO but might also cause other well defined mitochondrial syndromes. Thus, the diagnosis of CPEO either as a symptom or as a syndrome requires the subtle characterisation of the complete clinical phenotype as well as the precise genotype. Only on this basis a valid prognosis and information about the mode of inheritance are possible.

Metabolic disorders of energy production characterise the group of rare, mainly autosomal recessively inherited metabolic muscular diseases which are often associated with multi-systemic symptoms. In this report, an update on the clinics, pathophysiology, pathomorphology and current treatment options of metabolic myopathies will be given. Beyond classic phenotypes of these disorders, one should be aware of oligosymptomatic patients who can be easily missed. The relevant gene mutations and the pathophysiology and pathomorphology they cause are now known for almost all these metabolic diseases. Establishing the correct diagnosis has become even more important since highly specific therapy options are now available for at least some of these inherited disorders, e.g. enzyme replacement therapy in Pompe disease.

Storage disorders and neuromuscular disorders may lead to cardiac involvement which can be visualized by echocardiography. In storage disorders like hypothyroidism, haemochromatosis, amyloidosis, mucopolysaccharidosis and Fabry's disease, myocardial thickening and systolic dysfunction can be found. In amyloidosis, atrial enlargement and abnormal texture of the myocardium are additional findings. In advanced haemochromatosis all cardiac chambers may be dilated. In hypothyroidism and amyloidosis, a pericardial effusion can be present. In haemochromatosis and amyloidosis, a restrictive filling pattern may be detected using Doppler-sonography. Mucopolysaccharidosis and Gaucher's disease may lead to aortic and mitral stenosis. In neuromuscular disorders like glycogenosis, mitochondriopathy and myotonic dystrophy, myocardial thickening and systolic dysfunction are found, in spinal muscular atrophy myocardial thickening and in muscular dystrophy Becker/Duchenne systolic dysfunction. An abnormal myocardial texture may be present in glycogenosis, isolated left ventricular abnormal trabeculation (ILVAT) in mitochondriopathy, myotonic dystrophy and muscular dystrophy Becker/Duchenne. Using Doppler-sonography an impaired relaxation of the left ventricle may be detected in mitochondriopathy, myotonic dystrophy and spinal muscular atrophy. Most of these echocardiographic findings are unspecific and may be overlooked, especially if the storage or neuromuscular disorder is yet unknown. Establishing a correct diagnosis is important, since healing or functional improvement is possible in many of these disorders.

Human mitochondrial DNA (mtDNA) is a small, circular molecule, encoding for the translational machinery of the mitochondrion, as well as for 13 structural proteins that are all subunits of the respiratory chain. Point mutations, deletions, and copy-number variations are now functionally and genetically linked to human disease. Despite the fact that mtDNA is solely transmitted from the mother to the offspring, e.g. is maternally inherited, some mutations may occur spontaneously or may be acquired due to defects in nuclear DNA, e.g. are inherited in a mendelian fashion. The internist encounters predominantly myopathies, cardiomyopathies, lactic acidosis or diabetes mellitus but mtDNA-changes are also present with neurologic, hematologic and renal symptoms. Acquired mtDNA alterations are responsible for important drug side effects, such as ifosfamide, carboplatin, doxorubicin or nucleoside-analog reverse-transcriptase inhibitors. A specific mtDNA point-mutation predisposes to aminoglycoside-induced sensorineural deafness.

Cardiopulmonary exercise testing (CPX) is a non-invasive method of recording quantitative data from gas exchange and ventilation for the evaluation of oxidative metabolism at rest and during exercise. Determination of oxygen uptake (VO2) and carbon dioxide output (VCO2) describes the activity of anaerobic vs aerobic metabolism. An incremental exercise test measuring gas exchange, ventilation and lactate release was performed in healthy volunteers and in patients suffering from mitochondrial disorders. At rest as well as during exercise patients with mitochondrial disorders differ from healthy subjects with regard to gas exchange and ventilation parameters. During exercise, the decreased oxygen utilization of skeletal muscle and early activation of anaerobic metabolism in these patients are mirrored by a reduced anaerobic threshold, reduced maximal oxygen uptake and reduced oxygen pulse. Our study shows that CPX is a sensitive and practical clinical screening method of investigating mitochondrial disorders.

Exercise tests are widely used as simple, non-invasive screening methods in the differential diagnosis of metabolic myopathies. Exercise protocols have not been standardized with regard to duration of the test, workload, or monitored metabolic parameters. Potentially interfering parameters such as gender or maximal isometric force of the individuals have not been investigated. Here we describe a standardized bicycle ergometry protocol with a stepwise increasing workload between 30 and 100 watts. The venous lactate/pyruvate (L/P) ratio proved to be the one clinically most useful parameter in the functional diagnosis of mitochondrial myopathies with pathological exercise values in all nine examined patients. Additionally, the effects of coenzyme Q therapy in these patients were most clearly mirrored by changes in the L/P ratio. Nonspecifically elevated venous lactate concentrations above 5 mmol/l are rarely found in healthy female volunteers with low maximal isometric force of the M. quadriceps femoris. Other parameters such as serum free fatty acids, ketone bodies, intermediate products of the Krebs cycle or spirometric investigations add only little additional information. The exercise test described may be useful as an additional investigation in the differential diagnosis of metabolic myopathies.

Mitochondrial disease are a heterogeneous group, combining multiple symptoms resulting from defects in various organs. Thus identification of a particular mitochondrial disease due to clinical symptoms is not possible. However, simple biochemical tests can provide guiding and reliable results quickly. We present a classification of the mitochondrial diseases, describing important clinical symptoms and explaining a diagnostic plan to identify defects of biochemical mitochondrial pathways.

Defects of the mitochondrial energy production cab be expressed in many tissues and may lead to various types of diseases. Since defects can occur on many sites of the oxidative phosphorylation system, molecular diagnosis can be difficult. In typical mitochondrial syndromes, like MELAS- or MERRF-syndrome, diagnosis can be suspected already on clinical grounds. Lactate measured in various body fluids is still the best selective screening parameter. Loading tests, respectively ergometry is only necessary in the milder clinical forms of diseases or possibly in older children. The in vivo lactate determination e.g. In the CNS by 1H NMR spectroscopy can be helpful in evaluating prognosis. The diagnosis of a mitochondriopathy is usually confirmed enzymatically by tissue biopsies; skeletal muscle is still the tissue of the first choice because some enzyme deficiencies are not sufficiently expressed in cultured fibroblasts. If possible, intact mitochondria should be investigated polarografically along with histology and histochemistry. Finally several parts of the respiratory chain and pyruvate dehydrogenase complex are analyzed by single enzyme measurement. Also combined deficiencies have been described. Polypeptide subunits of respiratory chain complexes can be investigated by means of immunoblotting. The investigations of the mitochondrial DNA from the end of the diagnostic scale. The application of various new therapeutic agents, such as antioxidants, radical scavangers and cofactors have not come to any persuasive clinical result. But there is a number of reports about some successful treatment with coenzyme Q10, vitamin K3, vitamin C, riboflavin, thiamine, dichloroacetate and in PDHC -deficiency with ketogenic diet. Mitochondrial gene therapy appears only theoretical and speculative. Because of the enormous heterogeneity even on the DNA-level genetic counselling is reserved for some cases with exact molecular diagnosis.

By means of a comprehensive cardiologic examination "definite" cardiac involvement was found in 71% of patients with myotonic dystrophy (MD). In 50% of patients with Becker's muscular dystrophy (BMD) and in 70% of patients with mitochondrial myopathy (MMP). "Equivocal" cardiac involvement was found in 21% of patients with MD, in 50% of patients with BMD and in 20% of patients with MMP. The correlation between cardiac involvement and the neurological deficit was weak.

Measuring lactate during moderate exercise is a useful tool in the diagnosis of mitochondrial disorders. It was the aim of this study, to develop reference limits for lactate at rest, during exercise and after the exercise. We investigated 18 healthy subjects and 6 patients with a mitochondrial disorder. In controls, serum lactate levels were comparable to already reported findings. In 4 patients lactate levels were markedly increased during the exercise. Measurement of serum lactate is a simple and useful step in the diagnosis of mitochondrial disorders.

The mitochondrial respiratory chain, which consists of five enzyme complexes, plays a central part in cellular energy metabolism. Thirteen of the protein sub-units are encoded by the mitochondrial genome, a circular DNA molecule of about 16,500 base pairs. Knowledge of the mitochondrial genome and alterations to it is essential to reveal functional defects of the respiratory chain. Point mutations, deletions and duplications of this DNA are associated with a growing number of diseases, whose clinical presentations vary quite widely.

In the last few years morphological-cytochemical investigations and molecular genetic analysis have considerably increased the knowledge about disorders of mitochondrial functions. Molecular genetic studies have revealed that specific mutations of mitochondrial DNA are associated with specific clinical diseases and may therefore be of value in genetic counseling. Since the mitochondrial DNA is present in a high copy number in the cells a threshold exists for the biochemical manifestation of mutated mitochondrial DNA and there is no strict correlation between geno- and phenotype. Biochemical-cytochemical studies therefore are still the standard diagnostic procedures for demonstrating the clinical importance of mitochondrial mutations. During ageing similar mutations of mitochondrial DNA accumulate especially in postmitotic organs - although at a lower rate than in mitochondrial diseases - and probably contribute to the reduced organ functions in senescence.

Metabolic myopathies are subdivided into disturbances of anaerobic cytoplasmic and aerobic mitochondrial metabolism. With the exception of carnitine deficiency these myopathies are based on enzymopathies. Since gene therapy is not yet available no causal therapy is possible. This paper discusses possibilities for symptomatic therapy. Good results are found with carnitine substitution. Enzymopathies can be improved by using other metabolic pathways or by addition of co-factors of the impaired pathways. This leads to a reduction of myalgia, cramps, and endurance exercise intolerance.

Since 1983 we have been involved in the diagnostic work-up and emergency treatment of a female patient now 48 years old who has a mitochondrial myopathy resembling Luft's disease. The syndrome was first described in 1959, and in more detail in 1962, by Luft and et al., who reported a picture of hypermetabolism with high temperature, extreme sweating, tachycardia, dyspnoea at rest, polydipsia, polyphagia and irritability but normal thyroid function. In 1971 and 1976 Haydar and Di Mauro presented a second case and proposed treatment with chloramphenicol. Our patient has the third case of the syndrome reported so far: her case was initially published in 1987. CASE REPORT. Since her 17th year of life the patient had suffered from episodes of fever, tachycardia and sweating. At the age of 32 these attacks worsened, leading to unconsciousness and apnoea. The patient then had to be intubated, ventilated and sometimes resuscitated. The diagnosis of MH susceptibility and Luft's disease was made on biochemical grounds after the first muscle biopsy in 1983. Therapy with chloramphenicol failed. Therapy with beta blockers, vitamin C and K or E, coenzyme Q10 and a high-caloric diet was started in 1985. The patient was registered with an emergency service, which flew her to our ICU whenever she had a severe crisis. For milder episodes she was supplied with an oxygen breathing mask at home. Myalgia increased with the episodes starting in 1988, and the patient needed dantrolene infusions and analgesics at home. To facilitate venepuncture a Port-A-Cath system was implanted in 1987, which had to be removed four times due to infection and sepsis. A muscle biopsy was taken in Rotterdam, which revealed differences in mitochondrial function from the biochemical findings recorded in 1983 and not in keeping with Luft's disease. Unfortunately, the patient was not able to undergo further metabolic investigations or therapeutic trials. ANAESTHESIA. The patient received three local and six general anaesthetics in our clinic. The muscle biopsies, two in 1983 and one in 1985, were performed under local infiltration with procaine and were uneventful. The general anaesthetics were carried out without MH trigger substances following pretreatment with dantrolene for the following surgical procedures: the repair of an extensive arterio-venous fistula between the brachiocephalicus trunk and the right jugular and subclavian vein, revision of the sternum cerclage, implantations and explanations of infectious Port-A-Cath systems. We used etomidate, propofol and fentanyl or alfentanil with nitrous oxide and oxygen for induction and maintenance of anaesthesia. Muscle relaxation was induced with vecuronium or atracurium. All cardiovascular, respiratory, metabolic and temperature measurements stayed in normal ranges. After the extensive vascular repair (av fistula) the patient had to be mechanically ventilated for some hours until normal body temperature was restored. At the end of all other periods of anaesthesia she was extubated in the operating theatre. In five cases the postoperative period was uneventful. Only once she developed a crisis with hyperthermia, tachycardia, sweating and dyspnoea. INTENSIVE CARE. From 1985 to 1992 the patient was treated in our ICU 21 times. On 11 occasions she was already intubated and being ventilated by the emergency service on arrival. Extubation was usually possible within 2-20 h. During the crisis, heart rate was about 160-190 per minute and temperature above 40 degrees C. Serum values of CK, glucose, BUN, electrolytes, lactate and thyroid hormones were always in the normal ranges. Blood gas controls showed a constant respiratory alkalosis, arterial pCO2 values decreasing to 20 mm Hg or less. In addition to mechanical ventilation, treatment consisted in dantrolene infusions and droperidol injections, supplemented from 1989 onward with piritramide injections because of the increased severity of myalgia. In 1991 we gave propofol by