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Biomedical subjects

Stephan Zierz

Publications and source records attributed to Stephan Zierz.

At least 37 records · Page 2Linked to original sources
PubMed2005

[Congenital fibrosis of extraocular muscles (CFEOM) and other phenotypes of congenital cranial dysinnervation syndromes (CCDD)].

Currently, different syndromes with congenital, nonprogressive, sporadic, or familial developmental abnormalities of the cranial nerves and its nuclei are classified as congenital cranial dysinnervation syndromes (CCDD). One of these syndromes, congenital fibrosis of extraocular muscles (CFEOM), is characterized mainly by bilateral ophthalmoplegia of the oculomotor and trochlear nerves. Within the scope of an overview, the case of a 60-year-old patient with congenital fibrosis of extraocular muscles type 1 (CFEOM1) with autosomal dominant inheritance and typical phenotype, but additional progression of the ocular symptoms, is presented. Symptoms were caused by the common C2860-->T mutation in exon 21 of the KIF21A gene on chromosome 12. Further CCDD syndromes include the following phenotypes: congenital ptosis, Duane syndrome, horizontal gaze palsy, Möbius' syndrome, and congenital facial palsy. There are 13 different known gene loci for one of these phenotypes. Five gene products have been identified: the kinesin motor protein Kif21a, the transcription factors ARIX and SALL4, and the carboxypeptidase CPAH.

Fibrosis↗
PubMed2005

Compartmentation of energy metabolism in atrial myocardium of patients undergoing cardiac surgery.

The parameters of oxidative phosphorylation and its interaction with creatine kinase (CK)- and adenylate kinase (AK)-phosphotransfer networks in situ were studied in skinned atrial fibers from 59 patients undergoing coronary artery bypass surgery, valve replacement/correction and atrial septal defect correction. In atria, the mitochondrial CK and AK are effectively coupled to oxidative phosphorylation, the MM-CK is coupled to ATPases and there exists a direct transfer of adenine nucleotides between mitochondria and ATPases. Elimination of cytoplasmic ADP with exogenous pyruvate kinase was not associated with a blockade of the stimulatory effects of creatine and AMP on respiration, neither could it abolish the coupling of MM-CK to ATPases and direct transfer of adenine nucleotides. Thus, atrial energy metabolism is compartmentalized so that mitochondria form functional complexes with adjacent ATPases. These complexes isolate a part of cellular adenine nucleotides from their cytoplasmic pool for participating in energy transfer via CK- and AK-networks, and/or direct exchange. Compared to atria in sinus rhythm, the fibrillating atria were larger and exhibited increased succinate-dependent respiration relative to glutamate-dependent respiration and augmented proton leak. Thus, alterations in mitochondrial oxidative phosphorylation may contribute to pathogenesis of atrial fibrillation.

Adenine Nucleotides↗
PubMed2005

Update on chronic progressive external ophthalmoplegia.

Mitochondrial encephalomyopathies are clinically and genetically heterogeneous disorders. External ophthalmoplegia is the most frequent symptom. Other frequently involved tissues and organs include the retina, heart, limb muscles, peripheral and central nervous system, inner ear and endocrine system. The diagnosis is based on the finding of elevated serum lactate, the characteristic histopathological changes in the muscle biopsy, and decreased activities of mitochondrial respiratory chain enzymes. In many cases, the underlying molecular defect in the mtDNA can be identified. The efficacy of pharmacological therapies (e.g., coenzyme Q) has not been established so far. Symptomatic ophthalmological treatment includes ptosis and strabismus surgery. Early cardiac pacemaker implantation may be life-saving.

Humans↗
PubMed2004

The problem of interlab variation in methods for mitochondrial disease diagnosis: enzymatic measurement of respiratory chain complexes.

Due to the large importance of mitochondrial function for numerous diseases the detection of respiratory chain defects for diagnostic purposes is an important task of mitochondrial medicine. For comparing the methods, standard mitochondrial homogenate prepared from bovine skeletal muscle was sent on dry ice to 14 labs of 8 countries. Activities of complexes I, I + III, II, II + III, IV (cytochrome c oxidase) and V (F0F1ATPase) as well as of citrate synthase were measured. For all enzymes the results differed at more than one order of magnitude. From eight labs we were able to compare the results with their control values for human skeletal muscle. Four labs found normal activity of cytochrome-c-oxidase whereas three labs found higher and one lab found lower activities compared to the own controls. Since all labs used different temperatures (25, 30 and 37 degrees C) in one lab the temperature dependencies were measured experimentally. The temperature correction did not much reduce the divergence of the results. It is concluded that differences in the lab protocols are the reason for the large variation of results. Since the experimental results strongly depend on the used method a strict standardization is necessary.

Journal Article↗
PubMed2004

Rimmed vacuoles in facioscapulohumeral muscular dystrophy: a unique ultrastructural feature.

Rimmed vacuoles (RV) are a characteristic pathological feature in inclusion body myositis, but may also occur in other neuromuscular disorders, such as distal myopathies, oculopharyngeal myopathy, polymyositis, rigid spine syndrome, congenital myopathies, and some limb girdle muscular dystrophies, as well as in various neurogenic diseases. We describe a patient with RV in familial facioscapulohumeral muscular dystrophy (FSHD) associated with an FSHD-typical deletion on chromosome 4q35. Thus, FSHD should be included in the differential diagnosis of neuromuscular disorders with RV.

Diagnosis, Differential↗
PubMed2004

Different sensitivities of CPT I and CPT II for inhibition by l-aminocarnitine in human skeletal muscle.

l-Aminocarnitine (l-AC) has been shown to inhibit carnitine palmitoyltransferases (CPT) in rat muscle and in rat liver. However, there are no reports on interactions of l-AC with CPT II and CPT I of human muscle. Therefore, the aim of the present work was to characterize the inhibition of human muscle CPT I and CPT II by l-AC in muscle mitochondria, skinned fibers and muscle homogenates in comparison to the established action of malonyl-CoA. Both isoenzymes were inhibited by l-AC, but sensitivity was different (CPT I, K(d)=3.8 mM l-AC; CPT II, K(d)=21.3 microM l-AC). A mixed inhibition type in respect to carnitine was detected (K(i)=3.5 microM l-AC). At 0.5 mM l-AC, CPT II was completely inhibited without affection of CPT I. In contrast, CPT I was completely inhibited by 0.4 mM malonyl-CoA (K(d)=0.5 microM), whereas CPT II was nearly not affected by this inhibitor. Using these inhibitors in muscle homogenates, activities of CPT II and CPT I were detected to be 38+/-10% and 63+/-10% of total, respectively (n=21). In intact mitochondria and different fractions of muscle homogenates after selective solubilization of CPT II by Tween 20, the extent of specific CPT inhibition changed in relation to the accessible isoenzyme pattern. Palmitoyl-carnitine-dependent respiration in skinned fibers was inhibited by high concentrations of l-AC, indicating that the inhibitor can be transported via the acyl-carnitine transporter, too. The combined use of both inhibitors (l-AC and malonyl-CoA) allows the kinetic characterization of CPT I and CPT II in human muscle homogenates. In addition, it has been shown that l-AC can be used for the study of metabolic consequences of CPT II deficiency on function of intact mitochondria.

Betaine↗
PubMed2004

False-positive diagnosis of a single, large-scale mitochondrial DNA deletion by Southern blot analysis: the role of neutral polymorphisms.

Single, large-scale deletions of mitochondrial DNA (mtDNA) are a common finding in the molecular investigation of patients with suspected mitochondrial disorders and are typically detected by Southern blot analysis of muscle DNA that has been linearized by a single cutter enzyme (BamHI or PvuII). We describe our investigations of a 47-year-old woman with exercise intolerance, myalgia, and ptosis who underwent a muscle biopsy for a suspected mitochondrial genetic abnormality. Southern blot analysis after digestion of muscle DNA with BamHI revealed the apparent presence of two mtDNA species, indicative of a heteroplasmic deletion of 2.0-2.5 kb in length involving approximately 50% of all molecules. Contrary to this observation, longrange polymerase chain reaction (PCR) amplified only wild-type mtDNA. Sequence analysis revealed that the patient harbored two previously recognized control region polymorphisms, a homoplasmic 16390G>A variant that introduces a new BamHI site and a heteroplasmic 16390G>A change that abolishes this site, thus explaining the initial false-positive testing for a heteroplasmic mtDNA deletion. Our findings highlight the potential problems associated with the diagnosis of mitochondrial genetic disease and emphasize the need to confirm positive cases of mtDNA deletions using more than one enzyme or an independent method such as long-range PCR amplification.

Biopsy↗
PubMed2003

Calpain inhibitor (BSF 409425) diminishes ischemia/reperfusion-induced damage of rabbit heart mitochondria.

Calpains are involved in ischemia/reperfusion-induced changes of myocard. To obtain information on the action of calpain on mitochondria, the effect of a new developed calpain inhibitor (CI) BSF 409425 on the ischemia/reperfusion-induced damage of rabbit heart mitochondria was investigated. Rabbit hearts were subjected to 45 min of global ischemia followed by 60 min of reperfusion in the presence or absence of 10nM CI. Mitochondrial properties were characterized by skinned fiber technique with pyruvate+malate as substrates. In the presence of CI, the decrease of state 3 respiration and the increase of state 4 respiration after ischemia and reperfusion were clearly smaller than without CI resulting in significantly smaller changes of respiratory control index, too. Ischemia/reperfusion-caused leaks in mitochondrial inner and outer membranes were diminished by CI. It is concluded that mitochondria are a target of calpain which reinforces the damage of oxidative phosphorylation and mitochondrial membranes during ischemia/reperfusion.

Animals↗
PubMed2003

Increased metabolic muscle fatigue is caused by some but not all mitochondrial mutations.

CONTEXT: Excessive muscle fatigue occurs in patients with a mitochondrial encephalomyopathy (MEM), but it is also a frequent problem in patients with other neuromuscular disorders (ONMD). OBJECTIVE: To determine whether, and to what extent, metabolic muscle fatigue specifically occurs in patients with an MEM. DESIGN: Metabolic muscle fatigue was assessed in a series of 21 patients with an MEM, including 13 patients with chronic progressive external ophthalmoplegia and 8 patients with various mitochondrial point mutations; 27 patients with ONMD; and 25 healthy controls. Isometric twitch force of the ankle dorsiflexors was measured after supramaximal stimulation of peroneal nerves. Six trains of stimuli (of 1 minute's duration with rates from 0.2 to 5 stimuli per second) were given to each subject. RESULTS: An abnormal decrement of the twitch amplitude that occurred during a stimulation train was found in patients with MEM and in those with ONMD. The decrement of the twitch amplitude of controls and of patients with ONMD was strongly influenced by their muscle force (P<.001). After subtraction of the influence of the muscle force, specific fatigue was notably higher in patients with chronic progressive external ophthalmoplegia than in patients with ONMD and in controls, and it correlated well with elevations of serum lactate. Specific fatigue was also abnormal in a patient with a mitochondrial G7497A mutation, but normal in patients with an A3243G or a G11778A mutation. The heteroplasmy of mitochondrial DNA in muscle correlated neither with the force measures nor with the serum lactate levels. CONCLUSIONS: Generally, metabolic muscle fatigue accompanies muscular weakness. Specifically, some but not all mitochondrial mutations cause excessive metabolic muscle fatigue.

Action Potentials↗
PubMed2003

Atypical phenotypes in patients with facioscapulohumeral muscular dystrophy 4q35 deletion.

BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is associated with a deletion on chromosome 4q35. Recent studies have shown that this deletion is found in patients with other phenotypes in addition to those with the classic Landouzy-Dejerine FSHD phenotype. OBJECTIVE: To examine patients with atypical phenotypes and an FSHD deletion on chromosome 4q35. DESIGN: Clinical characterization and genotype-phenotype correlation. SETTING: University hospital. PATIENTS: Forty-one symptomatic subjects with deletions on chromosome 4q35. RESULTS: We found 6 patients with atypical FSHD. Three (from a single family with FSHD) had additional symptoms of chronic progressive external ophthalmoplegia (4q35 EcoRI/BlnI fragment size, 20 kilobase [kb]), and 3 patients (1 with sporadic disease and 2 from a single family) had facial-sparing scapulohumeral dystrophy (4q35 EcoRI/BlnI fragment size, 30 and 34 kb, respectively). CONCLUSIONS: The clinical presentations in patients with FSHD-associated short fragments on chromosome 4q35 are not restricted to the classic FSHD form, but constitute a variety of clinical manifestations. There seems to be no clear correlation between the atypical subtype and the DNA fragment size due to the deletion.

Adolescent↗
PubMed2003

Two novel mutations in the myophosphorylase gene in a patient with McArdle disease.

We identified two novel mutations in exon 2 of the myophosphorylase gene in a 33-year-old German women with McArdle disease. The patient was compound heterozygous for a novel nonsense mutation at codon 84 changing tyrosine to stop codon (Y84X) and for a novel missense mutation at codon 93 changing arginine to tryptophan (R93W). These mutations are the first to be described in exon 2 and expand the genetic heterogeneity in patients with McArdle disease.

Adult↗
PubMed2003

Typical facioscapulohumeral dystrophy phenotype in patients without FSHD 4q35 deletion.

There have been few reports on facioscapulohumeral dystrophy (FSHD) without 4q35 deletion. Most of them had either only mild FSHD phenotype or so called "borderline" EcoRI-fragments (35-38 kb). We analysed the clinical, electrophysiological, histological and genetic features of 46 consecutive patients from 31 families with a typical FSHD phenotype. Five patients from three families were identified with unequivocal clinical features of classical Landouzy-Dejerine FSHD, in which no typical FSHD 4q35 deletion could be seen, i. e. fragment sizes were well above 40 kb. Other possible diseases with similar phenotype were excluded. The FSHD gene itself has not been identified so far. The present study suggests that the FSHD phenotype might be caused by different molecular mechanisms.

Adult↗
PubMed2003

Babinski-Nageotte's syndrome and Hemimedullary (Reinhold's) syndrome are clinically and morphologically distinct conditions.

A hemimedullary infarction, in which medial and lateral medullary lesions occur simultaneously, is a rare cerebrovascular disease. It has been suggested that the Babinski-Nageotte's syndrome is the classical brainstem syndrome that corresponds to hemimedullary lesion. In this study we compare clinical symptoms and magnetic resonance imaging (MRI) data of two patients exhibiting classical Babinski-Nageotte's syndrome according to the original description with symptoms and MRI data of a patient with clinically complete hemimedullary lesion. Our study shows that Babinski-Nageotte's syndrome is neither clinically nor on MRI identical with hemimedullary lesion. Hypoglossal palsy, an invariable symptom of hemimedullary syndrome, is not part of the Babinski-Nageotte's syndrome according to the original description. Consistent with the original historical report, Babinski- Nageotte's syndrome is a lateral "Wallenbergian" medullary lesion with a spreading of the lesion to the more basal localised pyramidal tract. The clinical features of the hemimedullary syndrome, described in 1894 by Reinhold, and the MRI appearances in our patient with this syndrome are clearly different from other classical brainstem syndromes and should be called Reinhold's syndrome.

Adult↗
PubMed2003

A novel Twinkle gene mutation in autosomal dominant progressive external ophthalmoplegia.

Autosomal dominant progressive external ophthalmoplegia is a common neurological presentation of mitochondrial disease and is characterised by multiple deletions of mitochondrial DNA in muscle. We describe a family with autosomal dominant progressive external ophthalmoplegia caused by a novel heterozygous A to C transversion at nucleotide 956 of the Twinkle gene. The deltoid muscle biopsy of the index case revealed sparse respiratory deficient cells. Multiple mitochondrial DNA deletions were clearly evident in the index case by both long-range and real-time polymerase chain reaction assays but not by Southern blotting, highlighting the diagnostic difficulties associated with characterising patients with multiple mitochondrial DNA deletions.

Adult↗
PubMed2003

A splice junction mutation in muscle carnitine palmitoyltransferase II deficiency.

We report the first splice junction mutation to be described in the carnitine palmitoyltransferase (CPT) 2 gene in a patient with the muscle form of CPT II deficiency. The patient, a 25-year-old man, suffered from attacks of myalgia and muscle weakness in early adult life. There was biochemical evidence of CPT II deficiency. Molecular genetic analysis revealed the common S113L mutation on one allele whilst a novel mutation at the splice donor junction in intron 3 was identified on the other allele. Sequencing of reverse transcription polymerase chain reaction (RT-PCR) products clearly demonstrated that this mutation causes the skipping of exon 3, thus establishing its pathogenic role.

Adult↗
PubMed2003

Therapy of neurological disorders in systemic vasculitis.

Significant progress has been made in our understanding of the underlying cellular and molecular mechanisms associated with vasculitis. Simultaneous involvement of the nervous system and systemic organs points to shared antigenic targets or immune mechanisms operative at both sites. Although specific immunotherapy is not available, the old and new immunomodulatory therapies have been instrumental in providing effective therapy in most of these chronic autoimmune disorders. The treatment of giant cell arteritis, neurosarcoidosis, Wegener's granulomatosis, systemic lupus erythematosus, polyarteritis, Sjögren's syndrome, and Behcet disease will be reviewed.

Adjuvants, Immunologic↗
PubMed2003

Absence of known familial hemiplegic migraine (FHM) mutations in the CACNA1A gene in patients with common migraine: implications for genetic testing.

Mutations in the gene CACNA1A have been known to cause familial hemiplegic migraine (FHM); it has been suggested, based on indirect genetic studies, that this gene may also be involved in common forms of migraine. To obtain data from direct gene analysis to test this hypothesis, we investigated 143 patients with common migraine, irrespective of their family history, for the presence of mutations known to result in the FHM phenotype; the mutations V714A, R192Q, R583Q, T666M, V1457L, and 11811L were absent in our patient sample. Furthermore, exons 4, 16, 17, and 36 were completely screened by single-strand conformation polymorphism (SSCP), and no other, hitherto unknown, mutations were detected. Bearing in mind that, in particular, the T666M mutation contributes to a large proportion of FHM linked to chromosome 19, we conclude that common migraine is distinct from FHM in its molecular basis and, therefore, most likely also in its pathophysiology. The possibility, however, of the existence of allelic disorders, with mutations located in other regions of the CACNA1A gene, cannot be ruled out. Molecular testing, therefore, is at present not a feasible option for the diagnosis and classification of migraine.

Calcium Channels↗