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H Reichmann

Publications and source records attributed to H Reichmann.

At least 73 records · Page 4Linked to original sources
PubMed2000

New insights into the metabolic consequences of large-scale mtDNA deletions: a quantitative analysis of biochemical, morphological, and genetic findings in human skeletal muscle.

In order to study putative genotype phenotype correlations in mitochondrial disorders due to large-scale mtDNA deletions we performed a quantitative analysis of biochemical, morphological, and genetic findings in 20 patients. The size of the mtDNA deletions varied from 2 to 7.5 kb with a degree of heteroplasmy ranging from 16% to 78%. Applying improved methods for measuring respiratory chain enzyme activities, we found highly significant inverse correlations between the percentage of cytochrome c oxidase (COX)- negative fibers and citrate synthase (CS) normalized COX ratios. Significant correlations were also established between CS normalized complex I and complex IV ratios as well as between the degree of heteroplasmy of mtDNA deletions and the percentage of ragged red fibers, COX-negative fibers, and CS normalized complex I and complex IV ratios. Our results indicate that the degree of heteroplasmy of mtDNA deletions is mirrored on the histological as well as the biochemical level. Furthermore, our findings suggest that single large-scale deletions equally influence the activities of all mitochondrially encoded respiratory chain enzymes. Even low degrees of heteroplasmy of mtDNA deletions were found to result in biochemical abnormalities indicating the absence of any well-defined mtDNA deletion threshold in skeletal muscle.

Adolescent↗
PubMed2000

Contrast-enhanced transcranial color-coded duplexsonography in stroke patients with limited bone windows.

BACKGROUND AND PURPOSE: Thickening of the temporal bone in stroke-age patients may obviate sonographic evaluation of the circle of Willis in 20% to 30% of patients. We assessed the diagnostic efficacy of contrast-enhanced transcranial color-coded duplexsonography (TCCD) for noninvasive evaluation of the circle of Willis in stroke patients with limited bone windows. METHODS: Of 171 consecutive patients who presented with ischemic symptoms in the middle cerebral artery (MCA) territory, 49 patients (32 female, 17 male; age range, 70.5+/-10.6 years) had no detectable colorflow signals from the circle of Willis by TCCD because of limited acoustic windows. These 49 patients received an IV injection of a sonographic contrast-enhancing agent, Levovist (Schering; Berlin, Germany), and were re-examined. Correlative imaging studies of the circle of Willis were obtained in 42 of 49 of these patients. RESULTS: In 38 of 49 patients, contrast-enhanced TCCD enabled full visualization of the circle of Willis bilaterally; in an additional five patients, contrast-enhanced TCCD revealed only the portion of the circle of Willis ipsilateral to the probe through one temporal bone. In six of these 43 patients, contrast-enhanced TCCD showed MCA stenosis and MCA occlusion in three; three of the six cases of MCA stenosis and all three cases of the MCA occlusion were found on the symptomatic side. In six of 49 patients, no colorflow signals were obtained after contrast enhancement. All contrast-enhanced TCCD findings were confirmed by CT angiography, transfemoral digital subtraction angiography, MR angiography, or a combination of all three correlative studies. Levovist produced no serious adverse events. CONCLUSION: In stroke-age patients with limited acoustic windows, contrast-enhancement with Levovist can markedly increase the sensitivity of TCCD and increase the detection of clinically relevant intracranial arterial disease.

Aged↗
PubMed1999

Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA.

BACKGROUND: The mitochondrial myopathies typically affect many organ systems and are associated with mutations in mitochondrial DNA (mtDNA) that are maternally inherited. However, there is also a sporadic form of mitochondrial myopathy in which exercise intolerance is the predominant symptom. We studied the biochemical and molecular characteristics of this sporadic myopathy. METHODS: We sequenced the mtDNA cytochrome b gene in blood and muscle specimens from five patients with severe exercise intolerance, lactic acidosis in the resting state (in four patients), and biochemical evidence of complex III deficiency. We compared the clinical and molecular features of these patients with those previously described in four other patients with mutations in the cytochrome b gene. RESULTS: We found a total of three different nonsense mutations (G15084A, G15168A, and G15723A), one missense mutation (G14846A), and a 24-bp deletion (from nucleotide 15498 to 15521) in the cytochrome b gene in the five patients. Each of these mutations impairs the enzymatic function of the cytochrome b protein. In these patients and those previously described, the clinical manifestations included progressive exercise intolerance, proximal limb weakness, and in some cases, attacks of myoglobinuria. There was no maternal inheritance and there were no mutations in tissues other than muscle. The absence of these findings suggests that the disorder is due to somatic mutations in myogenic stem cells after germ-layer differentiation. All the point mutations involved the substitution of adenine for guanine, but all were in different locations. CONCLUSIONS: The sporadic form of mitochondrial myopathy is associated with somatic mutations in the cytochrome b gene of mtDNA. This myopathy is one cause of the common and often elusive syndrome of exercise intolerance.

Adult↗
PubMed1999

[Gait disorders].

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Diagnosis, Differential↗
PubMed1999

[The Charcot joint].

Charcot foot in its original sense is equivalent to stage 4 of hereditary motor and sensory neuropathy (HMSN) which is known as Charcot-Marie-Tooth disease since 1886. This entity, which can be subdivided into 3 groups including subgroups, predominantly begins during childhood and progresses slowly. The first symptom, often unnoticed by the patient for a long period, is weakness of the intrinsic foot muscles with consecutive hammer-toe formation and mobile pes cavus. Progredient atrophy of the peroneal, extensor, tibialis posterior and finally triceps surae muscles leads to fixed pes cavus varus excavatus with severe varus deformity of the hindfoot, secondary varus position of the talus at the ankle level and subsequent arthrosis of the medial compartment. Permanent varus deformity of the ankle almost invariably leads to stress fractures of the malleoli because of repetitive microtrauma (stage 5 of HMSN). Early detection of the disease with nerve conduction studies at clinical suspicion allows tibialis posterior transfer, correctional osteotomy of the hindfoot or arthrodesis of Chopart's or Lisfranc's joint and can postpone or prevent the otherwise inevitable triple arthrodesis which has a less favorable long-term prognosis. At stage 4 (manifest Charcot foot) and stage 5 (neuropathic fracture of the ankle) a reorientating ankle arthrodesis is advocated, with additional subtalar pathology correctional double arthrodesis becomes necessary. In diabetic arthropathy of the ankle (Type IV according to Sanders and Frykberg), which is often referred to as "Charcot Ankle", tibiocalcanear arthrodesis is indicated. In case of supervening infection or extensive necrosis a modified Pirogoff amputation is carried out as a salvage procedure. Doubled periods of non weight-bearing, immobilization and brace protection of the ankle help to reduce the frequently observed implant failure in both forms of osteoarthropathy. In addition to stable implants retrograde calcaneotalotibial transfixation with a Steinmann pin may help to protect the achieved result despite prolonged bone consolidation.

Adult↗
PubMed1998

Mutation analysis in myophosphorylase deficiency (McArdle's disease).

Inherited deficiency of myophosphorylase leads to glycogen storage disease type V (McArdle's disease). We performed mutation analysis in 9 patients of eight unrelated families from Germany with typical clinical presentation of myophosphorylase deficiency. Beside previously described mutations we identified four novel mutations in the myophosphorylase gene. Four patients were homozygous for a nonsense mutation Arg49Stop that has been reported to be the most common mutation in white patients. Two affected siblings were compound heterozygotes for a novel missense mutation Gly685Arg and the nonsense mutation Arg49Stop. One patient carried a novel nonsense mutation Arg575Stop and a previously identified missense mutation Gly204Ser. In another patient, we identified a novel missense mutation Gln665Glu and a single-base deletion delA in Lys753. One patient of Turkish ancestry carried a newly identified homozygous A-to-G transition (ATG to GTG) abolishing the translation initiation codon of the myophosphorylase gene. These results suggest that Arg49Stop also is the most common genetic error associated with myophosphorylase deficiency in the German population. Our findings further demonstrate molecular heterogeneity of myophosphorylase deficiency among the clinically homogeneous patients we studied.

Adolescent↗
PubMed1998

[Standardized bicycle ergometry test in mitochondrial myopathies. Indications, interferences and clinical parameters].

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.

Adult↗
PubMed1998

Metabolic changes in patients with mitochondrial myopathies and effects of coenzyme Q10 therapy.

We used a standardized bicycle ergometry protocol with a stepwise increasing workload (30-100 W) to evaluate various metabolic factors for the diagnosis and metabolic monitoring of mitochondrial encephalomyopathies. All patients (n = 9) showed pathological venous lactate/pyruvate (L/P) ratios, which normalized in three patients after 6 months of coenzyme Q10 (CoQ) therapy. Thus, the L/P ratio proved to be the clinically most useful parameter in the evaluation and monitoring of mitochondrial diseases, showing higher sensitivity than lactate measurements only. CoQ may exert a favourable effect in some patients with mitochondrial diseases.

Adolescent↗
PubMed1998

Levels and proteolytic processing of chromogranin A and B and secretogranin II in cerebrospinal fluid in neurological diseases.

Human cerebrospinal fluid (CSF) contains chromogranin A and B and secretogranin II which represent peptides secreted from neuronal large dense core vesicles. Within these vesicles these precursor peptides are at least partly processed to smaller peptides. We analysed the CSF levels of chromogranins/secretogranin by radioimmunoassay using specific antisera. The degree of their processing was characterized by molecular sieve column chromatography followed by radioimmunoassay. As previously shown secretogranin II is fully processed to smaller peptides including the peptide secretoneurin, whereas processing of chromogranin A was more limited. For chromogranin B we found in this study a high degree of processing comparable to that of secretogranin II. An analysis of CSF from patients with multiple sclerosis, essential tremor, Alzheimer and Parkinson disease, did not reveal any differences in proteolytic processing of chromogranins/secretogranin when compared to control CSF. We conclude that in the four diseases investigated there is no change in the proteolytic processing of the chromogranins/secretogranin within the large dense core vesicles. The absolute levels of chromogranins/secretogranin varied in CSF collected in different hospitals, however their relative ratios were remarkable constant. We suggest to use this ratio as a parameter to standardise CSF levels of other peptides, e.g. neuropeptides. In Parkinson patients the chromogranin A/secretogranin II ratio was significantly increased whereas in Alzheimer patients and those with essential tremor and multiple sclerosis no change of the ratios was observed. Apparently there are only limited changes in the biosynthesis, processing, secretion and CSF clearance of these peptides in pathological conditions.

Adult↗
PubMed1998

Acetylcholine in human CSF: methodological considerations and levels in dementia of Alzheimer type.

Four different methods to measure acetylcholine (ACh) and choline (Ch) concentration, i.e. thermospray/mass spectroscopy (TS/MS), high pressure liquid chromatography/mass spectroscopy (HPLC/MS), high pressure liquid chromatography/electrochemical detection (HPLC/ECD) and gas chromatography/mass spectroscopy (GC/MS), both latter methods coupled to a solid phase extraction system were compared for their applicability to human lumbar cerebrospinal fluid (CSF). Furthermore, samples from 15 control persons and 11 patients with dementia of Alzheimer-type (DAT) were compared to search for an ACh deficit in the CSF in DAT. GC/MS was the most sensitive, but most laborious method, and HPLC/ECD was acceptably sensitive, reliable and more specific. TS/MS was not specific enough for CSF extracts and HPLC/MS was more specific, but far less sensitive. Thus, only GC/MS and HPLC/ECD were qualified to detect ACh in human CSF extracts. Comparison of GC/MS and HPLC/ECD revealed highly correlated levels of ACh (r = 0.999). Using HPLC/ECD, ACh concentrations were greatly reduced in the DAT group (3.75 +/- 1.40 pmol/ml CSF) as compared to the controls (6.14 +/- 1.39 pmol/ml CSF), but the difference between controls and DAT patients was not statistically significant due to the number of samples below detection limit (8 out of 11 samples in DAT, 7 out of 15 in controls). Ch concentrations were not statistically significant between the two groups. The data show that methodological limitations preclude a widespread clinical application of determining ACh in the human CSF. Despite of reductions of ACh in the CSF in DAT, the determination of Ach in the CSF is not suitable for diagnostic purposes.

Acetylcholine↗
PubMed1998

Adult-onset glycogen storage disease type II: phenotypic and allelic heterogeneity in German patients.

Glycogen storage disease type II (GSDII, Pompe's disease) is an autosomal recessive inherited deficiency of lysosomal alpha-glucosidase (GAA). Clinical as well as biochemical and allelic heterogeneity have been described in GSDII. We identified mutations within the GAA gene in seven unrelated German patients, six with adult- and one with juvenile-onset GSDII. Beside previously described mutations [IVS1 (-13T --> G), delta(exon) 18, C1634T], we characterized four new mutations of GSDII: IVS6 (-22T --> G), 271delG, G1912T (Gly638Trp), and 2432insC. The IVS6 (-22T --> G) mutation gives rise to aberrant splicing, causing inframe deletions of 25 or 40 amino acids within the GAA coding sequence and the insertion of a sequence of seven missense amino acids. Two affected siblings and an unrelated patient with adult GSDII are apparently homozygous for the exon 18 deletion. Both siblings are also heteroallelic for IVS1 (-13T --> G). In conclusion, we observed pronounced allelic heterogeneity and an unexpectedly high frequency of homozygosity for larger in-frame deletions within the GAA coding sequence in German adult-onset GSDII patients.

Adult↗
PubMed1998

Follow-up in carriers of the 'MELAS' mutation without strokes.

Eight carriers of the A3243G mutation of mitochondrial DNA without stroke-like episodes were monitored for up to 7 years in clinical and metabolic studies, by magnetic resonance imaging (MRI) and positron emission tomography (PET). None developed mitochondrial encephalopathy (MELAS), but 2 developed diabetes mellitus, 1 terminal kidney failure and 2 cardiomyopathy. One patient improved markedly under ubiquinone. Electroencephalography showed progressive slowing in 2 cases, but electrophysiological tests and MRI were otherwise noncontributary. PET showed widespread cortical and basal ganglion metabolic deficits in 6 cases. We conclude that internal medical complications are more common than MELAS in adult carriers of the mutation. PET findings, firstly reported in such patients, suggest that chronic subclinical encephalopathy is very frequent, and PET may play a role in monitoring in the future.

Adolescent↗
PubMed1997

Pathophysiology of the MELAS 3243 transition mutation.

Single base substitutions of the mitochondrial genome are associated with a variety of metabolic disorders. The myopathy, encephalopathy, lactic acidosis, stroke-like episodes syndrome, most frequently associated with an A to G transition mutation at position 3243 of the mitochondrial tRNALeu(UUR) gene, is characterized by biochemical and structural alterations of mitochondria. To investigate the pathophysiology of the mutation, we established distinct Epstein-Barr virus-transformed B-cell lines for analyses that harbored 30-70% of the mutated genome. Interestingly, neither an alteration of the processing of primary transcripts nor a general impairment of individual mitochondrial protein subunit synthesis rates could be observed. Nevertheless a marked decrease of cytochrome-c oxidase activity and reduced content of mitochondrial encoded subunits in the assembled respiratory complex IV was recorded on the cell line harboring 70% mutated mtDNA. Quantitative analysis of incorporation rates of the amino acid leucine into newly synthesized mitochondrial proteins, representing the functionality of the tRNALeu(UUR) in protein biosynthesis, revealed a specific decrease of this amino acid in distinct mitochondrial translation products. This observation was supported by a variation in the proteolytic fingerprint pattern. Our results suggest that the malfunctioning mitochondrial tRNALeu(UUR) leads to an alteration of amino acid incorporation into the mitochondrially synthesized subunits of the oxidative phosphorylation system, thus altering it's structure and function.

B-Lymphocytes↗
PubMed1997

Ophthalmoplegia plus: clinical relevance of magnetic resonance tomogaphy findings.

The diagnostic value of magnetic resonance imaging (MRI) in patients with ophthalmoplegia plus was evaluated. Twenty patients in whom the diagnosis of opthalmoplegia plus was clinically and histochemically established underwent magnetic resonance and electrophysiological studies. Three types of neuroradiological abnormalities were found in 14 patients: (1) cerebral and/or cerebellar atrophy (n = 11), (2) hyperintense lesions of the white matter or pyramidal tract (n = 2), or (3) both (n = 1). The diagnostic yield of MRI was low, since clinically or electrophysiologically manifest lesions were missed in 4 cases and the pathological findings were non-specific, since they are seen in several demyelinating diseases. Our results suggest that MRI provides no additional information in patients with manifest ophthalmoplegia plus. We conclude that clinical presentation and evidence of ragged red fibers are the cornerstones in diagnosis of ophthalmoplegia plus.

Adult↗