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Biomedical subjects

Marcus Deschauer

Publications and source records attributed to Marcus Deschauer.

At least 19 recordsLinked to original sources
PubMed2006

Depletion of mitochondrial DNA in leucocytes harbouring the 3243A->G mtDNA mutation.

BACKGROUND: The 3243A-->G MTTL1 mutation is the most common heteroplasmic mitochondrial DNA (mtDNA) mutation associated with disease. Previous studies have shown that the percentage of mutated mtDNA decreases in blood as patients get older, but the mechanisms behind this remain unclear. OBJECTIVES AND METHOD: To understand the dynamics of the process and the underlying mechanisms, an accurate fluorescent assay was established for 3243A-->G heteroplasmy and the amount of mtDNA in blood with real-time polymerase chain reaction was determined. The amount of mutated and wild-type mtDNA was measured at two time points in 11 subjects. RESULTS: The percentage of mutated mtDNA decreases exponentially during life, and peripheral blood leucocytes in patients harbouring 3243A-->G are profoundly depleted of mtDNA. CONCLUSIONS: A similar decrease in mtDNA has been seen in other mitochondrial disorders, and in 3243A-->G cell lines in culture, indicating that depletion of mtDNA may be a common secondary phenomenon in several mitochondrial diseases. Depletion of mtDNA is not always due to mutation of a nuclear gene involved in mtDNA maintenance.

Adult↗
PubMed2006

Lactate production upon short-term non-ischemic forearm exercise in mitochondrial disorders and other myopathies.

BACKGROUND: The nonischemic forearm exercise test (NIFET) has been shown to be as effective as the classic ischemic forearm exercise test (IFET) in the diagnosis of patients with McArdle disease. Recently, the lactate increase normalized to the mechanical energy production in NIFET was suggested to have a intermediate sensitivity and satisfactory specifity for the screening of mitochondrial disorders. METHODS: NIFET at 80% maximal contraction force (MCF) was performed in normal controls (n = 41), patients with mitochondrial disorders (n = 15) and other myopathies (diseased controls, n = 20). 26 healthy volunteers also underwent IFET at 80% MCF. The ratio of lactate increase and workload was defined as specific lactate production (mmol x s/N x l). RESULTS: In normal controls there was no significant different lactate increase during NIFET and IFET. The workload performed showed only a weak significant positive correlation with the lactate increase in the NIFET in normal controls (r(2) = 0.20) but not in IFET and NIFET with patients. A moderate negative correlation of specific lactate production and the absolute workload was found in all groups and in both protocols (r(2) = 0.22-0.34). The specific lactate production was highest in patients with other myopathies, intermediate in patients with mitochondrial disorders and lowest in normal controls. NIFET showed a sensitivity of only 20 % and a specifity of 95% for normal controls, but only 75 % for diseased controls. CONCLUSION: The specific lactate production during NIFET is neither sufficiently specific nor sensitive for the diagnosis of mitochondrial disorders. Increased specific lactate production during rest-to-work transition period might be caused by increased acetyl group deficits.

Adolescent↗
PubMed2006

Lactate increase and oxygen desaturation in mitochondrial disorders--evaluation of two diagnostic screening protocols.

BACKGROUND: Mitochondrial disorders are characterized by an accumulation of lactate and an insufficient oxygen extraction from blood during exercise. Therefore, both parameters (lactate and oxygen saturation) can be used as screening tests in mitochondrial disorders. However, conflicting results regarding sensitivities and specifities of both tests have been reported. METHOD: We examined 27 patients with genetically defined mitochondrial disorders (single deletions n = 15, multiple deletions n = 5, A3243G mutation n = 7), patients with other neuromuscular disorders, and healthy controls. In the first test subjects performed intermittent isometric handgrip exercise (0.5 Hz) at 80% (3 minutes) and 30% (3 and 15 minutes) of maximal contraction force (MCF). Oxygen saturation and partial pressure in cubital venous blood from the exercising arm were measured. In the second test subjects underwent cycle ergometry at 30 W for 15 minutes. Venous lactate at rest, during and 15 minutes postexercise was determined. RESULT: Both tests showed specificities of 92-96%. Sensitivities for changes of venous oxygen partial pressure and oxygen saturation ranged from 21-26% at 80% MCF for 3 minutes to 47-58% at 30% MCF for 15 minutes. Sensitivities for venous resting, peak, and post-exercise lactate was 33%, 58%, and 67%, respectively. The degree of deoxygenation, however,was independent of the intensity and duration of the applied forces. Oxygen desaturation and lactate increase in patients with mitochondrial disorders were not different in patients with and without clinical symptoms of myopathy. There were significant correlations between the heteroplasmy and both the degree of oxygen desaturation and lactate increase in patients with single deletions. In patients who performed both protocols (n = 16) a combination of both tests increased sensitivity up to 87%. CONCLUSION: Oxygen desaturation in forearm exercise tests and lactate increase in cycle ergometry tests show a high specifity but only moderate sensitivity. Combination of the two screening test clearly increases the sensitivity.

Adolescent↗
PubMed2006

Novel mitochondrial transfer RNA(Phe) gene mutation associated with late-onset neuromuscular disease.

BACKGROUND: An extensive range of molecular defects have been identified in the human mitochondrial genome (mitochondrial DNA); many are associated with well-characterized, progressive neurological syndromes, but a minority of patients have uncharacteristic phenotypes in which symptoms may be relatively mild. OBJECTIVE: To describe a novel transfer RNA(Phe) mutation of mitochondrial DNA in a late-onset case with a mild phenotype of mitochondrial disease. DESIGN: Case report. PATIENT: A 66-year-old woman presented with a 4-year history of walking difficulties due to exercise intolerance and paresthesia in the feet. Clinical examination results were normal. Her deceased mother had similar walking difficulties, but her sister and 2 children were unaffected. RESULTS: The demonstration of a marked histochemical defect in cytochrome c oxidase activity on muscle biopsy prompted molecular investigation of mitochondrial DNA, revealing a novel maternally inherited mutation in the variable loop of the mitochondrial transfer RNA(Phe) gene. This 622G>A transition was heteroplasmic and segregated with cytochrome c oxidase deficiency in single fibers. CONCLUSION: This case serves to illustrate that primary defects of the mitochondrial genome should be considered even in older patients with late-onset, mild neuromuscular symptoms.

Age of Onset↗
PubMed2006

Successful treatment of MuSK antibody-positive myasthenia gravis with rituximab.

We report on a 56-year-old woman with muscle-specific receptor tyrosine kinase (MuSK) antibody-positive myasthenia with predominant bulbar symptoms and respiratory insufficiency. Conventional immunosuppression (prednisolone, azathioprine, mycophenolate mofetil) could not maintain the clinical improvement initially achieved by repeated plasma exchanges. Therefore, treatment with rituximab was initiated. After 2 months of rituximab treatment, remarkable clinical improvement correlating with a reduction of MuSK serum antibodies was seen. The patient continued to remain stable 12 months after initiation of therapy. This case report demonstrates that rituximab may be an effective and tolerable treatment in MuSK antibody-positive myasthenia gravis.

Adrenal Cortex Hormones↗
PubMed2005

Late-onset mitochondrial myopathy with dystrophic changes due to a G7497A mutation in the mitochondrial tRNA(Ser(UCN)) gene.

Mutations of mitochondrial tRNA genes are usually associated with multi-systemic disorders with onset of symptoms in childhood or early adulthood. Dystrophic myopathic changes are not typical features of these disorders. We report two siblings with a severe progressive myopathy of late onset without external ophthalmoplegia and without involvement of the central and peripheral nervous system. Muscle biopsy specimens showed severe myopathic changes similar to those found in muscular dystrophies. Molecular analysis revealed a G7497A mutation in the mitochondrial tRNA(Ser(UCN)) gene. In both patients, the proportion of mutated mitochondrial DNA in muscle was more than 97%. Mitochondrial disorder associated with the G7497A mutation has to be included into the differential diagnosis of severe progressive late-onset myopathy with histopathological dystrophic myopathic changes. Mitochondrial myopathy and high level of mutated mtDNA might be a characteristic of the G7497A tRNA(Ser(UCN)) mutation.

Adult↗
PubMed2005

Mitochondrial changes in skeletal muscle in amyotrophic lateral sclerosis and other neurogenic atrophies.

Previous findings suggested specific mitochondrial dysfunction in skeletal muscle of patients with amyotrophic lateral sclerosis (ALS). To answer the question of whether the dysfunction is specific, we investigated the histochemical distribution of mitochondrial marker activities, the ratio of mitochondrial (mt) versus nuclear (n) DNA, and the activities of citrate synthase (CS) and respiratory chain enzymes in muscle biopsies of 24 patients with sporadic ALS. The data were compared with those in 23 patients with other neurogenic atrophies (NAs), and 21 healthy controls. Muscle histology revealed similar signs of focally diminished mitochondrial oxidation activity in muscle fibres in both diseased groups. There was only minimal decline of mt/nDNA ratios in ALS and NA patients in comparison with healthy controls. The specific activities of mitochondrial markers CS and succinate dehydrogenase were significantly increased in both ALS and NA patients. The specific activities of respiratory chain enzymes were not significantly different in all three groups. It is concluded that the histochemical, biochemical and molecular mitochondrial changes in muscle are not specific for ALS, but accompany other NAs as well.

Adult↗
PubMed2005

A novel ANT1 gene mutation with probable germline mosaicism in autosomal dominant progressive external ophthalmoplegia.

Only four different mutations in the adenine nucleotide translocator 1 (ANT1) gene have been found in families with progressive external ophthalmoplegia (PEO). We report a novel heterozygous C to A transversion at nucleotide 269 in the ANT1 gene in a German family with PEO, predicted to convert a highly conserved alanine at codon 90 to aspartic acid. The mutation was identified in three siblings with PEO, one of them additionally suffered from schizoaffective disorder. Microsatellite analysis showed that the mutation was dominant and inherited from the mother who did not carry the mutation in blood, indicating germ-line mosaicism.

Adenine Nucleotide Translocator 1↗
PubMed2005

Muscle carnitine palmitoyltransferase II deficiency: clinical and molecular genetic features and diagnostic aspects.

Muscle carnitine palmitoyltransferase (CPT) II deficiency is an autosomal recessive disorder of fatty acid oxidation characterized by attacks of myalgia and myoglobinuria. This review summarizes the clinical features of this disease, analyzing data of 28 patients with biochemically and genetically confirmed CPT II deficiency. The review shows that exercise-induced myalgia is the most frequent symptom, whereas myoglobinuria, known as the clinical hallmark, is missing in 21% of the patients. Typically, myalgia starts in childhood, whereas attacks with myoglobinuria mostly emerge in adolescence or early adulthood. However, there are also patients with only myalgia, patients with attacks triggered by factors other than exercise, and patients with late-onset disease. Molecular or biochemical analysis is necessary for diagnosis, since no myopathologic hallmark exists. For screening patients, analysis of not only the common S113L mutation but also the P50H and Q413fs-F448L mutations is recommended. The phenotype of muscle CPT II deficiency might be influenced by the underlying mutation, and patients with a truncating mutation on 1 allele might be affected more severely.

Adolescent↗
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

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

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

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↗
PubMed2002

Mitochondrial respiratory rates and activities of respiratory chain complexes correlate linearly with heteroplasmy of deleted mtDNA without threshold and independently of deletion size.

To clarify the importance of deleted protein and tRNA genes on the impairment of mitochondrial function, we performed a quantitative analysis of biochemical, genetic and morphological findings in skeletal muscles of 16 patients with single deletions and 5 patients with multiple deletions of mtDNA. Clinically, all patients showed chronic progressive external ophthalmoplegia (CPEO). The size of deletions varied between 2.5 and 9 kb, and heteroplasmy between 31% and 94%. In patients with single deletions, the citrate synthase (CS) activity was nearly doubled. Decreased ratios of pyruvate- and succinate-dependent respiration were detected in fibers of all patients in comparison to controls. Inverse and linear correlations without thresholds were established between heteroplasmy and (i) CS referenced activities of the complexes of respiratory chain, (ii) CS referenced maximal respiratory rates, (iii) and cytochrome-c-oxidase (COX) negative fibers. In patients with single and multiple deletions, all respiratory chain complexes as well as the respiratory rates were decreased to a similar extent. All changes detected in patients with single deletions were independent of deletion size. In one patient, only genes of ND5, ND4L as well as tRNA(Leu(CUN)), tRNA(Ser(AGY)), and tRNA(His) were deleted. The pronounced decrease in COX activity in this patient points to the high pathological impact of these missing tRNA genes. The activity of nuclear encoded SDH was also significantly decreased in patients, but to a lesser extent. This is an indication of secondary disturbances of mitochondria at CPEO. In conclusion, we have shown that different deletions cause mitochondrial impairments of the same phenotype correlating with heteroplasmy. The missing threshold at the level of mitochondrial function seems to be characteristic for large-scale deletions were tRNA and protein genes are deleted.

Citrate (si)-Synthase↗
PubMed2002

A novel nonsense mutation (515del4) in muscle carnitine palmitoyltransferase II deficiency.

We identified a novel nonsense mutation in the carnitine palmitoyltransferase (CPT; EC 2.3.1.21) II gene in a patient with biochemical evidence of CPT II deficiency. The 39-year-old man suffered from the muscle form of CPT II deficiency. Attacks of myalgia and muscle weakness started in childhood and led to renal failure five times. A mild proximal weakness of the lower limbs was left as a residue. Molecular genetic analysis revealed the common S113L mutation on one allele. On the other allele a novel 4-bp deletion starting at codon 515 (515del4) was found leading to frameshift that results in a stop codon 15 codons upstream. Our data further expand the genetic heterogeneity in patients with CPT II deficiency.

Adult↗
PubMedDate not supplied

Risk of developing a mitochondrial DNA deletion disorder.

BACKGROUND: Pathogenic mitochondrial DNA (mtDNA) mutations are found in at least one in 8000 individuals. No effective treatment for mtDNA disorders is available, making disease prevention important. Many patients with mtDNA disease harbour a single pathogenic mtDNA deletion, but the risk factors for new cases and disease recurrence are not known. METHODS: We did a multicentre study of 226 families in which a single mtDNA deletion had been identified in the proband, including patients with chronic progressive external ophthalmoplegia, Kearns Sayre syndrome, or Pearson's syndrome. We studied the relation between maternal age and the risk of unaffected mothers having an affected child, and determined the recurrence risks among the siblings and offspring of affected individuals. FINDINGS: We noted no relation between maternal age and the risk of unaffected mothers having children with an mtDNA deletion disorder. None of the 251 siblings of the index cases developed clinical features of mtDNA disease. Risk of recurrence among the offspring of affected women was 4.11% (95% CI 0.86-11.54, or one in 117 to one in nine births). Only one of the mothers who had an affected child had a duplication of mtDNA in skeletal muscle. INTERPRETATION: Unlike nuclear chromosomal rearrangements, incidence of mtDNA deletion disorders does not increase with maternal age, and unaffected mothers are unlikely to have more than one affected child. Affected women were previously thought to have a negligible chance of having clinically affected offspring, but the actual risk is, on average, about one in 24 births.

Adult↗