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D Pongratz

Publications and source records attributed to D Pongratz.

At least 19 recordsLinked to original sources
PubMed2002

A G468-T AMPD1 mutant allele contributes to the high incidence of myoadenylate deaminase deficiency in the Caucasian population.

Myoadenylate deaminase deficiency is the most common metabolic disorder of skeletal muscle in the Caucasian population, affecting approximately 2% of all individuals. Although most deficient subjects are asymptomatic, some suffer from exercise-induced myalgia suggesting a causal relationship between a lack of enzyme activity and muscle function. In addition, carriers of this derangement in purine nucleotide catabolism may have an adaptive advantage related to clinical outcome in heart disease. The molecular basis of myoadenylate deaminase deficiency in Caucasians has been attributed to a single mutant allele characterized by double C to T transitions at nucleotides +34 and +143 in mRNA encoded by the AMPD1 gene. Polymerase chain reaction-based strategies have been developed to specifically identify this common mutant allele and are considered highly sensitive. Consequently, some laboratories preferentially use this technique over other available diagnostic tests for myoadenylate deaminase deficiency. We previously identified a G468-T mutation in one symptomatic patient who was only heterozygous for the common AMPD1 mutant allele. In this report, nine additional individuals with this compound heterozygous genotype are revealed in a survey of 48 patients with documented deficiency of skeletal muscle adenosine monophosphate deaminase and exercise-induced myalgia. Western blot analysis of leftover biopsy material from one of these individuals does not detect any immunoreactive myoadenylate deaminase polypeptide. Baculoviral expression of the G468-T mutant allele produces a Q156H substitution enzyme exhibiting labile catalytic activity. These combined results demonstrate that the G468-T transversion is dysfunctional and further indicate that AMPD1 alleles harboring this mutation contribute to the high incidence of partial and complete myoadenylate deaminase deficiency in the Caucasian population. Consequently, genetic tests for abnormal AMPD1 expression designed to diagnose patients with metabolic myopathy, and to evaluate genetic markers for clinical outcome in heart disease should not be based solely on the detection of a single mutant allele.

AMP Deaminase↗
PubMed2002

De novo missense mutation in a constitutively expressed exon of the slow alpha-tropomyosin gene TPM3 associated with an atypical, sporadic case of nemaline myopathy.

We describe an atypical case of nemaline myopathy with an unusual distribution of muscle weakness who presented at 14 years of age with kyphoscoliosis. In this patient, we demonstrate heterozygosity for a de novo CGT-CAT (Arg167His) mutation in a constitutively expressed exon (exon 5) of slow alpha-tropomyosin (TPM3). This is the first mutation identified in a constitutively expressed exon of TPM3 in a nemaline myopathy patient, but is similar to recently described mutations in beta-tropomyosin (TPM2) associated with nemaline myopathy and mutations in fast alpha-tropomyosin (TPM1) which cause hypertrophic cardiomyopathy.

Adenosine Triphosphatases↗
PubMed2002

Screening for carnitine palmitoyltransferase II deficiency by tandem mass spectrometry.

Mitochondrial carnitine palmitoyltransferase II (CPT II) deficiency is the most common inherited disorder of lipid metabolism in adults. Currently the routine diagnosis is based on the determination of CPT enzyme activity in muscle tissue. We have analysed the tandem mass spectra of serum acylcarnitines of nine CPT II-deficient patients. These spectra were compared to those of a cohort of 99 patients with other neuromuscular disorders and metabolic conditions supposed to cause alterations of the long-chain acylcarnitines. The spectra in CPT II deficiency showed characteristic elevations of C16:0 and C18:1 acylcarnitines while acetylcarnitine C2 was not elevated. In the present study, the ratio (C16:0+C18:1)/C2 has detected all CPT II deficiencies and discriminated them from unspecific alterations of serum acylcarnitines. The ratios of CPT II-deficient patients showed virtually no overlap with those observed in patients with other neuromuscular disorders. We suggest mass spectrometry of serum acylcarnitines as a rapid screening test that should be included early in the diagnostic work-up of patients with recurrent myoglobinuria, recurrent muscular weakness and myalgia.

Adolescent↗
PubMed2002

[26-year-old female patient with elevated liver enzymes].

A 26-year-old woman presented with elevated liver enzymes, which were diagnosed two months ago. Examination revealed mild proximal muscle weakness, though the patient herself did not realise any impairment. The abdominal ultrasound and the histology of the liver remained unsuspicious. Muscle biopsy showed vacuolar degeneration, which could be ultrastructurally identified as large deposits of membrane-bound glycogen. The morphological findings prompted biochemical investigations which showed an excess of muscle glycogen. Acid maltase activity was reduced to < 10 % of normal, leading together with the clinical findings to the diagnosis of glycogenosis type II (Pompe's disease) of the adult type. Because of the modest impairment of the patient and the limited therapeutic possibilities, the patient remained thus untreated for.

Adult↗
PubMed2001

[What helps in back pain? Guideline for symptomatic therapy].

Both in acute and chronic, unspecific back pain, the myofascial pain syndrome resulting in muscular dysbalance is a major factor. For the differential diagnosis, however, consideration must always be given to concomitant symptoms (neurological deficits, general symptoms, signs of osteopathy). Pathophysiologically, the active trigger point corresponds to a contraction in the muscle fibers that forms in the region of the a neuromuscular endplate, and leads, via biochemical processes, to the stimulation of mesochymal nociceptors. Symptomatic treatment of acute and chronic back pain may be broken down into a) physical measures, b) local therapeutic regimens, c) systemic pharmacotherapy. As medication, non-steroidal antiinflammatory drugs, non-opioid analgesics, opioid analgesics, muscle relaxants and antidepressives are available, and are dose-matched to the severity and stage of the condition. The spectrum of therapeutic options is outlined.

Analgesics↗
PubMed2001

[New insights in pathogenesis and therapy of sporadic inclusion body myositis (s-IBM)].

Sporadic inclusion body myositis (s-IBM) is a chronic progressive inflammatory myopathy which occurs preferentially in older patients. Histologic hallmarks are rimmed vacuoles and eosinophilic cytoplasmatic inclusions. The etiology is still unknown, but different pathogenetic mechanisms such as slow virus infection, autoimmunopathogenesis, myonuclear alterations, and mitochondrial defects have been implicated. A relation to neurodegenerative disorders and prion diseases has also been suggested. There is a poor response if any to immunosuppressive therapy. Stabilization of disease progression was shown only by intravenous immunoglobulin (IVIG) therapy. Future findings in the field of s-IBM pathogenesis may result in better therapeutic options.

Aged↗
PubMed2001

[Fibromyalgia].

The classification of fibromyalgia is based on the criteria of the American College of Rheumatology. For diagnostic reasons autonomic disturbances and mental features have to be considered. The distinction between fibromyalgia (tender points) and myofascial pain syndrome (trigger points) is essential. Internal and neurological disorders as a primary cause of fibromyalgia have to be excluded. The aetiology and pathogenesis of fibromyalgia still remain uncertain. The myopathological patterns in fibromyalgia are non-specific: type-II-fiber-atrophy, a slight increase in lipid droplets, a proliferation of mitochondria and a slightly elevated incidence of ragged red fibers. Biochemically alterations of the serotonin system and high levels of substance P in the cerebrospinal fluid of fibromyalgia patients are important. Animal experiments showed that the central stimulation by nociceptor input from muscles is exaggerated in skeletal muscle pain conditions, suggesting central hyperexcitability. The diagnosis of fibromyalgia requires a thorough exclusion of other rheumatologic and neurologic disorders. The differential diagnosis is complicated by an overlap to other chronic somatoform pain disorders.

Diagnosis, Differential↗
PubMed2001

Frequency of mitochondrial transfer RNA mutations and deletions in 225 patients presenting with respiratory chain deficiencies.

OBJECTIVE: To evaluate the frequency of pathogenic mtDNA transfer RNA mutations and deletions in biochemically demonstrable respiratory chain (RC) deficiencies in paediatric and adult patients. METHODS: We screened for deletions and sequenced mitochondrial transfer RNA genes in skeletal muscle DNA from 225 index patients with clinical symptoms suggestive of a mitochondrial disorder and with biochemically demonstrable RC deficiency in skeletal muscle. RESULTS: We found pathogenic mitochondrial DNA mutations in 29% of the patients. The detection rate was significantly higher in adults (48%) than in the paediatric group (18%). Only one pathogenic mutation was detected in the neonatal group. In addition, we describe seven novel transfer RNA sequence variations with unknown pathogenic relevance (six homoplasmic and one heteroplasmic) and 13 homoplasmic polymorphisms. One heteroplasmic transfer RNA(Leu(UUR)) A>G mutation at position 3274 is associated with a distinct neurological syndrome. CONCLUSIONS: We provide an estimation of the frequency of mitochondrial transfer RNA mutations and deletions in paediatric and adult patients with respiratory chain deficiencies.

Adolescent↗
PubMed2001

Effects of heat and cold application on turns and amplitude in surface EMG.

The purpose of this study was to investigate the effects of cooling and heating of muscles on parameters of surface EMG (SEMG) under various well defined grades of isometric muscle contraction. In 32 healthy volunteers, aged 20-30 years, turns and amplitude (RMS) analysis was done in SEMG from the hand extensors. Muscle strength was defined by a new developed hand dynamometer. Values for RMS and turns in case of maximal voluntary contraction (MVC) over periods of 20 sec were determined for each volunteer and subsequently RMS and turns were measured during isometric contractions of 10%, 30%, 50% and 80% of MVC, interrupted each by rest periods. This procedure was repeated after cooling and warming the forearm with thermo packs. For control purposes the same investigations with three measurement periods of SEMG were done following the same time schedule without thermic stimuli. With increasing isometric contractions turns increased after heat application and decreased after ice application, compared to the values achieved without thermic stimuli. The differences were significant from a level of 30% of MVC (p < 0.05). No corresponding changes were seen for RMS. In the control experiment values of turns and RMS did not differ in the three measurement periods. It is concluded, that the amplitude in SEMG tracings seems to be a reliable parameter of muscle force, whereas turns are sensitive to temperature. They might be useful markers for therapeutic approaches targeted at the muscle.

Adult↗
PubMed2001

Short-term treatment of primary fibromyalgia with the 5-HT3-receptor antagonist tropisetron. Results of a randomized, double-blind, placebo-controlled multicenter trial in 418 patients.

We investigated the efficacy and tolerability of short-term treatment with tropisetron, a selective, competitive 5-HT3-receptor antagonist in fibromyalgia. The trial was designed as a prospective, multicenter, double-blind, parallel-group, dose-finding study. We randomly assigned 418 patients suffering from primary fibromyalgia to receive either placebo, 5 mg, 10 mg or 15 mg tropisetron once daily for 10 days. Clinical response was measured by changes in pain score, visual analog scale, tender point count and ancillary symptoms. Responders were prospectively defined as patients showing a 35% or higher reduction in pain score. Treatment with 5 mg tropisetron resulted in a significantly higher response rate (39.2%) than placebo (26.2%) (p < 0.05). In the visual analog scale, the group administered 5 mg tropisetron showed a significant improvement (p < 0.05) and the group administered 10 mg tropisetron showed a nonsignificant clinical benefit. The number of painful tender points was significantly reduced (p = 0.002) in the 5 mg tropisetron group. Regarding ancillary symptoms, the 5 mg tropisetron group showed a significant improvement (p < 0.05) in sleep and dizziness. The patients' overall assessment of efficacy was significantly higher for 5 mg (p = 0.016) and 10 mg (p = 0.002) tropisetron than for placebo. The safety and tolerability of tropisetron was good; gastrointestinal tract symptoms were the most frequently reported adverse events. Short-term treatment of fibromyalgia patients with 5 mg tropisetron for 10 days proved to be efficacious and well tolerated. In this study a bell-shaped dose-response curve was seen.

Adolescent↗
PubMed2000

A placebo-controlled crossover trial of creatine in mitochondrial diseases.

To test the efficacy and safety of creatine (Cr) monohydrate in mitochondrial diseases, 16 patients with chronic progressive external ophthalmoplegia or mitochondrial myopathy were randomized in a crossover design to receive double-blind placebo or 20 g Cr/day for 4 weeks. Cr was well tolerated, but there were no significant effects with regard to exercise performance, eye movements, or activities of daily life. The power of this pilot study was limited and future multicenter trials are needed.

Adult↗
PubMed2000

German open label trial of riluzole 50 mg b.i.d. in treatment of amyotrophic lateral sclerosis (ALS).

UNLABELLED: Riluzole is currently the only drug that holds any hope of prolonging life in amyotrophic lateral sclerosis (ALS) by slowing the rate of disease progression. METHODS AND RESULTS: Between 1995 and 1997 a total of 7916 ALS patients in 39 countries, were given 100 mg riluzole per day for a mean of 7.2 months. The present report focuses on the German results in comparison to the total population. Nine hundred and nineteen patients were treated in 25 German centres; 162 (17.6%) died from the disease during the course of the study. Serious adverse events attributed to the study medication occurred in 16 patients (1.7%). Most frequently these were reversible changes in liver enzymes (0.9%) occurring during the first 3 months, none resulted in death. In all, 413 patients (44.9%) reported an adverse event. The most frequent were reduced lung function (7.3%), nausea (7.1%), asthenia (5.8%), pneumonia (2.5%) and abdominal pain (2.5%). CONCLUSION: The results of the study allow the conclusion that riluzole is well tolerated. The majority of adverse events were symptoms of the underlying disease and were not attributed to riluzole. Overall the safety profile found in the German centres was very similar to the profile seen in the total patient population and was more favourable than in the two published double-blind studies [New Engl J Med 330 (1994) 585; Lancet 347 (1996) 1425].

Amyotrophic Lateral Sclerosis↗
PubMed2000

Creatine monohydrate in muscular dystrophies: A double-blind, placebo-controlled clinical study.

The authors assessed the safety and efficacy of creatine monohydrate (Cr) in various types of muscular dystrophies in a double-blind, crossover trial. Thirty-six patients (12 patients with facioscapulohumeral dystrophy, 10 patients with Becker dystrophy, 8 patients with Duchenne dystrophy, and 6 patients with sarcoglycan-deficient limb girdle muscular dystrophy) were randomized to receive Cr or placebo for 8 weeks. There was mild but significant improvement in muscle strength and daily-life activities by Medical Research Council scales and the Neuromuscular Symptom Score. Cr was well tolerated throughout the study period.

Activities of Daily Living↗
PubMed2000

Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients.

Mutations in human mitochondrial tRNA genes are associated with a number of multisystemic disorders. Using an assay that combines tRNA oxidation and circularization we have determined the relative amounts and states of aminoacylation of mutant and wild-type tRNAs in tissue samples from patients with MELAS syndrome (mito- chondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) and MERRF syndrome (myoclonus epilepsy with ragged red fibers), respectively. In most, but not all, biopsies from MELAS patients carrying the A3243G substitution in the mitochondrial tRNA(Leu(UUR))gene, the mutant tRNA is under-represented among processed and/or aminoacylated tRNAs. In contrast, in biopsies from MERRF patients harboring the A8344G substitution in the tRNA(Lys)gene neither the relative abundance nor the aminoacylation of the mutated tRNA is affected. Thus, whereas the A3243G mutation may contribute to the pathogenesis of MELAS by reducing the amount of aminoacylated tRNA(Leu), the A8344G mutation does not affect tRNA(Lys)function in the same way.

Acylation↗