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Petra Kaufmann

Publications and source records attributed to Petra Kaufmann.

15 recordsLinked to original sources
PubMed2006

Nerve conduction abnormalities in patients with MELAS and the A3243G mutation.

BACKGROUND: Mitochondrial DNA point mutations are especially deleterious to tissues with high energy demand, including the peripheral nervous system. Neuropathy has been associated with several mitochondrial diseases, including MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes). OBJECTIVE: To evaluate nerve conduction in a genotypically and phenotypically homogeneous group of patients with MELAS and the A3243G mutation. DESIGN: We studied 30 patients with MELAS and the A3243G mutation using neurophysiological techniques, medical history questionnaires, laboratory tests, and a standardized neurological examination. RESULTS: Twenty-three subjects (77%) had abnormal nerve conduction measures. Symptoms suggestive of neuropathy were present in only half of the patients, but almost all had decreased reflexes or distal sensory findings on examination. Nerve conduction abnormalities were predominantly axonal and sensory and mainly present in the legs. Patients with nerve conduction abnormalities tended to be older and were more likely male. CONCLUSIONS: Peripheral nerve impairment is common in those with MELAS and the A3243G mutation, and may be subclinical. Male sex and older age may add to the genetic disposition to develop neuropathy.

Adult↗
PubMed2005

Muscle coenzyme Q10 level in statin-related myopathy.

BACKGROUND: Statin drugs (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) reduce the level of cholesterol by inhibiting the synthesis of mevalonate, an intermediary in the cholesterol biosynthetic pathway. Use of statin drugs has been associated with a variety of skeletal muscle-related complaints. Coenzyme Q10 (CoQ10), a component of the mitochondrial respiratory chain, is also synthesized from mevalonate, and decreased muscle CoQ10 concentration may have a role in the pathogenesis of statin drug-related myopathy. OBJECTIVES: To measure the CoQ10 concentration and respiratory chain enzyme activities in muscle biopsy specimens from 18 patients with statin drug-related myopathy and to look for evidence of apoptosis using the TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling) assay. DESIGN: An open-labeled study of CoQ10 concentration in muscle from patients with increased serum creatine kinase concentrations while receiving standard statin drug therapy. SETTING: Neuromuscular centers at 2 academic tertiary care hospitals. RESULTS: Muscle structure was essentially normal in 14 patients and showed evidence of mitochondrial dysfunction and nonspecific myopathic changes in 2 patients each. Muscle CoQ10 concentration was not statistically different between patients and control subjects, but it was more than 2 SDs below the normal mean in 3 patients and more than 1 SD below normal in 7 patients. There was no TUNEL positivity in any patients. CONCLUSION: These data suggest that statin drug-related myopathy is associated with a mild decrease in muscle CoQ10 concentration, which does not cause histochemical or biochemical evidence of mitochondrial myopathy or morphologic evidence of apoptosis in most patients.

Adult↗
PubMed2005

Novel mitochondrial DNA ND5 mutation in a patient with clinical features of MELAS and MERRF.

BACKGROUND: The mitochondrial DNA gene encoding subunit 5 of complex I (ND5) has turned out to be a hot spot for mutations associated with mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS) and various overlap syndromes. OBJECTIVE: To describe a novel mutation in the ND5 gene in a young man man with an overlap syndrome of MELAS and myoclonus epilepsy with ragged-red fibers. DESIGN: Case report. PATIENT: A 25-year-old man had recurrent strokes, seizures, and myoclonus. His mother also had multiple strokes. A muscle biopsy specimen showed no ragged-red fibers but several strongly succinate dehydrogenase-reactive blood vessels. RESULTS: Biochemical analysis showed isolated complex I deficiency and molecular analysis revealed a novel heteroplasmic mutation (G13042A) in the ND5 gene. CONCLUSIONS: These data confirm that ND5 is a genetic hot spot for overlap syndromes, including MELAS and strokelike and myoclonus epilepsy with ragged-red fibers.

Adult↗
PubMed2005

Clinical and biochemical heterogeneity in an Italian family with CPT II deficiency due to Ser 113 Leu mutation.

BACKGROUND: Carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal recessive disorder which presents with recurrent myoglobinuria. Heterozygotes are usually asymptomatic. METHODS: We correlate the clinical, biochemical and molecular features of a family in which the proband is homozygous for CPT II deficiency, due to the common Ser 113 Leu mutation. RESULTS: The 20-year-old female proband presented at age three years with episodic myalgia and myoglobinuria, elevated creatine kinase (CK) of 3600 IU/L and had a 33% residual CPT II activity in cultured skin fibroblasts. Her 25-year-old dizygotic twin brothers presented with muscle stiffness following prolonged exercise but no overt pigmenturia and had interictal CKs up to 662 lU/L. Her parents and a 13-year-old brother are asymptomatic. An elder sister, not investigated, had recurrent pigmenturia and died at eight years with myoglobinuria. Molecular analysis revealed that the proband is homozygous for the Ser 113 Leu mutation. Her parents are heterozygotes with CPT II activities of 55% to 70%. Her younger brother is normal with 83% activity. The symptomatic twin brother are heterozygous but demonstrated unexpectedly low CPT II activities of 40%, which may explain their phenotype. CONCLUSION: We postulate that there may be genetic, environmental and sex hormonal factors accounting for this manifesting heterozygosity and biochemical heterogeneity in CPT II deficiency.

Adult↗
PubMed2004

Hypocitrullinemia in patients with MELAS: an insight into the "MELAS paradox".

L-citrulline, classified as a nonessential amino acid, is synthesized predominantly via Delta-1-pyrroline carboxylate synthase in the endothelial cells of the small intestine. In mammals, small quantities of citrulline are also produced in nitric oxide synthase-expressing cells. Considering the fact that the enzymes involved in the endogenous synthesis of L-citrulline are all located in the mitochondria and the fact that citrulline is a component of the citrulline-nitric oxide (NO) cycle, we hypothesized that the distinct clinical, biochemical, and morphological characteristics of MELAS, a maternally inherited mitochondrial disorder, might be due to alterations in nitric oxide homeostasis. Analysis of serum from MELAS patients showed that levels of plasma arginine were similar in both patients and in controls. However, levels of citrulline in MELAS patients were significantly lower than in controls, and there was a clear inverse correlation between arginine and citrulline levels in these patients. We found no correlation between the level of heteroplasmy and the plasma levels of either arginine or citrulline. We discuss the depressed citrulline levels in MELAS patients, who have an unusual and paradoxical pattern of vascular respiratory chain expression, in the context of NO homeostasis.

Adult↗
PubMed2004

Varying loads of the mitochondrial DNA A3243G mutation in different tissues: implications for diagnosis.

Testing for common mutations in mitochondrial DNA (mtDNA), including the A3243G MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) mutation, is routinely done in DNA isolated from blood. Since the blood level of the A3243G mutation may be low in probands and even lower in asymptomatic or oligosymptomatic maternal relatives, we assessed the proportion of A3243G mutant genomes in other accessible tissues. We studied five tissues (leukocytes, skin fibroblasts, hair roots, urinary sediment, and cheek mucosa) in 61 individuals from 22 families harboring the A3243G mutation. Although mutational loads varied widely among these tissues, as a rule DNA from urinary sediment had the highest and blood the lowest proportion of mutant genomes; individual hair roots differed markedly from one another; fibroblasts and cheek mucosa tended to have higher mutation loads than blood but lower than urinary sediment. In all individuals in whom the mutation was detectable in blood, it was also detected in other tissues. Conversely, in some individuals the mutation was undetectable in blood but clearly present in other tissues. We conclude that urinary sediment and cheek mucosa are tissues of choice for the diagnosis of mtDNA mutations, as they are easy to obtain and the mutation load is almost always greater than in blood.

DNA Mutational Analysis↗
PubMed2004

A pathogenic peripherin gene mutation in a patient with amyotrophic lateral sclerosis.

Peripherin is a neuronal intermediate filament protein that is expressed chiefly in motor neurons and other nerve cells that project into the peripheral nervous system. Transgenic mice that over-express peripherin develop motor neuron degeneration, suggesting that mutations in peripherin could contribute to the development of motor neuron disease. In this paper, we report the identification of a homozygous mutation in the peripherin gene (PRPH) in a patient with amyotrophic lateral sclerosis (ALS). The mutation resulted in a substitution of aspartate with tyrosine at amino acid position 141, which is located within the first linker region of the rod domain. Immunocytochemical analysis of the spinal cord of the patient upon autopsy revealed distinctive large aggregates within the cell bodies of residual spinal motor neurons that contained peripherin and was also immunoreactive with antibodies to the neurofilament proteins. In order to study the effect of the mutation on peripherin assembly, we performed transient transfections. Unlike wild-type peripherin, which self-assembles to form a filamentous network, the mutant peripherin was prone to form aggregates in transfected cells, indicating that the mutation adversely affects peripherin assembly. Moreover, the neurofilament light (NF-L) protein was not able to rescue the mutant protein from forming aggregates. These data imply that mutation of PRPH is a contributing factor for ALS.

Adult↗
PubMed2003

Amyotrophic lateral sclerosis and primary lateral sclerosis: evidence-based diagnostic evaluation of the upper motor neuron.

Magnetic resonance imaging and MR spectroscopy are important tools in the diagnostic evaluation of patients with suspected motor neuron disease. Further investigation is needed to determine and to compare the utility of various neuroimaging markers for diagnosis and disease progression [112]. Newer MR tools, such as diffusion tensor imaging, magnetization transfer imaging, and functional MR imaging, have substantial promise as scientific and clinical tools in this ongoing endeavor.

Amyotrophic Lateral Sclerosis↗
PubMed2002

Amyotrophic lateral sclerosis: objective upper motor neuron markers.

The diagnosis of amyotrophic lateral sclerosis (ALS) remains a clinical diagnosis. It is based on the combination of both upper and lower motor neuron signs in the neurologic examination. With several new therapeutic agents on the horizon, effective and objective disease markers for diagnosis and surrogate outcome measures in clinical trials are crucial. Whereas the presence of lower motor neuron signs on neurologic examination can be ascertained by electromyography, there is no widely accepted marker for upper motor neuron involvement. Neuroimaging changes of the corticospinal tract in ALS patients have been studied using magnetic resonance (MR) imaging, but appear to lack sensitivity and specificity. MR spectroscopy, a technique that allows one to evaluate biochemical tissue composition in vivo, has been widely used to establish the progressive decrease in N-acetylaspartate, a marker of neuronal integrity, in the course of ALS. More recently, diffusion tensor imaging, a newer MR technique, has demonstrated changes in diffusivity along the corticospinal tract in ALS patients. Metabolic aspects in the brains of ALS patients have been evaluated using positron emission tomography. Transcranial magnetic stimulation is a more established technique that evaluates the neurophysiologic integrity of upper motor neurons in ALS. This article reviews the progress that has been made over the past two decades towards establishing valid diagnostic and natural history markers of upper motor neuron involvement in ALS.

Amyotrophic Lateral Sclerosis↗