phosphocreatine and Metabolism--Inborn-Errors

31P MRS and 1H MRI of skeletal muscle have become major new tools allowing a complete non invasive investigation of muscle function both in the clinical setting and in basic research. The comparative analysis of normal and diseased muscle remains a major requirement to further define metabolic events surrounding muscle contraction and the metabolic anomalies underlying pathologies. Also, standardized rest-exercise-recovery protocols for the exploration of muscle metabolism by P-31 MRS in healthy volunteers as well as in patients with intolerance to exercise have been developed. The CRMBM protocol is based on a short-term intense exercise, which is very informative and well accepted by volunteers and patients. Invariant metabolic parameters have been defined to characterize the normal metabolic response to the protocol. Deviations from normality can be directly interpreted in terms of specific pathologies in some favorable cases. This protocol has been applied to more than 4,000 patients and healthy volunteers over a period of 15 years. On the other hand, MRI investigations provide anatomical and functional information from resting and exercising muscle. From a diagnostic point of view, dedicated pulse sequences can be used in order to detect and quantify muscle inflammation, fatty replacement, muscle hyper and hypotrophy. In most cases, MR techniques provide valuable information which has to be processed in conjunction with traditional invasive biochemical, electrophysiological and histoenzymological tests. P-31 MRS has proved particularly useful in the therapeutic follow-up of palliative therapies (coenzyme Q treatment of mitochondriopathies) and in family investigations. It is now an accepted diagnostic tool in the array of tests which are used to characterize muscle disorders in clinical routine. As a research tool, it will keep bringing new information on the physiopathology of muscle diseases in animal models and in humans and should play a role in the metabolic characterization of gene and cell therapy.

Topics: Adenosine Triphosphate; Calibration; Energy Metabolism; Equipment Design; Exercise Test; Humans; Hydrogen; Magnetic Resonance Spectroscopy; Metabolism, Inborn Errors; Mitochondrial Myopathies; Muscle Contraction; Muscle, Skeletal; Muscular Diseases; Myositis; Neuromuscular Diseases; Phosphates; Phosphocreatine; Phosphorus Isotopes; Rest

Magnetic resonance (MR) is rapidly entering many fields of clinical medicine following a long history as a powerful tool in physics and chemistry. The non-invasive and non-destructive property of this technique has enabled the chemical shift in higher magnetic fields to be exploited to identify and quantitate metabolites in both in vitro and in vivo analysis. High resolution proton spectroscopy of body fluids has been shown to be complementary with established analytical techniques, while the development of whole body large bore magnets is enabling both the study of structure and metabolism in humans in vivo. Phosphorus MR spectroscopy has provided a method of monitoring ATP production and utilisation in situ in both perfused preparation and intact tissue. In human muscle it has been possible to test established theories of tissue energy metabolism. It provides a unique method with which to evaluate the state of tissue oxidative metabolism. The opportunities afforded by other nuclei are being studied, but the low sensitivity of the MR technique forces limitations. Recent technical advances in tissue localization have as yet only been applied in a limited way. The use of MR in metabolic disease will be considered with specific reference to disorders of skeletal muscle metabolism.

Topics: Adenosine Triphosphate; Energy Metabolism; Humans; Magnetic Resonance Imaging; Metabolism, Inborn Errors; Mitochondria, Muscle; Phosphocreatine

The pathogenesis of neurological sequelae in glutaric aciduria I (GA I) is still unclear. Some evidence exists for compromised energy generation in the brain of patients with GA I resulting in 'slow-onset' excitotoxicity. Previously, we have shown a reduced activity of the mitochondrial ATPsynthase in cultured mixed cortex cells from neonatal rats incubated with 2-4mM 3-hydroxyglutarate (3-OH glut) for 24h. In the present study we measured cellular contents of high energy phosphate compounds (creatinephosphate CP, ATP, and ADP) in this model after a 24h incubation period with 2-4mM glutarate (glut) or 3-OH glut. 3-OH glut specifically led to a reduction of CP content in a dose-dependent manner, whereas concentrations of ATP, ADP, and AMP remained unchanged. The drop in CP-concentration could be prevented by preincubation with the non-competitive NMDA-receptor antagonist MK 801 or coincubation with 1mM creatine. NMDA-receptor associated ion channels may be opened due to a lack of energy inside the neurons caused by a reduction of CP. This is followed by membrane depolarization which could impair electrogenic creatine transport into the cell.

Topics: Adenine Nucleotides; Animals; Animals, Newborn; Cerebral Cortex; Creatine; Glutarates; Metabolism, Inborn Errors; Phosphocreatine; Rats

Maple syrup urine disease (MSUD) is an inborn error of amino acid metabolism, which affects the brain tissue resulting in impairment or death if untreated. Imaging studies have shown reversible brain edema during acute metabolic decompensation. The purpose of this paper is to describe the diffusion-weighted imaging (DWI) and spectroscopy findings during metabolic decompensation and to assess the value of these findings in the prediction of patient outcome. Six patients with the diagnosis of MSUD underwent conventional MR imaging with DWI during acute presentation with metabolic decompensation. Spectroscopy with long TE was performed in four of the six patients. Follow-up examinations were performed after clinical and metabolic recovery. DWI demonstrated marked restriction of proton diffusion compatible with cytotoxic or intramyelinic sheath edema in the brainstem, basal ganglia, thalami, cerebellar and periventricular white matter and the cerebral cortex. This was accompanied by the presence of an abnormal branched-chain amino acids (BCAA) and branched-chain alpha-keto acids (BCKA) peak at 0.9 ppm as well as elevated lactate on proton spectroscopy in all four patients. The changes in all six patients were reversed with treatment without evidence of volume loss or persistent tissue damage. The presence of cytotoxic or intramyelinic edema as evidenced by restricted water diffusion on DWI, with the presence of lactate on spectroscopy, could imply imminent cell death. However, in the context of metabolic decompensation in MSUD, it appears that changes in cell osmolarity and metabolism can reverse completely after metabolic correction.

Topics: 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); Amino Acids, Branched-Chain; Aspartic Acid; Basal Ganglia; Biomarkers; Brain Stem; Cerebellum; Cerebral Cortex; Creatine; Diffusion Magnetic Resonance Imaging; Female; Follow-Up Studies; Humans; Infant; Infant Welfare; Infant, Newborn; Ketone Oxidoreductases; Lactic Acid; Magnetic Resonance Spectroscopy; Male; Maple Syrup Urine Disease; Metabolism, Inborn Errors; Multienzyme Complexes; Phosphocreatine; Radiography; Statistics as Topic; Time Factors

In vivo phosphorus magnetic resonance spectroscopy (MRS) was used to investigate markers of the cerebral energy status in two patients with glutaric aciduria type I (GA-I). Besides an increased concentration of phosphomonoesters in one patient, no other significant alterations from controls were found. This might indicate increased resynthesis of dendritic processes secondary to preceding metabolic crises. In contrast to previous cell-culture studies, no cerebral depletion of phosphocreatine (PCr) was observed. In conclusion, a severe global and permanent depletion of cerebral energy supplies must be ruled out. The benefit of a permanent creatine substitution to stabilize mitochondrial energy metabolism seems thus questionable. However, as MRS was performed during stable clinical conditions, the possibility of a PCr decrease during acute metabolic crises cannot be assessed.

Topics: Adenosine Triphosphate; Cardiotonic Agents; Child; Child, Preschool; Energy Metabolism; Glutaryl-CoA Dehydrogenase; Humans; Infant; Magnetic Resonance Spectroscopy; Male; Metabolism, Inborn Errors; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Phosphates; Phosphocreatine; Pilot Projects; Telencephalon

In a patient with extrapyramidal movement disorder and extremely low creatinine concentrations in serum and urine, in vivo proton magnetic resonance spectroscopy disclosed a generalized depletion of creatinine in the brain. Oral substitution of arginine, a substrate for creatine synthesis, resulted in an increase of brain guanidinoacetate as the immediate precursor of creatine but did not elevate cerebral creatine levels. In contrast, oral substitution of creatine-monohydrate led to a significant increase of brain creatine, a decrease of brain guanidinoacetate, and a normalization of creatinine in serum and urine. Phosphorus magnetic resonance spectroscopy of the brain revealed no detectable creatine-phosphate before oral substitution of creatine and a significant increase afterward. Partial restoration of cerebral creatine concentrations was accompanied by improvement of the patient's neurologic symptoms. This is the first report of a patient with complete creatine deficiency in the brain. Magnetic resonance spectroscopy during arginine and creatine treatment point to an inborn error of creatine biosynthesis at the level of guanidinoacetete-methyltransferase.

Topics: Arginine; Brain; Creatine; Humans; Infant; Magnetic Resonance Spectroscopy; Male; Metabolism, Inborn Errors; Phosphocreatine

The bioenergetic capacity of skeletal muscle in a 17-year-old patient with a severe defect in complex III of the electron transport chain has been examined by 31P NMR measurements of the molar ratio of phosphocreatine to inorganic phosphate (PCr/Pi). Resting ratios were 1.3-2.5, which can be compared with roughly 8.6 for a young, normal female control at rest. Quantitative evaluation of the activity of oxidative metabolism was afforded by the rate of recovery of PCr/Pi from exercise and was found to be 2.5% of normal. After administration of menadione and ascorbate, we found a 21-fold increase of the recovery rate relative to the pretherapy value, to within 56% of the recovery rate of the young female control. Thus, NMR examinations of skeletal muscle at rest and in recovery from activity document marked improvement to specific drug therapy in the electron transport capabilities and the ATP synthesis rate of a patient with a deficiency in a cytochrome b-containing complex III. Improvements in functional ability, although not as dramatic as biochemical changes, are also apparent.

Topics: Adenosine Triphosphate; Ascorbic Acid; Electron Transport; Humans; Magnetic Resonance Spectroscopy; Metabolism, Inborn Errors; Mitochondria, Muscle; Oxidative Phosphorylation; Phosphocreatine; Vitamin K

Topics: Adenine Nucleotides; Adenosine Triphosphate; Blood Chemical Analysis; Contracture; Electromyography; Glycogen; Humans; In Vitro Techniques; Lactates; Metabolism, Inborn Errors; Muscle Contraction; Muscle Cramp; Muscle Proteins; Muscles; Muscular Diseases; Myoglobinuria; Phosphocreatine; Phosphotransferases; Physical Exertion; Spectrophotometry