MELAS syndrome with mitochondrial tRNA ^Leu[UUR] mutation

Abstract

We report a patient with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes treated with riboflavin and nicotinamide for 18 months, during which time previously frequent encephalopathic spells ceased. To confirm clinical benefit, we withdrew treatment and monitored response with muscle 31P magnetic resonance spectroscopy (MRS) and sural nerve conduction studies. Of three prospectively chosen MRS variables, two changed coincidentally with clinical end points; phosphocreatine (PCr)/adenosine triphosphate recovery rates fell in parallel with sural nerve sensory amplitudes, and a drop in muscle bioenergetic efficiency (relationship of inorganic phosphate/PCr to the accelerating force of contracting muscle) coincided with development of encephalopathy. Investigations revealed a deficiency of respiratory complex I and mutation of the mitochondrial tRNA(Leu)(UUR). We suggest that a defective cellular energy state in mitochondrial disease may be partially treatable and that changes seen in appropriate muscle spectroscopy studies may parallel improvement in brain and peripheral nerve function.

Gametocytocidal Activity and Synergistic Interactions of Riboflavin with Standard Antimalarial Drugs against Growth of Plasmodium falciparum In Vitro

“…The data presented here strongly suggest that riboflavin could be an effective agent in treating and blocking the transmission of malaria caused by P. falciparum. High doses of riboflavin are used to treat patients with several inborn errors of metabolism (2,3,10,12,15,19,24,29), in some cases up to 2 years, with no adverse side effects. Since the safety of riboflavin is well established, it should be possible in clinical trials to test its efficacy in combination with standard antimalarials against malaria caused by P. falciparum.…”

Muscle oxidative phosphorylation quantitation using creatine chemical exchange saturation transfer (CrCEST) MRI in mitochondrial disorders

“…Spectroscopic methods, such as 31 P magnetic resonance spectroscopy ( 31 P-MRS), have shown deficient OXPHOS and ATP synthesis in individuals with mitochondrial diseases, as reflected by delayed phosphocreatine (PCr) recovery after exercise (7)(8)(9)(10). The limited spatial resolution of 31 P-MRS makes the assessment of muscle group-specific OXPHOS capacity more challenging.…”

Rapid isolation of muscle and heart mitochondria, the lability of oxidative phosphorylation and attempts to stabilize the process in vitro by taurine, carnitine and other compounds

“…After that, when the drugs are known to be safe (several of them are already tested in other patients), they can be tested on patients with defects in oxidative phosphorylation. Of course together with other treatments that proved valuable in individual patients [20][21][22][23][24].…”

“…Rapid isolation of muscle mitochondria in high yield was based upon Bookelman et al [11], which on its turn was based upon Luft et al [21] and Dow [3]. We modified the mincing of the muscle and used shorter centrifugation times at higher forces.…”