Taurine supplementation for prevention of stroke-like episodes in MELAS: a multicentre, open-label, 52-week phase III trial.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of high-dose taurine supplementation for prevention of stroke-like episodes of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), a rare genetic disorder caused by point mutations in the mitochondrial DNA that lead to a taurine modification defect at the first anticodon nucleotide of mitochondrial tRNALeu(UUR), resulting in failure to decode codons accurately. METHODS: After the nationwide survey of MELAS, we conducted a multicentre, open-label, phase III trial in which 10 patients with recurrent stroke-like episodes received high-dose taurine (9 g or 12 g per day) for 52 weeks. The primary endpoint was the complete prevention of stroke-like episodes during the evaluation period. The taurine modification rate of mitochondrial tRNALeu(UUR) was measured before and after the trial. RESULTS: The proportion of patients who reached the primary endpoint (100% responder rate) was 60% (95% CI 26.2% to 87.8%). The 50% responder rate, that is, the number of patients achieving a 50% or greater reduction in frequency of stroke-like episodes, was 80% (95% CI 44.4% to 97.5%). Taurine reduced the annual relapse rate of stroke-like episodes from 2.22 to 0.72 (P=0.001). Five patients showed a significant increase in the taurine modification of mitochondrial tRNALeu(UUR) from peripheral blood leukocytes (P<0.05). No severe adverse events were associated with taurine. CONCLUSIONS: The current study demonstrates that oral taurine supplementation can effectively reduce the recurrence of stroke-like episodes and increase taurine modification in mitochondrial tRNALeu(UUR) in MELAS. TRIAL REGISTRATION NUMBER: UMIN000011908.

New TRPM6 mutation and management of hypomagnesaemia with secondary hypocalcaemia.

BACKGROUND: TRPM6 gene mutation has been reported to cause hypomagnesemia with secondary hypocalcemia (HSH). However, the genotype-phenotype correlation for TRPM6 gene mutations has not been clarified. OBJECTIVE: To elucidate the factors underlying the severe neurological complications in HSH and evaluate the potential association between the location of TRPM6 gene mutations and clinical data of HSH. METHODS: A Japanese patient diagnosed with HSH at 10 weeks of age exhibited neurological damage and failed to thrive. Magnesium supplements were therefore started at 12 weeks of age. Mutational analysis of the TRPM6 gene was performed using a direct sequencing method to determine the position and type of mutation. Using the data of 29 HSH patients reported in the literature, linear regression analysis was also performed to examine the association between TRPM6 gene mutation location and HSH onset age, initial serum magnesium and calcium concentrations, and dose of oral magnesium. RESULTS: A novel stop-codon homozygous mutation [c.4190 G>A] W1397X was identified in exon 26 of the patient's TRPM6 gene. No statistical correlation was found between the location of mutations in the TRPM6 gene and the clinical data for 4 clinical indicators of HSH. CONCLUSIONS: We identified the first Japanese HSH patient with a novel nonsense mutation in the TRPM6 gene. Regression analysis of mutation locations in the protein-coding region of TRPM6 and the reported clinical data for 4 clinical indicators of HSH in 30 HSH patients did not detect a genotype-phenotype correlation.

Beneficial effect of pyruvate therapy on Leigh syndrome due to a novel mutation in PDH E1α gene.

Leigh syndrome (LS) is a progressive untreatable degenerating mitochondrial disorder caused by either mitochondrial or nuclear DNA mutations. A patient was a second child of unconsanguineous parents. On the third day of birth, he was transferred to neonatal intensive care units because of severe lactic acidosis. Since he was showing continuous lactic acidosis, the oral supplementation of dichloroacetate (DCA) was introduced on 31st day of birth at initial dose of 50 mg/kg, followed by maintenance dose of 25 mg/kg/every 12 h. The patient was diagnosed with LS due to a point mutation of an A-C at nucleotide 599 in exon 6 in the pyruvate dehydrogenase E1α gene, resulting in the substitution of aspartate for threonine at position 200 (N200T). Although the concentrations of lactate and pyruvate in blood were slightly decreased, his clinical conditions were deteriorating progressively. In order to overcome the mitochondrial or cytosolic energy crisis indicated by lactic acidosis as well as clinical symptoms, we terminated the DCA and administered 0.5 g/kg/day TID of sodium pyruvate orally. We analyzed the therapeutic effects of DCA or sodium pyruvate in the patient, and found that pyruvate therapy significantly decreased lactate, pyruvate and alanine levels, showed no adverse effects such as severe neuropathy seen in DCA, and had better clinical response on development and epilepsy. Though the efficacy of pyruvate on LS will be evaluated by randomized double-blind placebo-controlled study design in future, pyruvate therapy is a possible candidate for therapeutic choice for currently incurable mitochondrial disorders such as LS.

MELAS and L-arginine therapy.

We investigated the endothelial function in MELAS patients and also evaluated the therapeutic effects of L-arginine. Concentrations of L-arginine during the acute phase of MELAS were significantly lower than in control subjects. L-arginine infusions significantly improved all symptoms suggesting stroke within 30 min, and oral administration significantly decreased frequency and severity of stroke-like episodes. Flow-mediated dilation (FMD) in patients showed a significant decrease than those in the controls. Two years of oral supplementation of L-arginine significantly improved endothelial function to the control levels and was harmonized with the normalized plasma levels of L-arginine in patients. L-arginine therapy showed promise in treating stroke-like episodes in MELAS.