About the lab
Dr. Yasutoshi Koga is a professor of Pediatrics and Child Health, Kurume University Graduate School of Medicine, Japan. After he established the biochemical screening system of mitochondrial disorders at NCNP (Prof. Nonaka I), he joined the Mitochondrial Research Group at the Department of Neurology, College of Physicians and Surgeons of Columbia University (Profs. DiMauro S and Schon EA), where he directed his research to mitochondrial genetics especially pathogenic mechanism of MELAS. He discovered a novel therapeutic procedure and has completed the investigator-mediated clinical trial of L-arginine on MELAS in Japan. He received the Kelsey Wright Award from UMDF in 2008. In 2012, he started the new national project to cure the lactic acidosis associated with mitochondrial disorders, sup
Featured research (134)
Biomarkers and two clinical rating scales—the Japanese mitochondrial disease-rating scale (JMDRS) and Newcastle mitochondrial disease adult scale (NMDAS)—are clinically used when treating patients with mitochondrial disease. We explored the biomarker(s) and clinical rating scale(s) that are appropriate in preparing the protocol for a future clinical trial of sodium pyruvate (SP) therapy. A 48-week, prospective, single-centre, exploratory, clinical study enrolled 11 Japanese adult patients with genetically, biochemically, and clinically confirmed mitochondrial disease; they had intractable lactic acidosis and received SP (0.5 g/kg t.i.d. PO). Plasma concentrations of lactate and pyruvate, lateral ventricular levels of lactate, and serum concentrations of growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 were measured at baseline and at weeks 12 and 48 of SP therapy. At week 48, plasma lactate (P =.004), the lactate/pyruvate ratio (P =.012), serum GDF15 (P =.020), and lateral ventricular lactate (P =.038) decreased significantly from the baseline values; the JMDRS and NMDAS scores did not decrease significantly, although the NMDAS overall score showed a strong tendency (P =.059). Two patients with end-stage MELAS at baseline died during SP therapy. The present study showed significant decreases in plasma and lateral ventricular lactate, the L/P ratio, and serum GDF15. Therefore, the protocol for a future clinical study of SP therapy in this patient population needs to include plasma and lateral ventricular lactate, the L/P ratio, and serum GDF15 as diagnostic indicators, and exclude patients with end-stage mitochondrial disease.
Objective To examine the efficacy and safety of the therapeutic regimen using oral and intravenous l-arginine for pediatric and adult patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Methods In the presence and absence of an ictus of stroke-like episodes within 6 h prior to efficacy assessment, we correspondingly conducted the systematic administration of oral and intravenous l-arginine to 15 and 10 patients with MELAS in two, 2-year, prospective, multicenter clinical trials at 10 medical institutions in Japan. Subsequently, patients were followed up for 7 years. The primary endpoint in the clinical trial of oral l-arginine was the MELAS scale, while that for intravenous l-arginine was the improvement rates of headache and nausea/vomiting at 2 h after completion of the initial intravenous administration. The relationships between the ictuses of stroke-like episodes and plasma arginine concentrations were examined. Results Oral l-arginine extended the interictal phase (p = 0.0625) and decreased the incidence and severity of ictuses. Intravenous l-arginine improved the rates of four major symptoms—headache, nausea/vomiting, impaired consciousness, and visual disturbance. The maximal plasma arginine concentration was 167 μmol/L when an ictus developed. Neither death nor bedriddenness occurred during the 2-year clinical trials, and the latter did not develop during the 7-year follow-up despite the progressively neurodegenerative and eventually life-threatening nature of MELAS. No treatment-related adverse events occurred, and the formulations of l-arginine were well tolerated. Conclusions The systematic administration of oral and intravenous l-arginine may be therapeutically beneficial and clinically useful for patients with MELAS.
Key Clinical Message Temple syndrome (TS14) leads to growth failure, precocious puberty, and diabetes mellitus. However, the long‐term prognosis, including the development of social behavior in TS14 patients, remains unclarified. We report the clinical course of a male patient with autism spectrum disorder that received a diagnosis of TS14 at 33 years of age.
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.
Hypertrophic cardiomyopathy is a heterogeneous disease caused by gene mutations. Most of the disease-causing mutations were found in the genes for sarcomeric proteins, but there are several cases carrying mutations in genes for extra-sarcomeric cytoskeletons. Desmin is a member of extra-sarcomeric cytoskeletons and plays an important role in muscle contraction. Mutations in the desmin gene cause various type of general myopathy and/or cardiomyopathy, known as desmin-related myopathies. We identified a novel desmin missense mutation, Thr219Pro, in the homozygous state in a patient, who first manifested with hypertrophic cardiomyopathy and later progressed to general myopathy. His parents were heterozygous for the mutation, but showed no clinical abnormality, suggesting the recessive inheritance of the mutation. We here report a severe phenotype of hypertrophic cardiomyopathy preceded the onset of general myopathy caused by a novel homozygous missense mutation in the 1B α-helix domain of desmin.