Mitochondrial disorder has an inherited multi-system mitochondrial dysfunction that often involves the nervous, endocrine, renal and cardiac system. Although many molecular and cellular mechanisms leading to mitochondrial cytopathy have... more
Mitochondrial disorder has an inherited multi-system mitochondrial dysfunction that often involves the nervous, endocrine, renal and cardiac system. Although many molecular and cellular mechanisms leading to mitochondrial cytopathy have been discovered, clinical management of the disorders remains largely supportive. Many therapeutic drugs and reagents have been published effective in the past 20 years, however, none of those have been approved their efficacy by a double blind randomized placebo-controlled, or open labeled trial. In this review, we describe the current situation for developing the therapeutic drugs in mitochondrial disorders by clinical trial registry. We also describe the investigator-mediated clinical trial of L-arginine, and taurin for MELAS, and new project for developing the therapeutic drug of sodium pyruvate for lactic acidosis associated with mitochondrial disorders in Japan.
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Background and Aims: The natural course and severity of rating scale of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke (MELAS) has not been clarified. The specific aim of the present study is to estimate the incidence,... more
Background and Aims: The natural course and severity of rating scale of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke (MELAS) has not been clarified. The specific aim of the present study is to estimate the incidence, natural course and severity of the disease based on a Japanese cohort study. Methods: Demography of MELAS is collected by questionnaire. The questionnaire was constructed based on Japanese mitochondrial disease rating scale. We analysed the age, symptoms of onset, survival rate and clinical progression of MELAS. Results: We found 233 MELAS patients in Japan. There is a bimodal distribution in the onset of the disease. First symptoms were noted at the mean age of 9 years in juvenile and 32.2 years in the adult type. Death was described at a mean age of 15 years in juvenile and 40 years in the adult type. Convulsion, stroke-like episodes, headache and muscle weakness were the most frequent first symptoms in both forms. Using the Japanese mitochondria...
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Fanconi syndrome is a functional disorder of the proximal tubule, characterized by pan-aminoaciduria, glucosuria, hypophosphatemia, and metabolic acidosis. With the advancements in gene analysis technologies, several causative genes are... more
Fanconi syndrome is a functional disorder of the proximal tubule, characterized by pan-aminoaciduria, glucosuria, hypophosphatemia, and metabolic acidosis. With the advancements in gene analysis technologies, several causative genes are identified for Fanconi syndrome. Several mitochondrial diseases cause Fanconi syndrome and various systemic symptoms; however, it is rare that the main clinical symptoms in such disorders are Fanconi syndrome without systematic active diseases like encephalomyopathy or cardiomyopathy. In this study, we analyzed two families exhibiting Fanconi syndrome, developmental disability and mildly elevated liver enzyme levels. Whole-exome sequencing (WES) detected compound heterozygous known and novel BCS1L mutations, which affect the assembly of mitochondrial respiratory chain complex III, in both cases. The pathogenicity of these mutations has been established in several mitochondria-related functional analyses in this study. Mitochondrial diseases with isolated renal symptoms are uncommon; however, this study indicates that mitochondrial respiratory chain complex III deficiency due to BCS1L mutations cause Fanconi syndrome with developmental disability as the primary indications.
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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... more
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.
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Mitochondrial diabetes mellitus is a subtype of diabetes linked to mutations in mitochondrial DNA. In patients with mitochondrial diabetes mellitus, the effect of glycemic control on the serum concentrations of fibroblast growth factor 21... more
Mitochondrial diabetes mellitus is a subtype of diabetes linked to mutations in mitochondrial DNA. In patients with mitochondrial diabetes mellitus, the effect of glycemic control on the serum concentrations of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) has not been evaluated. FGF21 and GDF15 have been reported to be useful biomarkers for the diagnosis and severity assessment of mitochondrial diseases like mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Recent studies have shown FGF21 acts in an endocrine fashion to regulate glucose and lipid metabolism in type 2 diabetes mellitus, while the exact biological functions of GDF15 remain unknown. Although mitochondrial diabetes mellitus is commonly found in cases with mitochondrial diseases, the comparison of FGF21 and GDF15 levels between those with and without diabetes has not been performed. Here, we report a 24-year-old woman with mitochondrial diabetes...
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Mitochondrial disorder has an inherited multi-system mitochondrial dysfunction that often involves the nervous, endocrine, renal and cardiac system. Although many molecular and cellular mechanisms leading to mitochondrial cytopathy have... more
Mitochondrial disorder has an inherited multi-system mitochondrial dysfunction that often involves the nervous, endocrine, renal and cardiac system. Although many molecular and cellular mechanisms leading to mitochondrial cytopathy have been discovered, clinical management of the disorders remains largely supportive. Many therapeutic drugs and reagents have been published effective in the past 20 years, however, none of those have been approved their efficacy by a double blind randomized placebo-controlled, or open labeled trial. In this review, we describe the current situation for developing the therapeutic drugs in mitochondrial disorders by clinical trial registry. We also describe the investigator-mediated clinical trial of L-arginine, and taurin for MELAS, and new project for developing the therapeutic drug of sodium pyruvate for lactic acidosis associated with mitochondrial disorders in Japan.
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Mitochondrial acyl-CoA dehydrogenase 9 (ACAD9) deficiency is one of the common causes of respiratory chain complex I deficiency, which is characterized by cardiomyopathy, lactic acidemia, and muscle weakness. Infantile cardiomyopathy is... more
Mitochondrial acyl-CoA dehydrogenase 9 (ACAD9) deficiency is one of the common causes of respiratory chain complex I deficiency, which is characterized by cardiomyopathy, lactic acidemia, and muscle weakness. Infantile cardiomyopathy is the most common phenotype and is usually lethal by the age of 5 years. Riboflavin treatment is known to be effective in ~65% of the patients; however, the remaining are unresponsive to riboflavin and are in need of additional treatment measures. In this report, we describe a patient with ACAD9 deficiency who developed progressive cardiomyopathy at 8 months of age. As the patient’s left ventricular ejection fraction (LVEF) kept decreasing to 45.4% at 1 year 8 months, sodium pyruvate treatment was introduced together with a beta-blocker and coenzyme Q10. This resulted in a steady improvement, with full and sustained normalization of cardiac function without riboflavin. The therapy, therefore, might be a useful addition for the treatment of ACAD9 defici...
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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... more
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.
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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... more
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 tRNA, resulting in failure to decode codons accurately. 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 tRNA was measured before and after the trial. The proportion of patients who reached the primary endpoint (100% responder rate) was 60% (95% CI 26.2% to 87.8%). The 50% responde...
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Mitochondrial diseases are a group of genetic disorders that are characterized by defects in oxidative phosphorylation and caused by mutations in genes in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) that encode structural... more
Mitochondrial diseases are a group of genetic disorders that are characterized by defects in oxidative phosphorylation and caused by mutations in genes in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) that encode structural mitochondrial proteins or proteins involved in mitochondrial function. Mitochondrial diseases are the most common group of inherited metabolic disorders and are among the most common forms of inherited neurological disorders. One of the challenges of mitochondrial diseases is the marked clinical variation seen in patients, which can delay diagnosis. However, advances in next-generation sequencing techniques have substantially improved diagnosis, particularly in children. Establishing a genetic diagnosis allows patients with mitochondrial diseases to have reproductive options, but this is more challenging for women with pathogenetic mtDNA mutations that are strictly maternally inherited. Recent advances in in vitro fertilization techniques, including mitoch...
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Mitochondrial disorder has an inherited multi-system mitochondrial dysfunction that often involves the nervous, endocrine, renal and cardiac system. Although many molecular and cellular mechanisms leading to mitochondrial cytopathy have... more
Mitochondrial disorder has an inherited multi-system mitochondrial dysfunction that often involves the nervous, endocrine, renal and cardiac system. Although many molecular and cellular mechanisms leading to mitochondrial cytopathy have been discovered, clinical management of the disorders remains largely supportive. Many therapeutic drugs and reagents have been published effective in the past 20 years, however, none of those have been approved their efficacy by a double blind randomized placebo-controlled, or open labeled trial. In this review, we describe the current situation for developing the therapeutic drugs in mitochondrial disorders by clinical trial registry. We also describe the investigator-mediated clinical trial of L-arginine, and taurin for MELAS, and new project for developing the therapeutic drug of sodium pyruvate for lactic acidosis associated with mitochondrial disorders in Japan.
Research Interests: Humans and MELAS Syndrome
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Mitochondrial diabetes is a rare form of diabetes mellitus accounting for up to 1% of all diabetes. Pyruvate therapy has been reported to be a potential therapeutic choice for patients with mitochondrial diseases. Water-based sodium... more
Mitochondrial diabetes is a rare form of diabetes mellitus accounting for up to 1% of all diabetes. Pyruvate therapy has been reported to be a potential therapeutic choice for patients with mitochondrial diseases. Water-based sodium pyruvate solutions (0.5 g/kg, thrice/day) were administrated orally to a 32-year-old Japanese male with mitochondrial diabetes and myopathy caused by m.14709T>C mutation. At the age of 20, he was diagnosed with diabetes mellitus and started insulin therapy. He tested negative for islet cell and glutamic decarboxylase antibodies. To evaluate favorable therapeutic improvements, we measured the lactate and pyruvate levels in plasma and cerebrospinal fluid, urinary C-peptide, glycated hemoglobin and glycoalbumin levels, and total daily insulin dose (TDD). The patient experienced no side effects such as diarrhea because of pyruvate therapy. His urinary C-peptide level improved from 4.3 to 17.2 μ g/day after 1 day and to 30.2 μ g/day after 6 months of pyruv...
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Mitochondrial disorder has an inherited multi-system mitochondrial dysfunction that often involves the nervous, endocrine, renal and cardiac system. Although many molecular and cellular mechanisms leading to mitochondrial cytopathy have... more
Mitochondrial disorder has an inherited multi-system mitochondrial dysfunction that often involves the nervous, endocrine, renal and cardiac system. Although many molecular and cellular mechanisms leading to mitochondrial cytopathy have been discovered, clinical management of the disorders remains largely supportive. Many therapeutic drugs and reagents have been published effective in the past 20 years, however, none of those have been approved their efficacy by a double blind randomized placebo-controlled, or open labeled trial. In this review, we describe the current situation for developing the therapeutic drugs in mitochondrial disorders by clinical trial registry. We also describe the investigator-mediated clinical trial of L-arginine, and taurin for MELAS, and new project for developing the therapeutic drug of sodium pyruvate for lactic acidosis associated with mitochondrial disorders in Japan.
Research Interests: Humans and MELAS Syndrome
Migraine headache is a heterogenous group of neurologic disorders with high prevalence in the general population and strong familial aggregation. Epidemiologic evidence for frequent maternal transmission has long suggested a role for an... more
Migraine headache is a heterogenous group of neurologic disorders with high prevalence in the general population and strong familial aggregation. Epidemiologic evidence for frequent maternal transmission has long suggested a role for an altered mitochondrial genetic background. This is supported by the observation of impaired energy metabolism and mitochondrial function in migraine patients as well as by the frequent association of migraine headache in MELAS. In the literature, some patients having migraine headache are reported to have mitochondrial DNA abnormalities, however, systematic screening studies have failed to demonstrate the clear relationship between migraine headache and mitochondrial DNA abnormalities. Migraine may be associated with mutations of nuclear genes which encode respiratory chain enzymes.
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Fatal infantile mitochondrial cytopathy associated with a C3303T mutation in the mitochondrial tRNA(Leu(UuR)) gene has been reported clinically, biochemically and genetically. Here we have analyzed the percentage of this mutation in... more
Fatal infantile mitochondrial cytopathy associated with a C3303T mutation in the mitochondrial tRNA(Leu(UuR)) gene has been reported clinically, biochemically and genetically. Here we have analyzed the percentage of this mutation in various autopsied tissues, and also in single muscle fibers using a micromanupulator, to evaluate the correlation between the pathology and heteroplasmic condition using polymerase chain reaction/restriction fragment length polymorphism. A 5-month-old Japanese girl was admitted to our hospital showing generalized muscle weakness, hepatomegaly, and cardiomegaly with lactic acidosis, and died at 6 months of age. Skeletal muscle showed severe degenerating myopathy found to be full of ragged-red fibers (RRFs), an increased number of lipid droplets, and severe cytochrome c oxidase (COX) deficiency. Microscopically hepatocytes showed massive accumulation in lipid droplets, and the heart muscle showed a network pattern suggesting metabolic cardiomyopathy. The a...
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Cytoplasts from two unrelated patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) harboring an A----G transition at nucleotide position 3243 in the tRNA(Leu(UUR)) gene of the... more
Cytoplasts from two unrelated patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) harboring an A----G transition at nucleotide position 3243 in the tRNA(Leu(UUR)) gene of the mitochondrial genome were fused with human cells lacking endogenous mitochondrial DNA (mtDNA) (rho 0 cells). Selected cybrid lines, containing less than 15 or greater than or equal to 95% mutated genomes, were examined for differences in genetic, biochemical, and morphological characteristics. Cybrids containing greater than or equal to 95% mutant mtDNA, but not those containing normal mtDNA, exhibited decreases in the rates of synthesis and in the steady-state levels of the mitochondrial translation products. In addition, NADH dehydrogenase subunit 1 (ND 1) exhibited a slightly altered mobility on polyacrylamide gel electrophoresis. The mutation also correlated with a severe respiratory chain deficiency. A small but consistent increase in the steady-state leve...
Research Interests: Immunohistochemistry, Mitochondria, Adolescent, Protein synthesis, Biological Sciences, and 14 moreCell line, Molecular and cellular biology, Mitochondrial DNA, Humans, Child, Mutation, Female, Hybrid Solar Cells, Oxygen Consumption, Cerebrovascular Disorders, Syndrome, Protein Biosynthesis, Lactic acidosis, and Medical and Health Sciences
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Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disorder associated with heteroplasmic point mutations in the mitochondrial tRNA(Leu)(UUR) gene. While previous studies have... more
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disorder associated with heteroplasmic point mutations in the mitochondrial tRNA(Leu)(UUR) gene. While previous studies have shown that the MELAS mutation at nt-3243 results in impairments in mitochondrial protein synthesis and respiratory chain function, it was not clear whether these were associated with structural alterations in mature RNAs derived from transcription of the region containing the mutation. We have performed fine mapping and high-resolution. Northern analysis of RNAs from cybrids derived from two MELAS patients harboring the nt-3243 mutation. No differences in the size or steady-state levels of transcripts from the 16S rRNA, tRNA(Leu)(UUR), or ND 1 genes (which are contiguous in the mtDNA) were observed between cell lines containing mutated or wild-type mtDNAs. Therefore, it is not likely that the protein synthesis defects observed in cybrids with the MELAS-3243 mutation are directly caused by qualitative alterations in either transcription termination or processing of these mitochondrial RNAs.
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Research Interests: Pediatrics, Adolescent, Mitochondrial DNA, Humans, Child, and 15 moreFemale, Male, Polymerase Chain Reaction, Infant, Differential Diagnosis, Pedigree, Aged, Middle Aged, Adult, Study design, Boolean Satisfiability, Cardiomyopathies, Clinical Presentation, Age of Onset, and Paediatrics and reproductive medicine
Research Interests: Biological Chemistry, Biological Sciences, Molecular chaperones, RNA interference, Humans, and 13 moreMice, Animals, Squamous Cell Carcinoma, CHEMICAL SCIENCES, Cell Proliferation, Species Specificity, Amino Acid Sequence, Base Sequence, Gene expression profiling, Mitochondrial Proteins, Molecular Sequence Data, conserved sequence , and Medical and Health Sciences
We describe an 8-day-old baby girl presenting a fatal infantile form of hypertrophic obstructive cardiomyopathy, associated with an A8296G mutation in the mitochondrial tRNA(Lys) gene. She was born from a healthy unrelated couple, and was... more
We describe an 8-day-old baby girl presenting a fatal infantile form of hypertrophic obstructive cardiomyopathy, associated with an A8296G mutation in the mitochondrial tRNA(Lys) gene. She was born from a healthy unrelated couple, and was the first infant of dizygotic twins. Soon after birth, she was noted to have tachypnea and generalized hypotonia. She had high levels of lactate and pyruvate, and was diagnosed as having hypertrophic cardiomyopathy using echocardiography. She died by cardiac failure. Mitochondrial DNA analysis was performed by sequencing after PCR-subcloning methods, and the percentage of mutation was measured using PCR-RFLP methods. In various tissues obtained at autopsy, analysis showed a heteroplasmic population of A8296G mutation in the mitochondrial tRNA(Lys) gene in all the tissues examined. Maternal inheritance was demonstrated in the family members. Our data demonstrated that an A8296G mutation in the mitochondrial tRNA(Lys) gene showed clinical heterogeneity from a milder form previously reported as mitochondrial diabetes mellitus, to a more severe form as hypertrophic obstructive cardiomyopathy, according to the spatial distribution of this mutation. Hum Mutat 15:382, 2000.