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Biomedical subjects

R Sakuta

Publications and source records attributed to R Sakuta.

At least 19 recordsLinked to original sources
PubMed1996

Hypertrophy of the cerebral white matter in hemimegalencephaly.

We morphometrically measured the cut surface of the cerebral hemisphere and localized epidermal growth factor (EGF)-like immunoreactivity in 4 patients with hemimegalencephaly. On the affected side, the area of cerebral white matter was more than twice as large as that on the unaffected side, while the area of the cerebral cortex on the affected side was relatively small. EGF-like immunoreactivity was demonstrated in cortical neurons (4 of 4 patients) and glial cells (3 of 4 patients), notably in astrocytes. Significant enlargement of the cerebral white matter compared to the cerebral cortex and the expression of EGF-like molecules in astrocytes suggest excessive proliferation in the white matter with hemimegalencephaly and the possible relevance of EGF to these events.

Brain↗
PubMed1995

Molecular analysis of holocarboxylase synthetase deficiency: a missense mutation and a single base deletion are predominant in Japanese patients.

Holocarboxylase synthetase (HCS) deficiency is an inherited disease of biotin metabolism characterized by a unique pattern of organic aciduria, metabolic acidosis, and skin lesions. By analysis of five patients in four unrelated families, two mutations were identified: a transition from T to C which causes an amino-acid substitution of proline for leucine at position 237 (L237P) and a single deletion of guanine (delG1067) followed by premature termination. One patient was homozygous for the L237P mutation, three patients in two families were compound heterozygotes of the missense and deletion alleles, and the other patient was heterozygous for the L237P mutation. Inheritance was successfully demonstrated in all of the patients' families by a modified PCR followed by restriction enzyme digestion. The two mutations accounted for seven of eight mutant alleles, while neither mutation was detected in 108 normal healthy Japanese children (216 alleles). Transient expression in cultured fibroblasts from a patient showed that the L237P mutation was responsible for decreased HCS activity. These results suggest that the L237P and delG1067 mutations are frequent disease-causing mutations in Japanese patients with HCS deficiency. This PCR-based technique may therefore be useful for detecting mutations among Japanese patients.

Amino Acid Sequence↗
PubMed1995

The 8,344 mutation in mitochondrial DNA: a comparison between the proportion of mutant DNA and clinico-pathologic findings.

Ten patients, two men and eight women with mitochondrial encephalomyopathy, had an A-G mutation at nucleotide pair 8,344 in the mitochondrial DNA, the most common genetic defect in myoclonus epilepsy with ragged-red fibers (MERRF). Eight patients had the clinical and pathologic characteristics of MERRF including myoclonus, seizures, cerebellar ataxia and myopathy with ragged-red fibers. Two patients had atypical symptoms such as early onset of fatal cardiac failure and late onset of rapid mental deterioration, respectively. The striking feature in our patients with the 8,344 mutation cardiac involvement and two developed progressive heart failure. In the typical MERRF patients, the proportion of mutant mitochondrial DNA in their skeletal muscles, quantified by a single strand conformation polymorphism analysis, was above 85%. However, there was no significant correlation between clinical severity, histopathological findings and the proportion of mutant mtDNA in muscle biopsy samples, suggesting that non-ragged-red fibers play an important role in the phenotype expression of the mutants.

Adolescent↗
PubMed1994

A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA.

BACKGROUND: Several families have been described in which a mutation of mitochondrial DNA, the substitution of guanine for adenine (A-->G) at position 3243 of leucine transfer RNA, is associated with diabetes mellitus and deafness. The prevalence, clinical features, and pathophysiology of diabetes with this mutation are largely undefined. METHODS: We studied 55 patients with insulin-dependent diabetes mellitus (IDDM) and a family history of diabetes (group 1), 85 patients with IDDM and no family history of diabetes (group 2), 100 patients with non-insulin-dependent diabetes mellitus (NIDDM) and a family history of diabetes (group 3), and 5 patients with diabetes and deafness (group 4) for the mutation. We also studied the prevalence and characteristics of diabetes in 39 patients with a syndrome consisting of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes who were known to have the mutation and 127 of their relatives (group 5). RESULTS: We identified 16 unrelated patients with diabetes associated with the A-->G mutation: 3 patients from group 1 (6 percent), 2 patients from group 3 (2 percent), 3 patients from group 4 (60 percent), and 8 patients from group 5 (21 percent). We also identified 16 additional subjects who had diabetes and the mutation among 42 relatives of the patients with diabetes and the mutation in groups 1, 2, 3, and 4 and 20 affected subjects among the 127 relatives of the patients in group 5. Diabetes cosegregated with the mutation in a fashion consistent with maternal transmission, was frequently (in 61 percent of cases) associated with sensory hearing loss, and was generally accompanied by impaired insulin secretion. CONCLUSIONS: Diabetes mellitus associated with the A-->G mutation at position 3243 of mitochondrial leucine transfer RNA represents a subtype of diabetes found in both patients with IDDM and patients with NIDDM in Japan.

Adolescent↗
PubMed1994

Mitochondrial myopathy with progressive decrease in mitochondrial tRNA(Leu)(UUR) mutant genomes.

A female patient with mitochondrial myopathy had a mitochondrial DNA mutation at nucleotide pair 3243, commonly seen in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS), but unlike MELAS patients, she had no central nervous system symptoms. Muscle weakness, which was most severe when she was 7 years old, improved gradually with age. Comparison of two muscle biopsies obtained at an interval of 12.5 years (7 and 20 years of age, respectively), revealed that the number of ragged-red fibers was markedly decreased and histochemical cytochrome c oxidase activity increased in parallel with the decrease in population of mutant genomes.

Adult↗
PubMed1994

Point mutations in mitochondrial tRNA genes: sequence analysis of chronic progressive external ophthalmoplegia (CPEO)

We have sequenced all mitochondrial tRNA genes from 9 Japanese patients with chronic progressive external ophthalmoplegia (CPEO) who had no detectable large mtDNA deletions nor mutations previously reported, and identified 6 different base substitutions in 6 patients. Since 5 of the 6 substitutions were homoplasmic in distribution and recognizable in some normal controls, they were thought to be polymorphisms in normal individuals. One mutation at nucleotide (nt) 12311 in the tRNA(Leu(CUN)) gene was not present in 90 normal controls nor in 103 patients with other mitochondrial myopathies. This mutation was in a heteroplasmic state, and the mutated site was conserved among other species during evolution, suggesting a disease-related mutation. However, the significance of this mutation has to be studied further. In Japanese CPEO patients without large deletions, a point mutation in the mitochondrial tRNA gene is not likely to be a frequent cause.

Adult↗
PubMed1994

A MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) mtDNA mutation that induces subacute dementia which mimicks Creutzfeldt-Jakob disease.

A 50-year-old woman with subacute dementia and brain atrophy on CT showed periodic synchronous discharge (PSD) on electroencephalogram (EEG) and myoclonus. She was initially suspected of suffering from Creutzfeldt-Jakob disease (CJD), but dramatically recovered over 5 months. Based on further investigations, the final diagnosis was mitochondrial encephalomyopathy with an A-to-G substitution at nucleotide position 3243 in mitochondrial DNA (mtDNA), commonly seen in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). This case suggests that patients suspected of suffering from CJD should be evaluated for mitochondrial encephalomyopathy.

Creutzfeldt-Jakob Syndrome↗
PubMed1994

[Muscle fiber involvement in Lowe syndrome].

Although it is well known fact that patients with Lowe syndrome have a delay in developmental milestones, muscle hypotonia and weakness, no detailed pathologic study to explain the muscle symptoms is available. In two patients with Lowe syndrome aged 22 years and 14 years, respectively, the biopsied biceps brachii muscles showed no significant morphologic changes except for small caliber fibers measuring almost 1/3 of the normal size. Although the muscle fiber type distribution is normal with no increase in undifferentiated type 2 C fibers, there remains a possibility of a certain defective neural influence on developing muscle fibers or metabolic defect. The muscle fiber immaturity is probably responsible for muscle weakness and hypotonia in this syndrome.

Adolescent↗
PubMed1994

[Mitochondrial encephalomyopathy associated with parkinsonism and a point mutation in the mitochondrial tRNA(Leu)(UUR)) gene].

We report a patient with mitochondrial encephalomyopathy presenting parkinsonism, as well as her brother who had ataxia but not parkinsonism. Both patients had myopathy, deafness, and insulin-dependent diabetes mellitus. The proband was a 55-year-old woman, who has developed progressive difficulty in walking and slowness of movement since 53 years of age, becoming bed-ridden at 55. Neurological examination revealed mental impairment, a masked face, Myerson's sign, vertical supranuclear ophthalmoplegia, and severe sensorineural deafness, hypokinesia, rigidospasticity, and weakness of the extremities. But tremor and cerebellar ataxia were absent. Her 48-year-old brother gradually developed weakness of the lower extremities and drunken gait over a few years. On neurologic examination, vertical supranuclear ophthalmoplegia, moderate sensorineural deafness, and cerebellar ataxia were present, but parkinsonism was absent. Three other siblings were reported to have died in early childhood. Cranial MR imaging showed cerebral atrophy and mild atrophy of the cerebellar vermis as well as mild periventricular hyperintensities in T2-weighted images in both patients. However, no infarcts were seen. Laboratory investigations revealed slightly elevated lactate and pyruvate levels in the proband and elevation of pyruvate in her brother. A biopsy specimen obtained from the quadriceps muscle showed ragged-red fibers with modified Gomori trichrome staining, and a decrease of complex I+III and complex II+III activity in the proband. Mitochondrial DNA (mtDNA) analysis using the polymerase chain reaction and restriction enzyme Apa I showed a point mutation in the tRNA(Leu)(UUR)) gene (an A to G transition at nucleotide 3243) in both patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Accumulation of mtDNA with a mutation at position 3271 in tRNA(Leu)(UUR) gene introduced from a MELAS patient to HeLa cells lacking mtDNA results in progressive inhibition of mitochondrial respiratory function.

A new mitochondrial DNA (mtDNA) mutation of tRNA(Leu)(UUR) at nucleotide position 3271 (MELAS3271) was determined to be involved in the pathogenic process of mitochondrial diseases MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) using intercellular transfer of patient-derived mtDNA to mtDNA-less HeLa cells (rho 0 HeLa cells). Cybrid clones containing imported mtDNA exclusively from a MELAS patient with MELAS3271 mtDNA were isolated, and the influence of MELAS3271 mtDNA on mitochondrial translation activity and mitochondrial respiratory complex I enzyme activity were examined. Accumulation of more than 87% MELAS3271 mutant mtDNA in the cybrid clones induced both low complex I activity and abnormal mtDNA-encoded polypeptide synthesis including at least complex I subunit ND6. suggesting involvement of the new MELAS-associated mutation in the pathogenesis.

Blotting, Southern↗
PubMed1993

Increased mitochondrial DNA in blood vessels and ragged-red fibers in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).

Using in situ hybridization, we studied muscle biopsy specimens from 4 patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Three of the 4 patients with MELAS had a mutation at position 3243 of mitochondrial DNA (mtDNA) in the transfer RNALeu(UUR) gene, and the other patient had a mutation at position 3271 in the same transfer RNALeu(UUR) gene. Quantitative analysis using Southern blot hybridization and polymerase chain reaction showed 80 to 90% mutant mtDNA in muscle. In situ hybridization analysis showed that total mtDNAs (both normal and mutant) were extremely increased in blood vessels with high succinate dehydrogenase activity (strongly succinate dehydrogenase-reactive blood vessels) and ragged-red fibers. Cytochrome c oxidase activity in most of these reactive blood vessels and ragged-red fibers was positive. The similar morphological behavior in these vessels and fibers suggests that an increase in mutant mtDNA is responsible for mitochondrial proliferation and dysfunction in both tissues where cytochrome c oxidase is not a primarily defective enzyme. The pattern of expression of genes for mtDNA-encoded ribosomal RNA and the protein-coding region cytochrome c oxidase subunit II were similar in muscle specimens of patients with MELAS, patients with chronic progressive external ophthalmoplegia, and normal control subjects, and also between the two MELAS mutations. These results do not support the hypothesis that impaired transcription termination is a molecular defect in MELAS.

Blood Vessels↗
PubMed1993

Mitochondrial DNA mutations at nucleotide positions 3243 and 3271 in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes: a comparative study.

Of 50 patients with the clinical characteristics of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), 38 had a point mutation at nucleotide position (nt) 3243 in the tRNA(Leu(UUR)) region in mitochondrial DNA and 6 at nt 3271 in the same tRNA(Leu(UUR)) gene. Except for the later onset of the disease in the patients with the 3271 mutation, there were no clinical, biochemical and pathological differences between the two groups. Since the nt 3271 region is not located in the binding site for mitochondrial transcription termination (mTERM) factor, which has been proposed to be defective in the 3243 mutation, a functional defect in tRNA itself might be responsible for the enzyme defects in MELAS patients; however the mechanism by which the defective tRNA(Leu(UUR)) induces the stroke-like episodes remains to be clarified.

Adolescent↗
PubMed1993

A T-to-G mutation at nucleotide pair 8993 in mitochondrial DNA in a patient with Leigh's syndrome.

We studied a patient with Leigh's syndrome using neurophysiologic, radiologic, enzymatic, biochemical, and molecular analysis. Her clinical course had started with acute encephalopathic symptoms at 7 months of age. With repeated remission and exacerbation, she developed hypotonia and symptoms of brainstem dysfunction, such as irregular respiration and swallowing difficulty. These symptoms were followed by epileptic seizures, including simple partial seizures and tonic spasms. Both serum lactate and serum pyruvate levels were elevated, and deficient activity was detected in cytochrome c oxidase in her quadriceps femoris muscle. From the early stages, we noted an abnormality in the auditory brainstem response and visual evoked potentials, and an abnormal symmetrical low-density area in the basal ganglia on the computed tomographic scan. We found a mitochondrial DNA point mutation at 8993 in blood samples from both the patient and her mother using a simple polymerase chain reaction method. The ratio of wild and mutant mitochondrial DNA calculated densitometrically on polymerase chain reaction products was 56.6% in the patient's blood cells and 8.4% in her mother's. This patient's disorder was thought to be maternally inherited Leigh's syndrome. Her brother had died of the identical clinical features at 1 year 9 months of age.

Base Composition↗