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Biomedical subjects

Y H Wei

Publications and source records attributed to Y H Wei.

At least 73 records · Page 4Linked to original sources
PubMed1998

Energy charge is not decreased in lymphocytes of patients with Leber's hereditary optic neuropathy with the 11,778 mutation.

OBJECTIVES: A defect in mitochondrial energy conservation is strongly suggested to be involved in the pathogenesis of Leber's hereditary optic neuropathy (LHON). The authors therefore compared the energy charge in lymphocytes among patients with LHON, their asymptomatic maternal lineages, and normal control subjects. MATERIALS AND METHODS: Blood samples were obtained from 7 patients, 10 asymptomatic maternal relatives, and 16 normal subjects. Molecular analysis confirmed that all had the homoplasmic 11,778 point mutation in the mtDNA of their blood cells. The concentrations of adenosine triphosphate (ATP), diphosphate (ADP), and monophosphate (AMP) were determined by high-performance liquid chromatography. The energy charge was calculated as (ATP + 1/2 ADP)/(ATP + ADP + AMP). RESULTS: The mean energy charges of lymphocytes were 0.871 +/- 0.049 in patients with LHON, 0.884 +/- 0.061 in their asymptomatic maternal relatives, and 0.885 +/- 0.061 in normal controls, respectively. No statistically significant difference was found among the three groups. CONCLUSIONS: Although the study did not find the anticipated change in energy charge in peripheral blood cells, this neither confirms nor rejects the notion that a defect in the mitochondrial oxidative phosphorylation system is involved in the pathogenesis of LHON.

Adenosine Diphosphate↗
PubMed1998

Mitochondrial myopathy with predominant respiratory dysfunction in a patient with A3243G mutation in the mitochondrial tRNA(Leu(UUR))gene.

We report a patient with the A3243G point mutation of mitochondrial DNA (mtDNA) who presented with severe impairment of respiratory function and only mild involvement of limb muscles. This 55-year-old woman had a history of repeated episodes of respiratory failure unexplained by lung disease or central nervous system lesions. Needle electromyography suggested myopathy and muscle biopsy showed many ragged-red fibers. Molecular analysis of mtDNA in blood and muscle cells showed an A3243G point mutation in the tRNA(Leu(UUR))gene; the percentages of mutant mtDNA in blood and muscle cells were 65% and 71%, respectively. These findings suggest that mitochondrial myopathy should be considered as a cause of respiratory failure due to neuromuscular disorders, and that pure myopathy with predominant respiratory dysfunction is one of the heterogeneous phenotypic features associated with the A3243G point mutation of mtDNA.

Female↗
PubMed1997

Smoking-associated mitochondrial DNA mutations in human hair follicles.

The mitochondrial DNA (mtDNA) of hair follicles was used for studying the genotoxicity of smoking-mediated carcinogens. We determined the incidences of the 4,977 bp and 7,436 bp mtDNA deletions, tandem duplication in the D-loop region and the proportion of the 4,977 bp deleted mtDNA (dmtDNA) in the total DNA of hair follicles from 213 male non-smokers and 74 male smokers, respectively. Twenty-three patients with lung cancer were also investigated. We found that the current cigarette smokers had a 3.1 times higher average incidence of the 4,977 bp dmtDNA (RR: 3.1, P < 0.001) as compared with non-smokers, and this mtDNA deletion was especially prevalent in the old heavy smokers. For the smokers of the age above 70, the average incidence of the 4,977 bp dmtDNA was 3.7 times higher in the group with a smoking index of 401-800 (RR: 3.7, P < 0.005) and 3.2 times higher in the group with a smoking index greater than 800 (RR: 3.2, P < 0.005). However, there was no statistically significant relationship between the incidence of the 7,436 bp dmtDNA and the smoking index, although there was a mild increase in the percentage of the 7,436 bp dmtDNA with the increase of the consumption of cigarettes. No tandem duplication of mtDNA in the D-loop region was disclosed in either smokers or non-smokers group. The proportions of the 4,977 bp dmtDNA in hair follicles were found to correlate with age, but did not keep increasing with cigarette consumption except in the group of subjects with a smoking index of less than 400. On the other hand, we found that the average proportion of the 4,977 bp dmtDNA in the hair follicles was 1.201 +/- 0.371% for the patients with lung cancer who had a smoking index greater than 400, while that was only 0.146% for the age-matched healthy smokers with the same smoking index. In conclusion, the high incidence of the 4,977 bp dmtDNA of hair follicles is not only associated with aging but also correlated with the amount of cigarette smoking. A high proportion of the 4,977 bp dmtDNA in the hair follicles may be considered one of the molecular events that are associated with the occurrence of smoking-associated cancers.

Adult↗
PubMed1997

In vitro and in vivo protective effect of honokiol on rat liver from peroxidative injury.

Honokiol, a compound extracted from the Chinese medicinal herb Magnolia officinalis, has a strong antioxidant effect on the inhibition of lipid peroxidation in rat heart mitochondria. To investigate the protective effect of honokiol on hepatocytes from peroxidative injury, oxygen consumption and malondialdehyde formation for in vitro iron-induced lipid peroxidation were assayed, and the mitochondrial respiratory function for in vivo ischemia-reperfusion injury were evaluated in rat liver, respectively. The inhibitory effect of honokiol on oxygen consumption and malondialdehyde formation during iron-induced lipid peroxidation in liver mitochondria showed obvious dose-dependent responses with a concentration of 50% inhibition being 2.3 x 10(-7) M and 4.96 x 10(-7) M, respectively, that is, 550 times and 680 times more potent than alpha-tocopherol, respectively. When rat livers were introduced with ischemia 60 min followed by reperfusion for 60 min, and then pretreated with honokiol (10 micrograms/kg BW), the mitochondrial respiratory control ratio (the quotient of the respiration rate of State 3 to that of State 4) and ADP/O ratio from the honokiol-treated livers were significantly higher than those of non-treated livers during reperfusion. The dose-dependent protective effect of honokiol on ischemia-reperfusion injury was 10 microgram-100 micrograms/Kg body weight. We conclude that honokiol is a strong antioxidant and shed insight into clinical implications for protection of hepatocytes from ischemia-reperfusion injury.

Animals↗
PubMed1997

Ageing-associated large-scale deletions of mitochondrial DNA in human hair follicles.

Hair follicles plucked from the bi-temporal region of the scalp of 433 Chinese subjects of different ages were used for the examination of ageing-associated mutations of human mitochondrial DNA (mtDNA). By use of PCR techniques, we detected the 4,977 bp and 7,436 bp deletions of mtDNA in hair follicles from aged individuals. The frequencies of occurrence of both mtDNA deletions were found to increase with age of the subject. Moreover, we employed a semi-quantitative PCR method to determine the proportion of the 4,977 bp deleted mtDNA (dmtDNA) in hair follicles. The results showed that the average proportion of the 4,977 bp dmtDNA in hair follicles were 0.05% +/- 0.01%, 0.00%, 0.55% +/- 0.05%, 0.52% +/- 0.24%, 0.65% +/- 0.17%, 1.33 +/- 0.25%, and 1.89% +/- 0.81% for the subjects in the age groups of 21-30, 31-40, 41-50, 51-60, 61-70, 71-80, and 81-99, respectively. Furthermore, we screened all the subjects harboring the 4,977 bp and/or 7,436 bp deletions for tandem duplications in the D-loop region of mtDNA by PCR with back-to-back primers. The results showed that none of the previously reported tandem duplications were present in all the hair follicles examined. This indicates that tandem duplications do not predispose to large-scale deletions of mtDNA. However, the data suggest that mtDNA deletions occur and accumulate in hair follicles during human ageing. As hair follicles can be easily and non-invasively obtained from the human, we suggest that the aged-dependent accumulation of dmtDNAs in hair follicles may be used for the monitoring of human ageing process.

Adolescent↗
PubMed1997

Hydroxyl radical-induced decline in motility and increase in lipid peroxidation and DNA modification in human sperm.

We employed the xanthine-xanthine oxidase system to produce H2O2 or simply used commercially available H2O2 solution to investigate the effects of exogenous hydroxyl radicals on the motility characteristics and on lipid peroxidation and DNA modification of human sperm. The functional parameters of sperm motility declined concomitantly upon incubation of sperm with hydroxyl radicals. After incubation of freshly ejaculated human sperm with 0.23 mM H2O2 in the presence of 1.8 mM ADP and 2.7 mM FeSO4 for 1 hr at 37 degrees C, 90% reduction of motility was observed. Effect of hydroxyl radicals on sperm motility was dependent on the concentrations of FeSO4 and H2O2, respectively. The remaining motility of sperm after 1 hr incubation showed negative linear correlation with FeSO4 concentration. The response of sperm motility to FeSO4 was also dependent on the concentration of H2O2. Except for the amplitude of lateral head displacement, functional parameters of sperm declined with the increase of H2O2 concentration. Moreover, we found that lipid peroxidation measured as malondialdehyde (MDA) and accumulation of modified DNA indicated by 8-hydroxy-2'-deoxyguanosine (8-OH-dG) in human sperm were significantly accelerated by exogenous hydroxyl radicals. The contents of lipid peroxides and 8-OH-dG in the spermatozoa were increased from 24.6 +/- 2.4 nmol MDA/1 x 10(7) sperm and 0.17 +/- 0.02% in the untreated group to 30.6 +/- 1.2 nmol MDA/1 x 10(7) sperm and 1.9 +/- 0.47%, respectively, in the sperm treated at 37 degrees C for 1 hr with 2.03 mM H2O2, 1.8 mM ADP and 4.5 mM FeSO4. Taken together, these results suggest that the detrimental effects of hydroxyl radicals on human sperm functions may be mediated, at least partly, through lipid peroxidation and DNA modification.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

Prevalence of apolipoprotein E genotypes in ischaemic cerebrovascular disease in end-stage renal disease patients.

BACKGROUND: Several studies have demonstrated that atherosclerotic complications are the major cause of morbidity and mortality in end-stage renal disease (ESRD) patients on dialysis. The allele epsilon 4 of apolipoprotein E (ApoE) gene has been associated with an increased risk for ischaemic cerebrovascular disease (ICVD) in general populations in recent preliminary cross-sectional studies. METHODS: The aim of our study was to prospectively investigate the risk of ischaemic cerebrovascular disease with respect to the presence of Apo epsilon 4 allele in 157 Chinese uraemic patients. RESULTS: During the 2 year follow-up, the incidence of stroke was 6.4% and the cumulative occurrence of ischaemic cerebrovascular disease was 9.6%. Further analysis showed that the cumulative occurrence of ischaemic cerebrovascular disease was 5.6% in subjects with no ApoE epsilon 4 allele and 36.8% in those with one or two ApoE epsilon 4 alleles. Univariate analysis showed that the prevalence of ischaemic cerebrovascular disease was significantly higher in the subjects with ApoE epsilon 4 allele. The mean ApoA1 plasma concentrations was significantly lower in those with ApoE epsilon 4 allele. A stepwise regression analysis showed that the presence of stroke was significantly related to the ApoE epsilon 4 genotype (P < 0.001). CONCLUSIONS: The ApoE epsilon 4 allele can be regarded as an important risk factor for ischaemic cerebrovascular disease in uraemic patients.

Adult↗
PubMed1997

Peripheral neuropathy in mitochondrial encephalomyopathies.

Seven patients with mitochondrial encephalomyopathies were studied for peripheral neuropathy by clinical, electrophysiological and pathological examinations. The clinical manifestation of neuropathy varied from asymptomatic to mild and moderate sensorimotor symptoms with painful paresthesia. Five patients (2 with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, and 3 with myoclonic epilepsy and ragged-red fibers, MERRF) had clinical symptoms and signs of polyneuropathy associated mainly with decreased amplitudes of the compound muscle or nerve action potentials in an electrophysiological study indicating axonal degeneration. Sural nerve biopsy from 1 MERRF patient, also confirmed an axonal degeneration with reduction of large myelinated fibers. Mitochondrial DNA analysis of the sural nerve from this patient showed a point mutation from A to G transition at the nucleotide position 8344 with 80% mtDNA mutation. The results of this study suggest that peripheral neuropathy is not uncommon in mitochondrial encephalomyopathies and is predominantly due to axonal degeneration.

Adolescent↗
PubMed1997

Phenytoin-mediated oxidative stress in serum of female epileptics: a possible pathogenesis in the fetal hydantoin syndrome.

1. The concentration of serum malondialdehyde (MDA) was measured as the index of lipid peroxidation in female epileptics with phenytoin (PHT) monotherapy. Sera from 20 female epileptics with PHT monotherapy, 12 female epileptics without anticonvulsant therapy and 20 female healthy controls were sampled. The levels of serum copper (S-Cu), serum zinc (S-Zn), copper/zinc superoxide dismutase (CuZn-SOD), and reduced glutathione (GSH) were analyzed as interactive factors of the oxidative stress. 2. For the female epileptics with PHT monotherapy, serum MDA concentration (2.6 +/- 0.7 microM vs control 1.8 +/- 0.6 microM, P < 0.05), CuZn-SOD activity (178.2 +/- 63.5 U/dL vs control 97/1 +/- 36.4 U/dL, P < 0.01), and S-Cu content (126.2 +/- 36.1 micrograms/dL vs control 98.4 +/- 16.7 micrograms/dL, P < 0.05) were significantly increased, but GSH level (27.5 +/- 6.8 microM vs control 32.2 +/- 5.7 microM, P < 0.05) was significantly decreased. The level of serum MDA was associated with the elevation of CuZn-SOD activity (r = 0.54, P < 0.05) and S-Cu content (r = 0.44, P < 0.05) in all the samples collected from epileptics and controls. However, there were no significant differences in all the above parameters between the female epileptics without anticonvulsant therapy and healthy controls. 3. These results indicated that oxidative stress was enhanced in the female epileptics with PHT-monotherapy. Apart from the reactive PHT intermediate, the abnormal metabolism of S-Cu, CuZn-SOD, and GSH was highly involved in the PHT-mediated toxicity. Supplement of GSH, modification of CuZn-SOD enzyme activity and reduction of the absorption of copper may prevent the incidence of fetal hydantoin syndrome during pregnancy.

Analysis of Variance↗
PubMed1997

Haplotyping of mitochondrial DNA in the D-loop region by PCR: forensic application.

A rapid and simple method using restriction enzymes to detect the restriction fragment length polymorphism (RFLP) pattern of hypervariable segment 1 in the D-loop region of human mitochondrial DNA (mtDNA) was developed. We first focused on the investigation of variations of DNA sequence in the D-loop region among Chinese subjects, as well as on the determination of RFLP patterns of each restriction enzyme. Seven restriction enzymes were used to digest a 618 bp polymerase chain (PCR) reaction product of the D-loop region of mtDNA. Frequency distribution of RFLP patterns of each restriction enzyme among 145 unrelated Chinese subjects in Taiwan was also established. For the purposes of practical forensic application, a routine typing system was designed on the basis of the RFLP data. Two short hypervariable, mtDNA fragments, which were contained within the 618 bp region, were selected for this purpose. In this haplotyping system, a 281 bp PCR-amplified DNA product was analyzed by five restriction enzymes: Mnl I, Nla III, Rsa l, Mse I and Hinf I, and a 237 bp fragment was analyzed by Kpn I. The RFLP patterns were determined by agarose gel electrophoresis of the restriction enzyme-digested DNA fragments. Six restriction enzymes. Mul I, Nla III, Rsa I. Msc I, Hinf I and Kpn 1, defined eight, four, four, five, two and four polymorphic patterns, respectively among the 145 Chinese subjects. The RFLP patterns of restriction fragments for each individual were systematically analyzed and the mtDNAs of the 145 Chinese subjects were grouped into 52 haplotypes. This PCR-RFLP haplotyping system revealed a high degree of variability and diversity of segment I in the D-loop region of human mtDNA. The power of discrimination and allelic diversity values were 0.923 and 0.929, respectively. Successful application of this haplotyping system in a murder case is also discussed.

DNA, Mitochondrial↗
PubMed1997

Mutation and oxidative damage of mitochondrial DNA and defective turnover of mitochondria in human aging.

Accumulation of somatic mutations in the mitochondrial DNA (mtDNA) is a major contributor to human aging and degenerative diseases. Rapid progress has been made in unraveling the molecular changes associated with aging. MtDNA mutations are likely early molecular events associated with human aging that may be responsible for the age-dependent decline in mitochondrial respiratory functions. Many types of mutations of the mitochondrial genome impair the function of the respiratory and oxidative phosphorylation systems. This not only results in the age-dependent decline in cellular functions, but also increases the generation of reactive oxygen species (ROS) through the respiratory chain. ROS may cause oxidative damage to mtDNA, further impairing cellular functions and thereby increasing the rate of aging. How aging is elicited by the relatively low amount (< 5%) of aging-associated mutated mtDNA in human tissues is poorly understood. Protein degradation may be a key mechanism in the formation of lipofuscin and possibly in cellular aging. The thiol proteases, critical for protein turnover and degradation, are particularly susceptible to free radical damage at their active sites. If the degradative pathway in mitochondria is defective, the mitochondrion-derived degradation intermediates accumulate within secondary lysosomes, leading to the formation of residual bodies. These degradation products may become another "stressor" to tissue cells. We therefore propose that defective mitochondrial turnover is a cause of accumulation of defective mitochondrial constituents and an important contributory factor to human aging.

Aging↗
PubMed1996

The unusual structures of the hot-regions flanking large-scale deletions in human mitochondrial DNA.

Large-scale deletions of mitochondrial DNA (mtDNA) are common events that have been found to occur in human ageing and in patients with mitochondrial myopathies. The mechanisms by which these deletions occur remain unclear, but several mechanisms have been proposed, such as slipped-mispairing, illegitimate recombination, and oxidative reactions elicited by free radicals. In addition, the DNA topological stress and local DNA structures have been suggested as the important factors in eliciting the recombinational events. Upon examination of 128 breakpoints of human mtDNA deletions that have been published in the past 8 years, we found that these large-scale deletions often occur at some 'hot-regions'. We thus hypothesized that there exist unusual structures in these regions of human mtDNA that are important for eliciting the deletions. To test this hypothesis, we used PCR techniques to amplify the sequences of the so-called hot-regions and analysed the PCR products by two-dimensional gel electrophoresis. We found that the sequences of nucleotide position (np) 5221-5988, np 6928-7493, np 7901-8732 and np 15327-16228 exhibited retarded mobilities like bent DNA structures; np 5989-6750, np 13282-13653 and np 13282-14850 showed increased mobilities like anti-bent DNA structures. Moreover, except for the sequences of np 1175-1766 found in 12 S and 16 S rRNA genes exhibiting abnormal mobility like bent DNA structures, we did not observe significant mobility abnormalities in the np 499-5545 region where deletions rarely occurred. We thus conclude that these hot-regions assume some kinds of unusual DNA structures, which may render these regions more sensitive to the attack of free radicals or serve as recognition motifs for certain recombination machinery that is involved in the large-scale deletions of human mtDNA.

Aging↗
PubMed1996

Altered mitochondrial function in fibroblasts containing MELAS or MERRF mitochondrial DNA mutations.

A number of human diseases are caused by inherited mitochondrial DNA mutations. Two of these diseases, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and MERRF (myoclonic epilepsy and ragged-red fibres), are commonly caused by point mutations to tRNA genes encoded by mitochondrial DNA. Here we report on how these mutations affect mitochondrial function in primary fibroblast cultures established from a MELAS patient containing an A to G mutation at nucleotide 3243 in the tRNA(Leu(UUR) gene and a MERRF patient containing an A to G mutation at nucleotide 8344 in the tRNA(Lys) gene. Both mitochondrial membrane potential and respiration rate were significantly decreased in digitonin-permeabilized MELAS and MERRF fibroblasts respiring on glutamate/malate. A similar decrease in mitochondrial membrane potential was found in intact MELAS and MERRF fibroblasts. The mitochondrial content of these cells, estimated by stereological analysis of electron micrographs and from measurement of mitochondrial marker enzymes, was similar in control, MELAS and MERRF cells. Therefore, in cultured fibroblasts, mutation of mitochondrial tRNA genes leads to assembly of bioenergetically incompetent mitochondria, not to an alteration in their amount. However, the cell volume occupied by secondary lysosomes and residual bodies in the MELAS and MERRF cells was greater than in control cells, suggesting increased mitochondrial degradation in these cells. In addition, fibroblasts containing mitochondrial DNA mutations were 3-4-fold larger than control fibroblasts. The implications of these findings for the pathology of mitochondrial diseases are discussed.

Cells, Cultured↗
PubMed1996

Simultaneous increase of mitochondrial DNA deletions and lipid peroxidation in human aging.

Human mtDNA is a naked circular double-stranded DNA, which is continually exposed to the matrix that contains high levels of ROS and free radicals. High oxidative stress and a lack of proofreading during mtDNA replication and efficient DNA repair mechanisms in the mitochondria have rendered mtDNA extremely vulnerable to oxidative damage. More than one dozen large-scale deletions in mtDNA have been identified in various tissues of old humans. The 4,977-bp and 7,436-bp deletions are the most prevalent and abundant ones. The onset age of various mtDNA deletions varies greatly with tissues of each individual and type of deletion. In this and previous studies, we have demonstrated with PCR techniques that the frequency of occurrence and the proportion of the 4,977-bp and 7,436-bp deleted mtDNAs are significantly increased with the age of the human. The mtDNA deletions are not detectable in any tissues from young healthy subjects or blood cells from normal individuals of any age, which indicates that the deletions are generated and accumulated only in postmitotic cells upon aging. Moreover, we found that these mtDNA deletions occur more frequently and abundantly in tissues with high energy demand (e.g., muscle) as compared to those with low energy demand. On the other hand, we found that the amount of lipid peroxides measured as malondialdehyde and the activity of manganese-superoxide dismutase in the mitochondria exhibit an age-dependent increase in various human tissues. The lipid peroxide level in muscle was significantly higher than that in the other tissues. Moreover, we found a positive correlation between the proportion of the 4,977-bp deleted mtDNA and lipid peroxide content in the mitochondria of human tissues during aging. Muscle the tissue of high energy demand, was found to be more vulnerable to oxidative damage that lead to most abundant mtDNA deletions and lipid peroxidation among all the tissues examined. Taking these results together, we suggest that the enhanced generation of reactive oxygen species and lipid peroxides in the mitochondria during the aging process occur simultaneously with large-scale deletions and the other types of mutations in mtDNA, which are early molecular events and major contributory factors of human aging.

Age Distribution↗
PubMed1996

Tandem duplications and large-scale deletions of mitochondrial DNA are early molecular events of human aging process.

Large-scale deletions and tandem duplications of mtDNA, which were originally identified in the patients with KSS or CPEO, have recently been found, although with lower abundance, in various tissues of aged individuals. By use of PCR techniques with back-to-back primers, we demonstrated for the first time that small tandem duplications occur in the D-loop of mtDNA in an age-dependent manner in human tissues. A total of 10 types of such tandem duplications were identified and confirmed by primer-shift PCR and DNA sequencing. Based on the sequence characteristics of the junction sites, we classified these small tandem duplications into 3 groups. Most of the tandem duplications were found to occur at hot spots containing poly C runs, and the number of C residues exhibited wide variations in type I, II, V, VI, VII, and VIII duplications. These observations suggest that these tandem duplications may be generated through similar recombination mechanisms. Among them, type I, II, III, IV and IX duplications were found to occur more frequently and abundantly in aging human tissues. They were not detectable in muscle, testis or skin tissues of young subjects or blood cells from subjects of any age. On the other hand, we also analyzed the samples for the aging-associated 4,977-bp and 7,436-bp mtDNA deletions. The results showed that these two deletions and some of the small tandem duplications could occur alone or in different combinations in human tissues in the aging process. From our data, no clear association between tandem duplications and large-scale deletions of mtDNA could be established. However, one common and important observation is that the incidence and abundance of some of the tandem duplications as well as the large-scale deletions were increased in an age-dependent manner. On the basis of these findings and data reported from this and other laboratories, we propose that tandem duplications and large-scale deletions of mtDNA are early molecular events of the human aging process.

Adolescent↗
PubMed1996

Leigh syndrome associated with mitochondrial DNA 8993 T-->G mutation and ragged-red fibers.

We report a 6-month-old girl with episodic hyperventilation, myoclonus, disturbed consciousness, and lactic acidosis. Brain sonogram revealed progressive ventriculomegaly, and MRI showed symmetric low densities over the putamen bilaterally with diffuse cortical cystic lesions. Ragged-red fibers were noted in the muscle biopsy. Molecular analysis revealed a heteroplasmic T-->G mutation at nucleotide position (np) 8993 of mitochondrial DNA (mtDNA). The proportion of the mutant mtDNA in the muscle of the proband was estimated to be 86%. Her mother and maternal uncle also harbored the same mutant mtDNA (54 and 48% in their leukocytes, respectively). One of her sisters carried 64% mutant mtDNA in her leukocytes, but another sister did not. These results suggest that this mutant mtDNA is transmitted through the maternal lineage in this family in a randomly segregated manner. To our knowledge, this is the first report of a Chinese patient with Leigh syndrome associated with the T-->G substitution at np 8993 of mtDNA.

DNA, Mitochondrial↗
PubMed1996

MELAS syndrome associated with a tandem duplication in the D-loop of mitochondrial DNA.

We describe a family with two cases of adult-onset mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome. Interestingly, the proband also had non-insulin dependent diabetes mellitus and hyperthyroidism. Endocrinological studies demonstrated a high titer of TSH receptor antibody in the proband and elevated levels in her maternal relatives. Analysis of mitochondrial DNA (mtDNA) showed an A-to-G transition at nucleotide position 3243 in the tRNA (Leu(UUR)) gene (A3243G) in the three generations of the family. Furthermore, a previously described -260 bp tandem duplication in the D-loop region of mtDNA was also found in the proband and her maternal relatives. To our knowledge, such kind of duplication has never before been reported in the MELAS syndrome. The proportions of mtDNA with the -260 bp tandem duplication and A3243G point mutation were 12.5% and 82% in the muscle, respectively, and 1.6% and 35% in the blood cells, respectively, of the proband. We conclude that the hyperthyroidism in this MELAS patient may be related to the tandem duplication in the D-loop of mtDNA. This study further substantiates the importance of searching for additional genetic mutations in mitochondrial encephalomyopathic patients with new clinical phenotypes.

Adult↗