. they can be caused by mutations in nuclear genes either relating to mitochondrial components or mitochondrial dna ( mtdna ) .
the prevalence of mitochondrial diseases due to mutations in mtdna and related nuclear genes is estimated to be 1 in 5000 .
mutations in mtdna are much higher than those in the related nuclear genes , probably because that mitochondrial genome has been exposed in reactive oxygen species(ros ) and lacked protection structure . in 1990 , the adenine to guanine transition at the mtdna position of 3243 encoding trna was found to be the molecular basis for mitochondrial encephalomyopathy with lactic acidosis and stroke - like episodes ( melas ) .
epidemiological studies showed that m.3243a > g mutation is the most frequent pathogenic mutation in mtdna .
the prevalence of m.3243a > g mutation in mtdna is 3.5/100,000 adults in the north east of england and approximately 1/6000 in an adult population in finland .
seizures , encephalopathy , and stroke - like episodes were found in about 80% patients with melas , and short stature , deafness , cognitive impairment , exercise intolerance , migraines , depression , cardiomyopathy , cardiac conduction defects , and diabetes mellitus were also found in some melas cases . here , we summarized the clinical spectrum of m.3243a > g mutation in chinese pediatric patients , to define the common clinical manifestations and study the correlation between heteroplasmic degree of the mutation and clinical severity of the disease .
clinical data of 100 chinese pediatric patients who were first diagnosed as mitochondrial diseases through gene test for m.3243a > g mutation in peking university first hospital from 2007 to 2013 were retrospectively reviewed .
this study was approved by the medical ethics committee of peking university first hospital ( no .
a total of ten clinical characteristics including vision impairment , hearing loss , encephalopathy , myopathy , and gastrointestinal disturbances were collected from these patients .
short stature was defined as the body height less than two standard deviations below the mean height of normal children .
the peripheral blood samples were collected from these patients when they were first screened for the gene mutation .
detection of m.3243a > g mutation ratio was performed by polymerase chain reaction ( pcr)-restriction fragment length polymorphism method .
the pcr product was digested with restriction enzyme apa i , and then separated in 2% agarose gel .
the patients were divided into three groups based on mutation ratio ( low level : 030% ; middle level : 3160% ; and high level : 61100% ) .
age and mutation ratio inconsistent with gaussian distribution were presented as median ( q1 , q3 ) .
correlation between m.3243a > g mutation ratio and age was evaluated with spearman 's rank correlation method .
the differences in clinical symptom frequency of patients with low , middle , and high levels of mutation ratio were analyzed by chi - square test .
clinical data of 100 chinese pediatric patients who were first diagnosed as mitochondrial diseases through gene test for m.3243a > g mutation in peking university first hospital from 2007 to 2013 were retrospectively reviewed .
this study was approved by the medical ethics committee of peking university first hospital ( no .
a total of ten clinical characteristics including vision impairment , hearing loss , encephalopathy , myopathy , and gastrointestinal disturbances were collected from these patients .
short stature was defined as the body height less than two standard deviations below the mean height of normal children .
the peripheral blood samples were collected from these patients when they were first screened for the gene mutation .
detection of m.3243a > g mutation ratio was performed by polymerase chain reaction ( pcr)-restriction fragment length polymorphism method .
the pcr product was digested with restriction enzyme apa i , and then separated in 2% agarose gel .
the patients were divided into three groups based on mutation ratio ( low level : 030% ; middle level : 3160% ; and high level : 61100% ) .
age and mutation ratio inconsistent with gaussian distribution were presented as median ( q1 , q3 ) .
correlation between m.3243a > g mutation ratio and age was evaluated with spearman 's rank correlation method .
the differences in clinical symptom frequency of patients with low , middle , and high levels of mutation ratio were analyzed by chi - square test .
the age of the diagnosis of mitochondrial disease ranged from 2 months to 18 years , with the median age of 9 years ( 5.8 years , 12.0 years ) .
the m.3243a > g mutation ratio varied from 5% to 93% , with a median level of 44% ( 36% , 54% ) .
there was no significant difference in m.3243a > g mutation ratio between males and females ( t = 0.691 , p = 0.491 ) .
patients at the onset had one or more symptoms , including seizures ( 54% ) , muscle weakness ( 29% ) , headache complicated with vomiting ( 25% ) , decreased vision ( 18% ) , hearing loss ( 10% ) , impaired verbal communication ( 6% ) , and heart preexcitation syndrome ( 5% ) .
the most prevalent symptom of these patients was seizures ( 76% ) , followed by short stature ( 73% ) , elevated plasma lactate ( 70% ) , abnormal magnetic resonance imaging / computed tomography ( mri / ct ) changes ( 68% ) , vomiting ( 55% ) , decreased vision ( 52% ) , headache ( 50% ) , and muscle weakness ( 48% ) .
most of the patients were multisymptomatic , only two patients had one symptom , and five patients manifested two symptoms .
seizures were present in 76 patients ( 76% ) , of which 13 patients had stroke during or shortly after seizures .
recurrent headaches were found in 50 patients ( 50% ) , of which most were complicated with vomiting and/or vision loss .
sixty - eight patients ( 68% ) were found to have mri / ct abnormalities , including abnormal asymmetric signals in occipital area ( 51/68 , 75% ) , temporal area ( 21/68 , 31% ) , parietal area ( 20/68 , 29% ) , bilateral basal ganglia calcification ( 16/68 , 24% ) , cerebral atrophy ( 10/68 , 15% ) , and thalamus and brainstem lesions ( 5/68 , 7% ) .
slurred speech was present in 16 patients , of whom 3 had progressively worsening speech , and 2 had delayed speech development ( at 1.5 and 3.0 years of age ) .
seventy - three patients ( 73% ) had a short stature and 69 patients ( 69% ) had a weight loss .
fifty - five patients ( 55% ) had experienced recurrent vomiting and 38 patients ( 38% ) had diarrhea or / and constipation .
plasma lactate ranged from 1.4 to 19.0 mmol / l ( normal range : 0.72.0 mmol / l ) .
elevated plasma lactate was detected in 70 patients ( 70% ) , of which 90% had a plasma lactate > 5 mmol / l .
vision impairment was found in 52 patients ( 52% ) , of which 33 experienced blurred vision and 16 had decreased visual acuity .
reduced muscle strength was reported in 48 patients ( 48% ) , of which 31 had minimal muscle weakness in upper limbs and shoulders and 17 manifested muscle weakness in lower limbs , and 2 had walk difficulties .
thirty - seven patients ( 37% ) complained of difficulties in maintaining stability , of them 18 experienced frequent tumbling , and 38 patients ( 38% ) had compromised exercise tolerance , which appeared during running or going upstairs in most cases and during walk on flat places in only two cases .
heart diseases were detected in 35 patients ( 35% ) , of which 17 were found to have abnormal electrocardiogram such as st - t changes and arrhythmias . left ventricular hypertrophy was found in eight patients , right ventricular hypertrophy in five patients , and preexcitation syndrome in five patients .
twenty - one patients ( 21% ) had hearing impairment , presenting tinnitus or hearing loss ( mild deafness in 14 patients , moderate deafness in 5 patients , and severe deafness in 2 patients ) .
the m.3243a > g mutation ratio in peripheral leukocytes was determined in all the patients , and 32% of them had a mutation ratio above 50% .
the relationship between m.3243a > g mutation ratio and onset age was analyzed by spearman 's rank correlation method , which showed that m.3243a > g mutation ratio was correlated negatively with onset age [ r = 0.470 , p < 0.001 ; figure 1 ] .
correlation between m.3243a > g mutation ratio in peripheral leukocytes and onset age ( r=0.470 , n=100 ) .
the differences in clinical symptom frequency among patients with low , middle , and high levels of mutation ratio were analyzed by chi - square test [ table 1 ] .
there were significant differences in the frequencies of hearing loss , decreased vision , myopathy , and gastrointestinal disturbance among three groups .
however , patients with a low or middle level of m.3243a > g mutation ratio were more likely to suffer from hearing loss , decreased vision , and gastrointestinal disturbance than high level group .
analysis of clinical symptom frequency in different distributions of 3243a > g mutation ratio , n low level : a mutation ratio range 030% ; middle level : a mutation ratio range 3160% ; high level : a mutation ratio range 61100% ; mri : magnetic resonance imaging ; ct : computed tomography .
patients at the onset had one or more symptoms , including seizures ( 54% ) , muscle weakness ( 29% ) , headache complicated with vomiting ( 25% ) , decreased vision ( 18% ) , hearing loss ( 10% ) , impaired verbal communication ( 6% ) , and heart preexcitation syndrome ( 5% ) .
the most prevalent symptom of these patients was seizures ( 76% ) , followed by short stature ( 73% ) , elevated plasma lactate ( 70% ) , abnormal magnetic resonance imaging / computed tomography ( mri / ct ) changes ( 68% ) , vomiting ( 55% ) , decreased vision ( 52% ) , headache ( 50% ) , and muscle weakness ( 48% ) .
most of the patients were multisymptomatic , only two patients had one symptom , and five patients manifested two symptoms .
seizures were present in 76 patients ( 76% ) , of which 13 patients had stroke during or shortly after seizures .
recurrent headaches were found in 50 patients ( 50% ) , of which most were complicated with vomiting and/or vision loss .
sixty - eight patients ( 68% ) were found to have mri / ct abnormalities , including abnormal asymmetric signals in occipital area ( 51/68 , 75% ) , temporal area ( 21/68 , 31% ) , parietal area ( 20/68 , 29% ) , bilateral basal ganglia calcification ( 16/68 , 24% ) , cerebral atrophy ( 10/68 , 15% ) , and thalamus and brainstem lesions ( 5/68 , 7% ) .
slurred speech was present in 16 patients , of whom 3 had progressively worsening speech , and 2 had delayed speech development ( at 1.5 and 3.0 years of age ) .
seventy - three patients ( 73% ) had a short stature and 69 patients ( 69% ) had a weight loss .
fifty - five patients ( 55% ) had experienced recurrent vomiting and 38 patients ( 38% ) had diarrhea or / and constipation .
plasma lactate ranged from 1.4 to 19.0 mmol / l ( normal range : 0.72.0 mmol / l ) .
elevated plasma lactate was detected in 70 patients ( 70% ) , of which 90% had a plasma lactate > 5 mmol / l .
vision impairment was found in 52 patients ( 52% ) , of which 33 experienced blurred vision and 16 had decreased visual acuity .
reduced muscle strength was reported in 48 patients ( 48% ) , of which 31 had minimal muscle weakness in upper limbs and shoulders and 17 manifested muscle weakness in lower limbs , and 2 had walk difficulties .
thirty - seven patients ( 37% ) complained of difficulties in maintaining stability , of them 18 experienced frequent tumbling , and 38 patients ( 38% ) had compromised exercise tolerance , which appeared during running or going upstairs in most cases and during walk on flat places in only two cases .
heart diseases were detected in 35 patients ( 35% ) , of which 17 were found to have abnormal electrocardiogram such as st - t changes and arrhythmias .
left ventricular hypertrophy was found in eight patients , right ventricular hypertrophy in five patients , and preexcitation syndrome in five patients .
twenty - one patients ( 21% ) had hearing impairment , presenting tinnitus or hearing loss ( mild deafness in 14 patients , moderate deafness in 5 patients , and severe deafness in 2 patients ) .
the m.3243a > g mutation ratio in peripheral leukocytes was determined in all the patients , and 32% of them had a mutation ratio above 50% .
the relationship between m.3243a > g mutation ratio and onset age was analyzed by spearman 's rank correlation method , which showed that m.3243a > g mutation ratio was correlated negatively with onset age [ r = 0.470 , p < 0.001 ; figure 1 ] .
correlation between m.3243a > g mutation ratio in peripheral leukocytes and onset age ( r=0.470 , n=100 ) .
the differences in clinical symptom frequency among patients with low , middle , and high levels of mutation ratio were analyzed by chi - square test [ table 1 ] .
there were significant differences in the frequencies of hearing loss , decreased vision , myopathy , and gastrointestinal disturbance among three groups .
however , patients with a low or middle level of m.3243a > g mutation ratio were more likely to suffer from hearing loss , decreased vision , and gastrointestinal disturbance than high level group .
analysis of clinical symptom frequency in different distributions of 3243a > g mutation ratio , n low level : a mutation ratio range 030% ; middle level : a mutation ratio range 3160% ; high level : a mutation ratio range 61100% ; mri : magnetic resonance imaging ; ct : computed tomography .
the m.3243a > g mutation has been shown to lead to reduced levels of the trna , decrease in aminoacylation , and absence of the normal modification with 5-taurinomethyl group at the wobble base .
mitochondrial disease caused by this mutation may result from the reduction of mtdna - encoded proteins and oxidative phosphorylation activity in mitochondrial translation .
several clinical syndromes including melas , myoclonic epilepsy with ragged - red fibers , chronic progressive external ophthalmoplegia , and leigh 's syndrome may associate with m.3243a > g mutation .
patients with m.3243a > g mutation but without clinical symptoms are not uncommon . to define the spectrum of clinical manifestations due to m.3243a > g mutation
, we retrospectively reviewed clinical data of 100 chinese pediatric patients with m.3243a > g mutation regardless of their clinical presentations .
central nervous system ( cns ) is frequently involved in mitochondrial diseases because of its higher energy demand .
seizures may result from neuronal energy depletion , oxidative stress , impaired calcium signaling , immune disturbances , and deficiencies of vitamins , cofactors , and amino acids . in this study ,
the prevalence of seizures was as high as 76% , and was nearly 100% in our previous study , similar to the prevalence of 70.5% in a report of pediatric mitochondrial disease from taiwan , china .
cns symptoms are , therefore , more common and severe in children than adults . the prevalence of seizures ranged from 9% to 20% in adults . in melas patients , recurrent stroke - like episodes were more frequent in those with m.3243a > g mutation than those without the mutation .
we found stroke - like episodes in 22% patients , higher than the prevalence from patients with mitochondrial mutations other than m.3243a > g mutation .
most of our patients showed abnormal brain image findings were probably not due to vascular injuries .
bilateral basal ganglia were the most vulnerable site in this disease , followed by temporal , parietal , and occipital area , similar to the previous report .
chae et al . also observed the tendency that basal ganglia were frequently involved in patients without m.3243a > g mutation .
vomiting was more frequent than constipation or / and diarrhea , and 68% vomiting cases were complicated with headaches . a higher prevalence ( 42% ) of these symptoms
therefore , mitochondrial diseases should be considered clinically in children with unexplained vomiting and headaches .
the prevalence of cardiac involvement was highly variable in patients with mtdna mutations , ranging from 17% to 40% .
in this study , 35% patients exhibited cardiac involvement with the main manifestations of abnormal electrocardiogram ( 17% ) and left ventricular hypertrophy ( 8% ) .
the prevalence of left ventricular hypertrophy was less in our patients than the patients with m.3243a > g mutation ( 56% ) reported by majamaa - voltti et al .
pediatric patients may be the reason of that lower prevalence of cardiac involvement was present in this study . for patients suspected of mitochondrial disease , routine electrocardiogram , and ultrasonocardiography
the m.3243a > g mutation ratio in peripheral leukocytes was negatively correlated with patients onset age .
myopathy was frequently seen in patients with high level of m.3243a > g mutation ratio .
however , patients with a low or middle level of m.3243a > g mutation ratio were more likely to suffer from hearing loss , decreased vision , and gastrointestinal disturbance . in conclusion , this study summarized the common symptoms and onset symptoms in a large cohort of chinese pediatric patients with m.3243a > g mutation . in view of the fact that the diagnosis of 66% of patients was delayed an average of 2 years
, we suggested that examination of m.3243a > g mutation in mtdna should be considered in children with one or more of the symptoms including seizures , short stature , muscle weakness , headache complicated with vomiting , decreased vision , and hearing loss .
although the mutation ratio in blood sample is an available test for diagnosis of mitochondrial disease , the m.3243a > g mutation ratio is usually higher in muscle and urine sample .
therefore , the mutation ratio in other tissues , such as muscle and urine cell , should be included in the future study .
this study was supported by grants from national natural science foundation of china ( no .
this study was supported by grants from national natural science foundation of china ( no . 81271256 and no .
 background : mitochondrial diseases are a group of energy metabolic disorders with multisystem involvements . 
 variable clinical features present a major challenge in pediatric diagnoses . 
 we summarized the clinical spectrum of m.3243a > g mutation in chinese pediatric patients , to define the common clinical manifestations and study the correlation between heteroplasmic degree of the mutation and clinical severity of the disease.methods:clinical data of one - hundred pediatric patients with symptomatic mitochondrial disease harboring m.3243a > g mutation from 2007 to 2013 were retrospectively reviewed . 
 detection of m.3243a > g mutation ratio was performed by polymerase chain reaction ( pcr)-restriction fragment length polymorphism . 
 correlation between m.3243a > g mutation ratio and age was evaluated . 
 the differences in clinical symptom frequency of patients with low , middle , and high levels of mutation ratio were analyzed by chi - square test.results:sixty-six patients ( 66% ) had suffered a delayed diagnosis for an average of 2 years . 
 the most frequent symptoms were seizures ( 76% ) , short stature ( 73% ) , elevated plasma lactate ( 70% ) , abnormal magnetic resonance imaging / computed tomography ( mri / ct ) changes ( 68% ) , vomiting ( 55% ) , decreased vision ( 52% ) , headache ( 50% ) , and muscle weakness ( 48% ) . 
 the mutation ratio was correlated negatively with onset age ( r = 0.470 , p < 0.001 ) . 
 myopathy was more frequent in patients with a high level of mutation ratio . 
 however , patients with a low or middle level of m.3243a > g mutation ratio were more likely to suffer hearing loss , decreased vision , and gastrointestinal disturbance than patients with a high level of mutation ratio.conclusions:our study showed that half of chinese pediatric patients with m.3243a > g mutation presented seizures , short stature , abnormal mri / ct changes , elevated plasma lactate , vomiting , and headache . 
 pediatric patients with these recurrent symptoms should be considered for screening m.3243a > g mutation . 
 clinical manifestations and laboratory abnormalities should be carefully monitored in patients with this point mutation . 
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Subjects
Mitochondrial DNA analysis
Statistic analysis
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Clinical features of patients
Correlation between m.3243A>G mutation ratio and onset age
Clinical symptom frequency of patients with different mutation ratio
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Financial support and sponsorship
Conflicts of interest