the patient was an 11-year - old boy with no family history of optic neuropathy or dystonia .
he presented with focal dystonia in the right upper limb at 3 years of age , and his disease progressed over 4 years to dystonia in both the upper and the lower limbs on his dominant right side . at 5 years of age
however , at 7 years of age , he had severe dysarthria and was unable to walk without support owing to dystonia and spasticity .
he had neither mental retardation ( verbal iq , 129 ; performance iq , 97 ; full - scale iq , 115 by the weschler intelligence scale for children ) nor short stature .
magnetic resonance imaging findings at 3 years of age showed high signal intensity lesions in bilateral putamina on fluid - attenuated inversion recovery images ( figure 1a - c ) and diffusion - weighted images ( figure 1d ) . with time , the high signal intensity lesions on diffusion - weighted images migrated from the putamina to the caudate nuclei ( figure 1e - l ) .
the mri findings obtained at 6 years of age showed that the high signal intensity lesions had spread to the bilateral caudate nuclei and the midbrain on fluid - attenuated inversion recovery images ( figure 1i - k ) and diffusion - weighted images ( figure 1l ) . on laboratory examination at 7 years of age , blood cell counts were normal , and the concentrations of lactate and pyruvate were not elevated in serum and cerebrospinal fluid .
the serum concentrations of copper and ceruloplasmin were normal . in the serum amino acid analysis ,
organic acid level in urine , and levels of lysosomal enzyme in white blood cells were found to be normal .
sequence analysis of the white blood cell mitochondrial dna from this patient showed the presence of a homoplasmic g > a transition mutation at nucleotide position 14 459 in the reduced nicotinamide adenine dinucleotide dehydrogenase subunit 6 gene ( figure 2 ) .
a - d , brain magnetic resonance imaging ( mri ) obtained at 3 years 2 months of age shows high signal intensity lesions with partially cystic lesions in the bilateral putamina on fluid - attenuated inversion recovery images ( a - c ) and diffusion diffusion - weighted imaging ( d ) .
e - h , brain mri obtained at 5 years 2 months of age show a high signal intensity lesion that is newly detected in the left caudate nucleus on fluid - attenuated inversion recovery images ( e - g ) .
diffusion - weighted imaging shows that the bilateral putamina are iso- or hypointense and the left caudate nucleus is hyperintense ( h ) .
i - l , brain mri obtained at 6 years 11 months of age shows high signal intensity lesions spread to bilateral caudate nuclei and the midbrain ( right substantia nigra ) on fluid - attenuated inversion recovery images ( i - k ) and diffusion - weighted imaging ( l ) , in addition to the putaminal hyperintensities .
m - o , brain mri obtained at 8 years 6 months of age shows high signal intensity lesions in the bilateral putamina and caudate nuclei on t2-weighted ( m - o ) and diffusion - weighted imaging ( p ) .
q - t , brain mri obtained at 10 years 5 months of age shows high signal intensity lesions in the bilateral putamina and caudate nuclei on t2-weighted ( q - s ) and diffusion - weighted imaging ( t ) .
a - c , e - g , i - k : fluid - attenuated inversion recovery images ; m - o , q - s : t2-weighted images ; and d , h , l , p , t : diffusion - weighted images .
sequence analysis of the white blood cell mitochondrial dna from this patient shows the presence of a homoplasmic g > a transition mutation at nucleotide position 14 459 in the reduced nicotinamide adenine dinucleotide dehydrogenase subunit 6 gene .
the patient had been treated with coenzyme q10 ( 2 mg / kg / d ) , l - carnitine ( 90 mg / kg / day ) , and vitamins since the age of 4 years . however , his symptoms and mri abnormalities progressed gradually despite treatment .
therefore , oral administration of sodium succinate ( 250 mg / kg / d ) was started from the age of 7 years , on the basis of the presence of g14459a mitochondrial dna mutation ( which can cause complex i deficiency ) and a previous case report of a patient with mitochondrial encephalomyopathy , lactic acidosis , and stroke - like episodes ( melas ) . 
 
on the follow - up mri examinations over the subsequent 4 years , progression of mri abnormalities appeared suppressed , but there was no improvement in dystonia ( figure 1m - t ) .
in the present case , mitochondrial dna analysis of the entire region revealed a g > a transition mutation at nucleotide position 14 459 , leading to alanine - to - valine amino acid substitution at position 72 of the reduced nicotinamide adenine dinucleotide dehydrogenase subunit 6 of complex i. the g14459a mitochondrial dna mutation has been reported in the following patients : 9 with childhood - onset dystonia , 6 with leber hereditary optic neuropathy , 4 with leber hereditary optic neuropathy plus dystonia , 4 with leigh or leigh - like syndrome , and 4 who were clinically asymptomatic .
the general features of cases reported to be of the dystonia phenotype were progressive generalized dystonia and/or optic neuropathy .
the clinical findings of leigh disease are optic involvement , early developmental delay , and hypotonia .
the patients with leigh - like encephalopathy showed visual dysfunction , ataxia , and hearing loss .
t2-weighted magnetic resonance images showed high signal intensity lesions in the medial thalamic nuclei , anterior pons , and cerebral peduncles in one patient and in the dorsal midbrain and red nucleus in other patients , in addition to a basal ganglia lesion .
the patient reported in our study presented with the dystonic phenotype and leigh - like findings on neuroimaging , showing degeneration in the bilateral striata and right substantia nigra .
the variation in clinical expression indicates that modifying nuclear factors are likely involved , playing a role in the clinical expression of mitochondrial diseases .
the diffusion - weighted mri findings in our patient are characteristic . with time , high signal intensity lesions on diffusion - weighted images migrated from the putamina to the caudate nuclei , which closely correlated with his disease progression .
diffusion - weighted images enhance the restricted mobility of water molecules in the brain , and it is a useful tool for detecting acute ischemic lesions in patients with stroke .
the pathophysiology of the diffusion abnormalities associated with mitochondrial diseases remains unclear , although it has been reported in some patients with leigh disease .
considering the finding that diffusion abnormalities migrated from the putamina to the caudate nuclei in parallel with the disease progression in this patient , diffusion abnormalities might be caused by the chronic mitochondrial respiratory dysfunction due to the mutation of the reduced nicotinamide adenine dinucleotide dehydrogenase subunit 6 gene .
they include coenzyme q10 , cytochrome c nicotinamide , dichloroacetate , l - arginine , and succinate . these drugs ( except for l - arginine ) are mitochondrial respiratory chain enzymes or its substrates and are considered to compensate for the defects in the corresponding pathways .
because the g14459a mitochondrial dna mutation could cause complex i deficiency , oral administration of sodium succinate was started on the basis of a previous case report of a patient with melas .
the proposed pharmacological mechanism is that the respiratory capacity with the defect in complex i can be improved or restored by succinate administration through the activation of the complex ii system .
it has been reported that succinate enhances electron flow from complex ii to complex iii ( coenzyme q cytochrome c reductase ) and to complex iv ( cytochrome c oxidase ) , enabling these 2 energy coupling sites to operate normally . in the present case ,
progression of mri abnormalities appears to have been suppressed for 4 years after treatment with sodium succinate .
there is a possibility that treatment with sodium succinate is helpful in patients with g14459a mitochondrial dna mutation , although further investigation is necessary .
 this article reports the case of an 11-year - old boy with progressive dystonia caused by the homoplasmic g14459a mitochondrial dna mutation . 
 the patient presented with focal dystonia in the right upper limb at 3 years of age , which progressed over 4 years to exhibit dystonia in both the upper and lower limbs . at 7 years of age , high signal intensity lesions in the bilateral striata and the midbrain were observed on fluid - attenuated inversion recovery images . 
 it was observed on diffusion - weighted images that with time , these high signal intensity lesions migrated from the putamen to the caudate nuclei , which closely correlated with disease progression . 
 because his symptoms and abnormal magnetic resonance imaging findings progressed despite treatment with coenzyme q10 and l - carnitine , at 7 years of age he was then started on sodium succinate , hoping to improve his complex i deficiency . 
 after treatment , progression of mri abnormalities appeared to have been suppressed for 4 years , although no improvement was observed in dystonia . 
Case Report
Discussion