paroxysmal dystonias are classified into paroxysmal kinesigenic dystonias ( pkds ) , paroxysmal nonkinesigenic dystonias , paroxysmal exertion induced dystonias ( peds ) , and paroxysmal hypnogenic dystonias .
transient sudden movements triggered by exercise , which may or may not be associated with pain involving the lower limbs more than the upper limbs are designated as peds .
mutation in glut-1 gene through slcza1 , which is a solute carrier for glucose transportation , causes energy deficiency on exertion .
increase in cerebrospinal fluid homovanillic acid and 5-hydroxyindoleacetic acid with ped is reported in some patients with associated young - onset parkinson 's disease , epilepsy and migraine , and linkage to chromosome 16q11.2-q22.1 , as well as in 16p11.2-q11.2 has been reported .
the role of mitochondria in movement disorders came to be known with reference to dystonia with the discovery of missense mutation in mitochondrial dna complex 1 , which is maternally inherited through mtnd6 gene .
the oxidative phosphorylation ( oxphos ) components of the mitochondria are assembled from the genes distributed between mitochondrial dna and nuclear dna ( ndna ) .
the components thus assembled are the inner membrane enzyme complexes i , ii , iii , iv , and v , protein kinases such as adenine dinucleotide translocators and mitochondrial biogenesis proteins which involves the apparatus to import cytoplasmically synthesized mitochondrial proteins needed for assembly and turnover .
fifty - five percent of reduction in complex i occurs when alanine at position 72 is converted to valine by a mutation in mitochondrial dna complex i gene mtnd6 in leber 's hereditary optic atrophy causing early - onset hereditary dystonia .
sixty - two percent reduction in platelet mitochondrial complex i is seen in patients with segmental and generalized dystonia and 37% reduction in focal dystonia .
dfn-1 gene defect causes x - linked mohr - tranebjaerg syndrome with deafness and dystonia and skd3 protein is linked with dystonia and its gene product is functionally similar to dyt1 gene product raising strong possible role of ndna encoded mitochondrial genes in neurodegenerative disorders including movement disorders .
leigh 's and leigh 's like syndromes due to complex v atpase 6 and complex i ndna subunits are reported to be associated with a wide variety of movement disorders but exertion induced dystonia due to mitochondrial disease has only a passing reference in the literature .
paroxysmal dyskinesias are episodic childhood onset movement disorders usually precipitated by normal or sudden unexpected motor activity .
the types of movements seen are sudden dystonia , chorea , athetosis , and ballism , or a combination of these .
it can occur spontaneously or may be precipitated by sudden movements , prolonged exercise , caffeine and alcohol consumption , emotional stress , or fatigue .
our patient is the second child of first degree consanguineous parents born naturally at full term .
after 2 years , it was noticed that while running he was experiencing pain in the limbs which forced him to take brief periods of rest .
he was poor in studies . from the age of 5 years , after walking some distance he used to experience abnormal twisting of the trunk to one side , most often to the right side with episodes of difficulty in speaking , and swallowing with abnormal posturing of the right upper and lower limbs .
this was more in the morning hours and used to last for few minutes to few hours occasionally .
however , unlike the typical kinesigenic dystonia , there was absolutely no response to diphenylhydantoin or carbamazepine .
patient had an elder sibling who presented with similar symptoms and was treated in the similar fashion .
later , at the age of 10 years , he developed poor vision , which was treated with steroids and vision improved .
however , his exertion induced abnormal movements did not respond to diphenylhydantoin or carbamazepine and he was started on sodium valproate . with a single dose of sodium valproate child became drowsy followed by myoglobinuria , renal shutdown , and passed away within 24 h. the second child was brought to our center in february 2012 . at the time of admission ,
the child was found to be short statured , his head circumference was 48 cm . in general examination
there was the mild prominence of the calf muscles and the paraspinal muscles with scoliosis to the left .
he had no evidence of involvement of other systems . however , when made to walk about 20 m child was slowly tilting to the right with dysarthria .
mother had cleft lip and father 's cousin had mental retardation [ figure 1 ] . in view of sudden deterioration and death in elder sibling with a single dose of 500 mgs sodium valproate ,
his blood routine , urine routine , renal functions , liver functions , calcium , and electrolytes were all normal .
his creatine kinase was 3177 iu ; his lactate dehydrogenase was 2728 , lactate 12.55 , ammonia 46.6 , and uric acid 2.7 mg / dl .
his urine ferric chloride test , benedict 's test , and cyanide nitroprusside tests were negative .
his auditory brainstem response , visual evoked potential , somatosensory evoked potential , electroencephalography , and ultrasound abdomen were normal .
magnetic resonance imaging brain showed mild hyperintensities in tectum and central tegmental tract and in the pontine tegmentum [ figure 2 ] .
family history of mental retardation , deafness found in the paternal side and cleft lip in the mother ( a - c ) magnetic resonance imaging brain shows mild hyperintensities in tectum and central tegmental tract and in the pontine tegmentum left biceps biopsy stained with eosin , hematoxylin , modified gomori 's trichrome , and periodic acid - schiff was negative for ragged red or ragged blue fibers .
mitochondrial genetics for t12706c , a13084 t , and g13513a in nd5 gene commonly associated with leigh 's syndrome was negative .
his repetitive nerve stimulation showed decremental response elsewhere but when repeated in our center was normal . in view of the sudden death in the elder sibling
, the child was clinically diagnosed as probable mitochondrial disease and started on a full mitochondrial cocktail . with
however , his symptoms relapsed in november 2014 . therefore , the patient was again reassessed .
his histopathology slide was reviewed with special stains and was reported as complex 1 deficiency .
polg gene sequencing of all the exons revealed 2 mutations ( c. 2021 g > a and c. 3644 - 27 t > g ) .
the c. 2021 g > a mutation was also found in the father suggesting a pathogenic mutation .
the surf1 gene analysis revealed a novel and pathogenic mutation at c. 237 g > t , which is pathogenic and inherited from the father as an autosomal dominant trait .
our patient is unique as both brothers showed the clinical phenotype of exertion induced dystonia and our only clue in the early phase of our management of this patient was the valproate induced death in his brother based on which he was put on mitochondrial cocktail .
this was lifesaving for the patient , and he was asymptomatic for more than 2 years and had a minor relapse at present .
reassessment genetically and histopathologically showed complex i deficiency with the novel , autosomal dominant , paternally inherited gene mutation .
this patient is a unique case of ped involving the trunk , upper limbs in addition to dysarthria in two siblings born to first degree consanguineous parents .
there was no response to treatment as pkd instead fatal complication occurred to the elder sibling with valproate which suggested the possibility of a mitochondrial disease and reinvestigation after 2 years showed a paternally inherited novel nuclear gene mutation causing complex i deficiency .
well known syndromes of peds are also due to energy failure due to defective glucose transport .
this constitutes the major entry point of electrons to oxphos system transferring it from nadh to ubiquinone , which is important for moving protons across the inner membrane essential for creating a negative membrane potential .
premature electron leakage to oxygen in this process makes complex i an important source of superoxide production .
complex i deficiency commonly presents with dystonia , failure to thrive , seizures , eye movement problems , lactic acidosis , and muscle weakness .
exertion induced dystonia as a manifestation of mitochondrial disease is an uncommon presentation , and there is only one case reported in the literature .
 paroxysmal dystonias are a group of relatively benign hyperkinetic childhood movement disorders of varied etiology . 
 mitochondrial diseases are well known to produce persistent dystonias as sequelae , but paroxysmal exertion induced dystonia has been reported in only one case to the best of our knowledge . 
 two siblings born to consanguineous parents presented with early - onset exertion induced dystonia , which was unresponsive to diphenylhydantoin and carbamazepine . 
 a trial with valproate in one of the siblings turned fatal within 24 h. based on this clue , the second child was investigated and found to suffer from complex i deficiency with a paternally inherited dominant nuclear dna mutation , which is responsive to the mitochondrial cocktail . 
 exertion induced dystonia can be a rare manifestation of complex i deficiency . 
Introduction
Case Report
Discussion and Conclusion
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