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CASE REPORT
Year : 2015  |  Volume : 10  |  Issue : 3  |  Page : 254-257
 

A case of mitochondrial cytopathy with exertion induced dystonia


1 Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
2 Department of Clinical Neurosciences, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India

Date of Web Publication18-Sep-2015

Correspondence Address:
Sadanandavalli Retnaswami Chandra
Department of Neurology, Faculty Block, Neuro Centre, National Institute of Mental Health and Neurosciences, Bengaluru - 560 029, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1817-1745.165683

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   Abstract 

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.


Keywords: Complex 1 deficiency, mitochondrial cytopathy, paroxysmal exertion induced dystonia


How to cite this article:
Chandra SR, Issac TG. A case of mitochondrial cytopathy with exertion induced dystonia. J Pediatr Neurosci 2015;10:254-7

How to cite this URL:
Chandra SR, Issac TG. A case of mitochondrial cytopathy with exertion induced dystonia. J Pediatr Neurosci [serial online] 2015 [cited 2021 May 16];10:254-7. Available from: https://www.pediatricneurosciences.com/text.asp?2015/10/3/254/165683



   Introduction Top


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. It may be familial or sporadic. Mutation in GLUT-1 gene through SLCZA1, which is a solute carrier for glucose transportation, causes energy deficiency on exertion. This is associated with hypoglycorrhachia and hypoglycemia. The nonexertion induced paroxysmal dystonias is not associated with above change. Prenatal diagnosis is possible in this condition with DNA analysis of fetal cells. 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. [1],[2]

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. [1] 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. [2] Sixty-two percent reduction in platelet mitochondrial complex I is seen in patients with segmental and generalized dystonia and 37% reduction in focal dystonia. [3] 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. [4],[5] 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. [5],[6],[7],[8]

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. The attacks can vary from seconds to several hours.


   Case Report Top


Our patient is the second child of first degree consanguineous parents born naturally at full term. His birth weight was 2.3 kg. His milestones were normal till 2½ years, and he was fully vaccinated. After 2½ years, it was noticed that while running he was experiencing pain in the limbs which forced him to take brief periods of rest. He also experienced intermittent stiffness of limbs. 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. The attacks were also precipitated by unexpected movements and prolonged walking. Based on these features, they were diagnosed as having kinesigenic dystonia. 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 showed café au lait spot in the abdomen. There was the mild prominence of the calf muscles and the paraspinal muscles with scoliosis to the left. His cranial nerve examination, reflexes, power, and sensations were normal. 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, the possibility of mitochondrial disease was considered and the child was investigated. 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. Forearm exercise test was not done in view of the risk of potential myoglobinuria. 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. Blood spot screening for inborn errors of metabolism by tandem mass spectrometry was negative. Magnetic resonance imaging brain showed mild hyperintensities in tectum and central tegmental tract and in the pontine tegmentum [Figure 2].

Left biceps biopsy stained with eosin, hematoxylin, modified Gomori's trichrome, and periodic acid-Schiff was negative for ragged red or ragged blue fibers. IQ assessment showed moderate mental retardation with IQ of 38. His thyroid functions and homocysteine were normal. Mitochondrial genetics for T12706C, A13084T, 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 that child became asymptomatic for 2½ years. 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. Molecular genetic analysis for PolG and SURF 1 genes was done. There were 32 variations in the mitochondrial DNA but they were nonpathogenic. 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.
Figure 1: Family history of mental retardation, deafness found in the paternal side and cleft lip in the mother

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Figure 2: (a-c) Magnetic resonance imaging brain shows mild hyperintensities in tectum and central tegmental tract and in the pontine tegmentum

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   Discussion and Conclusion Top


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 2½ 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. Similarly, in mitochondrial diseases, there is oxygen transport failure on exertion. Complex I is the largest of the five multiprotein complexes of mitochondria. This is also called as NADH: Ubiquinone oxidoreductase. 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. [6],[7],[8]

Exertion induced dystonia as a manifestation of mitochondrial disease is an uncommon presentation, and there is only one case reported in the literature. [8]

Acknowledgment

We acknowledge with gratitude Dr. Thangaraj, Principal Scientist from Center for Cellular and Molecular Biology Hyderabad, as well as Dr. M. Gayathri, Professor, Department of Neuropathology, National Institute of Mental Health and Neurosciences for their assistance.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
   References Top

1.
Unterberger I, Trinka E. Diagnosis and treatment of paroxysmal dyskinesias revisited. Ther Adv Neurol Disord 2008;1:4-11.  Back to cited text no. 1
    
2.
Wallace DC, Murdock DG. Mitochondria and dystonia : t0 he movement disorder connection? Proc Natl Acad Sci U S A 1999;96:1817-9.  Back to cited text no. 2
    
3.
Jun AS, Trounce IA, Brown MD, Shoffner JM, Wallace DC. Use of transmitochondrial cybrids to assign a complex I defect to the mitochondrial DNA-encoded NADH dehydrogenase subunit 6 gene mutation at nucleotide pair 14459 that causes Leber hereditary optic neuropathy and dystonia. Mol Cell Biol 1996;16:771-7.  Back to cited text no. 3
    
4.
Benecke R, Strümper P, Weiss H. Electron transfer complex I defect in idiopathic dystonia. Ann Neurol 1992;32:683-6.  Back to cited text no. 4
    
5.
Périer F, Radeke CM, Raab-Graham KF, Vandenberg CA. Expression of a putative ATPase suppresses the growth defect of a yeast potassium transport mutant : i0 dentification of a mammalian member of the Clp/HSP104 family. Gene 1995;152:157-63.  Back to cited text no. 5
    
6.
Mehndiratta MM, Agarwal P, Tatke M, Krishnamurthy M. Neurological mitochondrial cytopathies. Neurol India 2002;50:162-7.  Back to cited text no. 6
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7.
Moustris A, Edwards MJ, Bhatia KP. Movement disorders and mitochondrial disease, Handbook of Clinical neurology. 1 st ed., Ch. 10. Amsterdam, New York: American Elsevier Pub Co.; 2011. p. 173-92.  Back to cited text no. 7
    
8.
Distelmaier F, Koopman WJ, van den Heuvel LP, Rodenburg RJ, Mayatepek E, Willems PH, et al. Mitochondrial complex I deficiency : f0 rom organelle dysfunction to clinical disease. Brain 2009;132(Pt 4):833-42.  Back to cited text no. 8
    


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