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Table of Contents
CASE REPORTS
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 92-95

MT-ND5 gene mutation-associated mitochondrial complex I cytopathy in Leigh syndrome presenting as writer’s cramp: A case report


1 Gleneagles Global Health City, 439 Cheran Nagar, Perumbakkam, Chennai, Tamil Nadu, India
2 SM Hospital, Chapaguri Road, North Bongaigaon, Assam, India
3 Department of Neurology, Nanavati Hospital, Mumbai, Maharashtra, India
4 Aster MIMS Hospital, Mini Bypass Road, Govindpuram, Kozhikod, Kerala, India

Date of Submission10-Aug-2020
Date of Decision12-Mar-2021
Date of Acceptance28-Jul-2021
Date of Web Publication30-Aug-2021

Correspondence Address:
Dr. Vikash Agarwal
4C, BBCL Ananya, 17/34 Five Furlong Road, Guindy, Chennai 600032, Tamil Nadu.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AOMD.AOMD_38_20

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  Abstract 

Leigh syndrome is a classical mitochondrial cytopathy with multisystemic presentation that can lead to death in the first few years of life; however, cases in adults have also been reported. In this study, we report the case of an adolescent female presenting with writer’s cramp associated with the MT-ND5 gene mutation, diagnosed after observation of brain abnormalities on magnetic resonance imaging (MRI) and biochemical changes suggestive of mitochondrial cytopathy. The patient responded to botulinum toxin injection. To the best of our knowledge, ours is the first case report on focal dystonic presentation associated with the MT-ND5 gene mutation (with unclear pathogenicity) as a mild form of Leigh syndrome in adolescents.

Keywords: Focal dystonia, Leigh syndrome, mitochondrial cytopathy, MT-ND5 gene, writer’s cramp


How to cite this article:
Agarwal V, Mushahary D, Venkitachalam A, Babu SS, Nayak D. MT-ND5 gene mutation-associated mitochondrial complex I cytopathy in Leigh syndrome presenting as writer’s cramp: A case report. Ann Mov Disord 2021;4:92-5

How to cite this URL:
Agarwal V, Mushahary D, Venkitachalam A, Babu SS, Nayak D. MT-ND5 gene mutation-associated mitochondrial complex I cytopathy in Leigh syndrome presenting as writer’s cramp: A case report. Ann Mov Disord [serial online] 2021 [cited 2021 Dec 1];4:92-5. Available from: https://www.aomd.in/text.asp?2021/4/2/92/324802




  Introduction Top


Archibald Denis Leigh first described Leigh syndrome in 1951, and since then the knowledge of mitochondrial disorders has rapidly evolved. Complex I deficiency, a mitochondrial disorder, is the most common cause of Leigh syndrome.[1] The MT-ND5 gene mutation has recently been linked to persistent DNA damage responsible for causing oxidative stress in Parkinson’s disease and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.[2],[3] Mitochondrial disorders can present with pure hyperkinetic movement disorders such as focal dystonia.[4] Here, we report the case of an adolescent female presenting with writer’s cramp associated with the MT-ND5 gene mutation and MRI brain abnormalities suggestive of mitochondrial cytopathy. The patient’s writing ability was affected, which improved with botulinum toxin injection similar to that in idiopathic writer’s cramp. The pathogenicity of the mutation identified in our case is not entirely understood and needs to be further evaluated in future studies in a clinical setting.


  Case Report Top


A 17-year-old female, with normal birth and development, and without any remarkable family history, presented with gradual deterioration of writing ability since the previous two years. She experienced difficulty in holding objects, and buttoning and unbuttoning her clothes for the last six months. Clinical examination of her cognitive functions (Montreal Cognitive Assessment, 30/30) and cranial nerves was normal. Extraocular eye movements were full and horizontal and vertical saccades were normal without nystagmus. Her right upper limb showed a focal extensor type of writer’s dystonia with dystonic tremor. A 1/4-grade kinetic tremor of the right hand with mildly impaired finger-nose-finger test was observed, suggesting cerebellar pathway localization. The Archimedes spiral test was grossly abnormal for the right hand (Video 1). Muscle power was normal and tendon jerks were normally elicitable. Furthermore, sensory examination assessing joint position and vibration was normal. Flexor plantar reflex was bilateral. The patient’s tandem walk test showed mild abnormality. Serum ferritin levels were low (10ng/mL; reference range, 13–150), with a normal total iron-binding capacity of 324 mg/dL (reference range, 250–425). Her serum ceruloplasmin level was 25.6 mg/dL (reference range, 15–30). Cerebrospinal fluid (CSF) analysis showed a protein value of 32 mg/dL, sugar level of 61 mg/dL, and CSF lactate value of 1.1 mmol/L (reference value, <1.1); CSF pyruvate was 0.44 mg/dL (reference range, 0.37–0.88). Nerve conduction studies and visual evoked potentials were unremarkable. She underwent a 3T-magnetic resonance imagining (MRI) scan of the brain that revealed a moderate degree of mineral deposits in the bilateral globus pallidus, which was asymmetric (left more than right), along with hyperintensity in the bilateral thalamus, midbrain, and pons on T2-weighted imaging ([Figure 1]). There was no organomegaly and her fundus examination and systemic examination were normal.
Figure 1: (A) GPi mineral deposits in SWI–MRI brain sequence, (B) Pontine T2-weighted brain hyperintensity MRI.

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The patient underwent whole-exome sequencing (MedGenome Labs, MedGenome Labs Pvt. Ltd., Bangalore, India) for diagnosis of genetic disorders, the results of which were normal. However, 100% coverage of mitochondrial genes detected a homoplasmic missense mutation in the MT-ND5 gene (chrM:12937A>G; depth, 3401×), resulting in the amino acid substitution of Valine for Methionine at codon 201 (p.Met201Val; ENST00000361567.2) ([Figure 2]). DNA extracted from the patient’s blood was used to amplify the mitochondrial genome using long and accurate polymerase chain reaction, followed by preparation of samples using the TruSeq DNA library kit (Illumina, CA, United States). The libraries were sequenced to mean >80–100× coverage on the Illumina sequencing platform. The sequences obtained were aligned to the revised Cambridge Reference Sequence using the Burrows–Wheeler Aligner program and analyzed using the Picard and Genome Analysis Toolkit version 3.6 to identify the mutation relevant to the clinical indication.[5],[6]
Figure 2: Sequence chromatogram and alignment to the reference sequence showing the mutation in the MT-ND5 gene (chrM:12937A>G; c.601A>G; p.Met201Val) detected in homoplasmic conditions

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The patient was initially medically treated with primidone, which was titrated up to 200 mg, without remarkable clinical response. She was injected with botulinum toxin for right upper limb dystonia and showed marked subjective (up to 70%) and objective (serial writing and Archimedes spiral test samples) improvement in her symptoms ([Figure 3]). However, the effects of the toxin were temporary and lasted for only four months with the recurrence of dystonic tremor to a similar degree. She is currently being followed up and further botulinum injections are being planned.
Figure 3: (A) Pre-botulinum injection writing sample, (B) Ten days post-botulinum injection writing sample, (C) Three months post-botulinum injection writing sample

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  Discussion Top


Leigh syndrome is a neurodegenerative disease resulting from mitochondrial mutations with multisystemic presentation. It becomes apparent in infancy and can cause death in the early years of life; however, some cases have also been reported in adults.[7] Our patient presented with task-specific focal dystonia that affected writing; however, her MRI findings revealed Leigh syndrome involving the basal ganglia and brainstem, despite focal clinical phenomenology. Furthermore, she showed biochemical dysfunction as documented. As expected, the treatment response of focal dystonia with botulinum toxin was similar to that in idiopathic writer’s cramp. Leigh syndrome is associated with a high mutation load of >90%, although MT-ND5 mutations associated with complex I deficiency can cause diseases even when the mutation load is <50% in tissues including the brain, which may cause a milder phenotype. Interestingly, one study highlighted that mitochondrial ND5 protein-coding gene mutations are frequently associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, and the authors revealed that the biochemical analysis of muscle homogenates in samples from such cases showed normal or mildly reduced complex I activity.[3] In a recent series of 50 patients with genetically confirmed mitochondrial disease, three patients presented with adult-onset focal dystonia and ataxia. It has been postulated that the cerebellum is particularly vulnerable to energy deficiency in mitochondrial disorders.[4]MT-ND5 gene mutations have been reported in many mitochondrial diseases, such as Leber’s hereditary optic neuropathy (LHON).[8],[9],[10] The visual evoked potentials in our case were normal; similarly, ophthalmological check-up revealed no abnormalities, ruling out the clinical possibility of LHON. Future studies should investigate the mutation identified in our case in detail, to establish its pathogenicity. Through our study, we highlight that the MT-ND5 gene should be examined for pathogenic mutations in suspected mitochondrial cytopathies presenting as isolated focal dystonia with brain imaging and biochemical abnormalities.

Declaration of patient consent

The authors declare that they have obtained all appropriate signed patient consent forms. The patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity but anonymity cannot be guaranteed.

Author contributions

Vikash Agarwal: Conception and design of work, data analysis and interpretation, drafting primary manuscript; Dolly Mushahary: Genetic data collection, manuscript drafting; Anil Venkitachalam: Critical revision of the manuscript; Sachin Suresh Babu: Critical revision of the manuscript; Dinesh Nayak: Manuscript editing and approval for publication.

Ethical compliance statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Conflicts of interest

There are no conflicts of interest to declare.

Financial support and sponsorship

None.



 
  References Top

1.
Lake NJ, Compton AG, Rahman S, Thorburn DR. Leigh syndrome: One disorder, more than 75 monogenic causes. Ann Neurol 2016;79:190-203.  Back to cited text no. 1
    
2.
Pignataro D, Francia S, Zanetta F, Brenna G, Brandini S, Olivieri A, et al. A missense MT-ND5 mutation in differentiated Parkinson Disease cytoplasmic hybrid induces ROS-dependent DNA damage response amplifed by DROSHA. Sci Rep 2017;7:9528.  Back to cited text no. 2
    
3.
Liolitsa D, Rahman S, Benton S, Carr LJ, Hanna MG. Is the mitochondrial complex I ND5 gene a hot-spot for MELAS causing mutations? Ann Neurol 2003;53:128-32.  Back to cited text no. 3
    
4.
Schreglmann SR, Riederer F, Galovic M, Ganos C, Kägi G, Waldvogel D, et al. Movement disorders in genetically confirmed mitochondrial disease and the putative role of the cerebellum. Mov Disord 2018;33:146-55.  Back to cited text no. 4
    
5.
McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The genome analysis toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 2010;20:1297-303.  Back to cited text no. 5
    
6.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-24.  Back to cited text no. 6
    
7.
McKelvie P, Infeld B, Marotta R, Chin J, Thorburn D, Collins S, et al. Late-adult onset Leigh syndrome. J Clin Neurosci 2012;19:195-202.  Back to cited text no. 7
    
8.
Taylor RW, Morris AA, Hutchinson M, Turnbull DM. Leigh disease associated with a novel mitochondrial DNA ND5 mutation. Eur J Hum Genet 2002;10:141-4.  Back to cited text no. 8
    
9.
Mayorov V, Biousse V, Newman NJ, Brown MD. The role of the ND5 gene in LHON: Characterization of a new, heteroplasmic LHON mutation. Ann Neurol 2005;58: 807-11.  Back to cited text no. 9
    
10.
Coller HA, Khrapko K, Bodyak ND, Nekhaeva E, Herrero-Jimenez P, Thilly WG. High frequency of homoplasmic mitochondrial DNA mutations in human tumors can be explained without selection. Nat Genet 2001;28; 147-50.  Back to cited text no. 10
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

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