Hyperkinesias in Leigh-like Syndrome with Complex-I Deficiency Due to m.10191T>C in MT-ND3

Abstract

Hyperkinesias in a patient with complex-I deficiency due to the variant m.10191T>C in MT-ND3 have not been previously reported. The patient is a 32 years-old female with multisystem mitochondrial disease due to variant m.10191T>C in MT-ND3, who has been experiencing episodic, spontaneous or induced abnormal movements since age 23. The abnormal movements started as right hemi-athetosis, bilateral dystonia of the legs, or unilateral dystonia of the right arm and leg. They often progressed to severe ballism, involving the trunk, and limbs. The arms were more dystonic than the legs. In conclusion, complex-I deficiency due to the variant m.10191T>C in MT-ND3 may manifest as multisystem disease including hyperkinesias. Neurologists should be aware of hyperkinesias as a manifestation of complex-I deficiency.

INTRODUCTION

Movement disorders are a well-known manifestation of genetic mitochondrial diseases.[1] They may manifest with Parkinsonism, chorea, dystonia, myoclonus, ataxia, or tremor.[1] Hyperkinesias in a patient with complex-I deficiency due to a variant in MT-ND3 have not been reported.

The patient is a 32-year-old female with a multisystem mitochondrial disease due to the variant m.10191T>C in MT-ND3, who noticed episodic, spontaneous, or triggered abnormal movements from age 23 years. These movements begin either as right hemiathetosis, unilateral dystonia of the right arm and leg, or bilateral dystonia of the legs, all of which progress to generalized choreoathetosis. Sometimes, they progress to ballism involving the trunk and all four limbs, sometimes with facial grimacing and left-sided facial twitching. During choreoathetosis, the arms are more dystonic, while the legs are more athetotic [Video 1]. The face displays features of usually left tardive dyskinesia, although the patient has never taken antipsychotics. The patient is usually fine with hyperkinesias, but sometimes, it can cause suffering and severe muscle burning.

The patient experiences additional symptoms, which may or may not be related to the hyperkinesias. This includes a medium-amplitude 6–8 Hz intention tremor, which is neither cerebellar nor Parkinsonian. There is also jerking of certain leg and buttock muscles and occasionally of the tongue and lips. There is sometimes lateral thrusting of the jaw, which bears a resemblance to overdose on dopaminergic drugs, or to the abuse of cocaine or methamphetamine. Additional findings include ataxia on tandem gait, bilateral blepharospasm, left-sided facial twitch, nystagmus, and leg hyperreflexia.

There are no psychological triggers, including stress, fear, startlement, or distraction, including being asked to perform complex tasks during the hyperkinesias. While nothing psychologically triggers it, the patient is sometimes upset or humiliated by it. Physical triggers include wearing off medicines, withdrawals from antidopaminergic or anticholinergic drugs, propofol, theophylline, and anything that increases nigrostriatal dopamine, such as opioids, exercise, or L-DOPA.

On the few occasions, the patient received propofol, she took over an hour longer than normal to regain consciousness, and during that hour, experienced severe ballism. During these episodes, the patient often urinated herself and sustained extensive injuries, such as bruising, torn sutures, and sprains, all while still unconscious. Multiple doses of flumazenil were ineffective. At least once, during some kind of dystonic storm, hyperkinesias caused rhabdomyolysis, manifesting with the mild elevation of temperature, tachycardia, hypertension alternating with hypotension, hyperhidrosis, and hypoxia. The patient received baclofen and was maintained on supplemental oxygen. Cerebral magnetic resonance imaging demonstrated discrete periventricular white matter hyperintensities, bilateral T2 and FLAIR hypointense lesions within the globus pallidus and midbrain, and a “face of the giant panda” sign. The hyperkinesias respond well to amantadine, all anticholinergics, tetrabenazine, baclofen, and presumably also benzodiazepines. Baclofen has only a limited effect when given orally. Tetrabenazine causes sedation and depression, limiting its usefulness. Cannabinoids were not tried.

Because hyperkinesias in a patient with complex-I deficiency due to the variant m.10191T>C in ND3 has not been previously reported, neurologists should be aware of hyperkinesias as manifestation of Leigh or Leigh-like syndrome. In general, hyperkinesias in Leigh or Leigh-like syndrome are rare. Hyperkinesias in Leigh or Leigh-like syndrome have been only reported in association with mutations in nuclear genes, such as SUCLA2,[2] DMAJC30,[3] ECHS1,[4] NDUFAF6,[5] SLC19A3,[6] SLC39A8,[7] and several others. Hyperkinesias in these patients responded to treatment, but the therapeutic approach has to be individualized.

Author contribution

JF: Design, literature search, discussion, first draft, critical comments, final approval, SM: Literature search, discussion, critical comments, final approval.

Consent to participate

Consent to participate was obtained from the patient.

Written consent for publication

Consent for publication was obtained from the patient.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Ethics approval

Ethics approval was in accordance with ethical guidelines. The study was approved by the institutional review board.

Availability of data and material

All data are available from the corresponding author.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.