LINGUAL DYSKINESIA AND TICS: A NOVEL PRESENTATION OF A COPPER-METABOLISM DISORDER

by Helly R. Goez, MD, Francois D. Jacob, MD, Jerome Y. Yager, MD

Author Affiliations, Division of Pediatric Neurology, University of Alberta, Edmonton, Alberta, Canada

The Journal of Pediatrics, 2011; 127:2 e505-e508; published ahead of print January 3, 2011, doi:10.1542/peds.2010-2391

ABSTRACT

Copper is a trace element that is required for cellular respiration, neurotransmitter biosynthesis, pigment formation, antioxidant defense, peptide amidation, and formation of connective tissue.

Abnormalities of copper metabolism have been linked with neurologic disorders that affect movement, such as Wilson disease and Menkes disease.

However, the diagnosis of non-Wilson, non–Menkes-type copper-metabolism disorders has been more elusive, especially in cases with atypical characteristics.

We present here the case of an adolescent with a novel presentation of copper-metabolism disorder who exhibited acute severe hemilingual dyskinesia and prominent tics, with ballismus of the upper limbs, but had normal brain and spinal MRI results and did not show any signs of dysarthria or dysphagia.

His serum copper and ceruloplasmin levels were low, but his urinary copper level was elevated after penicillamine challenge. We conclude that copper-metabolism disorders should be included in the differential diagnosis for movement disorders, even in cases with highly unusual presentations, because many of them are treatable.

Moreover, a connection between copper-metabolism disorders and tics is presented, to our knowledge, for the first time in humans; further investigation is needed to better establish this connection and understand its underlying pathophysiology.

Key Words:

metabolic diseases, metabolic disorders, copper lingual dyskinesia, tics, movement disorders

Dr. Wilson’s comments: In our experience, just taking zinc often will not correct a copper imbalance. We believe the authors of this study were fortunate in that the young man responded well. For more about copper imbalances, read Copper Toxicity Syndromes.

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MAIN ARTICLE

Copper is needed in the body in trace amounts and serves as a cofactor of enzymes that are involved in many key processes required to sustain life; among these processes are cellular respiration, neurotransmitter synthesis, detoxification of free radicals, protein amidation, pigment production, iron oxidation, and formation of connective tissue.1,–,3 Despite these benefits, copper is also involved in the formation of free radicals; hence, its level needs to be kept within a narrow range.3

Abnormalities in copper metabolism have been described in a few disorders that affect the central nervous system, such as Wilson disease and Menkes disease.1^,4,–,6

In recent years, some reports were published of neurologic disorders associated with abnormal copper metabolism that did not fit the criteria for any known disease, which were generally referred to as non-Wilson, non-Menkes copper-metabolism disorders; many of the patients in these cases presented with movement disorders (dystonia, myoclonus, tremor, or parkinsonism), gait disturbances, dysarthria, cognitive degeneration, sensory deficits, and abnormal brain and spinal MRI results.7,–,17

We present here the case of an adolescent with a novel presentation of non-Wilson, non–Menkes-type copper-metabolism disorder that differs greatly from all other cases described to date.

CASE REPORT

A 16-year-old boy presented with complaints of abnormal tongue movements that had started ∼6 weeks before referral. The patient had been previously healthy.

He had no history of preceding infection, travel, or drug ingestion, and his family history was unrevealing. The tongue movements were described as “snake-like”; his tongue deviated to the left in a twisted fashion, and waveform movements of the right side of his tongue were noted (Fig 1).

The movements were continuous in nature and were greatly suppressed when the patient was asked to voluntarily extrude his tongue (Fig 2) (see also Supplemental Movie 1, from which the figures were taken, for better illustration of the tongue movements).

The movements did not interfere with swallowing or speech and did not persist during sleep. Over the course of the 3 weeks that followed, the activity progressed to involve his hands, which moved in a flapping-like motion.

Some movements were sudden and coarse, whereas others were jerking movements that involved proximal and distal parts of his upper limbs. Twitching leg movements that involved his thighs and feet, which resembled jumping movements, appeared as well. In parallel, some events of tilting of his neck and torso were noted; each lasted from a few hours to a day.

These tilting events resolved spontaneously and did not occur during sleep. Neither before nor during that period were any cognitive, mental, emotional, social, or academic changes observed. Moreover, no changes in eating or sleeping patterns were noted.

On neurologic examination, the patient was alert and attentive and in no distress. The unique tongue movements described above were noted, as were the limb movements (sudden ballismic movements, tic-like movements of the upper and lower limbs);

These limb movements could be suppressed voluntarily, although the patient stated that he needed to focus and put effort into it. He also complained of muscle pain after trying to suppress them for more than a few minutes. When asked to perform a complex unilateral motor task, occasional jerking movements were evident.

No neck- or torso-tilting was noted. The patient exhibited normal cranial nerves, cerebellar function, tone, muscle strength, deep-tendon reflexes, gait, and coordination. Results of a mini–mental status examination were normal.

Ophthalmologic evaluation, which included visual acuity and slit-lamp examinations, was unrevealing. No evidence of Kayser-Fleischer rings, retinal deposits, or cataract was noted.

Investigation revealed normal complete blood count, electrolyte, calcium, magnesium, vitamin D, E, and B₁₂, liver enzyme, lactate dehydrogenase, and albumin levels, renal function, and glucose, thyrotropin, free thyroxine, creatine kinase, and lactate levels. A peripheral blood smear did not reveal any acanthocytes.

A lipid profile included measurement of high- and low-density lipoprotein cholesterol, triglycerides, lipoprotein A, and apolipoproteins A and B, the results of which were all normal.

Serum and urine amino acid and organic acid levels were normal as well. Immunologic and serologic studies included antistreptolysin and anti-nuclear antibody screens, the results of which were both negative. His immunoglobulin G, M, A, and E levels were normal.

His α-fetoprotein level was normal, as were his levels of acute phase reactants and C-reactive protein and his sedimentation rate. Results of a throat swab and blood and urine cultures were all negative.

Results of a toxicological screen were also negative. His ceruloplasmin and copper levels were low: 0.13 g/L (normal range: 0.17–0.66 g/L) and 8 μmol/L (normal range: 11–28 μmol/L), respectively. These results were reproduced on 3 occasions.

A 24-hour urine collection revealed normal copper excretion; however, a penicillamine challenge revealed increased urinary copper levels of 6.2 μmol/day (normal range: 0.1–0.8 μmol/day).

These increased values were much higher than the norm but still significantly lower than the diagnostic value for Wilson disease, which is >25 μmol/day.18 After this challenge test there was significant worsening of the limb and tongue dyskinetic movements. Results of abdominal ultrasound and brain MRI were normal.

Results of ATP7B gene sequencing for Wilson disease were negative, which, combined with the absence of Kayser-Fleischer rings, the normal MRI, and the results of the penicillamine challenge, strongly argued against a diagnosis of Wilson disease.

Results of a molecular diagnostic test for Huntington disease also came back negative. Basal ganglia stroke was ruled out because of the normal MRI results, which showed no signs of lesions in the basal ganglia.

Psychogenic disorder was considered; however, the pathologic laboratory findings, combined with the fact that no cognitive, mental, emotional, social, or academic changes were reported, argued strongly against psychogenic etiology.

THERAPY

The patient was started on an oral zinc gluconate supplement at a dose of 50 mg 3 times per day because tetrathiomolybdate is not commercially available in Canada and trienthine has been reported to cause irreversible worsening of neurologic symptoms.1,–,4 Eight weeks after initiation of treatment, the movements disappeared, although his copper and ceruloplasmin levels had not yet been normalized.

DISCUSSION

Copper is a trace element that serves as a cofactor of enzymes that are involved in many key processes required to sustain life, such as tyrosinase, superoxide dismutase, cytochrome c oxidase, dopamine β-hydroxylase, and ceruloplasmin.5,–,7

However, this metal also causes the production of the free radical superoxide, which makes the healthy systemic range of copper very narrow.7

It has been established that both copper deficiency and excessive copper result in damage to the central nervous system, as evidenced by the neurologic disorders Menkes disease and Wilson disease. Menkes disease is caused by impaired copper transport into and within the central nervous system and results in neurodegeneration and demyelination. Wilson disease, on the other hand, results from copper accumulation and is characterized by dysarthria, a variety of movement disorders, and psychiatric symptoms.8,–,10

In the last 4 decades, it has been reported that some people suffer from abnormalities of copper metabolism that do not fall under the category of any known disease and are sometimes referred to as non-Wilson, non–Menkes-type copper-metabolism disorders.

Generally speaking, most cases of copper-metabolism disorder are characterized by movement disorders (dystonia, myoclonus, tremor, or Parkinsonism) and gait disturbances. Many patients with such a disorder also exhibit dysarthria, cognitive degeneration, sensory deficits, and abnormal brain and spinal MRI results.11,–,17^,19,–,22

Our patient exhibited acute severe hemilingual dyskinesia and prominent tics with ballismus of the upper limbs and normal brain and spinal MRI results. His serum copper and ceruloplasmin levels were low, and his urinary copper level was elevated after penicillamine challenge. Neither tics nor lingual dyskinesia have been described to date with relation to non-Wilson, non–Menkes-type copper-metabolism disorders.

Lingual dyskinesia has been described in a few cases of Wilson disease, but in contrast to our patient, who exhibited it in the resting state only, patients with Wilson disease demonstrate involuntary tongue movements during both rest and action that lead to difficulties in swallowing and in speech.23^,24 The presence of tics is another rare characteristic of our patient. We could not find any report of copper-metabolism disorder with tics.

A search of the literature did, however, reveal that a possible connection has been found between the tic disorder Tourette syndrome and abnormalities in copper metabolism. Robertson et al25 reported that of 80 examined patients with Tourette syndrome, 10 had abnormally low serum copper levels. In a further investigation in the same study, the authors found that such patients exhibited rapid disappearance of copper from the serum and an abnormally slow liver uptake of copper.

On the basis of these findings, it is possible that compromised copper metabolism may lead to the appearance of tics. Nevertheless, this assumption requires further validation.

In our case, despite the low serum levels of copper, the urinary levels after penicillamine challenge were high, which suggested a storage disorder that we chose to treat with zinc supplementation.

The rationale behind this treatment is that zinc induces cell metallothionein, which binds exogenously and endogenously secreted copper, thus preventing its absorption.5,–,8

The treatment has been successful in abolishing all clinical symptoms in our patient, which further validates the statements by Kumar et al26 that low serum copper is not always indicative of copper deficiency and that urinary copper levels should be taken into account when planning therapy.

CONCLUSIONS

We have presented here the case of an adolescent boy with unusual presentation of a copper-metabolism disorder. We conclude that such disorders should be included in the differential diagnosis of movement disorders, even when the presentation is extremely unusual, in the presence of lingual dyskinesia without dysarthria or dysphagia or in the absence of cognitive degeneration or pathologic MRI results.

It is important not to miss these disorders, because many of them are treatable. Moreover, a careful distinction should be made between storage disorders and true deficiency, which would be essential in determining suitable treatment.

Further investigation should be conducted to establish the nature of the connection between abnormalities in copper metabolism and the appearance of tics. Doing so may shed some light on the underlying pathophysiology of tic disorders and perhaps suggest a viable treatment to alleviate the presentation of tics.

FOOTNOTES

Accepted November 12, 2010.

Address correspondence to Helly R. Goez, MD, Division of Pediatric Neurology, Department of Pediatrics, Stollery Children's Hospital, 7319A Aberhart Centre 1, 11402 University Ave NW, Edmonton, Alberta, Canada T6G 2J3. E-mail: helly.goez@albertahealthservices.ca

All authors took part in designing, drafting, and critically revising this article for intellectual content, and all authors approved the final version of the article for publication.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

REFERENCES

. . 1.↵ Brewer GJ, Dick RD, Johnson VD, Brunberg JA, Kluin KJ, Fink JK. The treatment of Wilson's disease with zinc XV: long-term follow-up studies. J Lab Clin Med. 1998;132(4):264–278 CrossRefMedline Web