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
******
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 Òsnake-likeÓ; 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.
FIGURE
1
Lingual
dyskinesia in our patient: the tongue deviated to the left in a twisted
fashion, and waveform movements of the right side of the tongue were noted.
Figure
2
Suppression
of the movements when the patient was asked to voluntarily extrude his tongue.
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.
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 CrossRefMedlineWeb
http://pediatrics.aappublications.org/external-ref?access_num=000076536600006&link_type=ISI
http://pediatrics.aappublications.org/external-ref?access_num=000250943800023&link_type=ISI
Copyright 2011. The Journal of Pediatrics
http://pediatrics.aappublications.org/external-ref?access_num=000250943800023&link_type=ISI
http://pediatrics.aappublications.org/external-ref?access_num=000250943800023&link_type=ISI
http://pediatrics.aappublications.org/external-ref?access_num=000250943800023&link_type=ISI
The authors did not do a liver biopsy, which is
another standard method to identify copper overload.
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