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. WilsonÕs 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.
******
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.
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 CrossRefMedlineWeb
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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
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