Familial
Cervical Dystonia, Head Tremor and Scoliosis: A Case Report
Drake D. Duane
Arizona Dystonia Institute, Arizona State University,
Scottsdale, Arizona 85258.
Familial generalized dystonia has been linked to
a specific gene locus, q34 on chromosome 9, and has been labeled
DYT I (9). Although both tremor and dystonia not uncommonly occur
in dystonic individuals as well as their family members, essential
tremor (ET) does not link with the DYTI chromosome 9 locus (1,4).
Because individuals with generalized dystonia may have relatives
with focal dystonia, it is possible that the DYT I gene locus also
may be responsible for some forms of focal dystonia.
Likewise, patients with focal dystonia themselves
or their relatives may exhibit tremor. In some cases, this tremor
is a slower, less rhythmic or "dystonic" tremor; in others,
it shares characteristics observed in what is otherwise called "essential"
tremor (8). Tremor distribution in patients with focal dystonia
most commonly affects the head, followed by head and hands, followed
by hands only, and least commonly affects voice alone (3). A description
of tremor in relatives of those with cervical dystonia (CD) increases
the probability of tremor occurring in affected patients, as well
as increasing the probability that there will be dystonic manifestations
beyond the neck region (3).
The first published report of multiple family members
in the same generation affected with CD was in 1896 by Thompson,
in which two brothers and two sisters were described. As there were
allegedly no other family members demonstrating dystonic symptoms
or signs, the conclusion was drawn that the genetic mechanism was
likely autosomal recessive (12). The family was of Caucasian English
Christian ancestry.
Focal dystonia has been previously described in
multiple family members whether by history or by direct examination
(5,7,11,14), including twins (6,13). It is unclear in such families
what genetic mechanism underlies these associations, but autosomal
dominance appears likely. A recent report from Germany in one family
with multiple affected members with CD suggests linkage with chromosome
18p (10).
CURRENT CASE REPORT
This report is of a German Christian ancestry family
residing in Nebraska without history of consanguinity in which three
male members of generation II have adult-onset CD. The index case
(II, 4) has been in remission for nine years. A female sibling in
this generation had adolescent-onset scoliosis. The deceased father
of this nine-member generation was said to have had long-standing,
adult-onset head "shaking" but without recorded head rotation
or tilt.
The two female offspring of the index case demonstrate
in one (III, 11) adolescent-onset scoliosis and in the other (III,
10) a history of onset of CD at age 33 in which there have been
two periods of exacerbation with no period of remission. Their brother
is said to be asymptomatic but has not been examined. A granddaughter
of an unaffected sister from the index generation (II, 2) has late-childhood-onset
scoliosis. The abbreviated family tree is presented in Fig. 1.
Six of the nine members of the second generation
have been examined, and one additional sib submitted blood samples.
The scoliotic daughter of the index case (III, 11) was both examined
and supplied a blood sample. Her sister (III, 10) affected with
fluctuating CD has been examined and has provided blood samples
for analysis. Blood samples were sent to the National Hospital Queen
Square, London, England, for DNA analysis.
The oldest affected brother (II, 3) with torticollis
also exhibits a vertical head and mild postural hand tremor. The
father of this generation is described as having a chronic horizontal
head shaking. Neither of the other two brothers has tremor nor do
any of the relatives in this generation or in generation III that
have been examined nor are any others described as having tremor.
The onset of his CD was in 1982 at the age of 53 years. The characteristics
of the CD are a phasic retrocollis with slight right rotation and
dystonic vertical head and bilateral postural hand tremor with secondary
vocal tremor, as well as mild lower cranial dystonia. The patient
was examined by the author in September of 1992 in his home state
of Nebraska, at the same time and place as the other family members
in this report.
Patient II, 4, the index case, had onset of CD
in 1977 at the age of 47. The character then was tonic, right rotation
without tremor. Placed on oral anticholinergic therapy in 1985,
this patient went into remission within a few weeks of the introduction
of this medication. He had first been examined in 1985, was subsequently
reexamined in 1987, and like his older brother, was examined again
in September of 1992. Although subjectively feeling as though at
times the neck muscles are tight, there is no evidence of distorted
nuchal posture and range of motion of the cervical spine is completely
free.
Patient III, 6, had onset of CD in 1965 at the
age of 31. The CD is a tonic right rotation with slight right lateral
tilt but no evidence of cranial or other site of dystonia or tremor.
None of these three men have been aware of scoliosis and spine films
done on the index case in 1985 failed to reveal evidence of scoliosis.
In none of the affected or unaffected family members
was there a history of perinatal stress, painful injury antecedent
to the onset of symptoms, or evidence of autoimmune disorder by
history. In none was there elevated titers of antinuclear antibody
or rheumatoid factor, nor was there evidence of abnormalities of
copper or ceruloplasmin levels. The index case II, 4, has a slightly
elevated creatine kinase level whereas all the others studied do
not. The youngest examined sib (II, 8) has slightly elevated levels
of thyroglobulin antibody, whereas none of the others have this
or elevated levels of thyroid microsomal antibody. All three affected
brothers are right-handed as are all of their sibs except for one
unaffected sister (II, 2) who is left-handed. Only two of the sibship
are blue-eyed (II, 6 and II, 7). Both affected daughters (III, 10
and III, 11) are brown-eyed. The sister with scoliosis (III, 11)
holds a writing instrument in a tightened hand posture but not one
construed to represent dystonia. None of the three affected brothers
gave a history of transitory symptoms of dystonia or tremor antecedent
to the date of CD onset.
DISCUSSION
Whether
by direct examination or by history, patients with CD have increased
frequency of relatives with tremor most commonly described as affecting
the head. Next most frequent is the recalled occurrence of scoliosis
in first-degree relatives (2). The true occurrence of familial CD
is unclear but by history, in one study, was reported at 6% with
the same investigation describing facial dystonia in 5% of relatives
and spasmodic dystonia in 1%. Family history of parkinsonism was
similar in frequency to that of a control group of spine pain patients
(2). Demonstrations to all patients were given to distinguish rest
tremor with bradykinesia from postural tremor aiding in the distinction
between parkinsonism and nonparkinsonian tremor.
One
other family in the author's personal experience demonstrated multiple
family members with CD; in that instance, three family members were
known to have CD, two of whom were examined. The sister of one of
those affected with CD exhibited adductor spasmodic dysphonia and
head tremor. Tremor also occurred in three other family members,
head in two and hands in one. One of the CD patients in that family,
a woman with onset of her symptoms in her early 40s, succumbed suddenly
without identified cause in her mid50s. That patient's brain has
been placed in the brain bank at McLean Hospital, Belmont, Massachusetts.
Although genetic blood studies were drawn from several of those
family members the results of none of these, unfortunately, have
been reported to the author.
Personal
communication with the late Professor Anita Harding in 1995 and
reconfirmed in 1996 with Dr. Nicholas Wood of the National Hospital
Queen Square indicates no linkages to the DYTI gene locus in this
family "A." In light of the recent report of a similar
family with multiple affected with CD from Germany being linked
to chromosome 18p, our colleagues in England are currently investigating
whether that site may be linked in this family. A conundrum for
the genetic research is whether to include evidence of scoliosis
of adolescent or later onset as an affected family member or in
future studies whether to include as affected family members those
with scoliosis as well as those with only tremor.
Personal
observations with over 1,500 patients seen in the last 25 years
with CD suggest that up to 25% of patients with CD are aware of
scoliosis or have X-ray evidence of scoliosis antecedent to or concurrent
with the onset of their cervical symptomatology. This raises the
possibility that among the manifestations of dystonia may be scoliosis
in isolation. The extent to which, however, the general population
of scollotics represents dystonia is unclear, but would seem to
be low given the 4% in females and 2% in males frequency of scoliosis.
The
association of CD with tremor in this family and in general is interesting
because ET does not link to the DYTI gene locus. But whether other
gene loci may produce both dystonic head tremor and CD is not clear
because direct observation of affected family members is uncommon,
further complicating the already difficult decision making as to
whether the described family member has a dystonic or essential-type
tremor. The association, however, between rhythmic oscillation of
the head and dystonically induced distorted posture is robust and
improbably related to chance.
Efforts
are now under way to examine additional members of this family and
to draw serum samples from them for DNA analysis.
CONCLUSIONS
The
observations in this family argue for clinical investigators to
continue to study family history in depth and recurrently, as serial
inquiry often increases the yield. Whenever possible, one should
actually examine the allegedly affected as well as unaffected family
members. This case report reinforces the probability that a Wong
factor in the etiology of focal dystonic movement disorders and
tremor is genetic, although the relationship between these two clinical
phenomena is obscure. Whether the heterogeneity in clinical manifestation
is solely under genetic control is not clear; therefore, continued
efforts at investigating potential mitigating epigenetic factors
when patients are evaluated is appropriate. The eventual determination
of the genetic marker in this family may clarify etiology and pathogenesis
of focal dystonia and assist in determining whether there is a relationship,
genetic or otherwise, between CD, head and/or hand tremor, and scoliosis.
ACKNOWLEDGMENTS
This work was
supported in part by funds provided by the Foundation for Clinical
Neuroscience.
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Published
in: Dystonia 3:Advances in Neurology, Vol. 78, edited by S. Fahn,
C. D. Marsden, and M. DeLong Lippincott-Raven Publishers, Philadelphia
C 1998
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