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Dystonia in 61-year-old identical twins Observations over 45 years.

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Dystonia in
6 1-Year-Old Identical
Twins: Observations
over 45 Years
Roswell Eldridge, MD,* Susan E. Ince, MS,*
Bart Chernow, MD, FACP,t Sheldon Milstien, PhD,$
and C. Raymond Lake, MD, PhDO
We examined 61-year-old identical twin women of Jewish extraction with a probable autosomal recessive form
of torsion dystonia. The dystonia in each was relatively
mild and discovered only because a young relative developed dystonia. The twins were said to be discordant for
dystonia, but personal evaluation led to the diagnosis of
dystonia in both. Their slow course, with prolonged
spontaneous remission in one twin, is in contrast to that
described in most published reports. Although similar in
mode of onset and initial course, the twins were dissimilar in age at onset, influence of pregnancy, diurnal variation in symptoms, need for medication, later course, and
degree of disability at age 61. Normal plasma levels of
norepinephrine and dopamine-beta-hydroxylaseare consistent with autosomal recessive hereditary torsion dystonia.
The importance of personal evaluation of key family
members in establishing the correct genetic basis for a
heterogeneous group of disorders, such as the hereditary
dystonias, is stressed.
Eldridge R, Ince SE, Chernow B, Milstien S, Lake CR:
Dystonia in 61-year-old identical twins: observations
over 45 years. Ann Neurol 16:356-358, 1984
Dystonia refers to involuntary, irregular, sustained torsion spasm, which may be present at rest or brought on
only by movement or stress. Among the types of dystonia are at least three that are hereditary: autosomal
dominant, autosomal recessive, and X-linked recessive
163. These single gene disorders are characterized by
dystonia unaccompanied by additional involvement of
the nervous system or other organs. Among the
difficulties of the clinician faced with a new case are
From the *Clinical Neurogenetics Studies, Neuroepidemioiogy Section, National Institute of Neurological and Communicative Disorders and Stroke, and the $Laboratory of Neurochemistry, National
Institute of Mental Health, National Institutes of Health, Bethesda,
M D 20205 and the tDepartment of Critical Care Medicine, Naval
Hospital, Naval Medical Command, National Capital Region, and
the Departments of t Medicine and 9; Psychiatry and Pharmacology,
Uniformed Services University of the Health Sciences, Bethesda,
MD 20814.
Received Aug 16, 1983, and in revised form Feb 7, 1984. Accepted
for publication Feb 12, 1984.
Address reprint requests to Dr Eldridge.
determining what, if any, is the genetic contribution
and what, if anything, is necessary for management.
Among the features that may help determine the
basis of dystonia in a given patient or family are the
clinical features, familial pattern, and ethnic background 12). As yet the biochemical basis of any one of
the hereditary torsion dystonias (HTDs) is unknown,
although several observations suggest altered neurotransmitter or biopterin metabolism in autosomal dominant HTD 111, 12, 143.
No specific management of HTD is uniformly successful. Complicating evaluation of management attempts is our limited understanding of the natural history of each type of dystonia 133. Of the few reports
dealing with this question, most concern patients with
dystonia sufficiently disabled to have undergone neurosurgery or to have participated in formal drug trials.
In this report we describe the natural history of dystonia in identical twins who were ascertained not
through a treatment program but through an affected
younger relative, and discuss several etiological considerations.
The twins in this family were ascertained through an 1l-yearold daughter of a paternal cousin (see individual with arrow,
generation IV, in Figure 1). This child had had episodic curling of her toes and incurving of her left ankle for one year,
beginning at about age 10. The diagnosis of dystonia was
made when uncontrollable torsion spasms, primarily of the
right foot, were observed on repeat examination.
Family history suggested that one of a set of identical twins
on the maternal side had dystonia. The co-twin was said to
have had arthritis of the feet for many years but no dystonia.
Twin 1 was nearing her 6lst birthday. She was the secondborn twin and had had no neurological complaints until age
16, when she noted spontaneousonset of uncontrollable torsion spasm of her right foot that caused the foot to pull down
and in. She would frequently strike her left ankle with her
right foot as a result. The sustained nature of the spasm
resulted in her walking on the outside of the foot, causing her
right shoe to wear abnormally. The left toes soon curled
involuntarily.There was mild progression for two years, after
which the diagnosis of torsion dystonia was made. She was
given a guarded prognosis and advised against having children.
There was little change until her first pregnancy, at age 22,
when there was an increase in the dystonia of the lower limbs,
resulting in worsening of her gait. Following delivery there
was minimal change until she became pregnant again five
years later. The dystonia worsened during her second and
third pregnancies, but symptoms were always confined to the
lower limbs. Symptoms were never severe enough to require
a wheelchair or to prevent her from keeping house. When
she was 46 her brother, aged 34, who had a renal malformation, died as a consequence of chronic hypertension. Before
death he had “willed”her his healthy legs. Within a year after
his death, her lower limb symptoms were over 90% improved. (Three other members of the family independently
confirmed this phase of her history.) She became able to bowl
Fig 1 . Pedigree of the family. The three affteddfemles are indicated by solid circles. The index case is indicated by the awow.
Dots below five symbols indicate that these individuals were examined. Asteriskc are explained in text, pdge 358. Note the diversity of the family’s eastern EuropeanJewish origins. See text
for genetic implications of this familial pattern.
and to walk long distances once more, and this improvement
has continued. She has never taken specific medication for
her dystonia. The improvement in gait in twin 1 is suggested
in Figure 2, which consists of two film clips taken at ages 36
and 61. Recent examination has revealed mild dystonia
confined to the lower limbs to be the only neurological abnormality.
Twin 2, the firstborn, also had dystonia. She had no
neurological symptoms until 1943, when, at age 23, she developed uncontrollable “curling under” of the toes of her
right foot. She denied other problems at the time, but her
husband remarked that in that early period when they walked
together he would often be struck on the ankle on her right
side. Consequently, he tried to maneuver discreetly so that
he would be walking o n her left side. A diagnosis of torsion
dystonia was made without knowledge of the earlier diagnosis in twin 1.
The twins elected not to tell other family members of the
second diagnosis because of the implications they sensed for
an inherited basis, Instead, the toe and walking problems in
twin 2 were thereafter ascribed to “arthritis.”
There was little change in twin 2 until age 3 5 , when she
gave up goif because of increasing dystonia in both feet, Although there has been only minimal progression since, she is
now more limited than her twin (Fin
- 3). Medication consists
of 5 mg of diazepam as needed.
In contrast to her twin, twin 2 noted no exacerbation of
dystonia with pregnancy. H e r first pregnancy preceded the
onset of symptoms by two years. She has had far more diurnal variation, however, with worsening of symptoms as the
day progresses, especially if she is fatigued.
Examination showed dystonia confined to the lower limbs.
When she walked, the left leg swung out several inches and
ier toes, particularly on the right, curled under. She was
inable to tap either foot rapidly or rhythmically. Muscle tone
)f the left foot and calf were increased. This she could largely
,vercome by Concentration. Hammertoes were present bilat*rally,accompanied by calluses on the dorsum of most toes.
?he remainder of the neurological findings were normal.
Age 36
Age 61
Fig 2. Twin I walking. In the Idt panel note the circumduction
and elevation of the IeJt leg and the inversion of the leftfoot. In
the right panel left leg function i J nearly nomal, with dorsiflexion Of the left great toe the most noticeableabQomalitY.
Genotyping using red blood cells indicated the twins were
identical for thirteen markers.
Plasma catecholamine, plasma dopamine-beta-h ydroxylase,
and urine neopteridbiopterin levels were measured by
methods previously described [ 1 , 7 , 8 , 101and found to be in
the normal range.
expression Of disease in the three affected
subjects, their hared ancestry, the c ~ ~ ~ o r d a in
n cthe
identical twins, and the absence of disease in unrelated
spouses all suggest that the dystonia in this family is
genetically based.
Case Report: Eldridge et al: Dystonia in Twins
Fig 3. Course of dystonia in the twins. The solid line represents
the course in tuin I , and the dotted line the course in twin 2. P
indicates pregnancy, and “Will” the time at which their dying
brother “willed twin 1 his healthy legs.
In determining the specific type of inheritance, the
time and method of diagnosis in each case becomes
crucial [4}. For example, when only twin 1 was affected, in the late 1930s, an argument for a nongenetic
condition was reasonable, because an identical co-twin
was unaffected. Because the majority of Jewish patients
with dystonia have onset before age 17, the co-twin
was likely to remain unaffected [l3]. In 1943, however, when twin 2 developed dystonia spontaneously, a
genetic basis was a likely explanation for the dystonia in
the identical twins. Had they been reared apart, this
argument would have been even stronger, because the
existence of a common environmental agent would be
unlikely. But the mode of inheritance was still uncertain, because an autosomal or X-linked dominant mutation in a parental germ cell, autosomal recessive
inheritance, or polygenic inheritance could explain
concordance for a rare genetic disorder.
When the condition in the 11-year-old affected relative of the twins was diagnosed, the existence of the
affected twins was unknown to the attending neurologist. Because the father stuttered, as did his maternal
grandfather as a child, autosomal dominant inheritance
was proposed.
The additional information indicating that there
were related identical twins concordant for dystonia
makes autosomal dominant inheritance unlikely, however. Eight other adult first-degree relatives were unaffected, and at least four instances of nonpenetrance
would be required for this explanation (see asterisks in
Figure 1). Autosomal recessive inheritance is a far
more likely explanation for dystonia with such a familial pattern, especially in an ethnic group in which as
many as one in sixty-five may carry the gene [4}. The
findings of normal plasma dopamine-beta-hydroxylase
and norepinephrine levels additionally support the
view that this is not the autosomal dominant form 112,
The exacerbation of dystonia in eacti of three pregnancies in twin 1, whereas twin 2 had onset only after
her first pregnancy and no progression with subsequent
358 Annals of Neurology
Vol 16 No 3
pregnancies, supports our earlier observations that
pregnancy does not have a consistent effect on dystonia
121. Perhaps the emotional state contributed, because
the first twin but not the second had been advised not
to have children because of her dystonia [ 5 ] .
The course of dystonia in the twins, more benign
than often reported, probably reflects their method of
ascertainment [9}. Cases reported from large neurological centers probably include a disproportionate number with more serious symptoms. The spontaneous
partial remission experienced by the second-born twin
when in her 30s has persisted for over 20 years and is
the longest remission known to us [3].
1. Durrett LR,Ziegler MG: A sensitive radioenzymatic assay
catechol drugs. J Neurosci Res 5:587-598, 1980
2. Eldridge R: Torsion dystonia: literature review and genetic and
clinical studies. Neurology (Minneap) 20:57-60, 1970
3. Eldridge R: Variable course of the hereditary dystonias. Adv
Neurol 14:171-176, 1976
4. Eldridge R, Koerber F: Torsion dystonia: autosomal recessive
form. In Goodman RM, Motulsky AG (eds): Genetic Diseases
among Ashkenazi Jews. New York, Raven, 1979, pp 231-235
5. Eldridge R, Rikland M, Cooper IS: The limited role of
psychotherapy in torsion dystonia: experience with 44 cases.
JAMA 210:405-408, 1969
6. Fahn S, Eldridge R: Definition of dystonia and classification of
the dystonic states. Adv Neurol 14:l-5, 1976
7. Lake CR, Ziegler MG, Kopin IJ: Use of plasma norepinephrine
for evaluation of sympathetic neuronal function in man. Life Sci
18:1315-1326, 1976
8. Milstien S, Kaufman S, Summer GK: Hyperphenylalanemia due
to dihydropteridine reductase deficiency: diagnosis by measurement of oxidized and reduced pterins in urine. Pediatrics
65:806-810, 1980
9. Motulsky AG: Biased ascertainment and the natural history of
diseases. N Engl J Med 298:1196-1197, 1978
10. Weinshilboum RM, Axelrod J: Serum dopamine-betahydroxylase activity. Circulation 28:307-3 I S , 197 1
11. Williams A, Eldridge R, Levine R, et al: Low CSF hydroxylase
cofactor (tetrahydrobiopterin) levels in inherited dystonia. Iancet 2:410, 1979
12. Wooten F, Eldridge R, Axelrod J, Stern R Elevated plasma
dopamine beta hydroxylase activity in autosomal dominant torsion dystonia. N Engl J Med 283:284-287, 1973
13. Zador J: Le spasme de torsion: parall& des tableaux clinique
entre la race juive et les autres races. Rev Neurol (Paris)
66:365-389, 1936
14. Ziegler M, Lake R, Eldridge R, Kopin I: Serum norepinephrine,
serum doparnine-beta-hydroxylaseand dystonia. Adv Neurol
14:307-318, 1976
September 1984
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