Prevalence and Features of Unreported Dystonia in a Family Study of “Pure” Essential Tremor

Abstract

Background

Essential tremor (ET) is considered to be a highly heritable disorder, yet no susceptibility genes have been identified. The search for ET genes is severely hampered by clinical and genetic heterogeneity; the existence of this heterogeneity complicates the genetic analyses. We sought to determine the prevalence and clinical features of unreported dystonia in a family study of “pure” ET.

Methods

ET probands and their reportedly affected first-and second-degree relatives were enrolled in a genetics study, the Family Study of Essential Tremor (FASET) at Columbia University Medical Center. The goal was to enroll cases with “pure” ET (i.e., ET without dystonia or other neurological problems). Each enrollee underwent a detailed neurological evaluation.

Results

There were 100 enrollees (28 probands, 72 relatives). Dystonia (primarily torticollis) occurred in 9 (32.1%) of 28 families, with 5 cases in one family, 2 cases in two families, and 1 case in six families. Those affected with dystonia included 3 (10.7%) probands and 12 (16.7%) relatives. There was a gender predilection: 14/15 (93.3%) with dystonia vs. 41/85 (48.2%) without dystonia were women (p=0.001). Dystonia was previously undiagnosed in 14/15 (93.3%) cases.

Conclusions

Dystonia (esp. torticollis in women) was present in nearly one-third of the ET families in a genetics study, including 10.7% of ET probands. Dystonia was unreported and previously undiagnosed in nearly all of these individuals. The overarching biological issue is whether ET and dystonia should be regarded as one disease or two; this has obvious implications for the structuring of analyses in genetic studies.

Introduction

Essential tremor (ET) is considered to be a highly heritable disorder [1,2]. The search for underlying susceptibility genes has intensified in recent years [2]. The aim of these genetic studies is to identify etiological factors that will lead to an understanding of disease pathogenesis and will form a basis for the development of more effective pharmacotherapeutics. Despite this promising scenario, no susceptibility genes for ET have been identified to date, and a number of important methodological issues have been raised [3]. A central issue is that families with “pure ET” are less common than anticipated; for example, probands and family members may have features of dystonia. These “mixed-motor” families, in which affected members have ET, dystonia, or both, likely represent a sub-category of ET [4], and the existence of this heterogeneity complicates the genetic analyses, and reduces power for gene identification.

One strategy to reduce such heterogeneity is to exclude from genetic analyses individuals with dystonia or entire families in which one member has dystonia. However, this approach would be difficult to implement. First, as many as 50% of people with dystonia ascertained during family studies of DYT1 dystonia did not seek medical attention or were not diagnosed [5]. Individuals with mild, intermittent movements were most likely to be missed by screening [6]. Second, screening questions for dystonia may have reduced sensitivity in members of ET families because dystonic movements might be falsely attributed to ET.

ET cases (probands) and their relatives were enrolled in a genetics study of ET at Columbia University Medical Center (CUMC); the goal was to enroll cases with “pure” ET (i.e., ET without dystonia or other neurological problems). Here, we sought to determine the prevalence and clinical features of unreported dystonia in the first 100 enrollees (probands and relatives). In addition to estimating the magnitude of the problem, the goal was to increase awareness among investigators of this issue. The larger biological issue is whether ET and dystonia should be regarded as one disease or two; this has obvious implications for the structuring of analyses in genetic studies.

Methods

Ascertainment of Probands

ET cases (probands) and their reportedly affected first-and second-degree relatives were enrolled in a genetics study of ET, the Family Study of Essential Tremor (FASET) at CUMC. The three initial inclusion criteria for probands were: (1) a diagnosis of ET had been assigned by a doctor, (2) age of tremor onset ≤40 years, (3) ≥2 living relatives in the United States have ET that was diagnosed by a doctor, and these relatives were not reported to have dystonia or Parkinson’s disease (PD). The two exclusion criteria for probands were a prior diagnosis of dystonia or PD. Potential ET probands contacted the FASET study coordinator in response to advertisements on two ET society websites. Prior to final selection for enrollment, a set four Archimedes spirals (two right, two left) were submitted by probands, and rated by a senior movement disorder neurologist (E.D.L.) Probands were included if one or more of the spirals had a Washington Heights Inwood Genetic Study of Essential Tremor rating of 2 (moderate tremor) or higher [7].

Ascertainment of Relatives

Based upon a telephone interview with the proband, relatives with ET were identified. With the proband’s permission, these relatives were then contacted by telephone, and were pre-enrolled if they reported the presence of tremor in the absence of a prior diagnosis of dystonia or PD. Prior to final selection for enrollment, four Archimedes spirals were submitted by relatives and rated (E.D.L.) Relatives were included if one or more of the spirals had a rating ≥2 [7].

In-person Evaluation

After enrollment, an in-person evaluation was then conducted in the enrollees’ homes; this included a series of questionnaires and a videotaped neurological examination, which included a detailed assessment of postural, kinetic, intention and rest tremors, as well as dystonia and other movement disorders [8]. The use of videotaped neurological examinations is a standard and valid method to diagnose a wide range of movement disorders including ET, PD and dystonia [2, 5, 6, 9]. A senior movement disorders neurologist (E.D.L.) reviewed all videotaped examinations, and the severity of postural and kinetic arm tremors were rated (0 – 3), resulting in a total tremor score (range = 0 – 36 [maximum]) [8]. In addition to dystonic postures or tremor during sustained arm extension, the videotape was assessed for the presence of spasmodic torticollis, voice tremor and blepharospasm. The study was approved by the CUMC Institutional Review Board and all participants signed written informed consent.

Diagnoses

All ET diagnoses were reconfirmed based on review of questionnaires and videotaped neurological examination data. Diagnoses of ET were assigned by E.D.L. based on published diagnostic criteria (moderate or greater amplitude kinetic tremor during three or more activities or a head tremor in the absence of PD or another known cause) [7,10]. In addition to the presence or absence of dystonic postures during sustained arm extension, the videotape was assessed for the presence of spasmodic torticollis (while seated, while walking and while lying down), voice tremor and voice breaks (during spontaneous speech, reading, sustained vowel sounds) and blepharospasm. Diagnoses of dystonia were initially assigned (E.D.L.). A second neurologist specializing in movement disorders (R.N.A.) independently re-reviewed the videotaped neurological examinations of all 15 enrollees who had been diagnosed with dystonia. Criteria for dystonia followed those recommended by Fahn [11], and consisted of sustained muscle contractions, often causing abnormal postures, or twisting and repetitive movements [11]. Spasmodic torticollis was defined as the presence of twisting or tilting movements of the neck, jerk-like or sustained neck deviation, often with mild hypertrophy of neck muscles. Dystonic head tremor was distinguished from ET-related head tremor by the presence of directional or irregular tremor and the tendency for the tremor to continue while the patient was supine [12]. If present, voice tremor was attributed to ET or dystonia (tremor with voice breaks, strangled speech). The two neuorologists agreed on all 15 diagnoses of dystonia.

Statistical Analyses

Analyses were performed in SPSS (Version 19.0).

Results

There were 100 enrollees, including 28 probands and 72 relatives (58 first-degree, 11 second-degree, and 3 third-degree) (Table 1). Up to 6 relatives (excluding probands) were examined per family.

Table 1.

Demographic and Clinical Characteristics of 100 Enrollees

	Proband (N = 28)	Relative (N = 72)
Age (years)	64.6 ± 11.5, 37 – 83	56.9 ± 18.8, 19 – 95
Female Gender	16 (57.1)	39 (54.2)
White Race	25 (89.3)	63 (87.5)
Ashkenazi Jewish Ancestry	2 (7.1)	10 (13.9)
Relationship to Proband
Self	28 (100)	0 (0)
Child	0 (0)	27 (37.5)
Sibling	0 (0)	24 (33.3)
Parent	0 (0)	7 (9.7)
Grandchild	0 (0)	1 (1.4)
Aunt/Uncle	0 (0)	3 (4.2)
Nephew/Niece	0 (0)	7 (9.7)
Other (Third-degree)	0 (0)	3 (4.2)
Diagnosis
ET	25 (89.3)	54 (75.0)
Dystonia	2 (7.1)	4 (5.6)
ET + Dystonia	1 (3.6)	8 (11.1)
Not enough tremor to qualify for ET	0 (0)	6 (8.3)
Total tremor score on neurological examination	22.1 ± 4.8	15.9 ± 6.3
Voice tremor on neurological examination	9 (32.1)	7 (9.7)
Head (neck) tremor on neurological examination	14 (50.0)	10 (13.9)
Currently takes medication to treat ET	19 (67.9)	20 (27.8)
Age of tremor onset (years)	24.0 ± 16.3	29.6 ± 19.2
Duration of tremor (years)	40.6 ± 14.6	26.4 ± 19.8

All values are mean ± standard deviation, range or number (%), unless otherwise specified.

Despite our attempt to pre-screen for dystonia, we found that dystonia was present in 3 (10.7%) probands and 12 (16.7%) relatives; in 1 proband and 8 relatives dystonia occurred in the presence of ET, and in 2 probands and 4 relatives it occurred in the absence of ET (Tables 1, 2). Dystonia occurred in 9 (32.1%) of 28 families; with 5 cases in one family, 2 cases in two families, and 1 case in six families. After initial telephone contact (i.e., after enrollment), one of the probands (diagnosed in our study with ET + dystonia) reported having been diagnosed by with both ET and writer’s cramp. None of the other probands or family members had been diagnosed with dystonia. Hence, dystonia had been previously undiagnosed in 14 (93.3%) of 15 individuals.

Table 2.

Demographic and Clinical Characteristics of 15 Enrollees with Dystonia vs. 85 Enrollees without Dystonia

	Enrollees with Dystonia (N = 15)	Enrollees without Dystonia (N = 85)
Age (years)	64.9 ± 13.1	58.0 ± 17.0
Female GenderA	14 (93.3)	41 (48.2)
White Race	12 (80.0)	76 (89.4)
Ashkenazi Jewish Ancestry	2 (13.3)	10 (11.8)
Relationship to Proband
Self	3 (20.0)	25 (29.4)
Child	2 (13.3)	25 (29.4)
Sibling	7 (46.7)	17 (20.0)
Parent	1 (6.7)	6 (7.1)
Grandchild	0 (0)	1 (1.2)
Aunt/Uncle	0 (0)	3 (3.5)
Nephew/Niece	1 (6.7)	6 (7.1)
Other (Third-degree)	1 (6.7)	2 (2.4)
Diagnosis
ET	0 (0.0)	79 (92.9)
Dystonia	6 (40.0)	0 (0)
ET + Dystonia	9 (60.0)	0 (0)
Not enough tremor to qualify for ET	0 (0.0)	6 (7.1)
Total tremor score on neurological examination	15.9 ± 6.7	18.0 ± 6.4
Voice tremor on neurological examination	2 (13.3)	14 (17.3)
Head (neck) tremor on neurological examination	2 (13.3)	22 (25.9)
Currently takes medication to treat ET	3 (20.0)	36 (42.4)
Age of tremor onset (years)	37.1 ± 22.4	26.4 ± 17.5
Duration of tremor (years)	26.4 ± 17.5	31.4 ± 19.7

All values are mean ± standard deviation, range or number (%), unless otherwise specified.

^Ap< 0.05.

The dystonia was mild and the location of the dystonia was torticollis (n = 8), torticollis and spasmodic dysphonia (n = 2), torticollis and blepharospasm (n = 1), torticollis and arm (n = 3), and blepharospasm (n = 1). The large majority with dystonia (14, 93.3%) were women (Table 2).

Fourteen of the dystonia cases had torticollis, but none answered “yes” to the question “do you have involuntary twisting/turning of your head/neck?”, which was administered during the in-person assessment. This suggests that we would not have ascertained dystonia in these individuals prior to their in-person assessment.

Discussion

Dystonia (esp. torticollis in women) was present in nearly one-third of the reportedly “pure” ET families enrolled in a genetics study, including 10.7% of ET probands. Dystonia was unreported and previously undiagnosed in nearly all of these individuals. The existence of this source of heterogeneity may confound the genetic analyses, and could reduce the likelihood of identifying a susceptibility gene, especially using a linkage analysis approach. There are several concerns. First, families with dystonia might have different genes/genetic mechanism from other families. This potential source of heterogeniety should be removed from the proband group by appropriate detailed assessments, in order to be as sure as possible that one is dealing with a relatively pure ET group. Second, one might be misclassifying relatives who have dystonia but not ET as unaffected, when they really should be classified as affected. This would greatly lower the LOD scores.

There is a small but important literature documenting the occurrence of dystonia in some ET families. A large genetic study of 463 individuals from 97 kindreds noted that signs of dystonia were present in 98 individuals (21.2%) who were clustered within only 27 (28%) of the families [4]. Jankovic et al. [13] reported 4 large ET pedigrees in whom 84 individuals had ET; in three families (A, C and D), 11, 18 and 12 individuals (total = 41 individuals) had both ET and dystonia on examination; only one family (B) had “pure” ET [13]. In 2006, Ma et al. [3] reported four ET pedigrees (64 ET cases); “several women” in pedigree A were reported to have mild cervical dystonia in addition to ET. The pathological basis for both ET and dystonia are not fully understood, although increasing recognition of the involvement of the cerebellum in both disorders, provides a ready mechanism for the observed co-occurrence of the two movement disorders within individuals [14]. The unique feature of our study is that it is the only one that attempts to define the magnitude of the problem by studying a large sample of ET families (that is more than a handful of pedigrees) while attempting to restrict our analyses to probands with self-reported pure ET.

We pre-screened for a diagnosis of dystonia. Screening questionnaires for dystonic symptoms in individuals with other neurological disorders yield a large number of false positives (specificity 32%) [15]. While the use of such questionnaires could have screened out some of the dystonia we saw, it would not have been a good option in this study because it would have led to the exclusion of many false positives.

Only two (13.3%) of the 15 enrollees with dystonia had head (neck) tremor on neurological examination. The relative mildness of the dystonic features may have been a contributing factor to the low prevalence of neck tremor in this group.

This study had several limitations. Our probands were selected based on age of onset and other criteria (e.g., ≥2 living relatives). Whether our results would have differed from those derived from an unselected group of ET cases remains to be determined and is an interesting question. The study by Hedera et al. [4], which did not select probands based on age of onset, reported a current age of 48 years in ET cases and 52 years in cases with dystonia; these ages were lower than those of our cases.

Eight relatives and one proband had ET + dystonia. How does one interpret this situation, especially in the setting of a genetics study? There are several alternative possibilities. First, these cases had one disease (ET); dystonia (e.g., mild torticollis) was merely a neurological sign that may be present in longstanding ET. Second, these cases had one disease, dystonia (i.e., their “ET” was all merely dystonic tremor). However, the long duration (25+ years) of tremor, the severity of the ET tremor, the relative mildness of the dystonia, all in the setting of familial ET, make this unlikely. Third, these cases had one disease: ET/dystonia (a clinical spectrum arising out of a common pathogenesis and/or neuroanatomical substrate). Fourth, these cases had two diseases (ET + dystonia). There are no clear answers, yet the ultimate choice has obvious implications for the analyses of genetic studies. The observation of different phenotypes (e.g., ET with dystonia vs. ET without dystonia) raises the larger issue as to whether ET itself is a single disease, a collection or family of diseases, or a syndrome. The increasing recognition of the existence of clinical, genetic, and pathological heterogeneity lends support to the notion that ET is a family of diseases [16].