Functional status of men with the fragile X premutation, with and without the tremor/ataxia syndrome (FXTAS)
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INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY
Int J Geriatr Psychiatry 2009; 24: 1101–1109.
Published online 29 April 2009 in Wiley InterScience
(www.interscience.wiley.com) DOI: 10.1002/gps.2231
Functional status of men with the fragile X premutation,
with and without the tremor/ataxia syndrome (FXTAS)
Angela G. Brega1,2, Ann Reynolds3, Rachael E. Bennett1,4, Maureen A. Leehey5, Lanee S. Bounds1,
Jennifer B. Cogswell 6, Randi J. Hagerman 6,7, Paul J. Hagerman 8 and Jim Grigsby 1,4*
1
Department of Medicine, University of Colorado Denver, Aurora, CO, USA
2
Department of Community and Behavioral Health, University of Colorado Denver, Aurora, CO, USA
3
Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA
4
Department of Psychology, University of Colorado Denver, Denver, CO, USA
5
Department of Neurology, University of Colorado Denver, Aurora, CO, USA
6
M.I.N.D. Institute, University of California, Davis, Sacramento, CA, USA
7
Department of Pediatrics, University of California, Davis, Medical Center, Sacramento, CA, USA
8
Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Davis,
CA, USA
SUMMARY
Background Fragile X-associated tremor/ataxia syndrome (FXTAS), which occurs in some premutation carriers of the
fragile X mental retardation 1 (FMR1) gene, is a neurodegenerative disorder characterized by action tremor, gait ataxia, and
impaired executive cognitive functioning.
Objective To evaluate the nature and severity of functional limitations among male carriers of the fragile X premutation,
both with and without FXTAS.
Methods Forty-two subjects with FXTAS and 24 asymptomatic premutation carriers were compared to 32 control subjects
on measures of physical functioning, activities of daily living (ADLs; e.g. eating, bathing), and instrumental activities of
daily living (IADLs; e.g. shopping, managing medications). Ordinary least squares regression, controlling for age, education,
medical comorbidity, and pain, was used to examine group differences in physical and functional performance.
Results Men with FXTAS performed significantly worse than control subjects on all dependent measures, showing greater
limitations in physical functioning, as well as ADL and IADL performance ( p < 0.05). Subsequent analyses suggested that
physical and functional impairments among men with FXTAS result largely from deficits in motor and executive functioning
and that CGG repeat length is associated with functional impairment. Asymptomatic carriers of the fragile X premutation
performed similarly to control subjects on all measures.
Conclusions This study provides the first comprehensive evaluation of functional status among male premutation carriers.
Although carriers without FXTAS performed similarly to control subjects, men with FXTAS showed evidence of significant
physical and functional impairment, which appears to result largely from motor and executive deficits characteristic of the
syndrome. Copyright # 2009 John Wiley & Sons, Ltd.
key words — fragile X; fragile X-associated tremor/ataxia syndrome; FXTAS; functional status; activities of daily living;
instrumental activities of daily living
INTRODUCTION with the fragile X premutation. The premutation is
characterized by 55–200 CGG repeats in the 50
Fragile X-associated tremor/ataxia syndrome (FXTAS; untranslated region of the fragile X mental retardation
Hagerman et al., 2001) affects a subset of individuals 1 (FMR1) gene. Symptoms of FXTAS include action
tremor and gait ataxia, and often are accompanied by
*Correspondence to: Dr J. Grigsby, Department of Psychology, Uni-
parkinsonism, dysautonomia, peripheral neuropathy,
versity of Colorado Denver, Campus Box 173, P.O. Box 173364, weakness, and other neurologic signs (Jacquemont
Denver, CO 80217-3364, USA. E-mail: jim.grigsby@ucdenver.edu et al., 2003; Leehey et al., 2007). FXTAS involves
Received 22 August 2008
Copyright # 2009 John Wiley & Sons, Ltd. Accepted 7 January 20091102 a. g. brega ET AL.
substantial impairment of the executive cognitive were three years younger than controls (mean age 60.9
functions (ECF; Grigsby et al., 2006; Berry-Kravis vs 64.2 years), this difference was not significant
et al., 2007a,b; Grigsby et al., 2007; Leehey et al., ( p > 0.10). To eliminate confounding by age, all men
2007; Brega et al., 2008; Grigsby et al., 2008), inclu- under the age of 53—the age of the youngest FXTAS
ding deficits in behavioral self-regulation, attention, participant—were excluded. Omitting these subjects
and working memory. A majority of males with the pre- (four APCs and seven controls) eliminated the signi-
mutation develop FXTAS (Jacquemont et al., 2004). ficant age difference between FXTAS and controls.
We studied physical limitations, and deficits in
activities of daily living (ADLs) and instrumental
ADLs (IADLs), among male carriers of the premuta-
Assessment of functional status
tion. Whereas ADLs (e.g. eating, bathing) represent
simple aspects of self-care, IADLs (e.g. meal prepara- ECF deficits have been reported among premutation
tion) are cognitively more complex. We expected that carriers (e.g. Grigsby et al., 2006, 2007; Brega et al.,
men with FXTAS would suffer impairment of 2008; Grigsby et al., 2008), and because such
functional status as a result of the motor and ECF individuals may have limited insight and be unable
deficits characteristic of the disorder. to evaluate their functional status accurately, we report
data collected from informants. For 91% of cases, the
informant was a spouse or significant other who lived
METHODS with the subject. An additional 4% of informants were
siblings or adult children of participants.
Subjects
Physical limitations were measured using the Nagi
Participants provided written informed consent and and Rosow/Breslau physical disability items (Nagi,
Health Insurance Portability and Accountability Act 1976), which assess ability to walk a quarter of a mile;
(HIPAA) authorization. The research was approved by climb ten steps without resting; stoop, crouch, or
institutional review boards (IRBs) at the University of kneel; reach overhead; use fingers to grasp objects;
Colorado Denver and the University of California and carry up to 10 lbs. Informants indicated whether
Davis. The authors have no financial or personal the subject had difficulty completing each activity by
interests to disclose. himself, without special equipment. The mean of yes/
Participants were 98 men aged 53–89, each of no (1/0) responses across the six items, reflecting the
whom was assigned to one of three study groups. The proportion of the physical activities for which difficulty
FXTAS group included 42 subjects with definite or was reported, was used as a measure of physical limitations.
probable FXTAS (Jacquemont et al., 2003). Men with Measures from the Longitudinal Study on Aging
the FMR1 premutation without signs of FXTAS (Katz et al., 1963; Duke University, 1988) were used
(n ¼ 24) were classified as asymptomatic premutation to assess ADL/IADL independence. Informants
carriers (APC). The control group included 32 men indicated whether the subject had difficulty complet-
with normal FMR1 alleles. Participants were native ing seven ADLs by himself, without special equip-
English speakers with no history of any neurologic ment: bathing/showering; dressing; eating; using the
disorder other than FXTAS. Each subject had a family toilet; transferring in and out of bed or chair; walking
member or friend who was knowledgeable and willing across a small room; getting outside. The ADL
to answer questions about the individual’s functional limitations score, the mean of these seven dichot-
status. Premutation carriers were identified through omous yes/no (1/0) variables, represents the pro-
earlier studies, fragile X meetings or support groups, portion of ADLs performed with difficulty.
and the clinical practices of study co-investigators; The IADL limitations score provides a measure of
control subjects were recruited from the families of subjects’ difficulty engaging in eight IADLs indepen-
carriers, medical clinics, and advertisements. dently (without special equipment): meal preparation;
Of the 124 men enrolled in the study, 14 were driving; shopping; using the phone; managing
excluded from these analyses because of missing medications; managing money; strenuous housework;
functional status data. One man, a mosaic having a light housework. As with ADLs, the score reflects that
‘smear’ CGG repeat pattern ranging from the normal proportion of IADLs performed with difficulty. IADL
to the full mutation range, also was excluded. In the items included an additional response option indicat-
remaining sample of 109 participants, men with ing that a subject does not perform a task for reasons
FXTAS were older than controls (mean age 68.6 vs other than disability (e.g. wife always does the
64.2 years; p < 0.05). Although asymptomatic carriers cooking). Such responses were coded as missing.
Copyright # 2009 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2009; 24: 1101–1109.
DOI: 10.1002/gpsfunctional status in fxtas 1103
To examine subtle deficits in functional status, et al., 2005; Grigsby et al., 2006, 2007; Brega et al.,
informants were asked to indicate whether subjects 2008; Grigsby et al., 2008). Higher scores (out of a
had changed either: (a) the frequency of performing an total of 27) reflect better functioning.
individual ADL/IADL, or (b) the manner of perform-
ance (Guralnik et al., 1999; Fried et al., 2000). The
three frequency response options were no; yes, less Data analysis
frequently; and yes, doesn’t do it anymore). The two Regression models compared physical and functional
‘yes’ responses were collapsed to yield dichotomous performance across groups. For each dependent vari-
(yes/no) variables and the average value for ADL and able, separate models examined the impact of two
IADL variables, respectively, were computed. The group-comparison variables: (a) APC [1] vs control
degree to which a subject had changed the way he [0], and (b) FXTAS [1] vs control [0]. To evaluate the
completed ADL/IADLs was computed as the mean of contribution of motor and ECF deficits to differences
the yes/no (1/0) method change variables. The ADL/ in functional performance, regression models compar-
IADL frequency change variables and the ADL/IADL ing FXTAS to control subjects were repeated using
method change variables represent the proportion of PPT dominant hand score as a covariate, and again
ADLs or IADLs, respectively, for which a subject had using BDS as a covariate.
changed frequency or method.
Covariates. We adjusted for age and years of
Motor and executive impairments education in all analyses. Further, because perform-
ance of functional tasks can be influenced by
We hypothesized that FXTAS-related motor impair-
comorbidity and pain (Bryant et al., 2007), we
ment would contribute to group differences in physical
controlled for these variables in all analyses as well.
limitations and ADL/IADL performance. Although
To capture co-existent medical illness, we used the
not all functional tasks depend on fine motor skills,
Charlson Comorbidity Index (CCI), a weighted
several are likely to be impaired as a result of tremor
measure of medical comorbidity (Charlson et al.,
(e.g. dressing, eating). The Purdue Pegboard Test
1987), based on a set of 17 differently weighted ICD-9
(PPT; Tiffin and Asher, 1948) was used to quantify
diagnoses. The degree to which pain interfered with
motor impairment. The PPT is a test of motor function
subjects’ regular activities (e.g. moving around, work,
in which subjects rapidly insert small metal pegs into
sleeping) was measured using items from the San Luis
holes on a pegboard. The number of pegs inserted
Valley Health and Aging Study (SLVHAS; Hamman
during a 30-sec trial using the dominant hand was used
et al., 1999), controlled for the influence of pain on
to quantify fine motor deficits.
functional status. The mean of these dichotomous
Men with FXTAS have impaired ECF (Grigsby
responses, reflecting the proportion of activities
et al., 2006, 2007; Leehey et al., 2007; Brega et al.,
negatively affected by pain, was used as a covariate
2008; Grigsby et al., 2008). ECF impairment limits an
in all analyses.
individual’s ability to regulate his/her behavior
through planning, initiating appropriate activity, and
inhibiting inappropriate behaviors. We hypothesized RESULTS
that ECF deficits would contribute to functional
Sample descriptives
impairment. IADLs, which require planning and step-
by-step execution of goal-directed activity, were Table 1 provides descriptive information about the
expected to be particularly affected by ECF deficits. sample. Although truncation of the sample ensured
As ADLs are less complex activities, for which that the two carrier groups did not differ significantly
behavioral self-regulation over time is less crucial, we from the control group with regard to age, men with
expected ADLs as well as physical limitations to be FXTAS were older on average than APCs ( p < 0.01).
less severely affected by ECF deficits. This age difference likely reflects the fact that the
The measure of ECF used in this study was the prevalence of FXTAS increases with age (Jacquemont
Behavioral Dyscontrol Scale (BDS), a measure of the et al., 2004). Note that no premutation carrier over the
capacity for behavioral self-regulation (Grigsby et al., age of 73 was classified as asymptomatic. Because of
1992; Diesfeldt et al., 2004; Ecklund-Johnson et al., the marked age difference between APCs and men
2004). The BDS has consistently demonstrated with FXTAS, we did not compare functional status
deficits among persons with both the fragile X full between the carrier groups, but instead compared each
mutation and FXTAS (Hagerman et al., 2001; Loesch premutation group separately to controls.
Copyright # 2009 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2009; 24: 1101–1109.
DOI: 10.1002/gps1104 a. g. brega ET AL.
Table 1. Participant characteristics by group: mean (range)a
FXTAS (n ¼ 42) Asymptomatic carrier (n ¼ 24) Control (n ¼ 32)
Ageb 68.6 (53–89) 63.7 (55–73) 67.2 (54–89)
Years of Educationb 15.3** (8–21) 16.0* (12–19) 17.3 (10–21)
CGG Repeatc 95.9 (67–142) 79.2 (60–112) 30.5 (18–45)
a
Table 1 presents unadjusted means (and ranges) for participants in the three study groups.
b
When appropriate, significant differences between each premutation group and the control group are indicated.
c
Men with FXTAS had significantly higher CGG repeat expansions than did their asymptomatic counterparts ( p < 0.0001).
*p < 0.10; **p 0.01.
Participants were relatively highly educated. In early as their late forties (minimum age of onset was
each study group, subjects had 15 or more years of 47 for ataxia and 48 for tremor), for some subjects,
education on average. Controls had significantly more these symptoms first appeared in the late seventies
years of education than did men with FXTAS ( p < (maximum age of onset was 78 for ataxia and 79 for
0.01) and marginally more than APCs ( p < 0.10). tremor). Mean age of onset of tremor and ataxia was
Whereas the majority of APCs (71%) and controls 61. Men in this sample developed FXTAS
(75%) in this sample had 16 or more years of symptoms 9.1 years prior to assessment, on
education, only 43% of men with FXTAS had attained average, although duration of disease ranged from 0
a similar degree of education. Analyses therefore to 22 years.
controlled for education. The two defining neurologic signs of FXTAS
The premutation carrier groups differed with regard developed at similar ages for most subjects. Sixty
to CGG repeat length (Table 1). Men with FXTAS had percent of subjects with tremor and ataxia experienced
significantly more repeats than did APCs ( p < 0.0001). onset of both symptoms within a 3-year period.
Although both carrier groups had members with CGG Typically, however, tremor predated ataxia. Whereas
repeats in the sixties, large expansions were more 40% of FXTAS subjects developed tremor prior to
common among men with FXTAS. Whereas only one ataxia, 37% developed ataxia first. For 23%, the onset
asymptomatic carrier had a CGG repeat length greater of tremor and ataxia occurred at the same age.
than 94, 22 men with FXTAS (52%) had 95 repeats or
more.
Group differences in functional performance
Among men with FXTAS, most had both tremor
and ataxia (79%). An additional 12% had ataxia only, Regression analyses provided evidence of functional
whereas 10% had tremor only. Age of onset of the two impairment among men with FXTAS (Table 2). In
key neurologic signs of FXTAS ranged widely and comparison with controls, men with FXTAS showed
was not correlated with CGG repeat length ( p > 0.10). more physical limitations ( p < 0.01). Whereas
Although some subjects developed tremor/ataxia as FXTAS subjects had difficulty with 42% of the six
Table 2. Functional status: premutation groups vs controlsa
FXTAS Asymptomatic carrier Control
(Mean) (n ¼ 42) (Mean) (n ¼ 24) (Mean) (n ¼ 32)
Physical Limitations Score 0.42*** 0.18* 0.11
ADL Limitations Score 0.19** 0.03 0.03
ADL Frequency Change Score 0.20** 0.01 0.05
ADL Method Change Score 0.25*** 0.02 0.02
IADL Limitations Score 0.26*** 0.04 0.03
IADL Frequency Change Score 0.25*** 0.02 0.04
IADL Method Change Score 0.15*** 0.00 0.02
a
Table 2 presents mean scores by group as well as the results of separate regression analyses comparing control subjects to subjects in the two
premutation groups.
*p < 0.10; **p 0.05; ***p 0.01.
Copyright # 2009 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2009; 24: 1101–1109.
DOI: 10.1002/gpsfunctional status in fxtas 1105
physical limitation items, on average, controls interfered with daily activities was a significant
experienced difficulty with only 11%. predictor of physical limitations (p < 0.001, r2 ¼ 0.23),
ADL performance also was impaired among men ADL limitations ( p < 0.01, r2 ¼ 0.20), ADL fre-
with FXTAS. These subjects experienced limitations quency change ( p < 0.01, r2 ¼ 0.21), ADL method
in a larger proportion of ADLs ( p < 0.05) than did change ( p < 0.05, r2 ¼ 0.14), and IADL method
controls (19% vs 3%, respectively). In addition, men change ( p < 0.05, r2 ¼ 0.16). Age was a significant
with FXTAS were more likely than controls to have predictor of ADL method change ( p < 0.05, r2 ¼ 0.08)
changed the frequency of ADL performance and was marginally related to ADL limitations
( p < 0.05) as well as their method for performing ( p < 0.10). Comorbidity predicted ADL frequency
these tasks ( p < 0.01). FXTAS subjects had changed change ( p < 0.05, r2 ¼ 0.07) and was marginally
the frequency with which they performed 20% of associated with IADL limitations and IADL method
ADLs and had changed the method for completing change ( p < 0.10). Education was marginally associ-
25%. In contrast, controls had changed the frequency ated with IADL method change (p < 0.10).
for completing 5% of ADLs and the method for Among men with FXTAS, CGG repeat length
completing 2% of these activities. predicted functional status. Post-hoc analyses regres-
Compared with controls, FXTAS subjects scored sing functional measures on CGG repeat length
significantly worse on IADLs ( p < 0.01). Whereas showed that men with larger repeat expansions scored
controls had difficulty with 3% of the eight IADLs, on significantly worse on ADL frequency change
average, men with FXTAS had difficulty with 26% of ( p < 0.05), IADL limitations ( p < 0.01), and IADL
IADLs. FXTAS subjects also were more likely than frequency change ( p < 0.001), and marginally worse
controls to have changed the frequency ( p ¼ 0.01) and on physical and ADL limitations ( p < 0.10).
method with which IADLs were performed ( p < 0.01). APCs showed little evidence of the functional
Whereas men with FXTAS had changed the frequency limitations experienced by FXTAS subjects. Although
with which they conducted 25% of IADLs and the there was a trend for APCs to experience greater physical
method with which they completed 15%, controls had limitations than controls ( p < 0.10), this difference
changed frequency or method for only a small was not significant. APCs performed similarly to
percentage of tasks (4% and 2%, respectively). controls on all other measures of functional status.
Regression analyses examining group differences Table 3 provides information about impairment of
in functional status controlled for age, education, specific ADLs and IADLs by group. Among ADLs,
comorbidities, and pain. The degree to which pain men with FXTAS were particularly likely to
Table 3. Impairment of specific ADLs and IADLs
Limitations reported (%) Frequency has changed (%) Method has changed (%)
FXTAS Asymptomatic Control FXTAS Asymptomatic Control FXTAS Asymptomatic Control
Carrier Carrier Carrier
ADLs
Bathing 14.3% 0.0% 0.0% 19.0% 0.0% 3.2% 28.6% 0.0% 3.2%
Dressing 19.0% 8.7% 3.2% 9.5% 0.0% 3.2% 33.3% 4.4% 3.2%
Eating 11.9% 0.0% 6.4% 7.3% 0.0% 6.4% 21.4% 0.0% 3.2%
Toileting 9.5% 4.4% 3.2% 10.0% 0.0% 0.0% 14.3% 0.0% 0.0%
Transferring 35.7% 8.7% 6.4% 21.4% 0.0% 6.4% 35.7% 8.7% 3.2%
Crossing a Room 21.4% 0.0% 0.0% 26.2% 4.4% 6.4% 24.4% 4.4% 0.0%
Getting Outside 21.4% 0.0% 3.2% 40.5% 0.0% 9.7% 14.6% 0.0% 0.0%
IADLs
Meal Preparation 15.2% 4.6% 0.0% 11.9% 0.0% 6.4% 2.6% 0.0% 0.0%
Driving 31.0% 0.0% 0.0% 33.3% 0.0% 0.0% 18.0% 0.0% 0.0%
Shopping 27.5% 4.6% 3.4% 21.4% 4.6% 3.2% 22.5% 0.0% 0.0%
Telephone 4.8% 0.0% 3.2% 9.5% 0.0% 3.2% 5.0% 0.0% 0.0%
Managing Medication 19.0% 0.0% 0.0% 7.1% 0.0% 0.0% 9.8% 0.0% 0.0%
Managing Money 23.5% 4.8% 0.0% 19.0% 4.4% 0.0% 15.0% 0.0% 0.0%
Strenuous Housework 62.2% 17.4% 18.5% 59.5% 4.4% 22.6% 37.5% 0.0% 12.9%
Light Housework 18.9% 0.0% 0.0% 34.2% 0.0% 0.0% 14.6% 0.0% 0.0%
Copyright # 2009 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2009; 24: 1101–1109.
DOI: 10.1002/gps1106 a. g. brega ET AL.
experience difficulty transferring to or from a bed or Table 4. Number of impaired ADLs and IADLs: percentages by
chair (36%). Further, about one-fifth of FXTAS groupa
subjects were reported to have difficulty with FXTAS Asymptomatic Control
ambulation (i.e. crossing a room, getting outdoors) (n ¼ 42) Carrier (n ¼ 24) (n ¼ 32)
and dressing. Changes in the frequency for completing
the transferring, ambulation, and bathing ADLs were ADLs
0 50.0% 87.0% 83.9%
common among men with FXTAS (19–40%). A 1 11.9% 8.7% 9.7%
substantial proportion of men with FXTAS had 2 14.3% 0.0% 6.4%
changed their method for bathing, dressing, eating, 3 14.3% 4.4% 0.0%
transferring, and crossing a room (21–36%). 4 or more 9.5% 0.0% 0.0%
With respect to IADLs, strenuous housework was
IADLs
particularly problematic for men with FXTAS, with 0 38.1% 73.9% 80.6%
difficulty reported for over one-half. Approximately 1 23.8% 21.7% 16.1%
one-fifth to one-third experienced difficulty with 2 4.8% 4.4% 3.2%
driving, shopping, managing medications, managing 3 14.3% 0.0% 0.0%
4 or more 19.0% 0.0% 0.0%
money, and light housework. A substantial proportion
of FXTAS subjects had changed the frequency for a
Not all totals equal 100% due to rounding.
activities related to driving, shopping, managing
money, and housework. Changing the method for
driving, shopping, and completing strenuous house-
work was common. third of men with FXTAS experienced limitations with
Table 4 shows the number of functional items with three or more IADLs, but no APCs or controls did so.
which members of each group had difficulty. Whereas
50% of men with FXTAS experienced no difficulty
Motor and executive impairment
with ADLs, 87% and 84% of APCs and controls,
respectively, had no ADL limitations. Difficulty with In secondary sets of analyses, we explored the degree
multiple ADLs was more common among men with to which motor and ECF impairment contribute to
FXTAS. Whereas 24% of individuals with FXTAS had functional limitations among men with FXTAS
difficulty with three or more ADLs, this was true for (Table 5). We recomputed regression models reported
only 4.4% of APCs and none of the controls. previously, controlling for motor performance in one
A similar pattern of results was found related to set of models and BDS score in a second set of models.
IADLs. The percentage of men with no IADL When motor functioning was controlled, group
limitations was lower in the FXTAS group (38%) differences became nonsignificant for all dependent
than the APC (74%) and control (81%) groups. One- measures except ADL and IADL method change
Table 5. Mediating role of motor and executive functioning: FXTAS vs control subjectsa
Effect of group (t) Independent effect of mediator (t, r2)
No mediators Motor score BDS score Motor BDS
controlled controlled controlled score score
Physical Limitations 3.01*** 1.91* 3.17*** 1.75* (0.10) 1.08 (0.00)
ADL Limitations 2.18** 0.87 1.47 2.27** (0.11) 0.98 (0.04)
ADL Frequency Change 2.12** 1.08 1.52 1.51 (0.07) 0.76 (0.03)
ADL Method Change 3.04*** 2.06** 2.47** 1.22 (0.08) 0.44 (0.03)
IADL Limitations 2.82*** 1.26 1.44 2.42** (0.14) 2.47** (0.14)
IADL Frequency Change 2.59*** 1.29 1.15 1.72* (0.10) 2.69*** (0.15)
IADL Method Change 2.91*** 2.35** 2.07** 0.02 (0.02) 1.08** (0.06)
a
Table 5 presents the results of regression analyses comparing the impact of the group comparison variable (FXTAS vs control) when motor
functioning and executive functioning are controlled and are not controlled. T values and significance for the group variable as well as
t values, significance, and effect sizes for the motor and executive functioning variables are reported.
*p < 0.10; **p 0.05; ***p 0.01.
Copyright # 2009 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2009; 24: 1101–1109.
DOI: 10.1002/gpsfunctional status in fxtas 1107
variables, for which the group effect was reduced but among men with FXTAS. Although controlling for
not eliminated. Similarly, inclusion of BDS score motor and executive functioning did reduce group
eliminated group differences for all dependent differences in the ADL and IADL method change
measures except the physical limitations score and variables, FXTAS subjects still performed signifi-
the ADL and IADL method change variables. cantly worse than their healthy counterparts. These
Motor and ECF scores were not always independent results suggest that functional impairment among men
predictors of the dependent measures. Motor score with FXTAS is largely a result of the motor symptoms
was a significant predictor of ADL and IADL and executive dysfunction that accompany the
limitations scores, and was marginally related to syndrome.
physical limitations and IADL frequency change. As This finding of a contribution by both ECF and
expected, ECF was more closely related to IADL than motor impairment is reasonable given that fine motor
ADL functioning, serving as a significant predictor of control is necessary for performance of most ADL/
all three IADL scores. Even when not significantly IADLs. ECF fundamentally represents the capacity to
related to dependent measures, however, the addition plan, initiate, monitor, adjust, and complete purpose-
of these mediating variables had a strong effect on the ful activity. Hence, significant ECF deficits may affect
relationship between group and functional perform- functional status even when one has the motor
ance. These results suggest that functional limitations capacity to perform ADLs and IADLs (Grigsby
among men with FXTAS result largely from impair- et al., 1998).
ment in motor and executive functioning. APCs demonstrated no significant functional impair-
ment. Although they had marginally higher physical
limitations scores, average performance on the ADL
DISCUSSION
and IADL dependent measures in this group was similar
The results provide a comprehensive picture of the to that of control subjects. Given that motor function-
nature and severity of functional impairment in FXTAS. ing–which is normal in this group–is a key contributor to
Men with FXTAS had significantly more physical and physical and functional deficits, it is reasonable that
functional limitations than did control subjects. Both APCs would show no ADL/IADL deficits.
ADL and IADL performance was affected, although Our data are consistent with those of Mioshi et al.
men with FXTAS showed impairment of a greater (2007), who studied ADLs in persons with fronto-
proportion of IADLs than ADLs. Among men with temporal dementia (FTD) and Alzheimer disease. In
FXTAS, larger CGG repeat expansions were associ- particular, they noted significant problems in func-
ated with greater functional impairment. tional status among individuals with the behavioral
It is possible that IADL impairment was more variant of FTD (bv-FTD). Interestingly, they noted
common than ADL deficits because the former cate- that bv-FTD subjects scored well on the Mini Mental
gory of functional activities relies somewhat more on State Exam (MMSE; Folstein et al., 1975), a finding
complex motor skills. Bivariate correlations showed a similar to what we have reported in FXTAS (Grigsby
slightly stronger relationship between motor score and et al., 2007; Brega et al., 2008).
IADL limitations (r ¼ 0.51, p < 0.0001) than bet- Individuals with FXTAS may have significant needs
ween motor score and ADL limitations (r ¼ 0.46, for assistance with ADLs and IADLs as the syndrome
p < 0.0001). Further, perhaps IADLs are cognitively progresses, although both the present study and that of
more demanding than ADLs. Previous research has Mioshi and associates, were limited to cross-sectional
demonstrated that ECF, is consistently a stronger data. Longitudinal studies will provide more useful
predictor of IADLs than ADLs (Kaye et al., 1990; and compelling data on the nature and progression of
Suchy et al., 1997; Grigsby et al., 1998, 2000, 2002). FXTAS. This study complements the work of Leehey
Functional impairment among men with FXTAS et al. (2007), who found that in FXTAS, tremor creates
was heavily influenced by deficits in motor and considerable disability within approximately 13 years
executive functioning. As expected, motor function- from onset of motor symptoms. By 16 years post-
ing, but not ECF, accounted for some of the physical onset, half of patients with FXTAS show significant
limitations experienced by men with FXTAS. Both ADL difficulty.
motor ability and ECF accounted for group differences
in ADL and IADL limitations as well as ADL and
CONCLUSION
IADL frequency change. Impairment of fine motor
skills and of the capacity for behavioral self-regulation This study provides the first detailed description of the
each contributed to these functional impairments nature and severity of functional impairment among
Copyright # 2009 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2009; 24: 1101–1109.
DOI: 10.1002/gps1108 a. g. brega ET AL.
Dyscontrol Scale (BDS). Int J Geriatr Psychiatry 19: 1065–
KEY POINTS 1073.
Duke University Center for the Study of Aging and Human Devel-
Men with FXTAS demonstrate significant opment. 1988. Multidimensional Functional Assessment: The
impairment of physical and functional abilities. OARS Methodology. Duke University Press: Durham, NC.
Asymptomatic carriers of the fragile X pre- Ecklund-Johnson E, Miller SA, Sweet JJ. 2004. Confirmatory factor
mutation perform similarly to control subjects analysis of the behavioral dyscontrol scale in a mixed clinical
with regard to physical and functional status. sample. Clin Neuropsychol 18: 395–410.
Folstein MF, Folstein SE, McHugh PR. 1975. ‘Mini-Mental State’.
Motor and executive impairment are key A practical method for grading the cognitive state of patients for
contributors to physical and functional impair- the clinician. J Psychiatr Res 12: 189–198.
ment among men with FXTAS. Fried LP, Bandeen-Roche K, Chaves PH, Johnson BA. 2000. Pre-
clinical mobility disability predicts incident mobility disability in
older women. J Gerontol A Biol Sci Med Sci 55: M43–52.
Grigsby J, Brega AG, Engle K, et al. 2008. Cognitive profile of
fragile X premutation carriers with and without fragile X-associ-
male carriers of the fragile X premutation. Although ated tremor/ataxia syndrome. Neuropsychology 22: 48–60.
men with FXTAS experience significant functional Grigsby J, Brega AG, Jacquemont S, et al. 2006. Impairment in the
deficits, asymptomatic carriers show no significant cognitive functioning of men with fragile X-associated tremor/
ataxia syndrome (FXTAS). J Neurol Sci 248: 227–233.
sign of physical or functional limitations. Impaired motor Grigsby J, Brega AG, Leehey MA, et al. 2007. Impairment of
functioning and ECF appear to be key contributors to executive cognitive functioning in males with fragile X-associ-
functional impairment among men with FXTAS. ated tremor/ataxia syndrome. Mov Disord 22: 645–650.
Grigsby J, Kaye K, Baxter J, et al. 1998. Executive cognitive
abilities and functional status among community-dwelling older
CONFLICT OF INTEREST persons in the San Luis Valley Health and Aging Study. J Am
Geriatr Soc 46: 590–596.
None known. Grigsby J, Kaye K, Eilertsen TB, Kramer AM. 2000. The Behavioral
Dyscontrol Scale and functional status among elderly medical and
surgical rehab patients. J Clin Geropsychol 6: 259–268.
Grigsby J, Kaye K, Kowalsky J, Kramer AM. 2002. Relationship
ACKNOWLEDGEMENTS between functional status and the capacity to regulate behavior
Funding for this study was provided by National among elderly persons following hip fracture. Rehabilitative
Psychol 47: 291–307.
Institute of Neurological Disorders and Stroke Grigsby J, Kaye K, Robbins LJ. 1992. Reliabilities, norms and factor
(NINDS) grant number NS044299 (JG). structure of the Behavioral Dyscontrol Scale. Percept Mot Skills
We would like to express our gratitude to the 74: 883–892.
participants and their families for taking part in this Guralnik JM, Ferrucci L, Penninx BW, et al. 1999. New and
worsening conditions and change in physical and cognitive
study. performance during weekly evaluations over 6 months: The
Women’s Health and Aging Study. J Gerontol A Biol Sci Med
Sci 54: M410–422.
Hagerman RJ, Leehey M, Heinrichs W, et al. 2001. Intention tremor,
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