Abstract
Current outcomes used to evaluate adrenomyeloneuropathy are limited by rater bias, not sensitive to preclinical changes, and require years to decades to detect disease progression. Quantitative outcomes are needed that detect meaningful change in a short time period over a broad range of disability. The study aim was to track sensorimotor outcomes in adults with adrenomyeloneuropathy and evaluate differences in progression between men and women. This prospective observational cohort study analyzes data collected annually in the Phase III study of adults with adrenomyeloneuropathy. Outcomes include postural sway in four static standing conditions, great-toe vibration, hip strength, walking velocity, timed up-and-go, and 6-minute walk distance. Linear mixed model analysis was used to detect change in the outcomes in 2 years, correcting for age, sex, disability, symptom duration, and treatment across the cohort. Modeling was repeated for each sex to evaluate differences. Power computations were carried out by sex and for the full dataset. Sixty-one men and 87 women participated. Average age, 46 ± 12 years; Expanded Disability Status Scale, 3 (1–6.5); symptom duration, 10.8 ± 9.4 years. The cohort showed significant worsening in all standing conditions (P < .001), sensation (P = .0223) and strength (P = .001); but more stability in walking with only velocity (P < .0337) significantly declining. For each sex, postural sway declines significantly in all conditions (P < .01) except for eyes closed feet together for women. Strength declines significantly by sex for hip flexion (P < .03). Sex-specific significant decline is seen in walking (velocity P = .0276; distance P = .0072) for men only. Quantitative measures of postural sway, sensation strength, and walking are effective measures of adrenomyeloneuropathy progression in 2 years.
Keywords: balance, biomarkers, disease progression, leukodystrophy, myelopathy, peroxisomal disorder
1 |. INTRODUCTION
The adult variant of X-linked adrenoleukodystrophy, adrenomyeloneuropathy (AMN), a peroxisomal disorder due to mutations in ABCD1, has an incidence of 1:14 700.1,2 AMN affects almost all males who survive to adulthood and more than half of all adult females. In both men and women, AMN is defined by presentation of myelopathy including lower extremity weakness, sensory ataxia, and bowel/bladder dysfunction. In men, AMN may also include adrenal insufficiency and cerebral inflammatory disease. AMN is slowly progressive with clear clinical worsening measured over decades using standard clinical assessments.3 Quantitative measures of sensorimotor function have been shown to reflect biologically relevant endpoints in AMN and are informative to direct individualized treatment, but are underutilized.4 Clinical presentation of AMN is often first noted as abnormalities in walking. Changes in walking result from impairment of lower extremity sensation and strength, presumably from axonopathy of the corticospinal and dorsal column pathways.5 Subtle changes in vibration sensation and strength may go unnoticed by patients early in the disease course as they may compensate well to a point and providers may not be able to measure the change through standard clinical tests such as the tuning fork or manual muscle test. We have validated a protocol for quantitatively evaluating postural sway, strength, sensation, and walking in AMN men and women.4,6 Here we report on the results of longitudinal tracking of sensorimotor measures of men and women in the Lorenzo’s Oil study and indicate the measures which show change over 2 years. Of note, 2 years is less than half the time the parent study had predicted was necessary to detect progression. We also determined if any of the measures were specific to men or women.
2 |. METHODS
2.1 |. Participants
This study is a longitudinal analysis of sensorimotor data measured during 2005 to 2008 from 148 participants (61 men and 87 women) enrolled in the study: A Phase III Placebo Controlled, Double Blind Trial to Evaluate the Effect of Glyceryl Trioleate and Glyceryl Trierucate (Lorenzo’s Oil) in Adults with AMN. All participants gave informed consent according to the Institutional Review Board requirements. Quantitative sensorimotor measures of balance, sensation, strength, and walking were obtained annually to determine if any could serve as surrogate biomarkers of progression in adults with AMN in a shorter observation period than neurological exam. Data analyzed in this study are of baseline, 12 months and 24 months observations. Participants met the larger study criteria of >18 years old; AMN, confirmed by using the very-long-chain fatty acid assay (VLCFA) and/or mutation analysis; no brain MRI demyelination; and Kurtzke Expanded Disability Status Scale (EDSS) score of 1 to 6.5. Because symptoms of AMN are typically noted in retrospect, information regarding the initial onset of symptoms was based on participant report. Participants were grouped into one of three treatment groups: placebo (N = 74), Lorenzo’s Oil – compliant, Lorenzo’s Oil (N = 52) – noncompliant (N = 21). Lorenzo’s Oil noncompliance was determined based on VLCFA assay or by patient reported noncompliance if assay was unavailable at a particular assessment time point.
Table 1 indicates the number of participants tested for each measure at the annual time points (0, 12, 24 months) and those participants unable to complete the test for each measure.
TABLE 1.
Enrollment and testing table shows the number of participants at the annual time points for each measure
| Total enrolled, n = 148 | Time 0, n = 147 | Time 12, n = 94 | Time 24, n = 59 | |||
|---|---|---|---|---|---|---|
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| Female 87, Male 61 | Female, 86 | Male, 61 | Female, 53 | Male, 41 | Female, 34 | Male, 25 |
| Postural sway | ||||||
| EOFA | 0 (78) | 4 (54) | 3 (47) | 8 (32) | 1 (31) | 0 (25) |
| EOFT | 6 (72) | 10 (48) | 5 (45) | 13 (27) | 1 (31) | 2 (23) |
| ECFA | 4 (74) | 11 (47) | 5 (45) | 12 (28) | 2 (30) | 5 (20) |
| ECFT | 18 (60) | 24 (34) | 12 (38) | 18 (22) | 8 (24) | 8 (17) |
| Sensation | ||||||
| Vibration | 5 (78) | 11 (58) | 4 (50) | 8 (33) | 3 (31) | 12 (23) |
| Strength | ||||||
| Hip flexion | 0 (85) | 0 (61) | 1 (51) | 3 (38) | 1 (33) | 0 (25) |
| Hip extension | 4 (81) | 5 (54) | 3 (48) | 3 (38) | 1 (30) | 0 (23) |
| Walking | ||||||
| Velocity | 0 (78) | 5 (54) | 3 (47) | 3 (37) | 1 (31) | 1 (23) |
| Timed up-and-go | 3 (83) | 3 (58) | 3 (47) | 5 (34) | 2 (32) | 1 (23) |
| 6-minute walk | 9 (64) | 12 (39) | 6 (47) | 12 (26) | 6 (21) | 2 (19) |
Note: First row: Time in 0,12, 24 months. Total sample size for each time point. Table values listed as X(Y), where X is the number of participants unable to complete a measure as a result of severity of symptoms and Y parentheses is the total number of participants tested for each measure. Overall, this figure specifies both those participants who are unable to complete the test and those participants who were not tested because of time limitations and schedule conflicts. For example, in the first column, time 0 month, male (n = 61), for postural sway: EOFA, 4 were unable to do the test and the total sample tested is (n = 54) therefore 3 men were not tested because of time limitations or schedule conflicts. Whereas, in ECFT in that column still just 3 men were not tested, but 24 men could not do the test so subtotal n = 34 were measured for sway ECFT.
Abbreviations: A, apart; E, eyes; F, feet; O, open; T, together.
2.2 |. Outcome measures
Each of the sensorimotor measures are described briefly below. For detailed procedures please refer to Keller et al.6
2.3 |. Balance by posturography
Balance was assessed with static posturography by measuring the extent of postural sway in four conditions, each for two 20-second trials: (1) eyes open feet shoulder width apart (EOFA), (2) eyes closed feet shoulder width apart (ECFA), (3) eyes open feet together (EOFT), and (4) eyes closed feet together (ECFT). Foot spread in the feet apart condition was measured at baseline and repeated at this distance annually, and range was 9 to 35 cm. Data were collected at 1000 Hz using a Kistler 9281 force plate (Kistler Instrumente AG, Winterthur, Switzerland).7 Balance deficits were calculated as the magnitude of postural sway (sway amplitude, in mm) using custom Matlab software (TheMathWorks, Inc, Natick, Massachusetts).
2.4 |. Sensation by vibratory thresholds
Vibration thresholds were measured using a 2-alternative forced-choice procedure using the Vibratron II (Physitemp Instruments, Inc, Clifton, NJ). The average of both sides of great toe vibration thresholds are used in the analysis. For participants who could not sense the maximum amplitude of vibration (19.9VU) that value was assigned. Reference value range for 36- to 50-year olds from normal to severe sensory loss is 2.56 to 4.64 VU. Significant progression in vibratory thresholds has been measured in 18 months in diabetic neuropathy.8
2.5 |. Strength by hand held dynamometry
The average of two maximal effort break test trials for each side and muscle group was measured using a Microfet2 handheld dynamometer (Hoggan Industries, West Jordan, Utah) and documented in pounds. The left and right values were then summed for each muscle group. Hip flexor strength was measured in supine with the hip at 90 of flexion. Hip extensor strength was measured in prone with the hip at end range and the knee flexed to 90. Dynamometry has been shown to be more sensitive to change than clinical manual muscle testing in chronic spinal cord injury.9
2.6 |. Walking velocity by 3D motion capture
Fast walking speed was determined from the three fastest of six trials where participants walked as quickly as possible over a 9-m walkway. A three-dimensional Optotrak motion measurement system (Northern Digital, Inc, ON, Canada) was used to collect the ankle joint position data at 100 Hz. Custom Matlab software was used to calculate stride velocity between same side heel strikes (length/time).
2.7 |. Clinical timed walking
2.7.1 |. Timed up-and-go
This is a functional timed test where the subject rises from a chair walks 3 m, turns around, walks back and sits again. The test is done twice and the second time is recorded in seconds for analysis.10 In knee osteoarthritis, timed up-and-go (TUG) has shown responsiveness to demonstrate improvement from rehabilitation.11
2.7.2 |. Walking endurance by the 6-minute walk test
The 6-minute walk test measures how far a person is able to walk in 6 minutes. Standard protocol was followed with a track of 20-m in length. This test has been shown to demonstrate decline in people with pulmonary disease12 and in improvements within the first 6 months after spinal cord injury over rating scales.13
2.8 |. Data analysis
To investigate the longitudinal trends of each outcome, we implemented a linear mixed model including random effects for study participants. Each outcome of interest was modeled using a separate regression including study visit time as an independent variable as well as covariates age, EDSS, years of symptoms at baseline, treatment, and sex. The subject-specific random effect accounts for the variability of the outcome associated with the deviation from the mean caused by data collection from the same study participant. This approach is used for modeling the longitudinal data to account for between- and within-subject variability differences and since some participants had missing visits. All P-values were adjusted for multiple comparisons using the false discovery rate correction. The linear mixed models were implemented using the package lmer while the power computations were implemented using the package pwr in the R software.
3 |. RESULTS
The cohort included 87 women and 61 men diagnosed with AMN, with an average age of 46 ± 12 years (for men, 41 years and women, 49 years). All participants were asked how long they had symptoms, and for the overall group the average was 10.8 ± 9.4 years, for men: 8.6 ± 6.7 years, and for women it was 12.2 ± 10.7 years. Clinically, the cohort presented with moderate overall disability, with a median EDSS score of 3. Based on EDSS score, there was a range of walking ability from mildly through severely affected that increased slightly over the 2 years; EDSS scores for men ranged from 1 to 6.5, and for women: 1.5 to 6.5. The EDSS median changed little over the 2 years (sex: 0, 12, 24; men: 3.5, 3, 3; women: 3, 3, 3.5). Sensorimotor data measured at time 0, 12 and 24 months are shown in Figure 1 (postural sway conditions) and Figure 2 (sensation, hip flexion strength, walking endurance).
FIGURE 1.
Sway amplitude (mm) from posturography. Results are shown from the four static standing conditions of eyes open or closed and feet apart or together. E, Eyes; O, Open; F, Feet; T, Together; A, Apart. Line plots show individual participant values (dashed lines) and mean values (solid lines) at time 0, 12 and 24 months. Men in blue. Women in red. Comparing the eyes open conditions (top graphs) to the eyes closed conditions (bottom graphs) shows the reliance of men on vision for balance (greater sway) compared to the women
FIGURE 2.
Hip flexion, sensation, walking endurance of men and women with AMN over 2 years. Data shown by line plots for the individual participants (dashed lines) and mean values (solid lines) at time 0, 12, and 24 months. Men in blue. Women in red. For hip flexion and walking endurance smaller values are worse; for vibration sensation larger values are worse
Regression analyses were performed to evaluate change over 2 years. These are shown in Table 2. When evaluating the mixed cohort, some measures of postural sway, sensation, strength, and walking show significant decline (P < .05). However, only the TUG did not show measurable decline over 2 years.
TABLE 2.
Linear mixed model shows specific measures of postural sway, sensation, strength and walking are associated with change over 2 years, after controlling for the effects of age, gender, EDSS, and treatment
| Predictors | Beta | P-value | Adj P | 95% CI | |
|---|---|---|---|---|---|
| Postural sway | |||||
| Eyes open feet apart | All | 0.065 | <.0001 | .0003 | [0.034, 0.095] |
| Men | 0.064 | .0059 | .0133 | [0.020, 0.107] | |
| Women | 0.064 | .0029 | .0097 | [0.023, 0.106] | |
| Eyes open feet together | All | 0.077 | .0001 | .0003 | [0.040, 0.114] |
| Men | 0.074 | .0093 | .0133 | [0.021, 0.127] | |
| Women | 0.079 | .0029 | .0097 | [0.028, 0.130] | |
| Eyes closed feet apart | All | 0.119 | <.0001 | <.0001 | [0.082, 0.157] |
| Men | 0.113 | .0011 | .0064 | [0.049, 0.176] | |
| Women | 0.122 | <.0001 | <.0001 | [0.075, 0.169] | |
| Eyes closed feet together | All | 0.114 | .0002 | .0006 | [0.056, 0.172] |
| Men | 0.151 | .0019 | .0064 | [0.063, 0.241] | |
| Women | 0.085 | .0332 | .0663 | [0.009, 0.161] | |
| Sensation | |||||
| Vibration score at great toe | All | 0.046 | .0134 | .0223 | [0.010, 0.082] |
| Men | 0.065 | .0616 | .0770 | [−0.002, 0.131] | |
| Women | 0.029 | .1358 | .1939 | [−0.009, 0.068] | |
| Strength | |||||
| Hip flexion | All | −0.143 | .0005 | .0010 | [−0.221, −0.064] |
| Men | −0.222 | .0077 | .0133 | [−0.379, −0.064] | |
| Women | −0.087 | .0133 | .0332 | [−0.155, −0.020] | |
| Hip extension | All | 0.071 | .3515 | .3515 | [−0.078, 0.219] |
| Men | −0.075 | .5543 | .5543 | [−0.322, 0.172] | |
| Women | 0.173 | .0655 | .1092 | [−0.009, 0.345] | |
| Walking | |||||
| Walk speed | All | −0.0023 | .0236 | .0337 | [−0.004, −0.0003] |
| Men | −0.0044 | .0089 | .0133 | [−0.008, −0.001] | |
| Women | −0.0007 | .5874 | .6782 | [−0.003, 0.002] | |
| Timed up-and-go | All | −0.0143 | .3481 | .3515 | [−0.044, 0.015] |
| Men | −0.0252 | .1708 | .1897 | [−0.061, 0.010] | |
| Women | −0.0094 | .6782 | .6782 | [−0.054, 0.035] | |
| 6-minute walk | All | −0.9812 | .0426 | .0532 | [−1.918, −0.044] |
| Men | −2.619 | .0018 | .0064 | [−4.154, −1.086] | |
| Women | 0.2357 | .6755 | .6782 | [−0.862, 1.334] |
Note: Italic rows identify measures that show significant change (adjusted P < .05) in 2 years.
When the cohort is divided by sex, some measures show unique decline based on sex. Postural sway shows significant decline in both men and women in the conditions with the feet apart and eyes either open or closed (P < .05). However, in the feet together eyes closed condition, significant decline is only observed in men, following adjustment for multiple comparisons. Similarly, strength shows significant decline for each sex for hip flexion, but not for hip extension. On the other hand, sensation shows significance only for the whole cohort, men and women but not for either sex separately. By contrast, walking measures distinguish between men and women, with walk speed and 6 MW showing significant decline only in the men. TUG does not show significant changes over time for men or women.
Sample size calculations for the postural sway measure were determined using 80% power to obtain the significant changes observed in this study. As such, to detect significant associations in a 2-year study, for the four sway measures, the sample size needed would be 95 for a study of men only, 36 for women only and at most 50 for a cohort of men and women. Using the F-square, the largest effect size out of the four conditions of postural sway for men only is 0.349, for women only is 0.458, and for a mixed cohort is 0.655.
4 |. DISCUSSION
In this study, we show that quantitative measures of postural sway, sensation, strength, and walking each show significant AMN progression in 2 years. Postural sway emerged as a key measure for assessing progression across a broad spectrum of disability in an efficient time period in both men and women. Postural sway is an improvement over rating scales which require differing observation periods by sex, where EDSS requires 7 years in women and 2 or more years in men to show change.14,15 Specific to muscle group, hand held dynamometry showed there is measurable decline of hip flexion strength but not hip extension of the cohort and by sex. Measuring sensory impairment, vibration, relies on a mixed cohort to detect significant worsening. Data from the 6-minute walk test further confirm that walking dysfunction is important in men.15,16 Overall, the data provide strong evidence for the feasibility and effectiveness of these sensorimotor measures as relevant quantitative endpoints for future clinical trials in AMN men, women, or mixed cohorts.
From this longitudinal data, we highlight the benefit of quantitative measurement of balance by postural sway as an indicator of AMN disease progression. Our data show for the first time that sway amplitude is a significant measure in all four static standing conditions and in both sexes. The sway data also uncover that there are unique aspects of quiet standing in men compared with women. Eyes closed conditions show much greater sway in men than in women at each individual time point compared to the eyes open conditions. The poorer performance of men in the eyes closed conditions we postulate comes from a loss of proprioception so severe it cannot be compensated for in contrast to more moderate loss in women. As our data show here and in our previous work, vibratory sensation, a marker of proprioceptive loss, is much more impaired in men than women and is related to impaired balance.6 Similarly, we have shown weakness is a significant contributor to balance impairment.4,6 The sample size calculations for the postural sway measures provide a viable opportunity for planning therapeutic trials in this underserved population. We propose that postural sway is an important quantifiable endpoint affective across the disability spectrum, and associated with the characteristic distal axonopathy of the corticospinal and dorsal column medial lemniscal tracts affected in AMN.4,5,17
Postural sway has also been used in other populations as a measure of both disease and functional performance.18,19 In aging, the extent of postural sway during quiet standing identifies older people at high risk to falls.20 In fragile X carriers data show that sway was related to permutation expansions of CGG repeats and cerebellar volume and thereby placing people at risk for fragile x-associated tremor ataxia syndrome.21 In MS, one study shows that when vision is eliminated, atrophy of the spinal cord and demyelinating lesions in the brainstem significantly contributed to worse postural sway, resulting in a greater reliance on other sensory systems, including proprioceptive and vestibular input.22 Other studies have shown that measures of dynamic and static balance are measurable factors related to walking and functional activity.23 More practically activities of daily living such as washing one’s hair in the shower requires quiet standing with spread of feet narrowed and eyes closed. Postural sway measurement tools are moderately expensive and require more technical training to acquire and process the data. These limitations are outweighed however, in making the case for postural sway as a primary outcome with a quantifiable and unbiased means to feasibly detect of disease progression in ALD and other progressive diseases.
When looking solely at men with AMN, our data show that walking is an important measure for assessing change. Men have greater disease burden than women6,14,24 and they are affected younger and often more severely. Walking is a well-established marker of quality of life. Here we show that walking velocity measured by 3D motion capture is able to show significant slowing in 2 years over the clinical walking measure, the TUG. Our data also confirm what others have shown that walking endurance measured by the 6-minute walk test can assess for change in function and is a meaningful outcome for future clinical trials.15,16
For women, while walking does not change significantly, strength is an important measure for assessing change. Hip flexor strength we have shown is a relevant link to AMN disability.6 These data show that hip flexion weakness becomes significantly worse over 2 years. Compared to rating scales such as the Expanded Disability Status Scale which heavily weights walking ability and has been shown to take 8 years to show change in women, use of dynamometry can reduce this observation period by 6 years.14 For women with AMN, weakness may be compounded by muscle loss with aging. This also is an important finding because weakness is an impairment that can be targeted by rehabilitation. Future studies may want to look at progressive resistance training initiated at the early stages of AMN to prevent disuse atrophy in men and women to moderate disability depending on the degree of pathology.
A main strength of this study is the use of quantitative measures that have been shown to be related to both pathology and disability in AMN progression.4 A selection of both clinical and laboratory measures are significant in AMN, which adds options for quantitative clinical measurement (strength) as well as measures with potentially greater sensitivity and less subjective bias (vibration, postural sway). Postural sway offers a means to measure the disease progression from low through high disability. For the first time, this study accounts for a broad range of disability (EDSS 1–6.5) in the analysis which makes the results applicable to a larger AMN population for early through late stage assessment. Using the postural sway outcomes this study also provides, for the first time, rationale justification for sample sizes that can be used for therapeutic development in AMN.
As in any longitudinal study, a primary limitation of this study is loss of follow-up. This can result in the inability to look directly at the study group means over time to directly ascertain change; however, our linear mixed models account for the loss of follow-up and allow us to assess for significant change within each measure. The Lorenzo’s Oil study from which the data were obtained included yearly physical therapy evaluation with patient education directed to reduce the effects of secondary complications (ie, individualized balance and strengthening exercises). However, to what degree participants followed the education is unknown and cannot be accounted for in the analysis, regardless significant change was found in balance and strength. In the analysis, we factor in symptom duration; however, symptom duration is approximate based on a participant’s ability to recall onset. We chose to use recall of symptom duration since diagnosis is not typically associated with the onset of symptoms, and others have used this measure in order to have a sense of individual rates of progression.25 Treatment group (placebo, Lorenzo’s Oil – compliant, Lorenzo’s Oil – noncompliant) was controlled in the analysis for detecting change in the outcomes. Therefore, significant (adj P < .05) change in this study indicates that on average a variable (eg, postural sway eyes closed feet apart) significantly worsens over time regardless of treatment group. Treatment was not assessed as a main effect and therefore no conclusions can be made in the effectiveness of Lorenzo’s Oil in this analysis.
One obstacle to studies of people with rare disorders is the burden of travel to medical centers. Future studies are indicated to see if these measures can be obtained remotely. Accelerometry offers a unique opportunity to quantify both postural sway and gait speed (eg, OPALS, APDM) in the home environment. Remote measurement would open a greater opportunity for testing people with AMN and could minimize loss of follow-up and burden of travel to an academic center for future studies.
5 |. CONCLUSIONS
Quantifying change in postural sway, strength, and walking in AMN in 2 years allows for monitoring of function and faster evaluation of potential therapeutic and interventional treatments. The measures used in this study provide selective and relevant outcomes for future studies in rehabilitation and medicine to determine effective symptom management and potential disease modifying drug development.
ACKNOWLEDGMENTS
This work was supported by NICHD (P50 HD103538 and R01 HD39276) and FDA (FD003030). We have full access to all of the data and have the right to publish any and all data apart from any sponsor. The authors would like to thank Rhul Marasigan, Johnathan Kang, and Joseph Wang for their helpful review of this manuscript. Kathleen Zackowski accepts full responsibility for the work, the conduct of the study, access to the data, and decision to publish.
Funding information
Food and Drug Administration, Grant/Award Number: FD003030; National Institute of Child Health and Human Development, Grant/Award Numbers: P50 HD103538, R01 HD39276
Footnotes
CONFLICT OF INTEREST
Jennifer Keller is a consultant for Minoryx (Boston, MA) and Poxel (Lyons, France). Dr. Raymond is a consultant and investigator for BlueBird Bio (Cambridge, MA). Dr. Raymond is a consultant for Minoryx (Barcelona, Spain), Viking Therapeutics (San Diego, CA), and Bluebird Bio (Cambridge, MA). Dr. Fatemi is a consultant for Minoryx (Barcelona, Spain), Poxel (Lyons, France), Vertex (Boston, MA), Viking Therapeutics (San Diego, CA), and Bluebird Bio (Cambridge, MA). Dr. Fatemi has also received consulting fees from Aevi Genomic Medicine (Wayne, PA), Calico Labs (San Francisco, CA), and Stealth Biotherapeutics (Auburndale, MA) outside the submitted work. Dr. Zackowski is a consultant for Minoryx (Boston, MA).
ETHICS STATEMENT
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study. All participants signed a consent form, and this study was approved by the Institutional Review Board at both Johns Hopkins University and the Kennedy Krieger Institute. Clinical Trial Registration was listed on clinicaltrials.gov ID: NCT00545597. JHMI IRB number: NA_00080235.
Communicating Editor: Nancy Braverman
DATA AVAILABILITY STATEMENT
Please contact the corresponding author, Jennifer Keller, to inquire about access to the data analyzed in this study. The data are not currently publically available but the authors are able to grant access by establishing a proper data-sharing agreement. The data are stored according to procedures to protect the confidentiality of the data for research purposes according to Johns Hopkins and Kennedy Krieger Institute IT policies.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Please contact the corresponding author, Jennifer Keller, to inquire about access to the data analyzed in this study. The data are not currently publically available but the authors are able to grant access by establishing a proper data-sharing agreement. The data are stored according to procedures to protect the confidentiality of the data for research purposes according to Johns Hopkins and Kennedy Krieger Institute IT policies.