Digital gait markers to potentially distinguish fragile X-associated tremor/ataxia syndrome, Parkinson's disease, and essential tremor.

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disease that affects carriers of a 55-200 CGG repeat expansion in the fragile X messenger ribonucleoprotein 1 (FMR1) gene, may be given an incorrect initial diagnosis of Parkinson's disease (PD) or essential tremor (ET) due to overlapping motor symptoms. It is critical to characterize distinct phenotypes in FXTAS compared to PD and ET to improve diagnostic accuracy. Fast as possible (FP) speed and dual-task (DT) paradigms have the potential to distinguish differences in gait performance between the three movement disorders. Therefore, we sought to compare FXTAS, PD, and ET patients using quantitative measures of functional mobility and gait under self-selected (SS) speed, FP, and DT conditions. Methods: Participants with FXTAS (n = 22), PD (n = 23), ET (n = 20), and controls (n = 20) underwent gait testing with an inertial sensor system (APDM™). An instrumented Timed Up and Go test (i-TUG) was used to measure movement transitions, and a 2-min walk test (2MWT) was used to measure gait and turn variables under SS, FP, and DT conditions, and dual-task costs (DTC) were calculated. ANOVA and multinomial logistic regression analyses were performed. Results: PD participants had reduced stride lengths compared to FXTAS and ET participants under SS and DT conditions, longer turn duration than ET participants during the FP task, and less arm symmetry than ET participants in SS gait. They also had greater DTC for stride length and velocity compared to FXTAS participants. On the i-TUG, PD participants had reduced sit-to-stand peak velocity compared to FXTAS and ET participants. Stride length and arm symmetry index during the DT 2MWT was able to distinguish FXTAS and ET from PD, such that participants with shorter stride lengths were more likely to have a diagnosis of PD and those with greater arm asymmetry were more likely to be diagnosed with PD. No gait or i-TUG parameters distinguished FXTAS from ET participants in the regression model. Conclusion: This is the first quantitative study demonstrating distinct gait and functional mobility profiles in FXTAS, PD, and ET which may assist in more accurate and timely diagnosis.

Validity and Reliability of the Insole3 Instrumented Shoe Insole for Ground Reaction Force Measurement during Walking and Running.

Pressure-detecting insoles such as the Insole3 have potential as a portable alternative for assessing vertical ground reaction force (vGRF) outside of specialized laboratories. This study evaluated whether the Insole3 is a valid and reliable alternative to force plates for measuring vGRF. Eleven healthy participants walked overground at slow and moderately paced speeds and ran at a moderate pace while collecting vGRF simultaneously from a force plate (3000 Hz) and Insole3 (100 Hz). Intraclass correlation coefficients (ICC) demonstrated excellent vGRF agreement between systems during both walking speeds for Peak 1, Peak 2, the valley between peaks, and the vGRF impulse (ICC > 0.941). There was excellent agreement during running for the single vGRF peak (ICC = 0.942) and impulse (ICC = 0.940). The insoles slightly underestimated vGRF peaks (−3.7% to 0.9% bias) and valleys (−2.2% to −1.8% bias), and slightly overestimated impulses (4.2% to 5.6% bias). Reliability between visits for all three activities was excellent (ICC > 0.970). The Insole3 is a valid and reliable alternative to traditional force plates for assessing vGRF during walking and running in healthy adults. The excellent ICC values during slow walking suggests that the Insole3 may be particularly suitable for older adults in clinical and home settings.

Normative database of postural sway measures using inertial sensors in typically developing children and young adults.

OBJECTIVE: Reference values utilizing the APDM MobilityLab® inertial sensor system have not been established in children and young adults ages 5-30. These values are necessary for clinicians and researchers to compare to children with balance impairments. METHODS: A group of 144 typically developing children and young adults from age 5-30 years completed the instrumented SWAY test during 6 test conditions: normal stance, firm surface, eyes open (EO) and closed (EC); normal stance, foam surface, EO and EC; and tandem stance, firm surface, EO and EC. Selected variables for normative outcomes included total sway area, and the mean, sagittal and coronal values for RMS sway, jerk, sway velocity and path length. Sex differences were examined within age groups via t tests. The effect of age on postural sway variables was analyzed using a one-way ANOVA for the mean values of total sway area, RMS sway, velocity and jerk, followed by post-hoc pairwise comparisons. RESULTS: All sway parameters decreased significantly with age (p < 0.0001). Adult-like total sway area and jerk were achieved by ages 9-10 except for jerk during EC on foam. RMS sway and sway velocity reached adult levels by ages 11-13 during all EO and tandem stance conditions, and 14-21 with EC during normal stance on firm and foam surfaces for RMS sway and EC on firm surfaces for velocity. Females ages 5-6 performed more poorly during EO firm and EC foam for certain variables, but better during EO tandem and females ages 7-13 outperformed males when sex differences were found. SIGNIFICANCE: These reference values can now be used by clinicians and researchers to evaluate abnormal postural sway and response to interventions in children and young adults.

The Effects of Dual Task Cognitive Interference and Fast-Paced Walking on Gait, Turns, and Falls in Men and Women with FXTAS.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a genetic neurodegenerative disorder characterized by cerebellar ataxia, tremor, and cognitive dysfunction. We examined the impact of dual-task (DT) cognitive-motor interference and fast-paced (FP) gait on gait and turning in FXTAS. Thirty participants with FXTAS and 35 age-matched controls underwent gait analysis using an inertial sensor-based 2-min walk test under three conditions: (1) self-selected pace (ST), (2) FP, and (3) DT with a concurrent verbal fluency task. Linear regression analyses were performed to assess the association between FXTAS diagnosis and gait and turn outcomes. Correlations between gait variables and fall frequency were also calculated. FXTAS participants had reduced stride length and velocity, swing time, and peak turn velocity and greater double limb support time and number of steps to turn compared to controls under all three conditions. There was greater dual task cost of the verbal fluency task on peak turn velocity in men with FXTAS compared to controls. Additionally, stride length variability was increased and cadence was reduced in FXTAS participants in the FP condition. Stride velocity variability under FP gait was significantly associated with the number of self-reported falls in the last year. Greater motor control requirements for turning likely made men with FXTAS more susceptible to the negative effects of DT cognitive interference. FP gait exacerbated gait deficits in the domains of rhythm and variability, and increased gait variability with FP was associated with increased falls. These data may inform the design of rehabilitation strategies in FXTAS.

Prodromal Markers of Upper Limb Deficits in FMR1 Premutation Carriers and Quantitative Outcome Measures for Future Clinical Trials in Fragile X-associated Tremor/Ataxia Syndrome.

BACKGROUND: Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a rare, late-onset neurodegenerative disorder characterized by tremor and cerebellar gait ataxia, affecting premutation carriers (PMC) of CGG expansions (range, 55-200) in the fragile X mental retardation 1 (FMR1) gene. Discovery of early predictors for FXTAS and quantitative characterization of motor deficits are critical for identifying disease onset, monitoring disease progression, and determining efficacy of interventions. METHODS: A total of 39 PMC with FXTAS, 20 PMC without FXTAS, and 27 healthy controls performed a series of upper extremity (UE) motor tasks assessing tremor, bradykinesia, and rapid alternating movements that were quantified using an inertial-based sensor system (Kinesia One; Great Lakes NeuroTechnologies, Cleveland, OH, USA). Sub-scores from the clinician-rated FXTAS Rating Scale were correlated with the severity scores generated by the sensor system to determine its validity in FXTAS. RESULTS: PMC with FXTAS had significantly worse postural and kinetic tremor compared with PMC without FXTAS (P = 0.02, 0.03) and controls (P = 0.001, 0.0001), respectively, and slower finger tap (P = 0.001), hand movement (P = 0.0001), and rapid alternating movement speed (P = 0.003) and amplitude (P = 0.04) than controls. PMC without FXTAS had significantly worse right finger tap (P = 0.004), hand movement (P = 0.01), and rapid alternating movement speed (P = 0.003) and amplitude (P = 0.02) than controls. FXTAS Rating Scale subscores significantly correlated with all tremorography scores except for finger taps and left rapid alternating movement. CONCLUSIONS: These findings support the use of inertial sensor quantification systems as promising measures for preclinical FXTAS symptom detection in PMC, characterization of the natural history of FXTAS, assessment of medication responses, and outcome assessment in clinical trials.

Normative database of spatiotemporal gait parameters using inertial sensors in typically developing children and young adults.

BACKGROUND: Inertial sensors are increasingly useful to clinicians and researchers to detect gait deficits. Reference values are necessary for comparison to children with gait abnormalities. OBJECTIVE: To present a normative database of spatiotemporal gait and turning parameters in 164 typically developing children and young adults ages 5-30 utilizing the APDM Mobility Lab® system. METHODS: Participants completed the i-WALK test at both self-selected (SS) and fast as possible (FAP) walking speeds. Spatiotemporal gait and turning parameters included stride length, stride length variability, gait speed, cadence, stance, swing, and double support times, and foot strike, toe-off, and toe-out angles, turn duration, peak turn velocity and number of steps to turn. RESULTS: Absolute stride length and gait speed increased with age. Normalized gait speed, absolute and normalized cadence, and stride length variability decreased with age. Normalized stride length and all parameters of gait cycle phase and foot position remained unaffected by age except for greater FSA in children 7-8. Foot position parameters in children 5-6 were excluded due to aberrant values and high standard deviations. Turns were faster in children ages 5-13 and 7-13 in the SS and FAP conditions, respectively. There were no differences in number of steps to turn. Similar trends were observed in the FAP condition except: normalized gait speed did not demonstrate a relationship with age and children ages 5-8 demonstrated increased stance and double support times and decreased swing time compared to children 11-13 and young adults (ages 5-6 only). Females ages 5-6 demonstrated increased stride length variability in the SS condition; males ages 7-8 and 14-30 ha d increased absolute stride length in the FAP condition. Similarities and differences were found between our values and previous literature. SIGNIFICANCE: This normative database can be used by clinicians and researchers to compare abnormal gait patterns and responses to interventions.

Open-label pilot clinical trial of citicoline for fragile X-associated tremor/ataxia syndrome (FXTAS).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder that is characterized by tremor, cerebellar ataxia, frequent falls, cognitive decline, and progressive loss of motor function. There are currently no approved treatments for this disorder. The purpose of this study was to determine if citicoline was safe for the treatment of tremor and balance abnormalities and to stabilize cognitive decline in patients with FXTAS. Ten participants with diagnosed FXTAS were administered 1000 mg of citicoline once daily for 12 months. Outcome measures and neurological examination were performed at baseline, 3 months, 6 months, and 12 months. The primary outcome was the FXTAS Rating Scale score. Secondary outcomes included change in a battery of neuropsychological tests, an instrumented Timed up and go test, computerized dynamic posturography, 9-hole pegboard test, and balance confidence and psychiatric symptom questionnaires. Safety was also evaluated. Citicoline treatment resulted in minimal adverse events in all but one subject over the course of the study. There was a significant improvement in the Beck Anxiety Inventory (p = 0.03) and the Stroop Color-Word test (p = 0.03), with all other measures remaining stable over the course of 12 months. This open-label pilot trial of citicoline for individuals with FXTAS showed that it is safe and well tolerated in this population. Registration: This trial was registered at ClinicalTrials.gov. Identifier: NCT0219710.

Gait asymmetry in glucocerebrosidase mutation carriers with Parkinson's disease.

BACKGROUND: GBA mutation carriers with PD (PD-GBA) are at higher risk of cognitive decline, but there is limited data regarding whether there are differences in gait dysfunction between GBA mutation and non-mutation carriers with PD. OBJECTIVES/METHODS: The primary aim of this study was to use quantitative inertial sensor-based gait analysis to compare gait asymmetry in 17 PD-GBA subjects, 17 non-mutation carriers with PD, and 15 healthy control subjects using parameters that had gait laterality and were markers of bradykinesia, in particular arm swing velocity and arm swing range of motion and stride length. RESULTS: Arm swing velocity was more symmetric in PD-GBA subjects vs. non-mutation carriers in the OFF state (12.5 +/- 8.3 vs. 22.9 +/- 11.8%, respectively, p = 0.018). In the ON-medication state, non-mutation carriers with PD, but not PD-GBA subjects, exhibited arm swing velocity (16.8 +/- 8.6 vs. 22.9 +/- 11.8%, p = 0.006) and arm range of motion (26.7 +/- 16.3 vs. 33.4 +/- 18.6%, p = 0.02) that was more asymmetric compared with the OFF-medication state. CONCLUSIONS: In the OFF medication state, arm swing velocity asymmetry may be a useful parameter in helping to distinguish GBA mutation carriers with PD from non-mutation carriers.

The effects of dual-task cognitive interference on gait and turning in Huntington's disease.

Huntington's disease (HD) is characterized by motor, cognitive, and psychiatric dysfunction. HD progression causes loss of automaticity, such that previously automatic tasks require greater attentional resources. Dual-task (DT) paradigms and fast-paced gait may stress the locomotor system, revealing deficits not seen under single-task (ST). However, the impact of gait "stress tests" on HD individuals needs further investigation. Therefore, the aims of this study were to investigate whether: 1) fast-paced and dual-task walking uncover deficits in gait and turning not seen under single-task, 2) cognitive and gait outcomes relate to fall incidence, and 3) gait deficits measured with wearable inertial sensors correlate with motor symptom severity in HD as measured by the Unified Huntington's disease Rating Scale-total motor score (UHDRS-TMS). Seventeen HD (55 ± 9.7 years) and 17 age-matched controls (56.5 ± 9.3 years) underwent quantitative gait testing via a 25m, two-minute walk test with APDMTM inertial sensors. Gait was assessed under a 1) ST, self-selected pace, 2) fast-as-possible (FAP) pace, and 3) verbal fluency DT. The UHDRS-TMS and a cognitive test battery were administered, and a retrospective fall history was obtained. During ST, DT, and FAP conditions, HD participants demonstrated slower gait, shorter stride length, and greater lateral step and stride length variability compared to controls (p<0.00001 to 0.034). Significant dual-task costs (DTC) were observed for turns; HD participants took more time (p = 0.013) and steps (p = 0.028) to complete a turn under DT compared to controls. Higher UHDRS-TMS correlated with greater stride length variability, less double-support, and more swing-phase time under all conditions. Decreased processing speed was associated with increased gait variability under ST and FAP conditions. Unexpectedly, participant's self-reported falls did not correlate with any gait or turn parameters. HD participants demonstrated significantly greater DTC for turning, which is less automatic than straight walking, requiring coordination of body segments, anticipatory control, and cortical regulation. Turn complexity likely makes it more susceptible to cognitive interference in HD.

Tremorography in fragile X-associated tremor/ataxia syndrome, Parkinson's disease and essential tremor.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disease affecting carriers of a 55-200 CGG repeat in the fragile X mental retardation 1 gene, may receive an initial diagnosis of Parkinson's disease (PD) or essential tremor (ET) due to overlapping motor symptoms. Therefore, tremor and bradykinesia were compared in these disorders using quantitative tremorography. METHODS: The inertial sensor based Kinesia ™ system was used to quantify upper extremity tremor and bradykinesia in participants with FXTAS (n = 25), PD (n = 23), ET (n = 18) and controls (n = 20) and regression analysis was performed to determine whether tremorography measures distinguished between the groups. The FXTAS Rating scale (FXTAS-RS) was administered to determine whether sub-score items on the clinician rated scale correlated with tremorography variables. RESULTS: FXTAS participants had reduced finger tap speed compared to those with ET, and ET had increased kinetic tremor compared to PD. Higher kinetic tremor distinguished FXTAS from PD (p = .02), and lower finger tap speed distinguished FXTAS from ET (p = .004). FXTAS-RS tremor and bradykinesia items correlated with tremorography measures (p = .005 to <0.0001). CONCLUSIONS: This is the first quantitative study to compare tremor and bradykinesia in FXTAS, PD and ET. Kinetic tremor and bradykinesia measures using a quantitative inertial sensor system distinguished FXTAS from PD and ET, respectively. Such technologies may be useful for detecting precise tremor and bradykinesia abnormalities and distinguishing the tremor and bradykinesia profiles in each of these disorders.

The Effects of Dual-Task Cognitive Interference and Environmental Challenges on Balance in Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is characterized by chorea, balance and gait impairments, and cognitive deficits, which increase fall risk. Dual task (DT) and environmentally challenging paradigms reflect balance related to everyday life. Furthermore, the impact of cognitive deficits on balance dysfunction and falls in HD is unknown. OBJECTIVE: To determine the impact of DT interference, sensory feedback, and cognitive performance on balance and falls in HD. METHODS: Seventeen participants with HD (55 ± 9.7 years) and 17 age-matched controls (56.5 ± 9.3 years) underwent quantitative balance testing with APDM inertial sensors. Postural sway was assessed during conditions of manipulated stance, vision, proprioception, and cognitive demand. The DT was a concurrent verbal fluency task. Neuropsychological assessments testing multiple cognitive domains were also administered. RESULTS: HD participants exhibited significantly greater total sway area, jerk, and variability under single-task (ST) and DT conditions compared to controls (P = 0.0002 - < 0.0001). They also demonstrated greater DT interference with vision removed for total sway area (P = 0.01) and variability (P = 0.02). Significantly worse postural control was observed in HD with vision removed and reduced proprioception (P = 0.001 - 0.01). Decreased visuospatial performance correlated with greater total sway and jerk (P = 0.01; 0.009). No balance parameters correlated with retrospective falls in HD. CONCLUSIONS: HD participants have worse postural control under DT, limited proprioception/vision, and greater DT interference with a narrowed base and no visual input. These findings may have implications for designing motor and cognitive strategies to improve balance in HD.

Cognitive function impacts gait, functional mobility and falls in fragile X-associated tremor/ataxia syndrome.

BACKGROUND: Executive function and information processing speed deficits occur in fragile X premutation carriers (PMC) with and without fragile X-associated tremor/ataxia syndrome (FXTAS). Gait is negatively impacted by cognitive deficits in many patient populations resulting in increased morbidity and falls but these relationships have not been studied in FXTAS. RESEARCH QUESTION: We sought to investigate the associations between executive function and information processing speed and gait, turning and falls in PMC with and without FXTAS compared to healthy controls. METHODS: Global cognition and the cognitive domains of information processing speed, attention, response inhibition, working memory and verbal fluency were tested with a neuropsychological test battery in 18 PMC with FXTAS, 15 PMC without FXTAS, and 27 controls. An inertial sensor based instrumented Timed Up and Go was employed to test gait, turns and functional mobility. RESULTS: Lower information processing speed was significantly associated with shorter stride length, reflecting slower gait speed, in PMC with FXTAS (p = 0.0006) but not PMC without FXTAS or controls. Lower response inhibition was also significantly associated with slower turn-to-sit times in PMC with FXTAS (p = 0.034) but not in those without FXTAS or controls. Lower information processing speed (p = 0.012) and working memory (p = 0.004), were significantly correlated with a greater number of self-reported falls in the past year in FXTAS participants. SIGNIFICANCE: This is the first study demonstrating that worse executive function and slower information processing speed is associated with reduced gait speed and functional mobility, as well as with a higher retrospective fall history in participants with FXTAS. This information may be important in the design of cognitive and motor interventions for this neurodegenerative disorder.

Long-Term Treatment of Niemann-Pick Type C1 Disease With Intrathecal 2-Hydroxypropyl-ß-Cyclodextrin.

BACKGROUND: Intrathecal 2-hydoxypropyl-ß-cyclodextrin has been found to mobilize cholesterol, extend life, reduce cerebellar pathology, and delay onset of ataxia in the mouse and cat models of Niemann-Pick disease, type C1, a clinically variable progressive and ultimately fatal neurodegenerative storage disorder characterized by endolysosomal accumulation of unesterified cholesterol. OBJECTIVE: In this study, the long-term effects of intrathecal 2-hydoxypropyl-ß-cyclodextrin treatment for 2.5 to three years in humans with Niemann-Pick disease, type C, were evaluated. METHODS: Three patients with Niemann-Pick disease, type C, in different stages of progression and displaying varying disease manifestations were treated with intrathecal 2-hydoxypropyl-ß-cyclodextrin (VTS-270) delivered by lumbar puncture infusion through an intermediate-size patient population investigational new drug application for expanded access. Disease progression was monitored with the Niemann-Pick disease, type C, Neurological Severity Scale and numerous objective measures of function in five neurological domains typically impacted by the disease: cognitive/language, gait/balance, fine motor, swallowing, and eye movement. RESULTS: No worsening in any domain except eye movements (vertical pursuit gain) was seen for any of the three patients, and in the other domains, improved scores on measures were seen over time for one or more patients. The Niemann-Pick disease type C (NPC) Neurological Severity Scale (NSS) showed stable to slightly improved ratings. CONCLUSIONS: These trajectories are not consistent with the typical trajectory of the disease and suggest that intrathecal 2-hydoxypropyl-ß-cyclodextrin has stabilized the disease over an extended period of time, supporting the current phase 2/3 controlled registration trial with VTS-270.

Fragile X-associated tremor/ataxia syndrome: phenotypic comparisons with other movement disorders.

OBJECTIVE: The purpose of this paper is to review the typical cognitive and motor impairments seen in fragile X-associated tremor/ataxia syndrome (FXTAS), essential tremor (ET), Parkinson disease (PD), spinocerebellar ataxias (SCAs), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) in order to enhance diagnosis of FXTAS patients. METHODS: We compared the cognitive and motor phenotypes of FXTAS with each of these other movement disorders. Relevant neuropathological and neuroimaging findings are also reviewed. Finally, we describe the differences in age of onset, disease severity, progression rates, and average lifespan in FXTAS compared to ET, PD, SCAs, MSA, and PSP. We conclude with a flow chart algorithm to guide the clinician in the differential diagnosis of FXTAS. RESULTS: By comparing the cognitive and motor phenotypes of FXTAS with the phenotypes of ET, PD, SCAs, MSA, and PSP we have clarified potential symptom overlap while elucidating factors that make these disorders unique from one another. In summary, the clinician should consider a FXTAS diagnosis and testing for the Fragile X mental retardation 1 (FMR1) gene premutation if a patient over the age of 50 (1) presents with cerebellar ataxia and/or intention tremor with mild parkinsonism, (2) has the middle cerebellar peduncle (MCP) sign, global cerebellar and cerebral atrophy, and/or subcortical white matter lesions on MRI, or (3) has a family history of fragile X related disorders, intellectual disability, autism, premature ovarian failure and has neurological signs consistent with FXTAS. Peripheral neuropathy, executive function deficits, anxiety, or depression are supportive of the diagnosis. CONCLUSIONS: Distinct profiles in the cognitive and motor domains between these movement disorders may guide practitioners in the differential diagnosis process and ultimately lead to better medical management of FXTAS patients.

Update on the Clinical, Radiographic, and Neurobehavioral Manifestations in FXTAS and FMR1 Premutation Carriers.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder caused by a repeat expansion in the fragile X mental retardation 1 (FMR1) gene. The disorder is characterized by kinetic tremor and cerebellar ataxia, shows age-dependent penetrance, and occurs more frequently in men. This paper summarizes the key emerging issues in FXTAS as presented at the Second International Conference on the FMR1 Premutation: Basic Mechanisms & Clinical Involvement in 2015. The topics discussed include phenotype-genotype relationships, neurobehavioral function, and updates on FXTAS genetics and imaging.

X-inactivation in the clinical phenotype of fragile X premutation carrier sisters.

OBJECTIVE: The purpose of this study is to describe a case series of 4 sisters with discordant clinical phenotypes associated with fragile X-associated tremor/ataxia syndrome (FXTAS) that may be explained by varying CGG repeat sizes and activation ratios (ARs) (the ratio of cells carrying the normal fragile X mental retardation 1 [FMR1] allele on the active X chromosome). METHODS: Four sisters with premutation size FMR1 gene repeats underwent detailed clinical characterization. CGG repeat length was determined by PCR, and AR was determined using a newly developed commercial methylation PCR assay and was compared with the results from Southern blot with densitometric image analysis. RESULTS: Sister 1 had the largest CGG expansion (82) and the lowest AR (12%), with the most severe clinical presentation. Sister 2 had a lower CGG expansion (70) and an AR of 10% but had a milder clinical presentation.Sister 3 had a similar CGG expansion (79) but a slightly higher AR of 15% and less neurologic involvement. Sister 4 had a similar CGG expansion size of 80 but had the largest AR (40%) and was the only sister not to be affected by FXTAS or have any neurologic signs on examination. CONCLUSIONS: These results suggest that premutation carrier women who have higher ARs may be less likely to show manifestations of FXTAS. If larger studies show similar patterns, AR data could potentially be beneficial to supplement CGG repeat size when counseling premutation carrier women in the clinic.

Gait and Functional Mobility Deficits in Fragile X-Associated Tremor/Ataxia Syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) results from a "premutation" (PM) size CGG repeat expansion in the fragile X mental retardation 1 (FMR1) gene. Cerebellar gait ataxia is the primary feature in some FXTAS patients causing progressive disability. However, no studies have quantitatively characterized gait and mobility deficits in FXTAS. We performed quantitative gait and mobility analysis in seven FMR1 PM carriers with FXTAS and ataxia, six PM carriers without FXTAS, and 18 age-matched controls. We studied four independent gait domains, trunk range of motion (ROM), and movement transitions using an instrumented Timed Up and Go (i-TUG). We correlated these outcome measures with FMR1 molecular variables and clinical severity scales. PM carriers with FXTAS were globally impaired in every gait performance domain except trunk ROM compared to controls. These included total i-TUG duration, stride velocity, gait cycle time, cadence, double-limb support and swing phase times, turn duration, step time before turn, and turn-to-sit duration, and increased gait variability on several measures. Carriers without FXTAS did not differ from controls on any parameters, but double-limb support time was close to significance. Balance and disability scales correlated with multiple gait and movement transition parameters, while the FXTAS Rating Scale did not. This is the first study to quantitatively examine gait and movement transitions in FXTAS patients. Gait characteristics were consistent with those from previous cohorts with cerebellar ataxia. Sensitive measures like the i-TUG may help determine efficacy of interventions, characterize disease progression, and provide early markers of disease in FXTAS.

Erratum: Emerging topics in FXTAS.

[This corrects the article DOI: 10.1186/1866-1955-6-31.].

Characterization and Early Detection of Balance Deficits in Fragile X Premutation Carriers With and Without Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS).

Fragile X-associated tremor/ataxia syndrome (FXTAS) results from a "premutation" size 55-200 CGG repeat expansion in the fragile X mental retardation 1 (FMR1) gene. Core motor features include cerebellar gait ataxia and kinetic tremor, resulting in progressive mobility disability. There are no published studies characterizing balance deficits in FMR1 premutation carriers with and without FXTAS using a battery of quantitative measures to test the sensory integration underlying postural control, automatic postural reflexes, and dynamic postural stability limits. Computerized dynamic posturography (CDP) and two performance-based balance measures were administered in 44 premutation carriers, 21 with FXTAS and 23 without FXTAS, and 42 healthy controls to compare balance and functional mobility between these groups. Relationships between FMR1 molecular variables, age, and sex and CDP scores were explored. FXTAS subjects demonstrated significantly lower scores on the sensory organization test (with greatest reductions in the vestibular control of balance), longer response latencies to balance perturbations, and reduced stability limits compared to controls. Premutation carriers without FXTAS also demonstrated significantly delayed response latencies and disrupted sensory weighting for balance control. Advancing age, male sex, increased CGG repeat size, and reduced X activation of the normal allele in premutation carrier women predicted balance dysfunction. These postural control deficits in carriers with and without FXTAS implicate dysfunctional cerebellar neural networks and may provide valuable outcome markers for tailored rehabilitative interventions. Our findings suggest that CDP may provide sensitive measures for early detection of postural control impairments in at-risk carriers and better characterize balance dysfunction and progression in FXTAS.

Implementation of a markerless motion analysis method to quantify hyperkinesis in males with fragile X syndrome.

Hyperactive behavior - and implicitly, motion - in Fragile X syndrome (FXS) has been historically described using behavioral rating scales. While rating scales are the current standard outcome measures used in clinical research, they have limitations including their qualitative nature and subjectivity. The advent of new motion capture technologies has provided the opportunity to develop quantitative methods for measuring hyperactive motion. The hypotheses for this study were that a novel markerless motion analysis method (1) can quantitatively measure kinematic parameters, (2) can differentiate the level of hyperkinesis between control and FXS populations, and (3) will correlate with blind-reviewer synchronous video-capture methods and behavioral rating scale scores. Twenty young males (7-control, 13-FXS; ages 9-32) were studied using a standardized protocol in a markerless motion analysis suite. Behavioral scale questionnaires were filled out by parents and those scores were correlated with motion parameters (frequency and total traveled distance) of body segments during 30s of story listening while standing in the observation space. The markerless system was able to track subjects and the two populations displayed significantly different quantities of motion, with larger amounts of motion in the FXS group (p < 0.05). Pearson's correlation coefficients between frequency counts obtained from the markerless system and rater-based video capture were between 0.969 and 0.996 (p < 0.001). Significant correlations between rating scale scores and motion parameters ranged from 0.462 ≤ r ≤ 0.568 (p ≤ 0.040). These results suggest feasibility and validity of a markerless system as a non-invasive method able to quantify motion in individuals with hyperkinesis.