CSTB gene replacement improves neuroinflammation, neurodegeneration and ataxia in murine type 1 progressive myoclonus epilepsy.

EPM1 is the most common form of Progressive Myoclonus Epilepsy characterized by late-childhood onset, ever-worsening and disabling myoclonus, seizures, ataxia, psychiatric disease, and shortened lifespan. EPM1 is caused by expansions of a dodecamer repeat sequence in the promoter of CSTB (cystatin B), which dramatically reduces, but does not eliminate, gene expression. The relatively late onset and consistent presence of a minimal amount of protein product makes EPM1 a favorable target for gene replacement therapy. If treated early, these children's normally developed brains could be rescued from the neurodegeneration that otherwise follows, and their cross-reactive immunological material (CRIM) positive status greatly reduces transgene related toxicity. We performed a proof-of-concept CSTB gene replacement study in Cstb knockout mice by introducing full-length human CSTB driven by the CBh promoter packaged in AAV9 and administered at postnatal days 21 and 60. Mice were sacrificed at 2 or 9 months of age, respectively. We observed significant improvements in expression levels of neuroinflammatory pathway genes and cerebellar granule cell layer apoptosis, as well as amelioration of motor impairment. The data suggest that gene replacement is a promising therapeutic modality for EPM1 and could spare affected children and families the ravages of this otherwise severe neurodegenerative disease.

Comparing Cerebellar tDCS and Cerebellar tACS in Neurodegenerative Ataxias Using Wearable Sensors: A Randomized, Double-Blind, Sham-Controlled, Triple-Crossover Trial.

Cerebellar transcranial direct current stimulation (tDCS) represents a promising therapeutic approach for both motor and cognitive symptoms in neurodegenerative ataxias. Recently, transcranial alternating current stimulation (tACS) was also demonstrated to modulate cerebellar excitability by neuronal entrainment. To compare the effectiveness of cerebellar tDCS vs. cerebellar tACS in patients with neurodegenerative ataxia, we performed a double-blind, randomized, sham controlled, triple cross-over trial with cerebellar tDCS, cerebellar tACS or sham stimulation in twenty-six participants with neurodegenerative ataxia. Before entering the study, each participant underwent motor assessment with wearable sensors considering gait cadence (steps/minute), turn velocity (degrees/second) and turn duration (seconds), and a clinical evaluation with the scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS). After each intervention, participants underwent the same clinical assessment along with cerebellar inhibition (CBI) measurement, a marker of cerebellar activity. The gait cadence, turn velocity, SARA, and ICARS significantly improved after both tDCS and tACS, compared to sham stimulation (all p<0.010). Comparable effects were observed for CBI (p<0.001). Overall, tDCS significantly outperformed tACS on clinical scales and CBI (p<0.01). A significant correlation between changes of wearable sensors parameters from baseline and changes of clinical scales and CBI scores was detected. Cerebellar tDCS and cerebellar tACS are effective in ameliorating symptoms of neurodegenerative ataxias, with the former being more beneficial than the latter. Wearable sensors may serve as rater-unbiased outcome measures in future clinical trials. ClinicalTrial.gov Identifier: NCT05621200.

Effectiveness of High-Frequency Repetitive Transcranial Magnetic Stimulation in Patients With Spinocerebellar Ataxia Type 3.

OBJECTIVE: To investigate the effectiveness of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) on improvement of clinical symptoms in patients with spinocerebellar ataxia type 3 (SCA3). METHODS: Sixteen SCA3 participants diagnosed by genetic testing were enrolled in this sham-controlled and double-blind trial. They received either a 2-week 10-Hz rTMS intervention or sham stimulation targeting the vermis and cerebellum. The Scale for Assessment and Rating of Ataxia and the International Cooperative Ataxia Rating Scale were completed at baseline and poststimulation. RESULTS: Compared with baseline, the HF-rTMS group demonstrated a significant improvement in the total Scale for Assessment and Rating of Ataxia ( P < 0.0001) and the International Cooperative Ataxia Rating Scale scores ( P = 0.002). After 2-week treatment, the real group exhibited decreasing pattern in 3 subgroups, especially for limb kinetic function ( P < 0.0001). CONCLUSIONS: Short-term HF-rTMS treatment is a potentially promising and feasible tool for rehabilitation in patients with SCA3. Studies with long-term follow-up need to be carried out in the future and further need to assess gait, limb kinetic function, speech and oculomotor disorders.

[Gastrointestinal disorders in hyperkinetic movement disorders and ataxia]. / Gastrointestinale Störungen bei hyperkinetischen Bewegungsstörungen und Ataxien.

Disorders of the gastrointestinal tract in patients suffering from hypokinetic movement disorders, and in particular Parkinson's disease, have increasingly been the subject of more intensive neuromedical research. So far, few data are available for patients with hyperkinetic movement disorders and ataxias. This review article summarizes the currently available and relevant publications on this topic. The particular focus is on essential tremor, restless legs syndrome, Huntington's disease and the group of hereditary ataxias. Further intensive research will be necessary in the future to collect detailed information also for these disease symptoms about specific disturbance patterns, in order to understand the underlying pathological pathways and to derive specific treatment approaches.

A patient with neuropathy and ataxia: what do I have to consider?

PURPOSE OF REVIEW: An increasing number of peripheral neuro(no)pathies are identified as involving other components of the neurological system, particularly those that further impair balance. Here we aim to outline an evidence-based approach to the diagnosis of patients who present with a somatosensory disorder which also involves at least one other area of neurological impairment such as the vestibular, auditory, or cerebellar systems. RECENT FINDINGS: Detailed objective investigation of patients who present with sensory impairment, particularly where the degree of imbalance is greater than would be expected, aids the accurate diagnosis of genetic, autoimmune, metabolic, and toxic neurological disease. SUMMARY: Diagnosis and management of complex somatosensory disorders benefit from investigation which extends beyond the presenting sensory impairment.

Utility of Anorectal Testing to Predict Outcomes With Pelvic Floor Physical Therapy in Chronic Constipation: Pragmatic Trial.

BACKGROUND & AIMS: We performed a clinical trial that aimed to inform the clinical utility of anorectal manometry (ARM) and balloon expulsion time (BET) as up-front tests to predict outcomes with community-based pelvic floor physical therapy as the next best step to address chronic constipation after failing an empiric trial of soluble fiber supplementation or osmotic laxatives. METHODS: We enrolled 60 treatment-naïve patients with Rome IV functional constipation failing 2 weeks of soluble fiber supplementation or osmotic laxatives. All patients underwent ARM/BET (London protocol) followed by community-based pelvic floor physical therapy. Outcomes were assessed at baseline and 12 weeks. The primary end point was clinical response (Patient Assessment of Constipation-Symptoms instrument). RESULTS: Fifty-three patients completed pelvic rehabilitation and the post-treatment questionnaire. Contemporary frameworks define dyssynergia on balloon expulsion time and dyssynergic patterns (ARM), but these parameters did not inform clinical outcomes (area under the curve [AUC], <0.6). Squeeze pressure (>192.5 mm Hg on at least 1 of 3 attempts; sensitivity, 47.6%; specificity, 83.9%) and limited squeeze duration (inability to sustain 50% of squeeze pressure for >20 seconds; sensitivity, 71.4%; specificity, 58.1%) were the strongest predictors of clinical outcomes. Combining BET with squeeze duration (BET greater than 6.5 seconds and limited squeeze duration) improved predictive accuracy (AUC, 0.75; 95% CI, 0.59-0.90). BET poorly predicted outcomes as a single test (AUC, 0.54; 95% CI, 0.38-0.69). CONCLUSIONS: Using ARM to evaluate squeeze profiles, rather than dyssynergia, appears useful to screen patients with chronic constipation for up-front pelvic floor physical therapy based on likelihood of response. BET appears noninformative as a single screening test (ClinicalTrials.gov: NCT04159350).

Therapeutic Misestimation in Patients with Degenerative Ataxia: Lessons from a Randomized Controlled Trial.

BACKGROUND: The absence of effective treatments may render patients with degenerative cerebellar ataxias susceptible to a placebo response, which could affect the outcome of clinical trials. OBJECTIVE: To retrospectively examine expectations of benefit in participants of an ataxia trial and identify determinants of possible therapeutic misestimation. METHODS: Individuals with spinocerebellar ataxia type 3 who participated in a randomized, double-blind, sham-controlled trial received a custom-designed questionnaire about short-term and long-term treatment expectations, allocation preferences, and interpretation of treatment arm assignment based on the presence or absence of clinical improvement. To evaluate whether expectations were specifically related to the application of cerebellar transcranial direct current stimulation (tDCS) or more generally reflect an overly positive attitude of patients with ataxia toward trial participation and results, the last questions involved a hypothetical scenario in which an oral drug was tested against placebo with an aim identical to that of our tDCS study. RESULTS: All 20 trial participants completed the questionnaire. If allocated to the active treatment arm, 75% of patients expected short-term health benefits and 55% thought they would still have less severe ataxia at 1-year follow-up compared with baseline. After 2 weeks, an average reduction in ataxia severity of 31.5% (standard deviation, 22.2%) was anticipated. Conversely, 65% associated a lack of improvement with probable or definite allocation to the placebo group. High expectations of benefit were neither related to the type of intervention nor to clinical or demographic characteristics. CONCLUSION: Therapeutic misestimation is common in patients with degenerative ataxia and requires special attention in future trials. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

M1 and Cerebellar tDCS for MSA-C: a Double-Blind, Randomized, Sham-Controlled, Crossover Study.

The effect of transcranial direct current stimulation (tDCS) for cerebellar-dominant multiple-system atrophy (MSA-C) is not well elucidated, yet. This study aimed to investigate the effect of tDCS on the primary motor cortex (M1) and cerebellum in patients with MSA-C. We recruited probable MSA-C patients and performed three single sessions of tDCS at each visit in random order (M1, cerebellum or sham). Cerebellar ataxia was evaluated with the International Cooperative Ataxia Rating Scale (ICARS) and objective gait and static balance analyses both before and after each stimulation session. Additionally, we also evaluated the factors related with objective improvement from each stimulation. Sixteen participants were enrolled, and one dropped out after 2 sessions of stimulation due to consent withdrawal. The gait velocity, step time and single support time all significantly improved after the M1 and cerebellar tDCS treatment compared with the sham stimulation while there was no difference in the improvement of ICARS and posturography results among 3 stimulations. In terms of the related factors with improvement of gait velocity, the disease duration, baseline gait speed and single support times were correlated after M1 stimulation, while a higher ICARS score and baseline gait speed in cerebellar stimulation. There were no adverse effects reported after the tDCS sessions. Our results demonstrated that both M1 and cerebellar tDCS demonstrated benefits for MSA-C patients without significant complications. Considering the different related factors with improvement at each stimulation, the mechanism would be different between M1 and cerebellar stimulations.

ClearSpeechTogether: a Rater Blinded, Single, Controlled Feasibility Study of Speech Intervention for People with Progressive Ataxia.

BACKGROUND: Progressive ataxias frequently lead to speech disorders and consequently impact on communication participation and psychosocial wellbeing. Whilst recent studies demonstrate the potential for improvements in these areas, these treatments generally require intensive input which can reduce acceptability of the approach. A new model of care-ClearSpeechTogether-is proposed which maximises treatment intensity whilst minimising demands on clinician. This study aimed to establish feasibility and accessibility of this approach and at the same time determine the potential benefits and adverse effects on people with progressive ataxias. METHOD: This feasibility study targeted people with progressive ataxia and mild-moderate speech and gross motor impairment. ClearSpeechTogether consisted of four individual sessions over 2 weeks followed by 20 patient-led group sessions over 4 weeks. All sessions were provided online. Quantitative and qualitative data were collected for evaluation. RESULTS: Nine participants completed treatment. Feasibility and acceptability were high and no adverse effects were reported. Statistical tests found significantly reduced vocal strain, improved reading intelligibility and increased participation and confidence. Participant interviews highlighted the value of group support internalisation of speech strategies and psycho-social wellbeing. DISCUSSION: ClearSpeechTogether presented a feasible, acceptable intervention for a small cohort of people with progressive ataxia. It matched or exceeded the outcomes previously reported following individual therapy. Particularly notable was the fact that this could be achieved through patient led practice without the presence of a clinician. Pending confirmation of our results by larger, controlled trials, ClearSpeechTogether could represent an effective approach to manage speech problems in ataxia.

Neuroblastic Tumor Recurrence Associated With Opsoclonus Myoclonus Ataxia Syndrome Relapse a Decade After Initial Resection and Treatments.

Opsoclonus myoclonus ataxia syndrome (OMAS) is a rare disorder that causes significant neurodevelopmental sequelae in children. Approximately half of pediatric OMAS cases are paraneoplastic, typically associated with localized neuroblastic tumors. Since early persistence or relapse of OMAS symptoms is common even after tumor resection, OMAS relapses may not routinely prompt reevaluation for recurrent tumors. We report a 12-year-old girl with neuroblastic tumor recurrence associated with OMAS relapse a decade after initial treatment. Providers should be aware of tumor recurrence as a trigger for distant OMAS relapse, raising intriguing questions about the role of immune surveillance and control of neuroblastic tumors.

[Gene Therapy for Ataxias]. / Gentherapie für Ataxien.

Ataxias are progressive diseases that are usually the result of cerebellar degeneration. Ataxias are divided into genetic, sporadic degenerative and acquired (secondary) forms. While there are established therapies for acquired (secondary) ataxias, genetic and sporadic degenerative ataxias are currently not medically treatable. For these ataxias, the development of somatic gene therapies is a promising avenue. The goals of gene therapies for genetic ataxias are to inactivate deleterious genes by gene silencing or to replace or correct a non-functional gene. Another option, which may also be considered for sporadic degenerative ataxias, are therapies that involve transferring new or modified genes. Gene therapies are being actively developed for the more common ataxias, such as Friedreich's ataxia, certain spinocerebellar ataxias, and multiple system atrphy, and initial phase I trials are underway.

The Effects of Exergame on Postural Control in Individuals with Ataxia: a Rater-Blinded, Randomized Controlled, Cross-over Study.

Exergame trainings might have therapeutic value in ataxic patients. The aim of this study was to investigate the effect of exergame training with an exercise program on postural control by comparing it with traditional balance and coordination exercise program. Nineteen patients were randomly allocated to two groups. In the first group, exergame training and an exercise program (EEP) were applied together for the first 8 weeks; after 10 weeks washout, a conventional exercise program (CEP) was applied for the second 8 weeks. In the second group, the CEP was applied first followed by the EEP. Outcome measures were Limits of Stability test (LoS), International Classification Ataxia Ratio Scale (ICARS), Berg Balance Scale (BBS), and Timed-Up and Go test with a cognitive task (TUG-C), Reactive postural control and sensory orientation subscales of the Mini-BESTest. Seventeen patients (mean age ± SD, 32.53 ± 11.07 years) completed the study. ICARS, BBS scores improved only after EEP (p < 0.05). While there was no change in the RT and MVL parameters of the LoS test after EEP, the MXE, EPE, and DCL parameters improved significantly (p < 0.05). The MXE and MVL parameters of LoS improved after CEP (p < 0.05). There were no significant improvements in the Mini-BESTest's reactive postural control and sensory orientation subscale scores after both EEP and CEP (p > 0.05). The results of the present study demonstrated that exergame training can be used as a complementary training option in physiotherapy to improve postural control in patients with ataxia. ClinicalTrial.gov Identifier: NCT03607058.

Non-invasive electrical stimulation in patients with neurodegenerative ataxia and spasticity: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND PURPOSE: There are limited treatment options for patients with neurodegenerative ataxia and spasticity. Non-invasive electrostimulation (NES) is receiving increasing interest because of its ease of implementation, cost-effectiveness and safety. A meta-analysis was conducted to evaluate the efficacy of NES. METHODS: MEDLINE and Embase were screened for studies using NES in ataxias and spasticity. Key outcome measurements of effectiveness included changes in (1) Modified Ashworth Scale (MAS) scores, (2) cerebellar brain inhibition (CBI), (3) the nine-hole peg test (9HPT), (4) the 8-m walking time (8MWT), (5) International Cooperative Ataxia Rating Scale (ICARS) score and (6) the Scale for Assessment and Rating of Ataxia (SARA) scores. RESULTS: Seven randomized controlled trials involving 203 patients were included. There were significant improvements in MAS (mean difference [MD] -0.42, 95% confidence interval [CI] -0.76 to -0.08, p = 0.015), CBI (MD -0.35%, 95% CI -0.42 to -0.28, p < 0.001), 8MWT (MD -1.88 s, 95% CI -3.26 to -0.49, p = 0.008), ICARS (MD -7.84, 95% CI -11.90 to -3.78, p < 0.001) and SARA (MD -3.01, 95% CI -4.74 to -1.28, p < 0.001). There was almost no heterogeneity across all outcomes except for CBI (I2  = 79%). No significant changes in the 9HPT were observed comparing NES to a sham procedure (MD -3.52 s, 95% CI -9.15 to 2.10, p = 0.220). Most included studies were at low risk of bias, and no severe adverse effects were reported. CONCLUSION: It was demonstrated that NES is an effective treatment for improving coordination and balance and increased exercise capacity in patients with ataxia and spasticity. There was also a significant modulation of CBI in ataxic patients.

Dystonia, Chorea, and Ataxia: Three Challenging Cases.

Movement disorders comprise a heterogeneous and complex group of neurological disorders that increase (hyperkinetic) or decrease (hypokinetic) the speed or amplitude of movements, or disrupt their coordinated sequencing. In this article, we describe three instructive cases, exemplifying classic movement disorders, namely dystonia, chorea, and ataxia. We highlight the diagnostic approach based on clinical clues, syndromic reasoning, evaluation, and management recommendations. Each case ends with key messages for the clinicians.

The Efficacy of Biofeedback Therapy in Patients with Solitary Rectal Ulcer and Dyssynergic Defecation.

BACKGROUND: The treatment of solitary rectal ulcer (SRU) is challenging and controversial; generally, no response to conventional treatments can be obtained, particularly in patients with dyssynergic defecation (DD). We assessed the efficiency of biofeedback therapy (BFT) in patients who did not respond to conservative treatments and had coexistence of SRU and DD. METHODS: BFT responses, as well as anorectal manometry and rectoscopy results of 20 patients with the coexistence of SRU and DD, were assessed. RESULTS: Mean age was 32.5 years. Of the patients, 12 were female, and 8 of them were male. An average of 12 sessions of BFT was performed on the patients. Ulcer disappeared in 11 patients (55%) after BFT, and the ulcer size decreased in 3 patients (15%). However, ulcers healed in 9 (90%) of 10 patients whose DD pattern disappeared following BFT, and ulcers healed in only 20% of patients whose DD pattern continued (p = 0.005). The change in anal resting pressure after BFT was significant (p = 0.016). Ulcers were healed in 87.5% (7/8) of the patients whose anal resting pressure decreased after BFT and whose DD disappeared, while ulcers remained untreated in 85.7% of the patients whose anal resting pressure decreased, but the DD pattern continued (p = 0.005). CONCLUSIONS: SRU patients with DD are typically unresponsive to medical treatments. Ameliorating anorectal dyssynergia should be the priority of treatment in these patients. BFT is an effective treatment for DD. BFT enhances the healing of ulcers in patients with SRU by restoring coordination of the pelvic floor.

Efficacy of a Modified Training Program of Adaptive Biofeedback Therapy for Dyssynergic Defecation in Patients with Chronic Constipation.

BACKGROUND: Biofeedback therapy is highly effective and safe in treating dyssynergic defecation, which affects more than half of patients with chronic constipation. However, conventional biofeedback training has limitations. AIMS: This study aims to modify the adaptive biofeedback (ABF) previously established by the investigators and evaluate its efficacy for dyssynergic defecation. METHODS: A total of 42 constipation patients were enrolled and randomly assigned to receive either 4-week adaptive biofeedback (ABF) training (ABF group), or fixed biofeedback (FBF) training (FBF group). The ABF training program was modified, as follows: (1) the tailored training targets were set according to the ability of the individual subject, instead of the fixed values; (2) the outcome was scored on the basis of the rectal-anal pressure gradient; (3) the feedback information was delivered through multimedia. The outcomes were compared between the two groups. RESULTS: The number of weekly bowel movements (BM) was significantly greater in the ABF group than in the FBF group. The improvement in dyssynergic defecation was also noted with the modified ABF training, which performed significantly better than the conventional training on incomplete defecation, bloating, defecation time, staining, and urgency. Notably, the use of medications was significantly reduced upon completion of the 4-week adaptive training, and this was significantly lesser than that in the fixed training. Furthermore, there was significantly better improvement on anorectal motility and rectal sensation in the ABF group vs. the FBF group. CONCLUSION: The modified ABF training program significantly improves constipation-related symptoms, and its performance is superior to conventional FBF training for dyssynergic defecation.

Effects of a core stability exercise program on balance and coordination in children with cerebellar ataxic cerebral palsy.

OBJECTIVE: To evaluate the effects of a core stability exercise program on balance, coordination, and severity of ataxia in children with cerebellar ataxic cerebral palsy (CP). METHODS: Forty children with cerebellar ataxic CP (mean age: 6.75±1.35 years) were randomly assigned to a control group and an intervention group for 2 months of follow-up. The control group received a standard physical therapy program three times weekly (1 h per session), while the intervention group received a core stability program for 30 min, in addition to the selected physical therapy program. Both groups were evaluated pre-treatment and post-treatment using the Scale for the Assessment and Rating of Ataxia, the Balance Error Scoring Systems scale, Bruininks-Oseretsky tests of motor proficiency, and HUMAC balance system scores. RESULTS: We found statistically significant reductions in the severity of ataxia, as well as improved balance and coordination in both groups, with stronger effects observed in the intervention group (P<0.05). CONCLUSION: The core stability program can improve balance and coordination in children with cerebellar ataxic CP when incorporated with a standard physical therapy program.

Reducing Ataxic Side Effects from Ventral Intermediate Nucleus of the Thalamus Deep Brain Stimulation Implantation in Essential Tremor: Potential Advantages of Directional Stimulation.

OBJECTIVE: The aim of the study was to retrospectively evaluate the effect of directional deep brain stimulation (DBS) on ataxia in an essential tremor patient population. MATERIALS AND METHODS: A retrospective chart review of documented Scale for Assessment and Rating of Ataxia (SARA) scores were analyzed using a case-control design. All subjects we evaluated were treated at a single, tertiary care academic center. We reviewed 14 patients who underwent bilateral ventral intermediate nucleus of the thalamus (VIM) implantation with microelectrode recording, with electrodeposition and segmented contact orientation confirmed via postoperative computed tomography. The main outcome was to determine change in ataxia scores between directional versus monopolar circumferential stimulation. RESULTS: Fourteen patients (9 males, median age at implantation 69 [range 63-82]) underwent surgery between October 2017 and July 2020 at the UNC Movement Disorders Center. SARA scores between directional stimulation and monopolar circumferential stimulation demonstrated a significant reduction in total scores with best possible segmented stimulation (n = 13, p < 0.0001, 95% confidence interval [CI] -3.496 to -6.789). This difference remained statistically significant even after removing the SARA tremor subscore (n = 13, p < 0.0001, 95% CI -3.155 to -6.274). In line with prior reports, SARA score changes from the preoperative state were generally worsened when applying monopolar circumferential stimulation bilaterally (n = 13, p = 0.655; 95% CI -2.836 to 4.359), but improved with directional stimulation (n = 13, p = 0.010; 95% CI -1.216 to -7.547). CONCLUSION: This retrospective analysis appears to show evidence for improved outcomes through directional stimulation in bilateral VIM DBS implantation with reduction of ataxic side effects that have traditionally plagued postoperative results, all while providing optimized tremor reduction via stimulation.

[Diagnosis and Treatment of Ataxias: An Up-To-Date Overview]. / Ataxien ­ Eine aktuelle Übersicht über die weiter wachsende Anzahl möglicher Diagnosen.

Ataxias are a heterogeneous group of diseases. They can occur at any age and have various causes. Most ataxias are rare diseases and many are genetic disorders. A large and steadily increasing number of underlying gene defects are known. The path to the correct diagnosis is often challenging. This overview summarizes the typical findings for the most important acquired, hereditary and non-hereditary degenerative ataxias. The focus is on ataxias with adult onset.

Fragile X-associated tremor/ataxia syndrome: pathophysiology and management.

PURPOSE OF REVIEW: The purpose of this paper is to review the prevalence, pathophysiology, and management of fragile X-associated tremor/ataxia syndrome (FXTAS). RECENT FINDINGS: The pathophysiology of FXTAS involves ribonucleic acid (RNA) toxicity due to elevated levels of the premutation-expanded CGG (eoxycytidylate-deoxyguanylate-deoxyguanylate)-repeat FMR1 mRNA, which can sequester a variety of proteins important for neuronal function. A recent analysis of the inclusions in FXTAS demonstrates elevated levels of several proteins, including small ubiquitin-related modifiers 1/2 (SUMO1/2), that target molecules for the proteasome, suggesting that some aspect(s) of proteasomal function may be altered in FXTAS. Recent neuropathological studies show that Parkinson disease and Alzheimer disease can sometimes co-occur with FXTAS. Lewy bodies can be found in 10% of the brains of patients with FXTAS. Microbleeds and iron deposition are also common in the neuropathology, in addition to white matter disease (WMD) and atrophy. SUMMARY: The premutation occurs in 1:200 females and 1:400 males. Penetrance for FXTAS increases with age, though lower in females (16%) compared to over 60% of males by age 70. To diagnose FXTAS, an MRI is essential to document the presence of WMD, a primary component of the diagnostic criteria. Pain can be a significant feature of FXTAS and is seen in approximately 50% of patients.