Language use predicts symptoms of fragile X-associated tremor/ataxia syndrome in men and women with the FMR1 premutation.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an age-related neurodegenerative disorder caused by a premutation of the FMR1 gene on the X chromosome. Despite the pervasive physical and cognitive effects of FXTAS, no studies have examined language in symptomatic males and females, limiting utility as an outcome measure in clinical trials of FXTAS. The goal of this work is to determine (a) the extent to which male and female FMR1 premutation carriers with FXTAS symptoms differ in their language use and (b) whether language production predicts FXTAS symptoms. Thirty-one individuals with the FMR1 premutation (21M, 10F), ages 58-85 years with some symptoms of FXTAS, were recruited from a larger cross-sectional study. Participants completed a five-minute monologic language sample. Language transcripts were assessed for rate of dysfluencies, lexical-semantics, syntax, and speech rate. Multivariable linear and ordinal regressions were used to predict FXTAS-associated symptoms, cognitive functioning, and executive functioning. Males and females did not differ in their language use. Language production predicted FXTAS symptom severity, cognitive functioning, and executive functioning. Language production difficulties may co-occur with FXTAS-associated symptoms and may be a viable outcome measure in future clinical trials, with future research needed.

Psychiatric Manifestations in Early to Middle Stages of Fragile X-Associated Tremor-Ataxia Syndrome (FXTAS).

OBJECTIVE: The purpose of the present study was to assess the psychiatric manifestations of early to middle stages of fragile X-associated tremor-ataxia syndrome (FXTAS) and their relationship with executive function and FMR1 cytosine-guanine-guanine (CGG) repeat numbers across genders. METHODS: Cross-sectional data from 100 participants (62 men, 38 women; mean±SD age=67.11±7.90 years) with FXTAS stage 1, 2, or 3 were analyzed, including demographic information, cognitive measures, psychiatric assessments (Symptom Checklist-90-Revised and Behavioral Dyscontrol Scale-II [BDS-II]), and CGG repeat number. RESULTS: Participants with FXTAS stage 3 exhibited significantly worse psychiatric outcomes compared with participants with either stage 1 or 2, with distinct gender-related differences. Men showed differences in anxiety and hostility between stage 3 and combined stages 1 and 2, whereas women exhibited differences in anxiety, depression, interpersonal sensitivity, obsessive-compulsive symptoms, and somatization, as well as in the Global Severity Index, the Positive Symptom Distress Index, and the Positive Symptom Total. Among male participants, negative correlations were observed between BDS-II total scores and obsessive-compulsive symptoms, as well as between anxiety and CGG repeat number. CONCLUSIONS: These findings suggest that even at early FXTAS stages, patients have significant cognitive and other psychiatric symptoms, with notable gender-specific differences. This study underscores the clinical and prognostic relevance of comorbid psychiatric conditions in FXTAS, highlighting the need for early intervention and targeted support for individuals with relatively mild motor deficits.

Reversible encephalitis-like episodes in fragile X-associated tremor/ataxia syndrome: a case report.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by CGG repeat expansion of FMR1 gene. Both FXTAS and neuronal intranuclear inclusion disease (NIID) belong to polyglycine diseases and present similar clinical, radiological, and pathological features, making it difficult to distinguish these diseases. Reversible encephalitis-like attacks are often observed in NIID. It is unclear whether they are presented in FXTAS and can be used for differential diagnosis of NIID and FXTAS. CASE PRESENTATION: A 63-year-old Chinese male with late-onset gait disturbance, cognitive decline, and reversible attacks of fever, consciousness impairment, dizziness, vomiting, and urinary incontinence underwent neurological assessment and examinations, including laboratory tests, electroencephalogram test, imaging, skin biopsy, and genetic test. Brain MRI showed T2 hyperintensities in middle cerebellar peduncle and cerebrum, in addition to cerebellar atrophy and DWI hyperintensities along the corticomedullary junction. Lesions in the brainstem were observed. Skin biopsy showed p62-positive intranuclear inclusions. The possibilities of hypoglycemia, lactic acidosis, epileptic seizures, and cerebrovascular attacks were excluded. Genetic analysis revealed CGG repeat expansion in FMR1 gene, and the number of repeats was 111. The patient was finally diagnosed as FXTAS. He received supportive treatment as well as symptomatic treatment during hospitalization. His encephalitic symptoms were completely relieved within one week. CONCLUSIONS: This is a detailed report of a case of FXTAS with reversible encephalitis-like episodes. This report provides new information for the possible and rare features of FXTAS, highlighting that encephalitis-like episodes are common in polyglycine diseases and unable to be used for differential diagnosis.

Potential Prodromal Digital Postural Sway Markers for Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) Detected via Dual-Tasking and Sensory Manipulation.

FXTAS is a neurodegenerative disorder occurring in some Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene premutation carriers (PMCs) and is characterized by cerebellar ataxia, tremor, and cognitive deficits that negatively impact balance and gait and increase fall risk. Dual-tasking (DT) cognitive-motor paradigms and challenging balance conditions may have the capacity to reveal markers of FXTAS onset. Our objectives were to determine the impact of dual-tasking and sensory and stance manipulation on balance in FXTAS and potentially detect subtle postural sway deficits in FMR1 PMCs who are asymptomatic for signs of FXTAS on clinical exam. Participants with FXTAS, PMCs without FXTAS, and controls underwent balance testing using an inertial sensor system. Stance, vision, surface stability, and cognitive demand were manipulated in 30 s trials. FXTAS participants had significantly greater total sway area, jerk, and RMS sway than controls under almost all balance conditions but were most impaired in those requiring vestibular control. PMCs without FXTAS had significantly greater RMS sway compared with controls in the feet apart, firm, single task conditions both with eyes open and closed (EC) and the feet together, firm, EC, DT condition. Postural sway deficits in the RMS postural sway variability domain in asymptomatic PMCs might represent prodromal signs of FXTAS. This information may be useful in providing sensitive biomarkers of FXTAS onset and as quantitative balance measures in future interventional trials and longitudinal natural history studies.

Case Series: Vestibular Migraines in Fragile X Premutation Carriers.

BACKGROUND: Vestibular migraine (VM) is one of the most common causes of recurrent vertigo and presents with a history of spontaneous or positional vertigo with a history of migraine headaches. While research has identified a high prevalence of migraine headaches and vestibular deficits among fragile X premutation carriers, there has been no discussion about VM within this population. OBJECTIVE: This case series and review seeks to describe the clinical characteristics and pathophysiology of VM among individuals with the fragile X premutation. We also seek to discuss treatment and future steps in addressing VM in this population. METHODS: A review of the literature regarding vestibular migraine and presentation of migraine headaches and vestibular deficits among premutation carriers was performed. A detailed clinical history of migraine headaches and vertigo was obtained from three patients with the fragile X premutation seen by the senior author (RJH). RESULTS: All three cases first developed symptoms of migraine headaches earlier in life, with the development of VM near menopause. Two of the three cases developed progressive balance issues following the development of VM. All three cases found that their VM episodes were improved or resolved with pharmacological and/or lifestyle interventions. CONCLUSIONS: It is important to recognize VM among premutation carriers because beneficial treatments are available. Future studies are needed regarding the prevalence of VM and the relationship to subsequent FXTAS. The pathophysiology of VM remains uncertain but possibilities include mitochondrial abnormalities, cranial nerve VIII toxicity secondary to neurotoxic protein accumulation, and calcitonin gene-related peptide (CGRP) signaling dysfunction due to altered levels of fragile X messenger ribonucleoprotein (FMRP).

FMR1 Carriers Report Executive Function Changes Prior to Fragile X-Associated Tremor/Ataxia Syndrome: A Longitudinal Study.

BACKGROUND: Men with fragile X-associated tremor/ataxia syndrome (FXTAS) often develop executive dysfunction, characterized by disinhibition, frontal dyscontrol of movement, and working memory and attention changes. Although cross-sectional studies have suggested that earlier executive function changes may precede FXTAS, the lack of longitudinal studies has made it difficult to address this hypothesis. OBJECTIVE: To determine whether executive function deterioration experienced by premutation carriers (PC) in daily life precedes and predicts FXTAS. METHODS: This study included 66 FMR1 PC ranging from 40 to 78 years (mean, 59.5) and 31 well-matched healthy controls (HC) ages 40 to 75 (mean, 57.7) at baseline. Eighty-four participants returned for 2 to 5 follow up visits over a duration of 1 to 9 years (mean, 4.6); 28 of the PC developed FXTAS. The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) was completed by participants and their spouses/partners at each visit. RESULTS: Longitudinal mixed model regression analyses showed a greater decline with age in PC compared to HC on the Metacognition Index (MI; self-initiation, working memory, organization, task monitoring). Conversion to FXTAS was associated with worsening MI and Behavioral Regulation Index (BRI; inhibition, flexibility, emotion modulation). For spouse/partner report, FXTAS conversion was associated with worsening MI. Finally, increased self-report executive function problems at baseline significantly predicted later development of FXTAS. CONCLUSIONS: Executive function changes experienced by male PC represent a prodrome of the later movement disorder. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Blood Proteome Profiling Reveals Biomarkers and Pathway Alterations in Fragile X PM at Risk for Developing FXTAS.

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associated with the FMR1 premutation. Currently, it is not possible to determine when and if individual premutation carriers will develop FXTAS. Thus, with the aim to identify biomarkers for early diagnosis, development, and progression of FXTAS, along with associated dysregulated pathways, we performed blood proteomic profiling of premutation carriers (PM) who, as part of an ongoing longitudinal study, emerged into two distinct groups: those who developed symptoms of FXTAS (converters, CON) over time (at subsequent visits) and those who did not (non-converters, NCON). We compared these groups to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern blot and PCR analysis. The proteomic profile was obtained by liquid chromatography mass spectrometry (LC-MS/MS). We identified several significantly differentiated proteins between HC and the PM groups at Visit 1 (V1), Visit 2 (V2), and between the visits. We further reported the dysregulated protein pathways, including sphingolipid and amino acid metabolism. Our findings are in agreement with previous studies showing that pathways involved in mitochondrial bioenergetics, as observed in other neurodegenerative disorders, are significantly altered and appear to contribute to the development of FXTAS. Lastly, we compared the blood proteome of the PM who developed FXTAS over time with the CSF proteome of the FXTAS patients recently reported and found eight significantly differentially expressed proteins in common. To our knowledge, this is the first report of longitudinal proteomic profiling and the identification of unique biomarkers and dysregulated protein pathways in FXTAS.

A Longitudinal Study of Executive Function in Daily Life in Male Fragile X Premutation Carriers and Association with FXTAS Conversion.

Background: Men with fragile X-associated tremor/ataxia syndrome (FXTAS) often develop executive dysfunction, characterized by disinhibition, frontal dyscontrol of movement, and working memory and attention changes. Although cross-sectional studies have suggested that earlier executive function changes may precede FXTAS, the lack of longitudinal studies have made it difficult to address this hypothesis. Methods: This study included 66 FMR1 premutation carriers (PC) ranging from 40-78 years (Mean=59.5) and 31 well-matched healthy controls (HC) ages 40-75 (Mean 57.7) at baseline. Eighty-four participants returned for 2-5 follow up visits over a duration of 1 to 9 years (Mean=4.6); 28 of the PC developed FXTAS. The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) was completed by participants and their spouses/partners at each visit. Results: Longitudinal mixed model regression analyses showed a greater decline with age in PC compared to HC on the Metacognition Index (MI; self-initiation, working memory, organization, task monitoring). Conversion to FXTAS was associated with worsening MI and Behavioral Regulation Index (BRI; inhibition, flexibility, emotion modulation). For spouse/partner report, FXTAS conversion was associated with worsening MI. Finally, BRIEF-A executive function problems at baseline significantly predicted later development of FXTAS. Conclusions: These findings suggest that executive function changes represent a prodrome of the later movement disorder.

Atypical vocal quality in women with the FMR1 premutation: an indicator of impaired sensorimotor control.

Women with the FMR1 premutation are susceptible to motor involvement related to atypical cerebellar function, including risk for developing fragile X tremor ataxia syndrome. Vocal quality analyses are sensitive to subtle differences in motor skills but have not yet been applied to the FMR1 premutation. This study examined whether women with the FMR1 premutation demonstrate differences in vocal quality, and whether such differences relate to FMR1 genetic, executive, motor, or health features of the FMR1 premutation. Participants included 35 women with the FMR1 premutation and 45 age-matched women without the FMR1 premutation who served as a comparison group. Three sustained /a/ vowels were analyzed for pitch (mean F0), variability of pitch (standard deviation of F0), and overall vocal quality (jitter, shimmer, and harmonics-to-noise ratio). Executive, motor, and health indices were obtained from direct and self-report measures and genetic samples were analyzed for FMR1 CGG repeat length and activation ratio. Women with the FMR1 premutation had a lower pitch, larger pitch variability, and poorer vocal quality than the comparison group. Working memory was related to harmonics-to-noise ratio and shimmer in women with the FMR1 premutation. Vocal quality abnormalities differentiated women with the FMR1 premutation from the comparison group and were evident even in the absence of other clinically evident motor deficits. This study supports vocal quality analyses as a tool that may prove useful in the detection of early signs of motor involvement in this population.

Mouse models of fragile X-related disorders.

The fragile X-related disorders are an important group of hereditary disorders that are caused by expanded CGG repeats in the 5' untranslated region of the FMR1 gene or by mutations in the coding sequence of this gene. Two categories of pathological CGG repeats are associated with these disorders, full mutation alleles and shorter premutation alleles. Individuals with full mutation alleles develop fragile X syndrome, which causes autism and intellectual disability, whereas those with premutation alleles, which have shorter CGG expansions, can develop fragile X-associated tremor/ataxia syndrome, a progressive neurodegenerative disease. Thus, fragile X-related disorders can manifest as neurodegenerative or neurodevelopmental disorders, depending on the size of the repeat expansion. Here, we review mouse models of fragile X-related disorders and discuss how they have informed our understanding of neurodegenerative and neurodevelopmental disorders. We also assess the translational value of these models for developing rational targeted therapies for intellectual disability and autism disorders.

Structure and Alternative Splicing of the Antisense FMR1 (ASFMR1) Gene.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by an expansion of 55-200 CGG repeats (premutation) in the 5'-UTR of the FMR1 gene. Bidirectional transcription at FMR1 locus has been demonstrated and specific alternative splicing of the Antisense FMR1 (ASFMR1) gene has been proposed to have a contributing role in the pathogenesis of FXTAS. The structure of ASFMR1 gene is still uncharacterized and it is currently unknown how many isoforms of the gene are expressed and at what level in premutation carriers (PM) and if they may contribute to the premutation pathology. In this study, we characterized the ASFMR1 gene structure and the transcriptional landscape by using PacBio SMRT sequencing with target enrichment (IDT customized probe panel). We identified 45 ASFMR1 isoforms ranging in sizes from 523 bp to 6 Kb, spanning approximately 59 kb of genomic DNA. Multiplexing and sequencing of six human brain samples from PM samples and normal control (HC) were carried out on the PacBio Sequel platform. We validated the presence of these isoforms by qRT-PCR and Sanger sequencing and characterized the acceptor and donor splicing site consensus sequences. Consistent with previous studies conducted in other tissue types, we found a high expression of ASFMR1 isoform Iso131bp in brain samples of PM as compared to HC, while no differences in expression levels were observed for the newly identified isoforms IsoAS1 and IsoAS2. We investigated the role of the splicing regulatory protein Sam68 which we did not observe in the alternative splicing of the ASFMR1 gene. Our study provides a useful insight into the structure of ASFMR1 gene and transcriptional landscape along with the expression pattern of various newly identified novel isoforms and on their potential role in premutation pathology.

Screening for the FMR1 premutation in Greek patients with late-onset movement disorders.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset, X-linked, neurodegenerative disorder that affects premutation carriers of the FMR1 gene. FXTAS is often misdiagnosed as spinocerebellar ataxia (SCA) or Parkinson's disease (PD). Herein, we sought to investigate the frequency, genotypic and phenotypic profile of FXTAS in two cohorts of Greek patients with late-onset movement disorders, one with cerebellar ataxia and the other with PD. In total, 90 index patients with late-onset cerebellar ataxia and 171 with PD were selected. None of the cases had male-to-male transmission. Genetic screening for the FMR1 premutation was performed using standard methodology. The FMR1 premutation was detected in two ataxia patients (2.2%) and two PD patients (1.2%). Additional clinical features in FXTAS patients from the ataxia cohort included neuropathy, mild parkinsonism, cognitive impairment and pyramidal signs. The FXTAS patients from the PD cohort had typical PD. We conclude that, in the Greek population, the FMR1 premutation is an important, albeit rare, cause of late-onset movement disorders. Routine premutation screening should be considered in SCA panel-negative late-onset ataxia cases. Directed premutation screening should be considered in all ataxia and PD cases with additional features suggestive of FXTAS. Our study highlights the importance of FMR1 genetic testing in the diagnosis of late-onset movement disorders.

AAGGG repeat expansions trigger RFC1-independent synaptic dysregulation in human CANVAS Neurons.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late onset, recessively inherited neurodegenerative disorder caused by biallelic, non-reference pentameric AAGGG(CCCTT) repeat expansions within the second intron of replication factor complex subunit 1 (RFC1). To investigate how these repeats cause disease, we generated CANVAS patient induced pluripotent stem cell (iPSC) derived neurons (iNeurons) and utilized calcium imaging and transcriptomic analysis to define repeat-elicited gain-of-function and loss-of-function contributions to neuronal toxicity. AAGGG repeat expansions do not alter neuronal RFC1 splicing, expression, or DNA repair pathway functions. In reporter assays, AAGGG repeats are translated into pentapeptide repeat proteins that selectively accumulate in CANVAS patient brains. However, neither these proteins nor repeat RNA foci were detected in iNeurons, and overexpression of these repeats in isolation did not induce neuronal toxicity. CANVAS iNeurons exhibit defects in neuronal development and diminished synaptic connectivity that is rescued by CRISPR deletion of a single expanded allele. These phenotypic deficits were not replicated by knockdown of RFC1 in control neurons and were not rescued by ectopic expression of RFC1. These findings support a repeat-dependent but RFC1-independent cause of neuronal dysfunction in CANVAS, with important implications for therapeutic development in this currently untreatable condition.

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.

Non-canonical DNA/RNA structures associated with the pathogenesis of Fragile X-associated tremor/ataxia syndrome and Fragile X syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X syndrome (FXS) are primary examples of fragile X-related disorders (FXDs) caused by abnormal expansion of CGG repeats above a certain threshold in the 5'-untranslated region of the fragile X mental retardation (FMR1) gene. Both diseases have distinct clinical manifestations and molecular pathogenesis. FXTAS is a late-adult-onset neurodegenerative disorder caused by a premutation (PM) allele (CGG expansion of 55-200 repeats), resulting in FMR1 gene hyperexpression. On the other hand, FXS is a neurodevelopmental disorder that results from a full mutation (FM) allele (CGG expansions of ≥200 repeats) leading to heterochromatization and transcriptional silencing of the FMR1 gene. The main challenge is to determine how CGG repeat expansion affects the fundamentally distinct nature of FMR1 expression in FM and PM ranges. Abnormal CGG repeat expansions form a variety of non-canonical DNA and RNA structures that can disrupt various cellular processes and cause distinct effects in PM and FM alleles. Here, we review these structures and how they are related to underlying mutations and disease pathology in FXS and FXTAS. Finally, as new CGG expansions within the genome have been identified, it will be interesting to determine their implications in disease pathology and treatment.

Cerebellum neuropathology and motor skill deficits in fragile X syndrome.

Fragile X syndrome (FXS) is a leading form of inherited intellectual disability and single-gene cause of autism spectrum disorder (ASD) and is characterized by core deficits in cognitive flexibility, sensory sensitivity, emotion, and social interactions. Motor deficits are a shared feature of FXS and autism. The cerebellum has emerged as one of the target brain areas affected by neurodevelopmental diseases. Alterations in the cerebellar structure, circuits, and function may be the key drivers of impaired fine and gross motor skills in FXS and fragile X-associated tremor/ataxia syndrome (FXTAS). In this review, we briefly examined recent findings in FXS and present a discussion on the literature supporting motor skill deficits in FXS. Subsequently, we focused on neuropathological alterations in the cerebellum in FXS and FXTAS. We highlight studies that have directly examined the function of fragile X mental retardation protein and related epigenetic variations in the cerebellum. Overall, we obtained considerable supporting evidence for the hypothesis that cerebellar dysfunction is evident in FXS and FXTAS; however, compared with studies on other ASD models, studies on motor skills related to fragile X disorders are particularly rare and inconclusive. Hence, future research should address FXS-related motor and behavioral trajectories and examine the underlying mechanisms at both the cell and circuit levels.

Absence of diffusion-weighted imaging abnormalities in a patient with neuronal intranuclear inclusion disease.

INTRODUCTION: Herein, we report a genetically confirmed case of neuronal intranuclear inclusion disease without characteristic subcortical hyperintensities on diffusion-weighted imaging. CASE PRESENTATION: A 75-year-old man was admitted to our hospital with subacute onset of conscious disturbance. Except for gastric cancer, he had no apparent past medical or family history. He presented with transient fever, vomiting, and urinary retention. On admission, no apparent abnormal intensity was detected on diffusion-weighted imaging. The symptoms improved within 10 days, without any medical treatment. Additional inspections were performed under suspicion of neuronal intranuclear inclusion disease. Intranuclear inclusions were found not only from skin biopsy but also from his stomach specimens, which had been resected 6 years previously. Subsequent genetic testing revealed repeat expansion of GGC amplification in NOTCH2NLC. CONCLUSION: Characteristic neuroimaging and skin biopsy findings are important clues for diagnosing neuronal intranuclear inclusion diseases. Nonetheless, confirming a diagnosis is difficult due to the diversity of clinical manifestations and radiological features. Clinicians should suspect neuronal intranuclear inclusion disease in patients with transient encephalitic episodes, even if no abnormalities are detected on diffusion-weighted imaging.

The polyG diseases: a new disease entity.

Recently, inspired by the similar clinical and pathological features shared with fragile X-associated tremor/ataxia syndrome (FXTAS), abnormal expansion of CGG repeats in the 5' untranslated region has been found in neuronal intranuclear inclusion disease (NIID), oculopharyngeal myopathy with leukoencephalopathy (OPML), and oculopharyngodistal myopathy (OPDMs). Although the upstream open reading frame has not been elucidated in OPML and OPDMs, polyglycine (polyG) translated by expanded CGG repeats is reported to be as a primary pathogenesis in FXTAS and NIID. Collectively, these findings indicate a new disease entity, the polyG diseases. In this review, we state the common clinical manifestations, pathological features, mechanisms, and potential therapies in these diseases, and provide preliminary opinions about future research in polyG diseases.

A case of idiopathic normal pressure hydrocephalus with fragile X-associated tremor/ataxia syndrome.

Clinical management of patients with fragile X-associated tremor/ataxia syndrome (FXTAS) is a challenge, and there has been not an established treatment for FXTAS, which is now treated symptomatically. Diagnosis of coexistent idiopathic normal pressure hydrocephalus (iNPH) with FXTAS is also hard because clinical and imaging features can overlap between the FXTAS patients coexistent with and without iNPH. We present a 79-year-old male genetically diagnosed with FXTAS who was successfully treated by a shunt surgery and consequently diagnosed with iNPH, and suggest the management of coexistent iNPH with FXTAS when it is clinically suspicious.