Cognitive Safety Data from a Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Phase IIb Study of the Effects of a Cannabidiol and Δ9-Tetrahydrocannabinol Drug on Parkinson's Disease-Related Motor Symptoms.

BACKGROUND: Cannabis is increasingly available worldwide but its impact on cognition in Parkinson's disease (PD) is unknown. OBJECTIVE: Present cognitive safety data from study of an oral high-dose cannabidiol (CBD; 100 mg) and low-dose Δ9-tetrahydocannabinol (THC; 3.3 mg) drug in PD. METHODS: Randomized, double-blind, parallel-group, placebo-controlled study of a CBD/THC drug administered for 16.3 (SD: 4.2) days, with dosage escalating to twice per day. Neuropsychological tests were administered at baseline and 1-1½ hours after final dose; scores were analyzed with longitudinal regression models (alpha = 0.05). Cognitive adverse events were collected. RESULTS: When adjusted for age and education, the CBD/THC group (n = 29) performed worse than the placebo group (n = 29) on Animal Verbal Fluency. Adverse cognitive events were reported at least twice as often by the CBD/THC than the placebo group. CONCLUSION: Data suggest this CBD/THC drug has a small detrimental effect on cognition following acute/short-term use in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A Review of the Current Evidence Connecting Seborrheic Dermatitis and Parkinson's Disease and the Potential Role of Oral Cannabinoids.

Parkinson's disease (PD) is a neurodegenerative disorder associated with multiple comorbidities, including seborrheic dermatitis (SD), which develops in more than half of PD patients. SD in patients with PD can be severe and frequently intractable by traditional topical therapy. Cannabinoids possess anti-inflammatory and neuromodulatory properties working within the intrinsic endocannabinoid system, the activation of which may alleviate the motor symptoms of PD. The effect of cannabinoids on SD is unknown. Here we explore the pathophysiological mechanisms and possible therapeutic role of oral cannabinoids in PD patients with SD, and review speculative mechanisms underlying the association of PD and SD. Current data supporting the use of cannabinoids in both PD and SD, as well as oral cannabinoid safety and tolerability, are presented. Cannabinoids may provide the possibility of simultaneous treatment of both SD and PD. Specific SD studies and additional safety data on oral cannabinoids are needed.

Eye Movements in Fragile X-Associated Tremor/Ataxia Syndrome.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder characterized by ataxia, tremor, and parkinsonism. Eye motility abnormalities on the clinical examination of FXTAS patients have not been formally studied. METHODS: A case-control study with fragile X gene mutation carriers with and without FXTAS and normal controls was conducted and included a videotaping of ocular items of the International Cooperative Ataxia Rating Scale (ICARS). A neuro-ophthalmologist blinded to gene status rated nystagmus, ocular pursuit, and saccades. RESULTS: Forty-four cases and controls were recruited, with an average age of 55.2 years (±7.4) and 57% women. Gaze-evoked nystagmus was increased in fragile X gene carriers (odds ratio 1.44, 95% confidence interval: 0.33-7.36) but was not statistically significant. There was no difference in ocular pursuit nor saccade dysmetria between cases and controls. CONCLUSION: The results show that clinical examination findings of ocular abnormalities, using the ICARS oculomotor disorders movement subscale, are not more common in FXTAS or FMR1 premutation carriers than normal controls on examination in the clinic. Examining a larger cohort of patients with FXTAS would be an ideal next step.

An Atmospheric Pressure Chemical Ionization MS/MS Assay Using Online Extraction for the Analysis of 11 Cannabinoids and Metabolites in Human Plasma and Urine.

BACKGROUND: Although, especially in the United States, there has been a recent surge of legalized cannabis for either recreational or medicinal purposes, surprisingly little is known about clinical dose-response relationships, pharmacodynamic and toxicodynamic effects of cannabinoids such as Δ9-tetrahydrocannabinol (THC). Even less is known about other active cannabinoids. METHODS: To address this knowledge gap, an online extraction, high-performance liquid chromatography coupled with tandem mass spectrometry method for simultaneous quantification of 11 cannabinoids and metabolites including THC, 11-hydroxy-Δ9-tetrahydrocannabinol, 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid, 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide (THC-C-gluc), cannabinol, cannabidiol, cannabigerol, cannabidivarin, Δ9-tetrahydrocannabivarin (THCV), and 11-nor-9-carboxy-Δ9-tetrahydrocannabivarin (THCV-COOH) was developed and validated in human urine and plasma. RESULTS: In contrast to atmospheric pressure chemical ionization, electrospray ionization was associated with extensive ion suppression in plasma and urine samples. Thus, the atmospheric pressure chemical ionization assay was validated showing a lower limit of quantification ranging from 0.39 to 3.91 ng/mL depending on study compound and matrix. The upper limit of quantification was 400 ng/mL except for THC-C-gluc with an upper limit of quantification of 2000 ng/mL. The linearity was r > 0.99 for all analyzed calibration curves. Acceptance criteria for intrabatch and interbatch accuracy (85%-115%) and imprecision (<15%) were met for all compounds. In plasma, the only exceptions were THCV (75.3%-121.2% interbatch accuracy) and cannabidivarin (interbatch imprecision, 15.7%-17.2%). In urine, THCV did not meet predefined acceptance criteria for intrabatch accuracy. CONCLUSIONS: This assay allows for monitoring not only THC and its major metabolites but also major cannabinoids that are of interest for marijuana research and clinical practice.

Clinical Phenotype of Adult Fragile X Gray Zone Allele Carriers: a Case Series.

Considerable research has focused on patients with trinucleotide (CGG) repeat expansions in the fragile X mental retardation 1 (FMR1) gene that fall within either the full mutation (>200 repeats) or premutation range (55-200 repeats). Recent interest in individuals with gray zone expansions (41-54 CGG repeats) has grown due to reported phenotypes that are similar to those observed in premutation carriers, including neurological, molecular, and cognitive signs. The purpose of this manuscript is to describe a series of adults with FMR1 alleles in the gray zone presenting with movement disorders or memory loss. Gray zone carriers ascertained in large FMR1 screening studies were identified and their clinical phenotypes studied. Thirty-one gray zone allele carriers were included, with mean age of symptom onset of 53 years in patients with movement disorders and 57 years in those with memory loss. Four patients were chosen for illustrative case reports and had the following diagnoses: early-onset Parkinson disease (PD), atypical parkinsonism, dementia, and atypical essential tremor. Some gray zone carriers presenting with parkinsonism had typical features, including bradykinesia, rigidity, and a positive response to dopaminergic medication. These patients had a higher prevalence of peripheral neuropathy and psychiatric complaints than would be expected. The patients seen in memory clinics had standard presentations of cognitive impairment with no apparent differences. Further studies are necessary to determine the associations between FMR1 expansions in the gray zone and various phenotypes of neurological dysfunction.

Oral Cannabidiol for Seborrheic Dermatitis in Patients With Parkinson Disease: Randomized Clinical Trial.

BACKGROUND: Seborrheic dermatitis (SD) affects 18.6%-59% of persons with Parkinson disease (PD), and recent studies provide evidence that oral cannabidiol (CBD) therapy could reduce sebum production in addition to improving motor and psychiatric symptoms in PD. Therefore, oral CBD could be useful for improving symptoms of both commonly co-occurring conditions. OBJECTIVE: This study investigates whether oral CBD therapy is associated with a decrease in SD severity in PD. METHODS: Facial photographs were collected as a component of a randomized (1:1 CBD vs placebo), parallel, double-blind, placebo-controlled trial assessing the efficacy of a short-term 2.5 mg per kg per day oral sesame solution CBD-rich cannabis extract (formulated to 100 mg/mL CBD and 3.3 mg/mL THC) for reducing motor symptoms in PD. Participants took 1.25 mg per kg per day each morning for 4 ±1 days and then twice daily for 10 ±4 days. Reviewers analyzed the photographs independently and provided a severity ranking based on the Seborrheic Dermatitis Area and Severity Index (SEDASI) scale. Baseline demographic and disease characteristics, as well as posttreatment SEDASI averages and the presence of SD, were analyzed with 2-tailed t tests and Pearson χ2 tests. SEDASI was analyzed with longitudinal regression, and SD was analyzed with generalized estimating equations. RESULTS: A total of 27 participants received a placebo and 26 received CBD for 16 days. SD severity was low in both groups at baseline, and there was no treatment effect. The risk ratio for patients receiving CBD, post versus pre, was 0.69 (95% CI 0.41-1.18; P=.15), compared to 1.20 (95% CI 0.88-1.65; P=.26) for the patients receiving the placebo. The within-group pre-post change was not statistically significant for either group, but they differed from each other (P=.07) because there was an estimated improvement for the CBD group and an estimated worsening for the placebo group. CONCLUSIONS: This study does not provide solid evidence that oral CBD therapy reduces the presence of SD among patients with PD. While this study was sufficiently powered to detect the primary outcome (efficacy of CBD on PD motor symptoms), it was underpowered for the secondary outcomes of detecting changes in the presence and severity of SD. Multiple mechanisms exist through which CBD can exert beneficial effects on SD pathogenesis. Larger studies, including participants with increased disease severity and longer treatment periods, may better elucidate treatment effects and are needed to determine CBD's true efficacy for affecting SD severity. TRIAL REGISTRATION: ClinicalTrials.gov NCT03582137; https://clinicaltrials.gov/ct2/show/NCT03582137.

Higher Risk, Higher Reward? Self-Reported Effects of Real-World Cannabis Use in Parkinson's Disease.

Background: Despite limited evidence, people with Parkinson's disease (PD) use cannabis for therapeutic purposes. Given barriers to performing randomized trials, exploring real-world experiences with cannabis in PD is valuable. Objective: Investigate the frequency and magnitude of symptomatic effects reported with cannabis use in PD. Methods: An anonymous, 15-question, web-based survey was deployed on Fox Insight. Cannabis product types were defined (by relative tetrahydrocannabinol [THC] and cannabidiol [CBD] content) and respondents were asked to reference product labels. Questions focused on use patterns and subjective effects on 36 predefined symptoms (rated -2-markedly worse to +2-markedly better). Results: 1,881 people with PD responded (58.5% men; mean age 66.5; 50.5% <3 years of PD). 73.0% of respondents reported medicinal use, though 30.8% did not inform their doctor. 86.7% knew their type of cannabis product: 54.6% took higher CBD, 30.2% higher THC, and 15.2% took similar amounts of THC and CBD products. Most common use was oral administration, once daily, for less than six months. Frequent improvements were reported for pain, anxiety, agitation, and sleep (>50% of respondents, mean magnitude 1.28-1.51). Dry mouth, dizziness, and cognitive changes were common adverse effects (20.9%-30.8%, mean -1.13 to -1.21). Higher THC users reported more frequent improvements in depression, anxiety, and tremor, and more frequent worsening in dry mouth and bradykinesia than other product types. Conclusions: Respondents with PD reported using more CBD products, via oral administration, with mild subjective benefits primarily for sleep, pain, and mood. Higher THC products may be higher risk/higher reward for PD-related symptoms.

Fragile X-associated tremor ataxia syndrome rating scale: Revision and content validity using a mixed method approach.

Background: The original Fragile X-associated Tremor Ataxia Syndrome Rating Scale (FXTAS-RS) contained 61 items, some requiring modifications to better meet recommendations for patient-focused rating scale development. Purpose: Provide initial validation of a revised version of the FXTAS-RS for motor signs. Method: We conducted a two-phase mixed-method approach. In Phase 1, revision, we implemented a Delphi technique identifying pertinent domains/subdomains and developing items through expert consensus. In Phase 2, content validation, we conducted cognitive pretesting assessing comprehensibility, comprehensiveness, and relevance of items to FXTAS motor signs. Results: After five rounds of Delphi panel and two rounds of cognitive pretesting, the revised version of the FXTAS-RS was established with 18 items covering five domains and 13 subdomains of motor signs. Cognitive pretesting revealed adequate content validity for the assessment of FXTAS motor signs. Conclusion: The revised FXTAS-RS has been successfully validated for content and it is now ready for large-scale field validation.

Fibromyalgia in fragile X mental retardation 1 gene premutation carriers.

OBJECTIVE: FM is a disorder of altered pain regulation and is characterized by pain, fatigue, poor sleep and psychological impairments; thus, it is classified as a central sensitivity syndrome. Female carriers of a premutation in the fragile X mental retardation 1 (FMR1) gene frequently have widespread musculoskeletal pain and sometimes have been diagnosed with FM, especially if they have the motor signs of fragile X-associated tremor ataxia syndrome (FXTAS). Studies suggest that FM occurs in persons with a genetic predisposition. We describe the clinical features of female FMR1 premutation carriers with symptoms of FM. METHODS: A sample of patients was selected that participated in studies at two tertiary referral academic centres on the phenotype and therapy of FXTAS. RESULTS: This selected sample of patients, five female premutation carriers, has FM symptoms or diagnoses and other central sensitivity syndromes. CONCLUSION: Since FM affects 2-4% of the world's population and about 1 in 250 females are FMR1 carriers, a study screening females with FM for the presence of the FMR1 premutation is worthwhile. A finding of increased prevalence of FMR1 carriers among females with FM would impact the standard evaluation of FM. Presently, guidelines for FMR1 genetic testing includes early menopause, congenital intellectual disability, autism spectrum disorder, tremor or ataxia, and a family history of FXTAS or fragile X syndrome. The latter is a common cause of autism and developmental delay. Such testing is important because female carriers are at risk of having a child with fragile X syndrome.

FMR1 gray-zone alleles: association with Parkinson's disease in women?

Carriers of fragile X mental retardation 1 repeat expansions in the premutation range (55-200 CGG repeats), especially males, often develop tremor, ataxia, and parkinsonism. These neurological signs are believed to be a result of elevated levels of expanded CGG-repeat fragile X mental retardation 1 mRNA. The purpose of this study was to determine the prevalence of fragile X mental retardation 1 repeat expansions in a movement disorder population comprising subjects with all types of tremor, ataxia, and parkinsonism. We screened 335 consecutive patients with tremor, ataxia, or parkinsonism and 273 controls confirmed to have no movement disorders. There was no difference in fragile X mental retardation 1 premutation size expansions in the cases compared with controls. Eleven percent of the women with Parkinson's disease had fragile X mental retardation 1 gray-zone expansions compared with 4.4% of female controls (odds ratio of 3.2; 95% confidence interval, 1.2-8.7). Gray-zone expansions in patients with other phenotypes were not overrepresented in comparison with controls. Fragile X mental retardation 1 premutation range expansions are not more common in a mixed movement disorder population compared with controls. Our results, however, suggest that fragile X mental retardation 1 gray-zone alleles may be associated with Parkinson's disease in women.

Identifying susceptibility genes for primary ovarian insufficiency on the high-risk genetic background of a fragile X premutation.

OBJECTIVE: To identify modifying genes that explains the risk of fragile X-associated primary ovarian insufficiency (FXPOI). DESIGN: Gene-based, case/control association study, followed by a functional screen of highly ranked genes using a Drosophila model. SETTING: Participants were recruited from academic and clinical settings. PATIENT(S): Women with a premutation (PM) who experienced FXPOI at the age of 35 years or younger (n = 63) and women with a PM who experienced menopause at the age of 50 years or older (n = 51) provided clinical information and a deoxyribonucleic acid sample for whole genome sequencing. The functional screen was on the basis of Drosophila TRiP lines. INTERVENTION(S): Clinical information and a DNA sample were collected for whole genome sequencing. MAIN OUTCOME MEASURES: A polygenic risk score derived from common variants associated with natural age at menopause was calculated and associated with the risk of FXPOI. Genes associated with the risk of FXPOI were identified on the basis of the P-value from gene-based association test and an altered level of fecundity when knocked down in the Drosophila PM model. RESULTS: The polygenic risk score on the basis of common variants associated with natural age at menopause explained approximately 8% of the variance in the risk of FXPOI. Further, SUMO1 and KRR1 were identified as possible modifying genes associated with the risk of FXPOI on the basis of an untargeted gene analysis of rare variants. CONCLUSIONS: In addition to the large genetic effect of a PM on ovarian function, the additive effects of common variants associated with natural age at menopause and the effect of rare modifying variants appear to play a role in FXPOI risk.

Safety and Tolerability of Cannabidiol in Parkinson Disease: An Open Label, Dose-Escalation Study.

Background: Cannabis is increasingly used in Parkinson disease (PD), despite little information regarding benefits and risks. Objectives: To investigate the safety and tolerability of a range of doses of cannabidiol (CBD), a nonintoxicating component of cannabis, and it's effect on common parkinsonian symptoms. Methods: In this open-label study Coloradans with PD, substantial rest tremor, not using cannabis received plant-derived highly purified CBD (Epidiolex®; 100 mg/mL). CBD was titrated from 5 to 20-25 mg/kg/day and maintained for 10-15 days. Results: Fifteen participants enrolled, two were screen failures. All 13 participants (10 male), mean (SD) age 68.15 (6.05), with 6.1 (4.0) years of PD, reported adverse events, including diarrhea (85%), somnolence (69%), fatigue (62%), weight gain (31%), dizziness (23%), abdominal pain (23%), and headache, weight loss, nausea, anorexia, and increased appetite (each 5%). Adverse events were mostly mild; none serious. Elevated liver enzymes, mostly a cholestatic pattern, occurred in five (38.5%) participants on 20-25 mg/kg/day, only one symptomatic. Three (23%) dropped out due to intolerance. Ten (eight male) that completed the study had improvement in total and motor Movement Disorder Society Unified Parkinson Disease Rating Scale scores of 7.70 (9.39, mean decrease 17.8%, p=0.012) and 6.10 (6.64, mean decrease 24.7%, p=0.004), respectively. Nighttime sleep and emotional/behavioral dyscontrol scores also improved significantly. Conclusions: CBD, in the form of Epidiolex, may be efficacious in PD, but the relatively high dose used in this study was associated with liver enzyme elevations. Randomized controlled trials are needed to investigate various forms of cannabis in PD.

Conversion disorder in women with the FMR1 premutation.

Women with fragile X mental retardation (FMR1) gene premutations (55-200 CGG repeats) were until recently believed to be unaffected. It is now known that up to 8% of older female FMR1 premutation carriers develop fragile X-associated tremor/ataxia syndrome (FXTAS). Female carriers may also develop primary ovarian insufficiency, thyroid disease, hypertension, seizures, peripheral neuropathy, and fibromyalgia. We present a 60-year-old woman with FMR1 premutation who had depression, anxiety, and conversion disorder with seizures. The FMR1 premutation with its associated mRNA toxicity is postulated as an underlying neurobiological mechanism of conversion symptoms, through functional and structural neural dysconnectivity.

Parkinsonism in FMR1 premutation carriers may be indistinguishable from Parkinson disease.

Premutation carriers of repeat expansions in the fragile X mental retardation (FMR1) gene develop kinetic tremor and ataxia or the 'fragile X associated tremor/ataxia syndrome' (FXTAS). Affected FMR1 premutation carriers also have parkinsonism, but have not been reported to meet criteria for Parkinson disease. This case series illustrates that some patients who are FMR1 premutation carriers may appear by history and examination to have idiopathic Parkinson disease. Based on previous studies, it is likely that the genetic mutation and parkinsonism are associated. Although screening all PD patients is likely to be low yield, genetic testing of FMR1 in individuals with PD and a family history of fragile X syndrome, autism or developmental delay, or other related FMR1 phenotypes is warranted.

Functional status of men with the fragile X premutation, with and without the tremor/ataxia syndrome (FXTAS).

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS), which occurs in some premutation carriers of the fragile X mental retardation 1 (FMR1) gene, is a neurodegenerative disorder characterized by action tremor, gait ataxia, and impaired executive cognitive functioning. OBJECTIVE: To evaluate the nature and severity of functional limitations among male carriers of the fragile X premutation, both with and without FXTAS. METHODS: Forty-two subjects with FXTAS and 24 asymptomatic premutation carriers were compared to 32 control subjects on measures of physical functioning, activities of daily living (ADLs; e.g. eating, bathing), and instrumental activities of daily living (IADLs; e.g. shopping, managing medications). Ordinary least squares regression, controlling for age, education, medical comorbidity, and pain, was used to examine group differences in physical and functional performance. RESULTS: Men with FXTAS performed significantly worse than control subjects on all dependent measures, showing greater limitations in physical functioning, as well as ADL and IADL performance (p < 0.05). Subsequent analyses suggested that physical and functional impairments among men with FXTAS result largely from deficits in motor and executive functioning and that CGG repeat length is associated with functional impairment. Asymptomatic carriers of the fragile X premutation performed similarly to control subjects on all measures. CONCLUSIONS: This study provides the first comprehensive evaluation of functional status among male premutation carriers. Although carriers without FXTAS performed similarly to control subjects, men with FXTAS showed evidence of significant physical and functional impairment, which appears to result largely from motor and executive deficits characteristic of the syndrome.

Clinimetric Properties of the Fragile X-associated Tremor Ataxia Syndrome Rating Scale.

BACKGROUND: There are currently no proven treatments for fragile X-associated tremor and ataxia syndrome (FXTAS). Validated outcome measures are needed in order to plan and conduct clinical trials to aid in the development of therapy. METHODS: This study examined the reliability and construct validity of the FXTAS Rating Scale. The study was conducted by using ratings from movement disorder specialists, who were blinded to gene status, on the FXTAS Rating Scale. RESULTS: In 295 premutation carriers with and without FXTAS, 33 scale items showed a high level of overall reliability, adequate item-to-total correlations and construct validity. Factor analysis revealed four components. CONCLUSIONS: The result demonstrates that many items in the scale meet standard clinimetric criteria, but modification of the scale improved the overall utility.

Novel clinical features of glycine receptor antibody syndrome: A series of 17 cases.

Objective: To describe novel clinical features of GlyRα1-IgG-positive patients. Methods: Patients with a positive serum GlyRα1-IgG were identified during a 2-year period from July 2016 to December 2018 at 2 academic centers and followed prospectively. All patients in this series were evaluated in the Neuroimmunology and Autoimmune Neurology clinics at the University of Utah or the University of Colorado. Results: Thirteen of 17 patients had phenotypes more typically associated with glutamic acid decarboxylase (GAD65) antibody syndromes, consisting of stiff-person syndrome (SPS) with parkinsonism or cerebellar signs. One patient with parkinsonism had a presentation similar to rapidly progressive multiple system atrophy with severe dysautonomia. Ten of 17 patients had various visual symptoms including visual snow, spider web-like images forming shapes and 3-dimensional images, palinopsia, photophobia, visual hallucinations, synesthesia, and intermittent diplopia. Three of 17 patients presented with primarily autoimmune epilepsy accompanied by psychiatric symptoms. Conclusions: Clinicians should consider testing for GlyR antibodies in GAD65 antibody-negative or low-positive GAD65 antibody patients with SPS-like presentations, especially in the setting of atypical features such as visual disturbances, parkinsonism, or epilepsy.

Cognitive profile of fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) develops in a subset of fragile X premutation carriers and involves gait ataxia, action tremor, Parkinsonism, peripheral neuropathy, autonomic disorders, and cognitive impairment. The study was designed to define the nature of cognitive deficits affecting male premutation carriers with and without FXTAS. A sample of 109 men underwent motor, cognitive, genetic, and neurologic testing, as well as brain magnetic resonance imaging. Subjects were classified into 3 groups: (a) asymptomatic premutation carriers, (b) premutation carriers with FXTAS, and (c) normal controls. Men with FXTAS performed worse than controls on mental status, intelligence, executive cognitive functioning (ECF), working memory, remote recall of information, declarative learning and memory, information processing speed, and temporal sequencing, as well as 1 measure of visuospatial functioning. Language and verbal comprehension were spared. Asymptomatic carriers performed worse than controls on ECF and declarative learning and memory. This comprehensive examination of cognitive impairment in male premutation carriers suggests that FXTAS involves substantial executive impairment and diffuse deficits in other cognitive functions. Longitudinal research currently underway will provide insight into the progression of the disorder.

Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1.

Recent advances in our understanding of the clinical and molecular features of the fragile-X mental-retardation 1 gene, FMR1, highlight the importance of single-gene disorders. 15 years after its discovery, FMR1 continues to reveal new and unexpected clinical presentations and molecular mechanisms. Loss of function of FMR1 is a model for neurodevelopmental and behavioural disorders, including mental retardation, autism, anxiety, and mood instability. In addition, overexpression and CNS toxicity of FMR1 mRNA causes a late-onset neurodegenerative disorder, the fragile-X-associated tremor/ataxia syndrome (FXTAS). A similar mechanism is probably involved in premature ovarian failure, which affects up to 20% of female carriers of an altered FMR1 gene.