Publications by authors named "Randi J Hagerman"

238 Publications

Sulforaphane improves mitochondrial metabolism in fibroblasts from patients with fragile X-associated tremor and ataxia syndrome.

Neurobiol Dis 2021 Jun 19;157:105427. Epub 2021 Jun 19.

Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, United States of America; Medical Investigations of Neurodevelopmental Disorders (M.I.N.D.) Institute, University of California Davis, CA 95817, USA. Electronic address:

CGG expansions between 55 and 200 in the 5'-untranslated region of the fragile-X mental retardation gene (FMR1) increase the risk of developing the late-onset debilitating neuromuscular disease Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). While the science behind this mutation, as a paradigm for RNA-mediated nucleotide triplet repeat expansion diseases, has progressed rapidly, no treatment has proven effective at delaying the onset or decreasing morbidity, especially at later stages of the disease. Here, we demonstrated the beneficial effect of the phytochemical sulforaphane (SFN), exerted through NRF2-dependent and independent manner, on pathways relevant to brain function, bioenergetics, unfolded protein response, proteosome, antioxidant defenses, and iron metabolism in fibroblasts from FXTAS-affected subjects at all disease stages. This study paves the way for future clinical studies with SFN in the treatment of FXTAS, substantiated by the established use of this agent in clinical trials of diseases with NRF2 dysregulation and in which age is the leading risk factor.
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http://dx.doi.org/10.1016/j.nbd.2021.105427DOI Listing
June 2021

Deficits in Prenatal Serine Biosynthesis Underlie the Mitochondrial Dysfunction Associated with the Autism-Linked Gene.

Int J Mol Sci 2021 May 30;22(11). Epub 2021 May 30.

Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.

Fifty-five to two hundred CGG repeats (called a premutation, or PM) in the 5'-UTR of the gene are generally unstable, often expanding to a full mutation (>200) in one generation through maternal inheritance, leading to fragile X syndrome, a condition associated with autism and other intellectual disabilities. To uncover the early mechanisms of pathogenesis, we performed metabolomics and proteomics on amniotic fluids from PM carriers, pregnant with male fetuses, who had undergone amniocentesis for fragile X prenatal diagnosis. The prenatal metabolic footprint identified mitochondrial deficits, which were further validated by using internal and external cohorts. Deficits in the anaplerosis of the Krebs cycle were noted at the level of serine biosynthesis, which was confirmed by rescuing the mitochondrial dysfunction in the carriers' umbilical cord fibroblasts using alpha-ketoglutarate precursors. Maternal administration of serine and its precursors has the potential to decrease the risk of developing energy shortages associated with mitochondrial dysfunction and linked comorbidities.
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http://dx.doi.org/10.3390/ijms22115886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198117PMC
May 2021

Corrigendum: Human Cerebral Cortex Proteome of Fragile X-Associated Tremor/Ataxia Syndrome.

Front Mol Biosci 2021 11;8:695407. Epub 2021 May 11.

Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Davis, CA, United States.

[This corrects the article DOI: 10.3389/fmolb.2020.600840.].
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http://dx.doi.org/10.3389/fmolb.2021.695407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152804PMC
May 2021

Cerebral Microbleeds in Fragile X-Associated Tremor/Ataxia Syndrome.

Mov Disord 2021 Mar 24. Epub 2021 Mar 24.

Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, Sacramento, California, USA.

Background: Fragile X-associated tremor/ataxia syndrome is a neurodegenerative disease of late onset developed by carriers of the premutation in the fragile x mental retardation 1 (FMR1) gene. Pathological features of neurodegeneration in fragile X-associated tremor/ataxia syndrome include toxic levels of FMR1 mRNA, ubiquitin-positive intranuclear inclusions, white matter disease, iron accumulation, and a proinflammatory state.

Objective: The objective of this study was to analyze the presence of cerebral microbleeds in the brains of patients with fragile X-associated tremor/ataxia syndrome and investigate plausible causes for cerebral microbleeds in fragile X-associated tremor/ataxia syndrome.

Methods: We collected cerebral and cerebellar tissue from 15 fragile X-associated tremor/ataxia syndrome cases and 15 control cases carrying FMR1 normal alleles. We performed hematoxylin and eosin, Perls and Congo red stains, ubiquitin, and amyloid β protein immunostaining. We quantified the number of cerebral microbleeds, amount of iron, presence of amyloid β within the capillaries, and number of endothelial cells containing intranuclear inclusions. We evaluated the relationships between pathological findings using correlation analysis.

Results: We found intranuclear inclusions in the endothelial cells of capillaries and an increased number of cerebral microbleeds in the brains of those with fragile X-associated tremor/ataxia syndrome, both of which are indicators of cerebrovascular dysfunction. We also found a suggestive association between the amount of capillaries that contain amyloid β in the cerebral cortex and the rate of disease progression.

Conclusion: We propose microangiopathy as a pathologic feature of fragile X-associated tremor/ataxia syndrome. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28559DOI Listing
March 2021

Surveillance and prevalence of fragile X syndrome in Indonesia.

Intractable Rare Dis Res 2021 Feb;10(1):11-16

Division of Human Genetics, Center for Biomedical Research (CEBIOR), Faculty of Medicine, Diponegoro University/Diponegoro National Hospital, Semarang, Indonesia.

Fragile X syndrome (FXS) is the most prevalent inherited cause of intellectual disability (ID) and autism spectrum disorder (ASD). Many studies have been conducted over the years, however, in Indonesia there is relatively less knowledge on the prevalence of FXS. We reviewed all studies involving FXS screening and cascade testing of the high-risk population in Indonesia for two decades, to elucidate the prevalence, as well as explore the presence of genetic clusters of FXS in Indonesia. The prevalence of FXS in the ID population of Indonesia ranged between 0.9-1.9%, while in the ASD population, the percentage was higher (6.15%). A screening and cascade testing conducted in a small village on Java Island showed a high prevalence of 45% in the ID population, suggesting a genetic cluster. The common ancestry of all affected individuals was suggestive of a founder effect in the region. Routine screening and subsequent cascade testing are essential, especially in cases of ID and ASD of unknown etiology in Indonesia.
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http://dx.doi.org/10.5582/irdr.2020.03101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882090PMC
February 2021

Human Cerebral Cortex Proteome of Fragile X-Associated Tremor/Ataxia Syndrome.

Front Mol Biosci 2020 29;7:600840. Epub 2021 Jan 29.

Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Davis, CA, United States.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder associated with premutation CGG-repeat expansions (55-200 repeats) in the 5' non-coding portion of the () gene. Core features of FXTAS include progressive tremor/ataxia, cognitive decline, variable brain volume loss, and white matter disease. The principal histopathological feature of FXTAS is the presence of central nervous system (CNS) and non-CNS intranuclear inclusions. To further elucidate the molecular underpinnings of FXTAS through the proteomic characterization of human FXTAS cortexes. Proteomic analysis of FXTAS brain cortical tissue ( = 8) identified minor differences in protein abundance compared to control brains ( = 6). Significant differences in FXTAS relative to control brain predominantly involved decreased abundance of proteins, with the greatest decreases observed for tenascin-C (TNC), cluster of differentiation 38 (CD38), and phosphoserine aminotransferase 1 (PSAT1); proteins typically increased in other neurodegenerative diseases. Proteins with the greatest increased abundance include potentially novel neurodegeneration-related proteins and small ubiquitin-like modifier 1/2 (SUMO1/2). The FMRpolyG peptide, proposed in models of FXTAS pathogenesis but only identified in trace amounts in the earlier study of FXTAS inclusions, was not identified in any of the FXTAS or control brains in the current study. The observed proteomic shifts, while generally relatively modest, do show a bias toward decreased protein abundance with FXTAS. Such shifts in protein abundance also suggest altered RNA binding as well as loss of cell-cell adhesion/structural integrity. Unlike other neurodegenerative diseases, the proteome of end-stage FXTAS does not suggest a strong inflammation-mediated degenerative response.
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http://dx.doi.org/10.3389/fmolb.2020.600840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879451PMC
January 2021

Fragile X premutation and associated health conditions: A review.

Clin Genet 2021 Jun 24;99(6):751-760. Epub 2021 Jan 24.

Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand.

Fragile X syndrome (FXS) is the most common single gene disorder, which causes autism and intellectual disability. The fragile X mental retardation 1 (FMR1) gene is silenced when cytosine-guanine-guanine (CGG) triplet repeats exceed 200, which is the full mutation that causes FXS. Carriers of FXS have a CGG repeat between 55 and 200, which is defined as a premutation and transcription of the gene is overactive with high levels of the FMR1 mRNA. Most carriers of the premutation have normal levels of fragile X mental retardation protein (FMRP) and a normal intelligence, but in the upper range of the premutation (120-200) the FMRP level may be lower than normal. The clinical problems associated with the premutation are caused by the RNA toxicity associated with increased FMR1 mRNA levels, although for some mildly lowered FMRP can cause problems associated with FXS. The RNA toxicity causes various health problems in the carriers including but not limited to fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X-associated neuropsychiatric disorders. Since some individuals with neuropsychiatric problems do not meet the severity for a diagnosis of a "disorder" then the condition can be labeled as fragile X premutation associated condition (FXPAC). Physicians must be able to recognize these health problems in the carriers and provide appropriate management.
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http://dx.doi.org/10.1111/cge.13924DOI Listing
June 2021

Overlapping Molecular Pathways Leading to Autism Spectrum Disorders, Fragile X Syndrome, and Targeted Treatments.

Neurotherapeutics 2021 01 19;18(1):265-283. Epub 2020 Nov 19.

Department of Pediatrics, University of California Davis School of Medicine, Sacramento, CA, 95817, USA.

Autism spectrum disorders (ASD) are subdivided into idiopathic (unknown) etiology and secondary, based on known etiology. There are hundreds of causes of ASD and most of them are genetic in origin or related to the interplay of genetic etiology and environmental toxicology. Approximately 30 to 50% of the etiologies can be identified when using a combination of available genetic testing. Many of these gene mutations are either core components of the Wnt signaling pathway or their modulators. The full mutation of the fragile X mental retardation 1 (FMR1) gene leads to fragile X syndrome (FXS), the most common cause of monogenic origin of ASD, accounting for ~ 2% of the cases. There is an overlap of molecular mechanisms in those with idiopathic ASD and those with FXS, an interaction between various signaling pathways is suggested during the development of the autistic brain. This review summarizes the cross talk between neurobiological pathways found in ASD and FXS. These signaling pathways are currently under evaluation to target specific treatments in search of the reversal of the molecular abnormalities found in both idiopathic ASD and FXS.
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http://dx.doi.org/10.1007/s13311-020-00968-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116395PMC
January 2021

Characterization of the Metabolic, Clinical and Neuropsychological Phenotype of Female Carriers of the Premutation in the X-Linked Gene.

Front Mol Biosci 2020 22;7:578640. Epub 2020 Oct 22.

Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States.

The X-linked premutation (PM) is characterized by a 55-200 CGG triplet expansion in the 5'-untranslated region (UTR). Carriers of the PM were originally thought to be asymptomatic; however, they may present general neuropsychiatric manifestations including learning disabilities, depression and anxiety, among others. With age, both sexes may also develop the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS). Among carriers, females are at higher risk for developing immune disorders, hypertension, seizures, endocrine disorders and chronic pain, among others. Some female carriers younger than 40 years old may develop fragile X-associated primary ovarian insufficiency (FXPOI). To date, no studies have addressed the metabolic footprint - that includes mitochondrial metabolism - of female carriers and its link to clinical/cognitive manifestations. To this end, we performed a comprehensive biochemical assessment of 42 female carriers (24-70 years old) compared to sex-matched non-carriers. By applying a multivariable correlation matrix, a generalized bioenergetics impairment was correlated with diagnoses of the PM, FXTAS and its severity, FXPOI and anxiety. Intellectual deficits were strongly correlated with both mitochondrial dysfunction and with CGG repeat length. A combined multi-omics approach identified a down-regulation of RNA and mRNA metabolism, translation, carbon and protein metabolism, unfolded protein response, and up-regulation of glycolysis and antioxidant response. The suboptimal activation of the unfolded protein response (UPR) and endoplasmic-reticulum-associated protein degradation (ERAD) response challenges and further compromises the PM genetic background to withstand other, more severe forms of stress. Mechanistically, some of the deficits were linked to an altered protein expression due to decreased protein translation, but others seemed secondary to oxidative stress originated from the accumulation of either toxic mRNA or RAN-derived protein products or as a result of a direct toxicity of accumulated metabolites from deficiencies in critical enzymes.
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http://dx.doi.org/10.3389/fmolb.2020.578640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642626PMC
October 2020

Cardiovascular Problems in the Fragile X Premutation.

Front Genet 2020 8;11:586910. Epub 2020 Oct 8.

UC Davis MIND Institute, UC Davis Health, Sacramento, CA, United States.

There is a dearth of information about cardiovascular problems in fragile X premutation carriers who have 55-200 CGG repeats in fragile X mental retardation 1 () gene. The expansion in the premutation range leads to toxic RNA gain-of-function resulting in cellular dysregulation. The mechanism of RNA toxicity underlies all of the premutation disorders including fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X-associated neuropsychiatric disorder. Cardiovascular problems particularly autonomic dysfunction, hypertension, and cardiac arrhythmias are not uncommon in premutation carriers. Some arterial problems and valvular heart diseases have also been reported. This article reviews cardiovascular problems in premutation carriers and discusses possible contributing mechanisms including RNA toxicity and mild fragile X mental retardation protein deficiency. Further research studies are needed in order to prove a direct association of the cardiovascular problems in fragile X premutation carriers because such knowledge will lead to better preventative treatment.
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http://dx.doi.org/10.3389/fgene.2020.586910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578382PMC
October 2020

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

J Neuroophthalmol 2020 Oct 23. Epub 2020 Oct 23.

Department of Neurological Sciences (DAH), Rush University, Chicago, Illinois; Department of Neurology (MAL, VSP), University of Colorado School of Medicine, Aurora, Colorado; and MIND Institute (RJH), University of California Davis, Sacramento, California.

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.
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http://dx.doi.org/10.1097/WNO.0000000000001082DOI Listing
October 2020

Cortical gyrification and its relationships with molecular measures and cognition in children with the FMR1 premutation.

Sci Rep 2020 09 29;10(1):16059. Epub 2020 Sep 29.

Center for Mind and Brain, University of California-Davis, 267 Cousteau Place, Davis, CA, 95618, USA.

Neurobiological basis for cognitive development and psychiatric conditions remains unexplored in children with the FMR1 premutation (PM). Knock-in mouse models of PM revealed defects in embryonic cortical development that may affect cortical folding. Cortical-folding complexity quantified using local gyrification index (LGI) was examined in 61 children (age 8-12 years, 19/14 male/female PM carriers, 15/13 male/female controls). Whole-brain vertex-wise analysis of LGI was performed for group comparisons and correlations with IQ. Individuals with aberrant gyrification in 68 cortical areas were identified using Z-scores of LGI (hyper: Z ≥ 2.58, hypo: Z ≤ - 2.58). Significant group-by-sex-by-age interaction in LGI was detected in right inferior temporal and fusiform cortices, which correlated negatively with CGG repeat length in the PM carriers. Sixteen PM boys (hyper/hypo: 7/9) and 10 PM girls (hyper/hypo: 2/5, 3 both) displayed aberrant LGI in 1-17 regions/person while 2 control boys (hyper/hypo: 0/2) and 2 control girls (hyper/hypo: 1/1) met the same criteria in only 1 region/person. LGI in the precuneus and cingulate cortices correlated positively with IQ scores in PM and control boys while negatively in PM girls and no significant correlation in control girls. These findings reveal aberrant gyrification, which may underlie cognitive performance in children with the PM.
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http://dx.doi.org/10.1038/s41598-020-73040-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525519PMC
September 2020

Double Genetic Hit: Fragile X Syndrome and Partial Deletion of Protein Patched Homolog 1 Antisense as Cause of Severe Autism Spectrum Disorder.

J Dev Behav Pediatr 2020 12;41(9):724-728

Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California, Davis Medical Center, Sacramento, CA.

Background: Fragile X syndrome (FXS) is an X-linked genetic disorder caused by the absence of the fragile X mental retardation 1 protein. FXS is the most common inherited cause of intellectual disability and autism spectrum disorder (ASD). Approximately 60% of subjects with FXS present with ASD, and 2% to 4% of individuals diagnosed with ASD have FXS. Most individuals with ASD have a genetic disorder, so detailed molecular testing of individuals with ASD is medically indicated. Deletions of the protein patched homolog 1 antisense (PTCHD1-AS) gene have been associated with ASD. Here, we describe, for the first time, a boy with FXS because of a point mutation in the FMR1 gene and autism, and the latter comorbidity of ASD is likely because of a deletion of PTCHD1-AS. Thus, the observed phenotype of FXS with severe autism symptoms is likely caused by a double hit of genetic mutations.

Case Presentation: The case is a 5-year-old boy with phenotypic characteristics of FXS. The psychological assessment based on parent report and the Autism Diagnostic Observation Schedule, Second Edition identified severe difficulties on every item of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnostic criteria for ASD, with language impairment, anxiety, attention, and affective problems. Exome sequencing identified a de novo pathogenic variant in the FMR1 gene c.229delT (p.Cys77Alafs*5) and, coupled with comparative genomic hybridization, also diagnosed a maternally inherited partial deletion of the PTCHD1-AS gene.

Conclusion: Fragile X syndrome presents with clinical features in virtually all affected men, predominantly intellectual disability. However, there are other comorbidities present in a subset of patients, including ASD. We propose that the variable expressivity in FXS could be partially explained by the additive effect of a second genetic mutation that increases the individual susceptibility to the unique phenotypic findings, as is the case of the patient described here.
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http://dx.doi.org/10.1097/DBP.0000000000000850DOI Listing
December 2020

Cerebellar-cortical function and connectivity during sensorimotor behavior in aging FMR1 gene premutation carriers.

Neuroimage Clin 2020 2;27:102332. Epub 2020 Jul 2.

Life Span Institute and Kansas Center for Autism Research and Training (K-CART), Clinical Child Psychology Program, University of Kansas, 1000 Sunnyside Avenue, Lawrence, KS 66045, USA. Electronic address:

Introduction: Premutation carriers of the FMR1 gene are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disease characterized by motor, cognitive, and psychiatric decline as well as cerebellar and cerebral white matter pathology. Several studies have documented preclinical sensorimotor issues in aging premutation carriers, but the extent to which sensorimotor brain systems are affected and may represent early indicators of atypical neurodegeneration has not been determined.

Materials And Methods: Eighteen healthy controls and 16 FMR1 premutation carriers (including five with possible, probable, or definite FXTAS) group-matched on age, sex, and handedness completed a visually guided precision gripping task with their right hand during fMRI. During the test, they used a modified pinch grip to press at 60% of their maximum force against a custom fiber-optic transducer. Participants viewed a horizontal white force bar that moved upward with increased force and downward with decreased force and a static target bar that was red during rest and turned green to cue the participant to begin pressing at the beginning of each trial. Participants were instructed to press so that the white force bar stayed as steady as possible at the level of the green target bar. Trials were 2-sec in duration and alternated with 2-sec rest periods. Five 24-sec blocks consisting of six trials were presented. Participants' reaction time, the accuracy of their force relative to the target force, and the variability of their force accuracy across trials were examined. BOLD signal change and task-based functional connectivity (FC) were examined during force vs. rest.

Results: Relative to healthy controls, premutation carriers showed increased trial-to-trial variability of force output, though this was specific to younger premutation carriers in our sample. Relative to healthy controls, premutation carriers also showed reduced extrastriate activation during force relative to rest. FC between ipsilateral cerebellar Crus I and extrastriate cortex was reduced in premutation carriers compared to controls. Reduced Crus I-extrastriate FC was related to increased force accuracy variability in premutation carriers. Increased reaction time was associated with more severe clinically rated neurological abnormalities.

Conclusions: Findings of reduced activation in extrastriate cortex and reduced Crus I-extrastriate FC implicate deficient visual feedback processing and reduced cerebellar modulation of corrective motor commands. Our results are consistent with documented cerebellar pathology and visual-spatial processing in FXTAS and pre-symptomatic premutation carriers, and suggest FC alterations of cerebellar-cortical networks during sensorimotor behavior may represent a "prodromal" feature associated with FXTAS degeneration.
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http://dx.doi.org/10.1016/j.nicl.2020.102332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381687PMC
June 2021

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications.

Int J Mol Sci 2020 Jun 20;21(12). Epub 2020 Jun 20.

UC Davis MIND Institute, UC Davis Health, Sacramento, CA 95817, USA.

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55-200 CGG repeats) carriers of The premutation has excessive levels of mRNA that lead to toxicity and mitochondrial dysfunction. The clinical features usually begin in the 60 s with an action or intention tremor followed by cerebellar ataxia, although 20% have only ataxia. MRI features include brain atrophy and white matter disease, especially in the middle cerebellar peduncles, periventricular areas, and splenium of the corpus callosum. Neurocognitive problems include memory and executive function deficits, although 50% of males can develop dementia. Females can be less affected by FXTAS because of a second X chromosome that does not carry the premutation. Approximately 40% of males and 16% of female carriers develop FXTAS. Since the premutation can occur in less than 1 in 200 women and 1 in 400 men, the FXTAS diagnosis should be considered in patients that present with tremor, ataxia, parkinsonian symptoms, neuropathy, and psychiatric problems. If a family history of a fragile X mutation is known, then DNA testing is essential in patients with these symptoms.
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http://dx.doi.org/10.3390/ijms21124391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352421PMC
June 2020

Fragile X associated neuropsychiatric disorders in a male without FXTAS.

Intractable Rare Dis Res 2020 May;9(2):113-118

Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis Health, Sacramento, CA, USA.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder. In most cases, it is due to an expansion of the CGG triplet to more than 200 repeats within the promoter region of the gene. In the premutation (PM) the trinucleotide is expanded to 55-200 repeats. PM carriers can present with disorders associated with the PM including fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated ovarian insufficiency (FXPOI). Recently fragile X-associated neuropsychiatric disorders (FXAND) was proposed as an umbrella term to include the neuropsychiatric disorders that are more prevalent in PM carriers compared to the general population such as anxiety, depression, chronic fatigue, alcohol abuse, and psychosis, among others. The patient in our study was evaluated by a team of clinicians from the University del Valle in Cali who traveled to Ricaurte, a Colombian town known for being a genetic geographic cluster of FXS. A detailed medical history was collected and complete physical, neurological and psychiatric evaluations were performed in addition to molecular and neuroradiological studies. We report the case of a 78-year-old man, PM carrier, without FXTAS whose main clinical presentation consists of behavioral changes and psychosis. Brain imaging revealed white matter lesions in the periventricular region and mild cerebral atrophy. Although anxiety and depression are the most common neuropsychiatric manifestations in PM carriers, it is important to perform a complete psychiatric evaluation since some patients may present with behavioral changes and psychosis.
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http://dx.doi.org/10.5582/irdr.2020.01028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263992PMC
May 2020

Ataxia as the Major Manifestation of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Case Series.

Biomedicines 2020 May 25;8(5). Epub 2020 May 25.

Department of Pediatrics, University of California Davis School of Medicine, Sacramento, CA 95817, USA.

Fragile X-associated tremor and ataxia syndrome (FXTAS) is a neurodegenerative disease developed by carriers of a premutation in the fragile X mental retardation 1 ( gene. The core clinical symptoms usually manifest in the early 60s, typically beginning with intention tremor followed by cerebellar ataxia. Ataxia can be the only symptom in approximately 20% of the patients. FXTAS has a slow progression, and patients usually experience advanced deterioration 15 to 25 years after the initial diagnosis. Common findings in brain imaging include substantial brain atrophy and white matter disease (WMD). We report three cases with an atypical clinical presentation, all presenting with gait problems as their initial manifestation and with ataxia as the dominant symptom without significant tremor, as well as a faster than usual clinical progression. Magnetic resonance imaging (MRI) was remarkable for severe brain atrophy, ventriculomegaly, thinning of the corpus callosum, and periventricular WMD. Two cases were diagnosed with definite FXTAS on the basis of clinical and radiological findings, with one individual also developing moderate dementia. Factors such as environmental exposure and general anesthesia could have contributed to their clinical deterioration. FXTAS should be considered in the differential diagnosis of patients presenting with ataxia, even in the absence of tremor, and DNA testing should be sought in those with a family history of fragile X syndrome or premutation disorders.
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http://dx.doi.org/10.3390/biomedicines8050136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277845PMC
May 2020

Rapidly Progressing Neurocognitive Disorder in a Male with FXTAS and Alzheimer's Disease.

Clin Interv Aging 2020 26;15:285-292. Epub 2020 Feb 26.

Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, Sacramento, CA, USA.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that usually begins in the early 60s and affects carriers of premutation expansion (55-200 CGG repeats) of the fragile X mental retardation 1 () gene. Additional disorders can co-occur with FXTAS including Alzheimer's disease (AD). Here we discuss a case report of a male with 67 CGG repeats in who had mild late-onset FXTAS symptoms followed by neurocognitive disorder symptoms consistent with AD. The patient has developed tremor and ataxia that are the two characteristic symptoms of FXTAS. In addition, he shows rapid cognitive decline, brain atrophy most substantial in the medial temporal lobe, and decreased metabolism in the brain regions that are the characteristic findings of AD. The purpose of this study is to describe a patient profile with both diseases and review the details of an overlap between these two diseases.
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http://dx.doi.org/10.2147/CIA.S240314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051898PMC
September 2020

Spontaneous Coronary Artery Dissection in Females With the Fragile X Premutation.

JACC Case Rep 2020 Jan 15;2(1):40-44. Epub 2020 Jan 15.

Medical Investigation of Neurodevelopmental Disorders Institute, University of California Davis Medical Center, Sacramento, California.

This paper reports 2 cases of female carriers of the FMR1 premutation for developing spontaneous coronary artery dissection (SCAD). These women had classical presentations of premutation symptoms, including anxiety, depression, and connective tissue problems, all of which can contribute to SCAD. These cases suggest a possible connection between the fragile X premutation and a predisposition to SCAD.
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http://dx.doi.org/10.1016/j.jaccas.2019.11.058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062363PMC
January 2020

Fragile X- associated Neuropsychiatric Disorders: A Case Report.

Future Neurol 2019 May 24;14(2). Epub 2019 May 24.

Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis Health, Sacramento, CA, USA.

Mutations in the Fragile X Mental Retardation 1 () gene create a spectrum of developmental disorders in children in addition to neurodegenerative problems in older populations. Two types of mutations are recognized in the gene. The full mutation (>200 CGG repeats) in the gene leads to Fragile X Syndrome which is the most common inherited cause of intellectual disability and autism, while the premutation (55 to 200 CGG repeats) identified among carriers leads to a range of problems linked to elevated levels of the mRNA leading to mRNA toxicity and occasionally mildly deficient FMRP levels. Two disorders among premutation carriers have been recognized namely: the Fragile X-associated Primary Ovarian Insufficiency (FXPOI) and Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). Recently, in order to recognize a group of associated disorders commonly found in premutation carriers and extensively reported in co-morbidities studies, a new distinctive name was proposed: Fragile X-associated Neuropsychiatric Disorders (FXAND). This paper will present a case report of a female premutation carrier who has encountered predominantly psychiatric problems, but also chronic pain and sleep disturbances consistent with FXAND.
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http://dx.doi.org/10.2217/fnl-2018-0040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034938PMC
May 2019

Fragile X syndrome: clinical presentation, pathology and treatment.

Gac Med Mex 2020 ;156(1):60-66

Universidad de California en Davis, Escuela de Medicina, Instituto de Investigación Médica de los Trastornos del Neurodesarrollo. Sacramento, California, Estados Unidos.

Fragile X syndrome is the monogenetic condition that produces more cases of autism and intellectual disability. The repetition of CGG triplets (> 200) and their methylation entail the silencing of the FMR1 gene. The FMRP protein (product of the FMR1 gene) interacts with ribosomes by controlling the translation of specific messengers, and its loss causes alterations in synaptic connectivity. Screening for fragile X syndrome is performed by polymerase chain reaction. Current recommendation of the American Academy of Pediatrics is to test individuals with intellectual disability, global developmental retardation or with a family history of presence of the mutation or premutation. Hispanic countries such as Colombia, Chile and Spain report high prevalence of fragile X syndrome and have created fragile X national associations or corporations that seek to bring patients closer to available diagnostic and treatment networks.
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http://dx.doi.org/10.24875/GMM.19005275DOI Listing
October 2020

Association between IQ and FMR1 protein (FMRP) across the spectrum of CGG repeat expansions.

PLoS One 2019 31;14(12):e0226811. Epub 2019 Dec 31.

UC Davis MIND Institute, UC Davis Health, Sacramento, California, United States of America.

Fragile X syndrome, the leading heritable form of intellectual disability, is caused by hypermethylation and transcriptional silencing of large (CGG) repeat expansions (> 200 repeats) in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. As a consequence of FMR1 gene silencing, there is little or no production of FMR1 protein (FMRP), an important element in normal synaptic function. Although the absence of FMRP has long been known to be responsible for the cognitive impairment in fragile X syndrome, the relationship between FMRP level and cognitive ability (IQ) is only imprecisely understood. To address this issue, a high-throughput, fluorescence resonance energy transfer (FRET) assay has been used to quantify FMRP levels in dermal fibroblasts, and the relationship between FMRP and IQ measures was assessed by statistical analysis in a cohort of 184 individuals with CGG-repeat lengths spanning normal (< 45 CGGs) to full mutation (> 200 CGGs) repeat ranges in fibroblasts. The principal findings of the current study are twofold: i) For those with normal CGG repeats, IQ is no longer sensitive to further increases in FMRP above an FMRP threshold of ~70% of the mean FMRP level; below this threshold, IQ decreases steeply with further decreases in FMRP; and ii) For the current cohort, a mean IQ of 85 (lower bound for the normal IQ range) is attained for FMRP levels that are only ~35% of the mean FMRP level among normal CGG-repeat controls. The current results should help guide expectations for efforts to induce FMR1 gene activity and for the levels of cognitive function expected for a given range of FMRP levels.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226811PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938341PMC
April 2020

A Randomized Controlled Trial of Sertraline in Young Children With Autism Spectrum Disorder.

Front Psychiatry 2019 6;10:810. Epub 2019 Nov 6.

Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, UC Davis Health, Sacramento, CA, United States.

Selective serotonin reuptake inhibitors like sertraline have been shown in observational studies and anecdotal reports to improve language development in young children with fragile X syndrome (FXS). A previous controlled trial of sertraline in young children with FXS found significant improvement in expressive language development as measured by the Mullen Scales of Early Learning (MSEL) among those with comorbid autism spectrum disorder (ASD) in analysis, prompting the authors to probe whether sertraline is also indicated in nonsyndromic ASD. The authors evaluated the efficacy of 6 months of treatment with low-dose sertraline in a randomized, double-blind, placebo-controlled trial in 58 children with ASD aged 24 to 72 months. 179 subjects were screened for eligibility, and 58 were randomized to sertraline (32) or placebo (26). Eight subjects from the sertraline arm and five from the placebo arm discontinued. Intent-to-treat analysis showed no significant difference from placebo on the primary outcomes (MSEL expressive language raw score and age equivalent combined score) or secondary outcomes. Sertraline was well tolerated, with no difference in side effects between sertraline and placebo groups. No serious adverse events possibly related to study treatment occurred. This randomized controlled trial of sertraline treatment showed no benefit with respect to primary or secondary outcome measures. For the 6-month period, treatment in young children with ASD appears safe, although the long-term side effects of low-dose sertraline in early childhood are unknown. www.ClinicalTrials.gov, identifier NCT02385799.
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http://dx.doi.org/10.3389/fpsyt.2019.00810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851992PMC
November 2019

Interaction between ventricular expansion and structural changes in the corpus callosum and putamen in males with FMR1 normal and premutation alleles.

Neurobiol Aging 2020 02 24;86:27-38. Epub 2019 Sep 24.

Center for Mind and Brain, University of California-Davis, Davis, CA, USA; MIND Institute, University of California-Davis Medical Center, Sacramento, CA, USA; Department of Psychology, University of California-Davis, Davis, CA, USA.

Ventricular enlargement (VE) is commonly observed in aging and fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder. VE may generate a mechanical force causing structural deformation. In this longitudinal study, we examined the relationships between VE and structural changes in the corpus callosum (CC) and putamen. MRI scans (2-7/person over 0.2-7.5 years) were acquired from 22 healthy controls, 26 unaffected premutation carriers (PFX-), and 39 carriers affected with FXTAS (PFX+). Compared with controls, PFX- demonstrated enlarged fourth ventricles, whereas PFX+ displayed enlargement in both third and fourth ventricles, CC thinning, putamen atrophy/deformation (thinning and increased distance), and accelerated expansions in lateral ventricles. Common for all groups, baseline VE predicted accelerated CC thinning and putamen atrophy/deformation and conversely, baseline CC and putamen atrophy/deformation and enlarged third and fourth ventricles predicted accelerated lateral ventricular expansion. The results suggest a progressive VE within the 4 ventricles as FXTAS develops and a deleterious cycle between VE and brain deformation that may commonly occur during aging and FXTAS progression but become accelerated in FXTAS.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995416PMC
February 2020

Metformin treatment in young children with fragile X syndrome.

Mol Genet Genomic Med 2019 11 14;7(11):e956. Epub 2019 Sep 14.

Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis Medical Center, Sacramento, California.

Background: Metformin is a drug commonly used in individuals with type 2 diabetes, obesity, and impaired glucose tolerance. It has a strong safety profile in both children and adults. Studies utilizing the Drosophila model and knock out mouse model of fragile X syndrome (FXS) have found metformin to rescue memory, social novelty deficits, and neuroanatomical abnormalities. These studies provided preliminary evidence that metformin could be used as a targeted treatment for the cognitive and behavioral problems associated with FXS. Previously, a case series of children and adults with FXS treated with metformin demonstrated improvements in irritability, social responsiveness, language, and hyperactivity.

Methods: Here, we present nine children with FXS between 2 and 7 years of age who were treated clinically with metformin and monitored for behavioral and metabolic changes.

Results: Parent reports and developmental testing before and after metformin are presented. There were improvements in language development and behavior (such as lethargy and stereotypy) in most of the patients.

Conclusion: These results support the need for a controlled trial of metformin in children with FXS under 7 years old whose brains are in a critical developmental window and thus may experience a greater degree of clinical benefit from metformin.
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http://dx.doi.org/10.1002/mgg3.956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825840PMC
November 2019

Composition of the Intranuclear Inclusions of Fragile X-associated Tremor/Ataxia Syndrome.

Acta Neuropathol Commun 2019 09 3;7(1):143. Epub 2019 Sep 3.

Department of Biochemistry and Molecular Medicine, University of California Davis, School of Medicine, One Shields Ave, Davis, CA, USA.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder associated with a premutation repeat expansion (55-200 CGG repeats) in the 5' noncoding region of the FMR1 gene. Solitary intranuclear inclusions within FXTAS neurons and astrocytes constitute a hallmark of the disorder, yet our understanding of how and why these bodies form is limited. Here, we have discovered that FXTAS inclusions emit a distinct autofluorescence spectrum, which forms the basis of a novel, unbiased method for isolating FXTAS inclusions by preparative fluorescence-activated cell sorting (FACS). Using a combination of autofluorescence-based FACS and liquid chromatography/tandem mass spectrometry (LC-MS/MS)-based proteomics, we have identified more than two hundred proteins that are enriched within the inclusions relative to FXTAS whole nuclei. Whereas no single protein species dominates inclusion composition, highly enriched levels of conjugated small ubiquitin-related modifier 2 (SUMO 2) protein and p62/sequestosome-1 (p62/SQSTM1) protein were found within the inclusions. Many additional proteins involved with RNA binding, protein turnover, and DNA damage repair were enriched within inclusions relative to total nuclear protein. The current analysis has also allowed the first direct detection, through peptide sequencing, of endogenous FMRpolyG peptide, the product of repeat-associated non-ATG (RAN) translation of the FMR1 mRNA. However, this peptide was found only at extremely low levels and not within whole FXTAS nuclear preparations, raising the question whether endogenous RAN products exist at quantities sufficient to contribute to FXTAS pathogenesis. The abundance of the inclusion-associated ubiquitin- and SUMO-based modifiers supports a model for inclusion formation as the result of increased protein loads and elevated oxidative stress leading to maladaptive autophagy. These results highlight the need to further investigate FXTAS pathogenesis in the context of endogenous systems.
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http://dx.doi.org/10.1186/s40478-019-0796-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720097PMC
September 2019

New Targeted Treatments for Fragile X Syndrome.

Curr Pediatr Rev 2019 ;15(4):251-258

Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, Sacramento, CA, United States.

Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability with prevalence rates estimated to be 1:5,000 in males and 1:8,000 in females. The increase of >200 Cytosine Guanine Guanine (CGG) repeats in the 5' untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene results in transcriptional silencing on the FMR1 gene with a subsequent reduction or absence of fragile X mental retardation protein (FMRP), an RNA binding protein involved in the maturation and elimination of synapses. In addition to intellectual disability, common features of FXS are behavioral problems, autism, language deficits and atypical physical features. There are still no currently approved curative therapies for FXS, and clinical management continues to focus on symptomatic treatment of comorbid behaviors and psychiatric problems. Here we discuss several treatments that target the neurobiological pathway abnormal in FXS. These medications are clinically available at present and the data suggest that these medications can be helpful for those with FXS.
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http://dx.doi.org/10.2174/1573396315666190625110748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930353PMC
June 2020

Cognitive and behavioral improvement in adults with fragile X syndrome treated with metformin-two cases.

Mol Genet Genomic Med 2019 07 18;7(7):e00745. Epub 2019 May 18.

Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California Davis, Sacramento, California.

Background: The majority of individuals with fragile X syndrome (FXS) have intellectual disability, behavioral problems, autism, and language deficits. IQ typically declines with age in boys with the full mutation. The results of preclinical studies demonstrated that metformin, a biguanide used to treat type 2 diabetes, rescues multiple phenotypes of FXS in both Drosophila and mouse models. Preliminary studies of patients with FXS demonstrated improvements in behavior.

Methods: Here, we present two cases of individuals who have been treated with metformin clinically for one year.

Results: Both patients demonstrated significant cognitive and behavioral improvements. They also improved eating habits and normalization of their weight percentiles.

Conclusion: Metformin may be a candidate drug for treatment of several types of symptoms in individuals with FXS.
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http://dx.doi.org/10.1002/mgg3.745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625129PMC
July 2019

De novo and biallelic DEAF1 variants cause a phenotypic spectrum.

Genet Med 2019 09 29;21(9):2059-2069. Epub 2019 Mar 29.

GW Institute for Neuroscience, Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.

Purpose: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro.

Methods: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs.

Results: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001).

Conclusion: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.
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http://dx.doi.org/10.1038/s41436-019-0473-6DOI Listing
September 2019

Effects of mavoglurant on visual attention and pupil reactivity while viewing photographs of faces in Fragile X Syndrome.

PLoS One 2019 17;14(1):e0209984. Epub 2019 Jan 17.

Department of Pediatrics, Rush University Medical Center, Chicago, IL, United States of America.

Background: Numerous preclinical studies have supported the theory that enhanced activation of mGluR5 signaling, due to the absence or reduction of the FMR1 protein, contributes to cognitive and behavioral deficits in patients with fragile X syndrome (FXS). However multiple phase 2 controlled trials in patients with FXS have failed to demonstrate efficacy of compounds that negatively modulate mGluR5, including two phase 2b randomized controlled trials (RCT) of mavoglurant (AFQ056, Novartis Pharma AG), when the primary measures of interest were behavioral ratings. This has cast some doubt onto the translation of the mGluR5 theory from animal models to humans with the disorder.

Methods: We evaluated social gaze behavior-a key phenotypic feature of the disorder-and sympathetic nervous system influence on pupil size using a previously-validated eye tracking paradigm as a biobehavioral probe, in 57 adolescent or adult patients with FXS at baseline and following three months of blinded treatment with one of three doses of mavoglurant or placebo, within the context of the AFQ056 RCTs.

Results: Patients with FXS treated with mavoglurant demonstrated increased total absolute looking time and number of fixations to the eye region while viewing human faces relative to baseline, and compared to those treated with placebo. In addition, patients had greater pupil reactivity to faces relative to baseline following mavoglurant treatment compared to placebo.

Discussion: The study shows that negative modulation of mGluR5 activity improves eye gaze behavior and alters sympathetically-driven reactivity to faces in patients with FXS, providing preliminary evidence of this drug's impact on behavior in humans with the disorder.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209984PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336311PMC
September 2019
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