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Background Premutation-sized (55-200) CGG repeat expansions in the FMR1 gene cause fragile X-associated tremor/ataxia syndrome (FXTAS). Most studies of premutation carriers utilized reverse ascertainment to identify patients, leading to a selection bias for larger repeats. As shorter CGG premutation repeats are common in the population, understanding their impact on health outcomes has a potentially large public health footprint. Objective The study's objective was to compare an unselected group of premutation carriers (n = 35, 55-101 CGG repeats) with matched controls (n = 61, 29-39 CGG repeats) with respect to FXTAS-type signs using structured neurological assessments. Methods Three neurologists independently rated signs, using an adapted version of the FXTAS Rating Scale (Leehey MA, Berry-Kravis E, Goetz CG, et al. FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. Neurology. 2008). This was a double-blind study, as genetic status (premutation vs. control) was known neither by the participants nor by any of the neurologists. Analyses controlled potentially confounding comorbid conditions in the electronic health record (eg, osteoarthritis and stroke) and probed the association of age with signs. Results Although there was no overall difference between carriers and controls, among individuals without any potentially confounding comorbid diagnoses, there was a statistically significant age-associated elevation in FXTAS-type signs in premutation carriers compared to controls. Conclusions Among those who do not have other comorbid diagnoses, women who have CGG repeats at the lower end of the premutation range may be at greater risk for ataxia and parkinsonism than their age peers, although their overall risk of developing such clinical features is low. This study should provide reassurance to those who share characteristics with the present cohort. © 2021 International Parkinson and Movement Disorder Society.

Transcribed CGG repeat expansions cause neurodegeneration in Fragile X‐associated tremor/ataxia syndrome (FXTAS). CGG repeat RNAs sequester RNA‐binding proteins (RBPs) into nuclear foci and undergo repeat‐associated non‐AUG (RAN) translation into toxic peptides. To identify proteins involved in these processes, we employed a CGG repeat RNA‐tagging system to capture repeat‐associated RBPs by mass spectrometry in mammalian cells. We identified several SR (serine/arginine‐rich) proteins that interact selectively with CGG repeats basally and under cellular stress. These proteins modify toxicity in a Drosophila model of FXTAS. Pharmacologic inhibition of serine/arginine protein kinases (SRPKs), which alter SRSF protein phosphorylation, localization, and activity, directly inhibits RAN translation of CGG and GGGGCC repeats (associated with C9orf72 ALS/FTD) and triggers repeat RNA retention in the nucleus. Lowering SRPK expression suppressed toxicity in both FXTAS and C9orf72 ALS/FTD model flies, and SRPK inhibitors suppressed CGG repeat toxicity in rodent neurons. Together, these findings demonstrate roles for CGG repeat RNA binding proteins in RAN translation and repeat toxicity and support further evaluation of SRPK inhibitors in modulating RAN translation associated with repeat expansion disorders., Fragile X‐associated tremor/ataxia syndrome (FXTAS) is an adult‐onset neurodegenerative disease caused by a CGG trinucleotide repeat expansion in FMR1. This study identified CGG repeat RNA binding proteins and their kinases that regulate repeat associated non‐AUG (RAN) translation and neurotoxicity.

Objective: Repeat associated non-AUG (RAN) translation drives production of toxic proteins from pathogenic repeat sequences in multiple untreatable neurodegenerative disorders. Fragile X-associated tremor/ataxia syndrome (FXTAS) is one such condition, resulting from a CGG trinucleotide repeat expansion in the 5' leader sequence of the FMR1 gene. RAN proteins from the CGG repeat accumulate in ubiquitinated inclusions in FXTAS patient brains and elicit toxicity. In addition to the CGG repeat, an antisense mRNA containing a CCG repeat is also transcribed from the FMR1 locus. We evaluated whether this antisense CCG repeat supports RAN translation and contributes to pathology in FXTAS patients. Methods: We generated a series of CCG RAN translation specific reporters and utilized them to measure RAN translation from CCG repeats in multiple reading frames in transfected cells. We also developed antibodies against predicted CCG RAN proteins and used immunohistochemistry and immunofluorescence on FXTAS patient tissues to measure their accumulation and distribution. Results: RAN translation from CCG repeats is supported in all three potential reading frames, generating polyproline, polyarginine, and polyalanine proteins, respectively. Their production occurs whether or not the natural AUG start upstream of the repeat in the proline reading frame is present. All three frames show greater translation at larger repeat sizes. Antibodies targeted to the antisense FMR polyproline and polyalanine proteins selectively stain nuclear and cytoplasmic aggregates in FXTAS patients and colocalize with ubiquitinated neuronal inclusions. Interpretation: RAN translation from antisense CCG repeats generates novel proteins that accumulate in ubiquitinated inclusions in FXTAS patients. This article is protected by copyright. All rights reserved.

Fragile X syndrome is the most common cause of mental retardation known to be inherited. The syndrome results from the suppressed expression of a single protein, the fragile X mental retardation protein (FMRP). Understanding the function and regulation of FMRP can, therefore, offer insights into both the pathophysiology of fragile X syndrome and the molecular mechanisms of learning and memory. We provide an overview of current concepts of how FMRP functions in the nervous system, with special emphasis on recent evidence that FMRP has a role in metabotropic glutamate receptor-activated protein translation and synaptic plasticity.

Cerebellar ataxia is a frequent finding among patients seen in neurological practice and may result in a wide variety of aetiologies, both acquired and genetic. Inherited ataxia is a large and important subgroup of the ataxic disorders, and includes metabolic ataxias, autosomal recessive degenerative ataxias, autosomal dominant spinocerebellar ataxias (SCAs), X-linked and maternally inherited ataxias. Hereditary ataxia is reviewed in this article and acquired ataxias are covered in the accompanying article. Hereditary conditions account for the majority of ataxic syndromes in children and one-third to one-half of patients with adult-onset ataxic syndromes. Classification by mode of inheritance is a useful way of organizing the hereditary ataxias for both clinical and research purposes, and this approach will be used in this article. Key Concepts Understand that there are a wide variety of different inherited causes of ataxia. Some patients without a family history of ataxia still have the disorder on the basis of a genetic mutation. Nucleotide expansion disorders are a common cause of dominantly inherited cerebellar ataxia. The majority of these diseases result from a toxic gain-of-function mechanism and they demonstrate genetic anticipation, wherein intergenerational expansion leads to disease with earlier onset and often more severe symptom. Friedreich ataxia is the most common inherited cause of ataxia. It results from decreased expression of the Frataxin protein due to a nucleotide repeat expansion in a noncoding region. A variety of mitochondrial disorders are associated with ataxia as one of the number of neurologic and systemic symptoms. These diseases result from mutations in either nuclear DNA in genes involved in mitochondrial function or in mitochondrial DNA itself. Wilson disease is a disorder of copper metabolism that can present with dystonia, ataxia or neuropsychiatric symptoms and is also associated with liver failure. Early treatment can be curative. Defects in DNA repair underlie many childhood onset forms of inherited ataxia. Keywords: spinocerebellar ataxia; neurodegeneration; mitochondrial disorders; DNA repair; polyglutamine disorders

Most neurodegenerative disorders are thought to result primarily from the accumulation of misfolded proteins, which interfere with protein homeostasis in neurons. For a subset of diseases, however, noncoding regions of RNAs assume a primary toxic gain-of-function, leading to degeneration in many tissues, including the nervous system. Here we review a series of proposed mechanisms by which noncoding repeat expansions give rise to nervous system degeneration and dysfunction. These mechanisms include transcriptional alterations and the generation of antisense transcripts, sequestration of mRNA-associated protein complexes that lead to aberrant mRNA splicing and processing, and alterations in cellular processes, including activation of abnormal signaling cascades and failure of protein quality control pathways. We place these potential mechanisms in the context of known RNA-mediated disorders, including the myotonic dystrophies and fragile X tremor ataxia syndrome, and discuss recent results suggesting that mRNA toxicity may also play a role in some presumably protein-mediated neurodegenerative disorders. Lastly, we comment on recent progress in therapeutic development for these RNA-dominant diseases.