FMR1 – Fragile X-associated Tremor/Ataxia Syndrome

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset, X-linked neurodegenerative disorder caused by CGG-repeat expansion in the 5′ UTR of the FMR1 gene, typically in the premutation range (55–200 repeats). Affected individuals develop action tremor, cerebellar ataxia, parkinsonism, and cognitive decline after age 50. FXTAS pathogenesis is attributed to FMR1 mRNA toxicity leading to intranuclear inclusion formation in neurons and glia.

Genetic evidence for the FMR1-FXTAS association includes multiple independent reports of unrelated premutation carriers developing FXTAS. Recurrent case reports describe at least 11 unrelated probands with FXTAS features: intranuclear inclusions in a mosaic male (PMID:23692864), an unmethylated full-mutation mosaic male with progressive FXTAS (PMID:24028275), a methadone-exposed male with rapid progression (PMID:25900641), a female with PSP-CBS variant (PMID:27230899), and improvement after gamma-knife thalamotomy (PMID:29997574), plus population studies identifying premutation carriers among MSA patients (PMID:15947063) and ataxia cohorts (PMID:29316893).

Segregation analysis in the PSP-CBS family demonstrated FXTAS in both the index case and her father, confirming vertical transmission of the premutation allele and concordant phenotype in one additional affected relative (PMID:27230899).

Variant spectrum in FXTAS is dominated by noncoding CGG repeat expansions in FMR1; coding point mutations are rare but illustrate FMR1’s functional domains. A notable missense variant, c.911T>A (p.Ile304Asn), disrupts the KH2 RNA-binding domain and has been studied in FXS but also highlights FMRP function relevant to FXTAS pathobiology.

Functional studies support an RNA-gain-of-function mechanism. In cultured cortical neurons from an FXTAS mouse model, siRNA-mediated reduction of Fmr1 mRNA rescues dendritic abnormalities and normalizes the abundance of 29 proteins implicated in synaptic function (PMID:31671347). In Drosophila, dfmr1 mutations alter mushroom body morphology and behavior, consistent with neuronal toxicity (PMID:15215302). Mouse models exhibit intranuclear inclusions and motor deficits mirroring human FXTAS.

No studies directly refute the FMR1-FXTAS link; however, FXTAS is uncommon in typical multiple system atrophy when strict diagnostic criteria are applied (PMID:15947063).

Collectively, the genetic and experimental data establish a definitive association between FMR1 premutations and FXTAS. Identification of FMR1 expansion informs diagnosis, family screening, and therapeutic strategies targeting RNA toxicity.

Key Take-home: FMR1 premutation testing is clinically essential for adults with late-onset tremor-ataxia syndromes, as RNA toxicity drives FXTAS and represents a actionable target for emerging therapies.

References

• Brain : a journal of neurology • 2005 • The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA Study Group. PMID:15947063
• Translational neurodegeneration • 2013 • Intranuclear inclusions in a fragile X mosaic male. PMID:23692864
• Clinical genetics • 2014 • FXTAS in an unmethylated mosaic male with fragile X syndrome from Chile. PMID:24028275
• American journal of medical genetics. Part A • 2015 • Methadone use in a male with the FMRI premutation and FXTAS. PMID:25900641
• Cerebellum (London, England) • 2016 • PSP-CBS with Dopamine Deficiency in a Female with a FMR1 Premutation. PMID:27230899
• Frontiers in neurology • 2018 • Making a Difference-Positive Effect of Unilateral VIM Gamma Knife Thalamotomy in the Therapy of Tremor in Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). PMID:29997574
• BMC neurology • 2018 • Frequency of SCA8, SCA10, SCA12, SCA36, FXTAS and C9orf72 repeat expansions in SCA patients negative for the most common SCA subtypes. PMID:29316893
• Molecular therapy. Nucleic acids • 2019 • Reduction of Fmr1 mRNA Levels Rescues Pathological Features in Cortical Neurons in a Model of FXTAS. PMID:31671347

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