A novel intronic GAA repeat expansion in<i>FGF14</i>causes autosomal dominant adult-onset ataxia (SCA50, ATX-FGF14)

Rafehi, Haloom; Read, Justin; Szmulewicz, David J.; Davies, Kayli C.; Snell, Penny; Fearnley, Liam G.; Scott, Liam; Thomsen, Mirja; Gillies, Greta; Pope, Kate; Bennett, Mark F; Munro, Jacob E.; Ngo, Kathie J.; Chen, Liming; Wallis, Mathew; Butler, Ernest; Kumar, Kishore R.; Wu, Kathy H C; Tomlinson, Susan; Tisch, Stephen; Malhotra, Abhishek; Lee‐Archer, Matthew; Dolzhenko, Egor; Eberle, Michael A.; Roberts, Leslie; Fogel, Brent L.; Brüggemann, Norbert; Lohmann, Katja; Delatycki, Martin B.; Bahlo, Melanie; Lockhart, Paul J.

doi:10.1101/2022.10.21.22281020

Cited by 5 publications

(3 citation statements)

References 62 publications

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“…9 The most frequent group is SCA, with over fifty distinct types clinically described (SCA1-50). 10,11 Other autosomal dominant cerebellar ataxias comprise episodic ataxias, spastic ataxias, and a complex form (dentatorubralpallidoluysian atrophy, DRPLA). The frequency of individual subtypes of autosomal dominant cerebellar ataxias varies according to geographic region.…”

Section: Discussionmentioning

confidence: 99%

Ataxias in Brazil: 17 years of experience in an ataxia center

Massuyama,

Gama,

Silva

et al. 2024

Arq Neuropsiquiatr

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Background Cerebellar ataxias comprise sporadic and genetic etiologies. Ataxia may also be a presenting feature in hereditary spastic paraplegias (HSPs). Objective To report a descriptive analysis of the frequency of different forms of cerebellar ataxia evaluated over 17 years in the Ataxia Unit of Universidade Federal de São Paulo, Brazil. Methods Charts of patients who were being followed from January 2007 to December 2023 were reviewed. We used descriptive statistics to present our results as frequencies and percentages of the overall analysis. Diagnosed patients were classified according to the following 9 groups: sporadic ataxia, spinocerebellar ataxias (SCAs), other autosomal dominant cerebellar ataxias, autosomal recessive cerebellar ataxias (ARCAs), mitochondrial ataxias, congenital ataxias, X-linked ataxias, HSPs, and others. Results There were 1,332 patients with ataxias or spastic paraplegias. Overall, 744 (55.85%) of all cases were successfully diagnosed: 101 sporadic ataxia, 326 SCAs, 20 of other autosomal dominant cerebellar ataxias, 186 ARCAs, 6 X-linked ataxias, 2 mitochondrial ataxias, 4 congenital ataxias, and 51 HSPs. Conclusion This study describes the frequency of cerebellar ataxias in a large group of patients followed for the past 17 years, of whom 55% obtained a definitive clinical or molecular diagnosis. Future demographic surveys in Brazil or Latin American remain necessary.

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Section: Discussionmentioning

confidence: 99%

Ataxias in Brazil: 17 years of experience in an ataxia center

Massuyama,

Gama,

Silva

et al. 2024

Arq Neuropsiquiatr

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“…161 Recently, the intronic GAA repeat expansion in FGF14, a different type of mutation, was also identified as the cause of cerebellar ataxia revealed from an Australian cohort, named SCA50. 162 Interestingly, the intronic FGF14 GAA repeat expansion was found in patients who were previously diagnosed with ILOCA, including 61% in French Canadian, 18% in German, 15% in Australian, and 10% in Indian cohorts from a multicentered study. 163 These findings overall highlight that novel genetic mutations can account for a significant portion of sporadic late-onset ataxia cases.…”

Section: Degenerative Causes Of Ataxiamentioning

confidence: 94%

Ataxias: Hereditary, Acquired, and Reversible Etiologies

Lin

Kuo

2023

Semin Neurol

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A variety of etiologies can cause cerebellar dysfunction, leading to ataxia symptoms. Therefore, the accurate diagnosis of the cause for cerebellar ataxia can be challenging. A step-wise investigation will reveal underlying causes, including nutritional, toxin, immune-mediated, genetic, and degenerative disorders. Recent advances in genetics have identified new genes for both autosomal dominant and autosomal recessive ataxias, and new therapies are on the horizon for targeting specific biological pathways. New diagnostic criteria for degenerative ataxias have been proposed, specifically for multiple system atrophy, which will have a broad impact on the future clinical research in ataxia. In this article, we aim to provide a review focus on symptoms, laboratory testing, neuroimaging, and genetic testing for the diagnosis of cerebellar ataxia causes, with a special emphasis on recent advances. Strategies for the management of cerebellar ataxia is also discussed.

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“…More recently, GAA repeat expansions in FGF14 were identified in patients with late onset ataxias, now referred to as SCA27B (Pellerin et al, 2023;Rafehi et al, 2023aRafehi et al, ,2023bMohrens et al, 2024).…”

Section: Introductionmentioning

confidence: 99%

Loss of Intracellular Fibroblast Growth Factor 14 (iFGF14)Increasesthe Excitability of Mature Hippocampal and Cortical Pyramidal Neurons

Ransdell,

Carrasquillo,

Bosch

et al. 2024

Preprint

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Mutations in FGF14, which encodes intracellular fibroblast growth factor 14 (iFGF14), have been linked to spinocerebellar ataxia type 27 (SCA27), a multisystem disorder associated with progressive deficits in motor coordination and cognitive function. Mice (Fgf14-/-) lacking iFGF14 display similar phenotypes, and we have previously shown that the deficits in motor coordination reflect reduced excitability of cerebellar Purkinje neurons, owing to the loss of iFGF14-mediated regulation of the voltage-dependence of inactivation of the fast transient component of the voltage-gated Na+ (Nav) current, INaT. Here, we present the results of experiments designed to test the hypothesis that loss of iFGF14 also attenuates the intrinsic excitability of mature hippocampal and cortical pyramidal neurons. Current-clamp recordings from adult mouse hippocampal CA1 pyramidal neurons in acute in vitro slices, however, revealed that repetitive firing rates were higher in Fgf14-/-, than in wild type (WT), cells. In addition, the waveforms of individual action potentials were altered in Fgf14-/- hippocampal CA1 pyramidal neurons, and the loss of iFGF14 reduced the time delay between the initiation of axonal and somal action potentials. Voltage-clamp recordings revealed that the loss of iFGF14 altered the voltage-dependence of activation, but not inactivation, of INaT in CA1 pyramidal neurons. Similar effects of the loss of iFGF14 on firing properties were evident in current-clamp recordings from layer 5 visual cortical pyramidal neurons. Additional experiments demonstrated that the loss of iFGF14 does not alter the distribution of anti-Nav1.6 or anti-ankyrin G immunofluorescence labeling intensity along the axon initial segments (AIS) of mature hippocampal CA1 or layer 5 visual cortical pyramidal neurons in situ. Taken together, the results demonstrate that, in contrast with results reported for neonatal (rat) hippocampal pyramidal neurons in dissociated cell culture, the loss of iFGF14 does not disrupt AIS architecture or Nav1.6 localization/distribution along the AIS of mature hippocampal (or cortical) pyramidal neurons in situ.

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A novel intronic GAA repeat expansion inFGF14causes autosomal dominant adult-onset ataxia (SCA50, ATX-FGF14)

Cited by 5 publications

References 62 publications

Ataxias in Brazil: 17 years of experience in an ataxia center

Ataxias in Brazil: 17 years of experience in an ataxia center

Ataxias: Hereditary, Acquired, and Reversible Etiologies

Loss of Intracellular Fibroblast Growth Factor 14 (iFGF14)Increasesthe Excitability of Mature Hippocampal and Cortical Pyramidal Neurons

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