Familial episodic ataxia in lambs is potentially associated with a mutation in the fibroblast growth factor 14 (FGF14) gene

Dittmer, Keren E.; Jolly, R. D.; Mayhew, I. G.; Ridler, Anne; Chernyavtseva, Anastasia; Garrick, Dorian J.; Ht, Blair

doi:10.1371/journal.pone.0190030

Cited by 6 publications

(1 citation statement)

References 35 publications

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“…Similar to patients with SCA27, structural anomalies in the cerebellum or basal ganglia are not found in the fgf14 −/− mouse model despite the presence of motor and memory deficits [ 20 , 21 ]. In addition, lambs affected by episodic ataxia harbouring the mutation c.46C> T in FGF14 lack also gross histopathological abnormalities [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Broader phenotypic traits and widespread brain hypometabolism in spinocerebellar ataxia 27

et al. 2020

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Paucar M, Lundin J, Alshammari T, Bergendal Å, Lindefeldt M, Alshammari M, Solders G, Di Re J, Savitcheva I, Granberg T, Laezza F, Iwarsson E, Svenningsson P (Karolinska Institutet; Karolinska University Hospital; Astrid Lindgren’s Hospital, Stockholm, Sweden; The University of Texas Medical Branch, Galveston, TX, USA; King Saud University, Riyadh, Saudi Arabia). Broader phenotypic traits and widespread brain hypometabolism in spinocerebellar ataxia 27. Objective. The goal of this study was to characterize a Swedish family with members affected by spinocerebellar ataxia 27 (SCA27), a rare autosomal dominant disease caused by mutations in fibroblast growth factor 14 ( FGF14 ). Despite normal structural neuroimaging, psychiatric manifestations and intellectual disability are part of the SCA27 phenotype raising the need for functional neuroimaging. Here, we used clinical assessments, structural and functional neuroimaging to characterize these new SCA27 patients. Since one patient presents with a psychotic disorder, an exploratory study of markers of schizophrenia associated with GABAergic neurotransmission was performed in fgf14 −/− mice, a preclinical model that replicates motor and learning deficits of SCA27. Methods. A comprehensive characterization that included clinical assessments, cognitive tests, structural neuroimaging studies, brain metabolism with 18 F-fluorodeoxyglucose PET ([18F] FDG PET) and genetic analyses was performed. Brains of fgf14 −/− mice were studied with immunohistochemistry. Results. Nine patients had ataxia, and all affected patients harboured an interstitial deletion of chromosome 13q33.1 encompassing the entire FGF14 and integrin subunit beta like 1 ( ITGBL1 ) genes. New features for SCA27 were identified: congenital onset, psychosis, attention deficit hyperactivity disorder and widespread hypometabolism that affected the medial prefrontal cortex (mPFC) in all patients. Hypometabolism in the PFC was far more pronounced in a SCA27 patient with psychosis. Reduced expression of VGAT was found in the mPFC of fgf14 −/− mice. Conclusions. This is the second largest SCA27 family identified to date. We provide new clinical and preclinical evidence for a significant psychiatric component in SCA27, strengthening the hypothesis of FGF14 as an important modulator of psychiatric disease.

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Section: Discussionmentioning

confidence: 99%

Broader phenotypic traits and widespread brain hypometabolism in spinocerebellar ataxia 27

et al. 2020

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Seizures and epilepsy

2022

Large Animal Neurology

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The First Case of Autosomal Recessive Cerebellar Ataxia with Prominent Paroxysmal Non‐kinesigenic Dyskinesia Caused by a Truncating FGF14 Variant in a Turkish Patient

Türkdoğan,

Smolina,

Tekgül

et al. 2024

Movement Disorders

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BackgroundATX‐FGF/SCA27A has been exclusively associated with heterozygous variants in the FGF14 gene, presenting with postural tremor, slowly progressive cerebellar ataxia, and psychiatric and behavioral disturbances.ObjectivesThis study describes the first case of ATX‐FGF/SCA27A linked to a biallelic frameshift variant in the FGF14 gene.MethodsWhole‐exome sequencing (WES) was conducted using the Illumina NovaSeq 6000 platform, and the identified variant was confirmed using Sanger sequencing.ResultsWe report the first case of autosomal recessive FGF14‐related cerebellar ataxia caused by a c.75del variant resulting in p.Leu26Serfs*51 truncation of the FGF14 protein. This variant was found in a patient born to consanguineous parents and presented with a complex congenital nonprogressive cerebellar disorder accompanied by neurodevelopmental delay, intellectual disability, and prominent drug‐responsive paroxysmal non‐kinesigenic dyskinesia. Segregation analysis confirmed that the homozygous variant was inherited from heterozygous parents who developed mild gait ataxia and tremor in their 40s.ConclusionsBiallelic loss‐of‐function variants in FGF14 are a rare cause of inherited cerebellar ataxia and expand the current genetic spectrum of ATX‐FGF14. © 2024 International Parkinson and Movement Disorder Society.

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Familial episodic ataxia in lambs is potentially associated with a mutation in the fibroblast growth factor 14 (FGF14) gene

Cited by 6 publications

References 35 publications

Broader phenotypic traits and widespread brain hypometabolism in spinocerebellar ataxia 27

Broader phenotypic traits and widespread brain hypometabolism in spinocerebellar ataxia 27

Seizures and epilepsy

The First Case of Autosomal Recessive Cerebellar Ataxia with Prominent Paroxysmal Non‐kinesigenic Dyskinesia Caused by a Truncating FGF14 Variant in a Turkish Patient

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