Broader phenotypic traits and widespread brain hypometabolism in spinocerebellar ataxia 27

Abstract

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.

Differential Modulation of the Voltage-Gated Na+ Channel 1.6 by Peptides Derived From Fibroblast Growth Factor 14

“…Given the primacy of these structural motifs of FGF14 in enabling FGF14:Nav1.6 complex assembly, we investigated if short peptides corresponding to these motifs of FGF14 could confer functionally relevant modulation of the Nav1.6 channel macromolecular complex. Given that perturbation of the PPI between FGF14 and the CTD of Nav1.6 gives rise to neural circuitry aberrations that are linked to neurologic and neuropsychiatric disorders (Di Re et al, 2017 ; Paucar et al, 2020 ), such peptides could represent promising “small-molecular inhibitor starting points (SMISP)” to develop PPI-targeting neuromodulators ( Koes and Camacho, 2012a ; 2012b ). To pharmacologically evaluate the PLEV and EYYV tetrapeptides as potential SMISPs, we employed an amalgam of complementary and orthogonal approaches including in silico molecular modeling, the LCA, and whole-cell patch-clamp electrophysiology.…”

“…Specifically, this PPI regulates the transient and resurgent Na+ currents of neurons through a mechanism thought to depend upon the N-terminus of FGF14 ( Yan et al, 2014 ; White et al, 2019 ), as well as the action potential (AP) firing of neurons in clinically relevant brain regions, including the nucleus accumbens (NAc) ( Ali et al, 2018 ) and hippocampus ( Hsu et al, 2016 ). Translationally, perturbation of this PPI is increasingly being associated with a myriad of neurologic and neuropsychiatric disorders (Di Re et al, 2017 ; Paucar et al, 2020 ), highlighting its potential clinical relevance as a pharmacological target.…”

Clinical and Genetic Overview of Paroxysmal Movement Disorders and Episodic Ataxias

“…One year later, heterozygous mutations in FGF14 were identified as causative of an autosomal dominant form of spinocerebellar ataxia, successively classified as SCA type 27 [309]. Less than 50 cases are currently described in the literature [310][311][312]. A recent review of published cases [310] concludes that early-onset tremor (mean age of 12.1 ± 10.5 years) is the typical manifestation at the onset of disease and it is followed by gait ataxia later in life (mean age of 23.7 ± 16.7 years) accompanied by limb ataxia, dysarthria, or nystagmus.…”

“…Other features of SCA27 that may distinguish it from other SCAs are orofacial dyskinesias, psychiatric symptoms, cognitive impairment, and extrapyramidal features [310]. Congenital onset ataxia has been also reported [311]. Additionally, heterozygous variants in FGF14 have been discovered in a total of 12 patients from 6 families with EA [151,[313][314][315][316][317] and the phenotype of FGF14-related EA has been recently delineated: wide range of age at onset (from childhood to adulthood), fever as main triggering factor, variable duration (minutes to several days, thus potentially mimicking febrile cerebellitis) and frequency of attacks, and a variable association with additional findings at neurological examination such as nystagmus, postural upper limb tremor, and learning disabilities.…”

Pharmacologically Targeting the Fibroblast Growth Factor 14 Interaction Site on the Voltage-Gated Na+ Channel 1.6 Enables Isoform-Selective Modulation

“…In the brain, the Na v channel auxiliary protein fibroblast growth factor 14 (FGF14) interacts with the CTDs of the Na v 1.1, Na v 1.2, and Na v 1.6 channels, and its two splice variants, FGF14-1a and FGF14-1b, differentially regulate the gating and trafficking of the three CNS Nav channel isoforms [12,15,18,24]. Given these functionally unique protein-protein interactions (PPIs) between FGF14 splice variants and CNS Na v channel isoforms, in tandem with FGF14 being an important regulator of neuronal activity and behavior [25][26][27][28][29][30][31][32][33][34], the interaction sites of FGF14 on the CTDs of these Na v channel isoforms could potentially be pharmacologically targeted to develop novel neuromodulators.…”