A Variation in FGF14 Is Associated with Downbeat Nystagmus in a Genome-Wide Association Study

Abstract

Downbeat nystagmus (DBN) is a frequent form of acquired persisting central fixation nystagmus, often associated with other cerebellar ocular signs, such as saccadic smooth pursuit or gaze-holding deficits. Despite its distinct clinical features, the underlying etiology of DBN often remains unclear. Therefore, a genome-wide association study (GWAS) was conducted in 106 patients and 2609 healthy controls of European ancestry to identify genetic variants associated with DBN. A genome-wide significant association (p < 5 × 10 −8 ) with DBN was found for a variation on chromosome 13 located within the fibroblast growth factor 14 gene (FGF14). FGF14 is expressed in Purkinje cells (PCs) and a reduction leads to a decreased spontaneous firing rate and excitability of PCs, compatible with the pathophysiology of DBN. In addition, mutations in the FGF14 gene cause spinocerebellar ataxia type 27. Suggestive associations (p < 1 × 10 −05 ) could be detected for 15 additional LD-independent loci, one of which is also located in the FGF14 gene. An association of a region containing the dihydrofolate reductase (DHFR) and MutS Homolog 3 (MSH3) genes on chromosome 5 was slightly below the genome-wide significance threshold. DHFR is relevant for neuronal regulation, and a dysfunction is known to induce cerebellar damage. Among the remaining twelve suggestive associations, four genes (MAST4, TPPP, FTMT, and IDS) seem to be involved in cerebral pathological processes. Thus, this GWAS analysis has identified a potential genetic contribution to idiopathic DBN, including suggestive associations to several genes involved in postulated pathological mechanisms of DBN (i.e., impaired function of cerebellar PCs).

Update on Nystagmus and Other Ocular Oscillations

“…Genetic testing for infantile nystagmus 27 and DBN 28 29 may improve diagnoses. Implementing home-based vestibular event monitoring by patient-initiated capture of ictal nystagmus could help in detecting nystagmus during vertiginous attacks and in the differential diagnosis of three of the most commonly encountered causes of episodic vertigo: vestibular migraine (VM), Meniere's disease, and benign paroxysmal positional vertigo (BPPV).…”

“…FGF14 is expressed in Purkinje cells (PCs), and its reduction leads to decreases in the spontaneous firing rate and excitability of PCs, which are compatible with the pathophysiology of DBN. 29 In addition, mutations in the FGF14 gene cause episodic ataxia type 9 37 and spinocerebellar ataxia type 27 (SCA27). 28 FGF14-associated phenotypes also highlight the overlap between progressive and episodic ataxias, similar to those observed in mutations involving CACNA1A.…”

Genome-Wide Association Study Points New Direction for Downbeat Nystagmus Research

“…Despite numerous therapies, the success remains often unpredictable and incomplete. A recent study published in this volume of the Cerebellum has shed light towards better understanding of the "idiopathic" DBN [3]. A genome-wide association study of 106 patients of European ancestry identified genetic variants.…”

“…A genome-wide association study of 106 patients of European ancestry identified genetic variants. One of the most common variants was on chromosome 13 located within the fibroblast growth factor 14 (FGF14) gene, a gene heavily expressed in the cerebellar Purkinje neurons, the sole output of the cerebellar cortex circuitry [3]. Reduction of the FGF14 is known to cause decreased spontaneous firing and excitability of the Purkinje neurons via its role in modulating voltagegated ion channels [4][5][6][7][8].…”

“…Although FGF14 on chromosome 13 remained genomewide significant, there were additional suggestive associations for 15 linkage disequilibrium independent regions. The promising ones were localized to chromosome 5q14.1 where the two overlapping genes DHFR and MSH3 are found [3]. DHFR, an important enzyme in folate metabolism, influences basic cellular processes leading to regulation of genes and production of amino acids, nucleic acids, and neurotransmitters as well as preventing neurotoxicity and degeneration [16,17].…”