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).
Highlights
There is a wide range of hereditary and non-hereditary cerebellar ataxias (CA) with variable clinical symptoms, usually characterized by gait and limb ataxia, dysarthria, and oculomotor disorders, such as gaze-evoked nystagmus or saccadic smooth pursuit [1]
downbeat nystagmus (DBN) is often associated with other cerebellar ocular signs such as saccadic smooth pursuit or gaze-holding deficits
It is most often caused by a bilateral hypofunction of the flocculus or paraflocculus [7, 8] which – due to an impaired function of the Purkinje cells (PCs) – causes a disinhibition of superior vestibular nuclei neurons, leading to a slow upward drift of the eyes and a quick downward saccade [9]
Summary
There is a wide range of hereditary and non-hereditary cerebellar ataxias (CA) with variable clinical symptoms, usually characterized by gait and limb ataxia, dysarthria, and oculomotor disorders, such as gaze-evoked nystagmus or saccadic smooth pursuit [1]. DBN is often associated with other cerebellar ocular signs such as saccadic smooth pursuit or gaze-holding deficits The most common symptoms of DBN are unsteadiness of gait (89% idiopathic DBN vs 81% secondary DBN) and oscillopsia (44% vs 38%) [4]. It is most often caused by a bilateral hypofunction of the flocculus or paraflocculus [7, 8] which – due to an impaired function of the Purkinje cells (PCs) – causes a disinhibition of superior vestibular nuclei neurons, leading to a slow upward drift of the eyes and a quick downward saccade [9]. Several theories concerning the pathophysiology of DBN have been proposed: (A) an asymmetry of peripheral vestibular input [10], (B) a central imbalance in the vertical vestibulo-ocular system [9, Cerebellum (2020) 19:348–357
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