Molecular Characterization of Portuguese Patients with Hereditary Cerebellar Ataxia

Abstract

Hereditary cerebellar ataxia (HCA) comprises a clinical and genetic heterogeneous group of neurodegenerative disorders characterized by incoordination of movement, speech, and unsteady gait. In this study, we performed whole-exome sequencing (WES) in 19 families with HCA and presumed autosomal recessive (AR) inheritance, to identify the causal genes. A phenotypic classification was performed, considering the main clinical syndromes: spastic ataxia, ataxia and neuropathy, ataxia and oculomotor apraxia (AOA), ataxia and dystonia, and ataxia with cognitive impairment. The most frequent causal genes were associated with spastic ataxia (SACS and KIF1C) and with ataxia and neuropathy or AOA (PNKP). We also identified three families with autosomal dominant (AD) forms arising from de novo variants in KIF1A, CACNA1A, or ATP1A3, reinforcing the importance of differential diagnosis (AR vs. AD forms) in families with only one affected member. Moreover, 10 novel causal-variants were identified, and the detrimental effect of two splice-site variants confirmed through functional assays. Finally, by reviewing the molecular mechanisms, we speculated that regulation of cytoskeleton function might be impaired in spastic ataxia, whereas DNA repair is clearly associated with AOA. In conclusion, our study provided a genetic diagnosis for HCA families and proposed common molecular pathways underlying cerebellar neurodegeneration.

Genotype–phenotype relations for episodic ataxia genes: MDSGene systematic review

“…On review of the latest literature in the EA, published since the closing date of our initial systematic literature review (April 2021–June 2022), we identified a total of nine related articles (Table S4). These reported on 10 patients with novel variants in the CACNA1A [19–29]. In a case report of CACNA1A ‐related EA, dalfampridine 0.3 mg/kg was shown to resolve falls that had been unresponsive to acetazolamide (treatment was delayed due to insufficient literature on the topic) [30].…”

“…Our review of the latest literature (April 2021–June 2022) revealed a total of two related articles (Table S4). These were reported on two patients with novel variants in the PDHA1 gene [19–29].…”

“…These reported on 10 patients with novel variants in the CACNA1A [19][20][21][22][23][24][25][26][27][28][29]. In a case report of CACNA1A-related EA, dalfampridine 0.3 mg/kg was shown to resolve falls that had been unresponsive to acetazolamide (treatment was delayed due to insufficient literature on the topic) [30].…”

Golgi Dysfunctions in Ciliopathies

“…KIF1C-mediated transport to the cilium was proposed to involve a physical interaction with ASAP1, an ARF GTPase-activating protein serving as a scaffold protein to regulate ARF4, RAB8/RAB11-mediated ciliary receptor targeting [ 54 ]. Several studies have identified patients carrying mutations in the KIF1C gene as suffering from hereditary spastic paraparesis, a disorder characterized by spasticity predominantly in the lower limb that could be associated with cerebellar ataxia and upper cervical atrophy [ 6 , 7 , 8 , 55 ]. None of these studies investigated potential defects in ciliogenesis.…”

The kinesin motor KIF1C is a putative transporter of the exon junction complex in neuronal cells

“…Indeed, mutations in multiple members of the kinesin family have been implicated in causing axonopathy phenotypes, including conventional kinesin / kinesin-1 ( KIF5A – spastic paraplegia type 10 / #604187; KIF5C – complex cortical dysplasia with other brain malformations type 2 / #615282; KLC2 - spastic paraplegia, optic atrophy, and neuropathy / #609541), kinesin-3 ( KIF1A - hereditary sensory neuropathy type IIC / #614213 and spastic paraplegia type 30 / #610357; KIF1B - Charcot-Marie-Tooth disease, axonal, type 2a1 / #118210; KIF1C - Spastic ataxia type 2 / #611302), and kinesin-11 ( KIF26B - autosomal dominant spinocerebellar ataxia and pontocerebellar hypoplasia with arthrogryposis) (Kalantari and Filges 2020). Mutations in the kinesin-3 gene KIF1C have been shown to cause autosomal recessive HSP complicated by cerebellar involvement (Caballero Oteyza et al 2014; Dor et al 2014; Yucel-Yilmaz et al 2018; Marchionni et al 2019; Santos et al 2022). Mutation types observed in patients with HSP-KIF1C include missense variants in the kinesin-3 motor domain as well as truncating mutations scattered throughout the open reading frame and thus suggest loss of motor function as the relevant disease mechanism.…”