Autosomal recessive spinocerebellar ataxia 13 (SCAR13) is an extremely rare neurodegenerative disorder characterized by psychomotor delay, ranging from mild to severe intellectual disability with absent or poor speech development, nystagmus and stance ataxia. If ambulation is achieved, affected subjects often exhibit gait ataxia. Additionally, epilepsy and polyneuropathy have been reported in some patients. SCAR13 is caused by pathogenic variants in the GRM1 gene, which is predominantly expressed in the cerebellum, with lower levels in the other parts of the brain. To date, only seven reports of this rare ataxia have been published globally. Our study aimed to investigate clinical and mutation spectrum of GRM1-associated SCAR13 disorder in nine patients of two consanguineous Pakistani families (designated here to as NP35 and NP36). We performed whole exome sequencing in the probands of the two families followed by Sanger sequencing to test variant segregation. We identified a novel GRM1 frameshift variant (NM_001278064.2):c.3525_3529del; p.(Asn1176IlefsTer71) in both families as a cause of SCAR13. It was classified as a variant of uncertain significance (PM2: pathogenic moderate 2 and PVS1: pathogenic very strong 1) according to the ACMG guidelines. The novel variant exhibited clinical heterogeneity in the two families. Moreover, scoliosis was observed in all four patients of the family NP35, a feature previously documented in only one patient worldwide. Our study expands the limited mutation spectrum of the GRM1-associated SCAR13. Next-generation sequencing plays a pivotal role in the elucidation of inherited neurological disorders and in a better understanding of the convergent phenotypes.

Kv3.3 potassium channels are highly expressed in cerebellar Purkinje neurons and contribute to the ability of these neurons to fire at high rates. In addition to their role in regulating excitability, Kv3.3 channels form a complex with several cytoplasmic proteins, including Hax-1, Arp2/3, Rac1, and TBK1. This stimulates the nucleation of actin filaments under the plasma membrane. Using biochemical and confocal laser scanning microscopy techniques, we have found that the Kv3.3 channel binds and colocalizes with Plekhg4, a guanine nucleotide exchange factor (GEF) that regulates Rac1 activity, in Purkinje neurons and in Kv3.3-expressing auditory brainstem neurons. In addition to binding Kv3.3, Plekhg4 immunoreactivity is distributed uniformly in the cytoplasm of these cells, as well as in CHO cells expressing wild-type Kv3.3. The Kv3.3-G592R mutation differs from wild-type channels in that it fails to trigger actin nucleation, constitutively activates Tank-Binding Kinase-1 (TBK1), and, in humans, leads to spinocerebellar ataxia. We find that Plekhg4 forms cytoplasmic aggregates in the cells expressing Kv3.3-G592R, and that the formation of these aggregates is further enhanced by depolarization of the plasma membrane. Pharmacological inhibition of TBK1 reduces the number of Plekhg4 aggregates in Kv3.3-G592R-expressing cells. These results suggest that Purkinje cell activity, mediated by Kv3.3 channels, may regulate Pelkhg4 aggregation and provide a potential new therapeutic approach for the treatment of spinocerebellar ataxias.

Pathogenic variants in KCNC3, which encodes the voltage-gated potassium channel Kv3.3, are associated with spinocerebellar ataxia type 13. SCA13 is a neurodegenerative disease characterized by ataxia, dysarthria and oculomotor dysfunction, often in combination with other signs and symptoms such as cognitive impairment. Known disease-causing variants are localized in the protein coding regions and predominantly in the transmembrane and voltage sensing domains. In a patient with an ataxic movement disorder and progressive cognitive decline, the c.-6C>A variant was detected in the Kozak sequence of KCNC3. The Kozak sequence is responsible for efficient initiation of translation. Functional analysis of the new c.-6C>A variant and the upstream 5'-UTR region of KCNC3 by luciferase assays, quantitative PCR and methylation analysis shows increased protein expression but no effect on transcription rate. Therefore, increased translation initiation of KCNC3 transcripts compared to wild-type Kozak sequence seems to be the cause of the increased expression. Variants in the regulatory elements of disease-causing genes probably play an underestimated role.

Potassium channels (KCN) are transmembrane complexes that regulate the resting membrane potential and the duration of action potentials in cells. The opening of KCN brings about an efflux of K+ ions that induces cell repolarization after depolarization, returns the transmembrane potential to its resting state, and enables for continuous spiking ability. The aim of this work was to assess the role of KCN dysfunction in the pathogenesis of hereditary ataxias and the mechanisms of action of KCN opening agents (KCO). In consequence, a review of the ad hoc medical literature was performed. Among hereditary KCN diseases causing ataxia, mutated Kv3.3, Kv4.3, and Kv1.1 channels provoke spinocerebellar ataxia (SCA) type 13, SCA19/22, and episodic ataxia type 1 (EA1), respectively. The K+ efflux was found to be reduced in experimental models of these diseases, resulting in abnormally prolonged depolarization and incomplete repolarization, thereby interfering with repetitive discharges in the cells. Hence, substances able to promote normal spiking activity in the cerebellum could provide symptomatic benefit. Although drugs used in clinical practice do not activate Kv3.3 or Kv4.3 directly, available KCO probably could ameliorate ataxic symptoms in SCA13 and SCA19/22, as verified with acetazolamide in EA1, and retigabine in a mouse model of hypokalemic periodic paralysis. To summarize, ataxia could possibly be improved by non-specific KCO in SCA13 and SCA19/22. The identification of new specific KCO agents will undoubtedly constitute a promising therapeutic strategy for these diseases.

This article at hand described a 4-year-old child patient who initially presented with the symptoms of toe walking. As part of the diagnostic process, the patient was genetically tested to find the cause of the gait anomaly. The genetic test found a mutation in the KCNC3 gene. The variant c.1268G > A; p.Arg423. His was found in a heterozygotic state. This variant is frequently described as a cause for spinocerebellar ataxia type 13 (SCA13) in the literature. Apart from toe walking as the most pronounced symptom, the patient displayed an instable gait with frequent falls and delayed speech development. The genetic test to determine the cause of the gait anomaly successfully diagnosed the patient with a previously undiscovered SCA13 and subsequently enabled the recommendation of personalized further treatment.