KCND3-Related Neurological Disorders: From Old to Emerging Clinical Phenotypes

Luca Pollini,Serena Galosi,Caterina Caputi,Antonio Angeloni,Manuela Tolve,Carla Carducci,Vincenzo Leuzzi

doi:10.3390/ijms21165802

Luca Pollini, Serena Galosi + Show 5 more

Open Access

https://doi.org/10.3390/ijms21165802

Copy DOI

Abstract

KCND3 encodes the voltage-gated potassium ion channel subfamily D member 3, a six trans-membrane protein (Kv4.3), involved in the transient outward K+ current. KCND3 defect causes both cardiological and neurological syndromes. From a neurological perspective, Kv4.3 defect has been associated to SCA type 19/22, a complex neurological disorder encompassing a wide spectrum of clinical features beside ataxia. To better define the phenotypic spectrum and course of KCND3-related neurological disorder, we review the clinical presentation and evolution in 68 reported cases. We delineated two main clinical phenotypes according to the age of onset. Neurodevelopmental disorder with epilepsy and/or movement disorders with ataxia later in the disease course characterized the early onset forms, while a prominent ataxic syndrome with possible cognitive decline, movement disorders, and peripheral neuropathy were observed in the late onset forms. Furthermore, we described a 37-year-old patient with a de novo KCND3 variant [c.901T>C (p.Ser301Pro)], previously reported in dbSNP as rs79821338, and a clinical phenotype paradigmatic of the early onset forms with neurodevelopmental disorder, epilepsy, parkinsonism-dystonia, and ataxia in adulthood, further expanding the clinical spectrum of this condition.

Highlights

Voltage-gated potassium ion channels (Kvs), considered highly sophisticated voltage-gated ion channels from both a functional and a structural standpoint, play a fundamental role in the generation and propagation of the action potential in all living beings [1]
In order to better delineate the neurological phenotype associated with KCND3 gene deficiency, we reviewed the literature, focusing on clinical presentation and evolution according to age of onset and highlighting less frequent and underrecognized clinical features of this condition
Oculomotor disturbances, developmental delay (DD) later evolving to ID, cognitive decline, movement disorder, epilepsy, pyramidal signs, neuropathy, EA, and other paroxysmal neurological disturbances were added to the clinical spectrum of this condition over time, as detailed in this review

Summary

Introduction

Voltage-gated potassium ion channels (Kvs), considered highly sophisticated voltage-gated ion channels from both a functional and a structural standpoint, play a fundamental role in the generation and propagation of the action potential in all living beings [1]. Kvs are involved in a large variety of biological processes including neurotransmitter release, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, cell volume, and regulation of apoptosis [2,3]. Kv4 channels, including the Kv4.1, Kv4.2, and Kv4.3 subtypes, are a sub-group of the large Kvs family expressed in brain, heart, and smooth muscles [4]. Kv4.3 or Potassium Voltage-Gated Channel Subfamily D Member 3, encoded by KCND3, is a six trans-membrane segmented (S1–S6) ion channel, involved in the transient outward K+ current. Kv4.3 is highly expressed in the central nervous system, in cerebellar Purkinje cells, deep nuclei, granule cells, and interneurons [6]

Methods

Results

Conclusion