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

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.

Novel KCND3 Variant Underlying Nonprogressive Congenital Ataxia or SCA19/22 Disrupt KV4.3 Protein Expression and K+ Currents with Variable Effects on Channel Properties

“…According to a recent review of 68 cases with KCND3 -related neurological disorders, in the early-onset cohort (comprising 15 patients) intellectual disability and epilepsy were the most frequently presenting signs whereas ataxia had a less predictable course in terms of age of onset, severity and progression rate. A patient carrying a de novo p.Ser301Pro variant, presented neurodevelopmental delay and focal epilepsy but developed a complex movement disorder with cervical and upper limb dystonia and a mixed parkinsonian-ataxic gait in adulthood [ 15 ].…”

Rare Gain-of-Function KCND3 Variant Associated with Cerebellar Ataxia, Parkinsonism, Cognitive Dysfunction, and Brain Iron Accumulation

“…Table 3 outlines the genotype–phenotype relationship of known disease-associated KCND3 variants. Patients with KCND3 -related neurological disorders are characterized by heterogeneous clinical presentations including cerebellar ataxia, cognitive dysfunction, and movement disorders such as parkinsonism [ 10 ]. KCND3 -related ataxia is further known to be associated with a wide range of disease onset (from very early ages to later stages of life), as well as distinctly different clinical courses (including episodic, non-progressive, and slowly progressive).…”

“…Loss-of-function mutations in the human KCND3 gene, which encodes the K V 4.3 channel, have been associated with spinocerebellar ataxia type 19 and 22 (SCA19/22), a clinically heterogeneous group of neurodegenerative disorders characterized by variable degrees of cerebellar ataxia, parkinsonism, cognitive dysfunction, epilepsy, and extrapyramidal signs (MIM#607346) [ 6 , 7 , 8 , 9 , 10 ]. In contrast, gain-of-function mutations in the KCND3 gene are linked to cardiac arrhythmia, the Brugada syndrome [ 11 ].…”

“…In contrast, gain-of-function mutations in the KCND3 gene are linked to cardiac arrhythmia, the Brugada syndrome [ 11 ]. Nonetheless, some of the cardiopathogenic gain-of-function KCND3 mutations may also be related to neurological disorders such as ataxia, cognitive dysfunction, and epilepsy [ 10 , 12 , 13 , 14 ].…”

Translocation of TMEM175 Lysosomal Potassium Channel to the Plasma Membrane by Dynasore Compounds

“…It remains to be examined whether TMEM175 is present in the plasma membrane of native cells, e.g., in the dopaminergic neurons of the substantia nigra pars compacta under the pathological conditions of Parkinson’s disease. It may require substantially different methodology from those applied in the present study to investigate this challenging problem [ 58 , 59 , 60 , 61 , 62 ], and identify the 4-AP-sensitive Cs + current of TMEM175 channels at −100 mV in the plasma membrane of native cells.…”