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