Parkinsonism with Reduced Striatal Uptake on DAT-SPECT in a Patient Harboring a Novel KCND3 Variant

Abstract

KCND3 encodes the voltage-gated potassium channel Kv4.3, and pathogenic variants in KCND3 are associated with spinocerebellar ataxia type 19/22 (SCA19/22) and related neurological phenotypes. Here, we report a Japanese patient harboring a novel KCND3 missense variant, classified as a variant of uncertain significance, who presented with a clinical phenotype compatible with SCA19/22, including slowly progressive cerebellar ataxia beginning in childhood, accompanied by asymmetric parkinsonism. Dopamine transporter single-photon emission computed tomography demonstrated reduced striatal uptake. Parkinsonian symptoms exhibited a partial response to dopaminergic therapy; however, the improvement was primarily based on clinical observation, with limited objective evidence supporting treatment efficacy. To our knowledge, abnormal dopamine transporter imaging has not been previously reported in patients with SCA19/22-related phenotypes. Although it was difficult to determine whether the parkinsonism was attributable to the KCND3 variant or to coexisting Lewy body disease, we reviewed the literature on parkinsonism associated with SCA19/22 and discussed the potential contributions of both pathologies in the present case.

Introduction

Spinocerebellar degeneration (SCD) is a group of neurodegenerative disorders characterized primarily by cerebellar ataxia. In addition to ataxia, patients may present with a variety of neurological manifestations, including parkinsonism, pyramidal signs, peripheral neuropathy, cognitive impairment, and epilepsy. In Japan, approximately one-third of SCD cases are hereditary, the majority of which follow an autosomal dominant inheritance pattern. Spinocerebellar ataxia (SCA) type 3, SCA6, dentatorubral–pallidoluysian atrophy (DRPLA), and SCA31 are the most prevalent subtypes [1]. SCA19/22 (Online Mendelian Inheritance in Man, OMIM #607346) is a channelopathy caused by pathogenic variants in KCND3 (OMIM: *605411), which encodes the voltage-gated potassium channel Kv4.3. SCA19/22 is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia [2]. Although cases of SCA19/22 are being increasingly reported worldwide, reports from Japan remain limited. In the Japanese literature, a KCND3 mutation (c.1174G > A, p.Val392Ile) has been described in patients presenting with both cardiac phenotypes, including early repolarization syndrome and paroxysmal atrial fibrillation, and cerebral manifestations such as epilepsy and intellectual disability [3]. In addition, a KCND3 mutation (c.1150G > A, p.Gly384Ser) has been reported in association with intellectual disability, cerebellar ataxia, myoclonus, and dystonia [4]. Beyond the typical presentation of cerebellar ataxia, various extracerebellar features—including cognitive impairment, parkinsonism, and peripheral neuropathy—have been reported in patients with SCA19/22; however, the etiology of parkinsonism in this condition remains poorly understood [2]. Although several reports have described parkinsonian features in patients with SCA19/22, dopamine transporter single-photon emission computed tomography (DAT-SPECT) with [123I]N-ω-fluoropropyl- 2β-carbomethoxy-3β-(4-iodophenyl) nortropane ([123I]FP- CIT) has rarely been performed, and previously reported cases showed normal DAT-SPECT findings [5]. Here, we describe a patient with a novel KCND3 missense variant presenting with cerebellar ataxia and DAT-SPECT-positive parkinsonism.

Case Report

A 62-year-old Japanese man was admitted to our hospital because of progressive gait instability. Since childhood, he had difficulty balancing on curbstones and had struggled academically. 20 years earlier, he developed dysarthria and recurrent falls. 5 years prior to presentation, he noted left-dominant upper-limb dysmetria and tremor, which extended to the left lower limb 3 years later. At the time of presentation, he required a walker. He had no hyposmia, rapid eye movement sleep behavior disorder, or restless legs syndrome. There was no family history of neurological disease among his parents or two siblings (Fig. 1). Neurological examination revealed asymmetric cerebellar ataxia, predominantly affecting the left side, characterized by saccadic pursuit, slurred speech, dysmetria (more pronounced on the left during the finger-to-nose and heel-to-shin tests), and a wide-based gait. In addition, asymmetric parkinsonism was observed, predominantly on the left side, including axial and limb rigidity (more pronounced in the left upper extremity), resting tremor, akinesia, and a shuffling gait. No other ocular motor abnormalities, including nystagmus, were noted, and dystonia was absent. There were no signs of peripheral neuropathy or pyramidal tract involvement. Mild constipation was reported, without apparent significant cognitive impairment (Mini-Mental State Examination score, 30/30; Hasegawa’s Dementia Scale-Revised, 29/30; Frontal Assessment Battery, 14/18). His Unified Parkinson’s Disease Rating Scale (UPDRS) part III score was 24. Blood, electrocardiogram, respiratory function, and cerebrospinal fluid tests yielded no remarkable findings. Brain magnetic resonance imaging (MRI) demonstrated right-dominant cerebellar atrophy, with preservation of the swallow tail sign and no apparent abnormalities in the basal ganglia (Fig. 2), and brain perfusion single-photon emission computed tomography (SPECT) showed concordant hypoperfusion. DAT-SPECT revealed reduced uptake in the right-dominant striatum (striatal binding ratios: right, 2.78; left, 3.37; mean, 3.07; Fig. 3). Compared with the age-adjusted reference mean of 7.98 ± 1.35 in our database, the corresponding z-scores were − 3.86 on the right, − 3.42 on the left, and − 3.64 on average, indicating a marked reduction in striatal DAT uptake, particularly on the right side.

Fig. 1.

Family tree of the presented case. The arrow indicates the proband

Fig. 2.

MRI T1-weighted image shows right-dominant cerebellar atrophy

Fig. 3.

DAT-SPECT demonstrated reduced bilateral striatal uptake, with right-sided predominance (SBRs: 2.78 on the right and 3.37 on the left)

Genetic testing for SCA1, 2, 3, 6, 7, 8, and 31 and dentatorubral–pallidoluysian atrophy, genes relatively frequent in Japan, did not show the presence of abnormal alleles. Next, whole-genome sequencing identified a candidate variant in the KCND3 gene, while no candidate pathogenic variants were detected in other genes associated with spinocerebellar degeneration. The KCND3 variant was subsequently confirmed by direct Sanger sequencing. This revealed the presence of the single-base substitution (c.652T > C, p.Cys218Arg), which is absent from the Genome Aggregation Database (gnomAD v4.1.1, GRCh38) and previously unreported. Next, we employed four computer algorithms to predict the effect of this novel variant: Sorting Intolerant From Tolerant (SIFT, http://sift.bii.a-star.edu.sg/), Polymorphism Phenotyping v2 (PolyPhen-2, http://genetics.bwh.harvard.edu/pph2/), MutationTaster (http://www.mutationtaster.org) and Combined Annotation Dependent Depletion (CADD, https://cadd.gs.washington.edu/snv). In silico predictions were discordant (‘tolerated’, ‘possibly damaging’, and ‘deleterious’), with a high CADD PHRED score of 31. Although the in silico predictions were not fully concordant, the overall computational evidence supported application of PP3 as supporting evidence. Because neither segregation analysis nor functional validation was available, the KCND3 c.652T > C (p.Cys218Arg) variant was classified as a variant of uncertain significance according to the American College of Medical Genetics and Genomics (ACMG) criteria based on PM2, PP2, and PP3. At admission, levodopa/benserazide was initiated at 200 mg/day, resulting in slight improvement in motor symptoms (UPDRS part III score: 24 to 23). One month later, the dose was increased to 300 mg/day, with mild clinical improvement in rigidity. At 14 months after admission, zonisamide (25 mg/day) was added but discontinued because of lack of efficacy and adverse effects, including somnolence and palpitations. Ropinirole was introduced at 18 months (2 mg/day) and increased to 4 mg/day, with reported improvement in freezing of gait. Rasagiline (0.5–1 mg/day), initiated at 21 months, showed no apparent benefit and was discontinued at 24 months because of falls. Selegiline was subsequently started at 25 months and increased to 5 mg/day, with partial improvement in rigidity. Additional levodopa/benserazide was introduced at 34 months (total dose 350 mg/day), but peripheral edema developed, leading to discontinuation of ropinirole at 35 months. Further adjustment of levodopa/benserazide (400 mg/day) and selegiline (5 mg/day) resulted in additional improvement in rigidity. At 39 months, opicapone (25 mg/day) was added, with reported improvement in head tremor. Overall, treatment response was partial and was documented mainly by clinical observations, with limited objective confirmation. Despite these treatment adjustments, the patient’s symptoms gradually progressed, and he eventually became wheelchair-dependent. At 69 months after admission, he was receiving levodopa/benserazide 400 mg/day, selegiline 5 mg/day, and opicapone 25 mg/day, with a UPDRS part III score of 34.

Discussion

This report describes a patient with a novel KCND3 missense variant who presented with slowly progressive cerebellar ataxia beginning in childhood, accompanied by asymmetric parkinsonism. DAT-SPECT demonstrated reduced striatal uptake, and the parkinsonian symptoms showed a partial response to dopaminergic therapy, although the treatment response was documented mainly by clinical observation with limited objective confirmation. We summarized previously reported cases of parkinsonism associated with SCA19/22 (Table 1). According to these reports, SCA19/22-related parkinsonism has generally been described as mild and relatively symmetric; however, at least two cases with lateralized parkinsonism have been described [5–8]. DAT-SPECT findings have rarely been reported in SCA19/22; in one previous case, striatal uptake was normal [5]. The presence of reduced dopamine transporter uptake suggests presynaptic nigrostriatal dysfunction [9]. One possible explanation for the reduced striatal uptake observed on DAT-SPECT is degeneration of the substantia nigra related to the KCND3 variant, although this association remains unproven. In support of this hypothesis, KCND3 is highly expressed in the midbrain and cerebellum according to the Human Protein Atlas [10], and moderate neuronal degeneration of the dopaminergic pars compacta of the substantia nigra has been reported in SCA19/22 [11]. Therefore, nigral degeneration could be considered as one possible contributor to the reduced striatal uptake observed on DAT-SPECT in the present case. In addition, there have been no previous reports of a response to dopaminergic therapy in SCA19/22. In the present case, the parkinsonism showed a partial response to dopaminergic therapy, documented mainly through clinical observations and with limited objective confirmation. Although the efficacy of dopaminergic therapy in SCA19/22-related parkinsonism has not been systematically evaluated, levodopa-responsive parkinsonism has been reported in other spinocerebellar ataxias, including SCA2, SCA3, and SCA17 [12]. However, coexisting Parkinson’s disease or Lewy body disease remains a plausible alternative explanation, particularly given the abnormal DAT-SPECT findings and partial dopaminergic responsiveness. Therefore, whether the parkinsonism in the present case was related to the KCND3 variant or represented coexisting Parkinson’s disease/Lewy body disease remains uncertain. However, if the parkinsonism in this case were related to the KCND3 variant, the present findings raise the possibility that KCND3-associated parkinsonism may, in some cases, be accompanied by abnormal DAT-SPECT findings and partial responsiveness to dopaminergic therapy. Further pathological investigations and accumulation of additional cases are warranted to clarify this issue. KCND3 variants are known to cause both Brugada syndrome and SCA, with gain-of-function mutations typically located near the C-terminus and associated with cardiac phenotypes, whereas loss-of-function mutations are associated with cerebellar degeneration. The p.Cys218Arg variant is located in the first extracellular loop of the six-transmembrane Kv4.3 channel, relatively close to the N-terminus; this localization is compatible with variants associated with SCA, although its relationship to parkinsonism remains unclear [13]. Cardiac evaluation was limited to electrocardiography, and no findings suggestive of Brugada syndrome were observed. To our knowledge, this is the first report of a patient harboring a novel KCND3 variant and a clinical phenotype compatible with SCA19/22 who presented with parkinsonism accompanied by reduced striatal uptake on DAT-SPECT. Parkinsonism associated with KCND3 variants remains insufficiently understood, highlighting the need for further accumulation of cases and clinicopathological studies, including DAT-SPECT imaging and neuropathological examination.

Table 1.

Reported cases of SCA19/22 with parkinsonian features

Age at ataxia onset	Symmetry	Parkinsonian features	DAT-SPECT	Variant	Response to antiparkinsonian therapy	Reference
40	Asymmetric	Bradykinesia, tremor	Normal	p.Ser346Phe (c.1037C>T)	No response	[5]
45	NR	Bradykinesia	Normal	p.Ser346Phe (c.1037C>T)	NR	[5]
50	NR	Unspecified parkinsonismᵃ	NE	p.Ser346Phe (c.1037C>T)	NR	[5]
18	Asymmetric	Rigidity	NE	p.Thr377Met (c.1130C>T)	NR	[8]
66	NR	Parkinsonismb	NE	p.F227del (c.679_681delTTC)	NR	[6]
15	NR	Parkinsonismb	NE	p.F227del (c.679_681delTTC)	NR	[6]
35	NR	Parkinsonismb	NE	p.F227del (c.679_681delTTC)	NR	[6]
16	NR	Parkinsonismb	NE	p.F227del (c.679_681delTTC)	NR	[6]
23	NR	Parkinsonismb	NE	p.F227del (c.679_681delTTC)	NR	[6]
29	NR	Parkinsonismb	NE	p.F227del (c.679_681delTTC)	NR	[6]
20	NR	Parkinsonismb	NE	p.F227del (c.679_681delTTC)	NR	[6]
10	NR	Parkinsonismb	NE	p.F227del (c.679_681delTTC)	NR	[6]
35	NR	Rigidity	NE	p.F227del (c.679_681delTTC)	NR	[7]
51	NR	Rigidity	NE	p.F227del (c.679_681delTTC)	NR	[7]
31	NR	Tremor	NE	p.F227del (c.679_681delTTC)	NR	[7]
30	NR	Tremor	NE	p.F227del (c.679_681delTTC)	NR	[7]
Childhood	Asymmetric	Akinesia, rigidity, tremor	Abnormal	p.Cys218Arg (c.652T>C)	Partial clinical response	This case

NE Not examined, NR Not reported

^aUnspecified parkinsonism indicates cases in which detailed definitions were not provided in the original reports

^bParkinsonism was defined as the classical combination of rigidity and akinesia, with or without resting tremor

Authors’ Contributions

All authors contributed to the study’s conception and design. Material preparation and data collection were performed by KK, MT, and CK. The first draft of the manuscript was written by KK, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by the Japan Agency for Medical Research and Development (AMED) through the AMED-JCAT program (JP21ek0109532, JP24ek0109734) and HK²-MIRAI program (JP256f0137011), and by the Research Program on Rare and Intractable Diseases of the Ministry of Health, Labour and Welfare of Japan (JPMH19FC1009, JPMH23FC1010). Open Access funding provided by Kobe University.

Data Availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request. All data are derived from the patient’s medical records and are not publicly available due to privacy and ethical restrictions.

Declarations

Ethics approval and consent to participate

Ethical approval was waived by the Kobe University Clinical Research Ethical Committee because this was a single case report. All study procedures were performed in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments. The authors confirm that they have read the journal’s position on issues involved in ethical publication and confirm that this work is consistent with those guidelines. The patient provided their written informed consent to participate in this study.

Consent for publication

Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.

Competing interests

The authors declare no competing interests.