Discussion

This study aimed to present a multidimensional assessment of 23 genetically confirmed ChA patients, with particular attention to underexplored domains, including oculomotor impairment, psychiatric features and olfactory dysfunction. While chorea is commonly observed in ChA, it is a shared feature across several neurodegenerative disorders. ^{Reference Walker20} Our findings suggest that ChA may exhibit more distinctive motor features; approximately 75% of the patients demonstrated oculomotor disturbances, affecting saccadic initiation and velocity as well as smooth pursuit, especially in the vertical plane. Similarly, Hardie et al. described 19 cases of neuroacanthocytosis (NA) syndrome, among which five patients had identified saccade and smooth pursuit abnormalities, upward gaze limitation and poor convergence; however, their study lacked detailed reporting and did not include genetic confirmation of ChA. ^{Reference Hardie, Pullon and Harding21} Another study using magnetic search coil techniques in three ChA cases described frequent hypometric and fragmented vertical saccades, smooth pursuit impairment and fixation instability. ^{Reference Gradstein, Danek, Grafman and Fitzgibbon22} In 2016, a review incorporating these studies revealed some similarities in eye movement abnormalities between NA and two other choreatic disorders. ^{Reference Attoni, Beato, Pinto and Cardoso23} In Sydenham’s chorea, hypometric saccades were observed in 80% of patients. ^{Reference Attoni, Beato, Pinto and Cardoso23} HD has shown a high prevalence of saccadic velocity impairment (96%), initiation latency (91%) and smooth pursuit involvement. ^{Reference Attoni, Beato, Pinto and Cardoso23} These findings reinforce the possibility of midbrain involvement or its connecting pathways with the basal ganglia in ChA. ^{Reference Gradstein, Danek, Grafman and Fitzgibbon22}

All patients in our study exhibited at least one neuropsychiatric symptom. These symptoms can precede motor manifestations by over a decade, ^{Reference Rodrigues, Walker, Bader, Danek, Marques and Tumas24,Reference Walterfang, Yucel and Walker25} as four of our patients primarily presented with psychiatric features. Orbitofrontal and anterior cingulate dysfunction may contribute to the presence of OCD, depression and psychosis in ChA. ^{Reference Huang, Rong and Chen26} Although behavioral disturbances were common in this study group, approximately 40% of our participants exhibited mild to no impairment on each psychiatric measure; this, together with the limited sample size, may account for the weak and insignificant correlations observed between TBS and other clinical variables. Nearly 20% of the cases reported suicidal ideas; notably, these patients had markedly better cognitive and functional status and worse behavioral condition compared to those without suicidal thoughts. This could reflect that patients with more intact cognition may have greater insight into their illness, which is not treatable and has a devastating outcome, leading to emotional distress and suicidal thoughts. Similar findings occur in HD and dementia, where suicide risk is highest when insight is still preserved. ^{Reference Paulsen, Hoth, Nehl and Stierman27–Reference Choi, Lee and Han29} The presence of suicidal ideation in one-fifth of our patients emphasizes the need for multidisciplinary care by neurologists, psychiatrists and supporting systems.

Olfactory dysfunction, which is common in PD, AD, HD and NBIA disorders, ^{Reference Amini, Rohani and Habibi11–Reference Chowdhury, Das, Mishra, Jayashree and Bodakhe14} can predate motor or cognitive symptoms. ^{Reference Chen and Kostka30} To our knowledge, there is currently no research regarding olfaction in ChA patients. We found that 50% of our ChA patients had hyposmia, which is lower than the reported rates in PD, AD and HD. ^{Reference Amini, Rohani and Habibi11,Reference Son, Jahanshahi and Yoo12,Reference Chowdhury, Das, Mishra, Jayashree and Bodakhe14} The etiology of olfactory loss in neurodegenerative disorders remains unclear. ^{Reference Amini, Rohani and Jalessi13,Reference Gu, Zhang and Zhao31} In PD, alpha-synuclein (Lewy bodies/neurofilaments) and tau pathology contribute to olfactory deficits. ^{Reference Guo and R-d32–Reference Beauchamp, Chan and Hung34} In HD, huntingtin deposits in the olfactory bulb may play a role in olfactory dysfunction. ^{Reference Highet, Dieriks, Murray, Faull and Curtis35} A postmortem study of seven ChA patients revealed tau pathology in the hippocampus, midbrain and pons. ^{Reference Ditzel, Walker and Nirenberg36} Mild Lewy pathology and glial tau inclusions were also observed, though typical Lewy bodies were absent. ^{Reference Ditzel, Walker and Nirenberg36}

In the present study, OI was the most impaired olfactory subtest (55%), followed by OD, whereas OT did not differ significantly between patients and matched controls. A prior investigation of olfactory impairment profiles conducted by Whitcroft et al. has shown that deficits in OI and OD are more pronounced in PD than in sinonasal disorders, which primarily affect OT. In the absence of specific pathological alterations in the olfactory epithelium in PD, they concluded that OI and OD reflect central olfactory pathway function, whereas OT is more sensitive to peripheral pathology. ^{Reference Whitcroft, Cuevas, Haehner and Hummel37} Subsequent work has further supported this distinction, attributing OT impairment to peripheral nervous system dysfunction and OD/OI deficits, which rely on higher-order cognitive processes, to central mechanisms. ^{Reference Marin, Vilas and Langdon38} Moreover, associations between OT – but not OI – and the nasal microbiome ^{Reference Thangaleela, Sivamaruthi, Kesika, Bharathi and Chaiyasut39} may further support the peripheral basis of OT dysfunction.

Accordingly, our findings suggest predominant involvement of central olfactory pathways rather than peripheral sensory dysfunction. Central olfactory system involvement has also been documented in PD, ^{Reference Whitcroft, Cuevas, Haehner and Hummel37,Reference Marin, Vilas and Langdon38,Reference Iannilli, Stephan, Hummel, Reichmann and Haehner40} with impairments typically observed across all subtests, ^{Reference De Cleene, Schwarzová and Labrecque41} but more marked in OI than in OT. ^{Reference Franco, Garrigós and Lillo42} In contrast, a recent study in HD identified OT as the most affected domain, suggesting a greater contribution of peripheral mechanisms. ^{Reference Amini, Rohani and Habibi11} Although reported olfactory deficits in HD vary across studies, OT impairment appears prominent in manifest – but not in premanifest – HD compared with controls. ^{Reference De Cleene, Schwarzová and Labrecque41} These differences in olfactory profiles may aid in the differential diagnosis of ChA. However, the small sample size and limited adjustment for confounding factors require cautious interpretation. Validation in larger, well-controlled studies is necessary.

The primary correlation patterns identified in this study remained largely unaffected by family clustering. Significant associations were robust to relatedness, whereas weaker, nonsignificant associations showed reduced stability in this small sample. Among the observed associations, moderate-to-strong correlations between the TFC score and both the TDI and OD scores suggest that olfactory performance may be relatively preserved in patients with better functional status. As the TFC score can reflect the severity of disease, this relationship may imply that olfactory impairment is another sign of the underlying neurodegeneration. Although this correlation did not survive FDR correction, the magnitude of the effect suggests a potentially meaningful relationship warranting further investigation. In addition, functional measures were strongly correlated with MMSE score, supporting the concept of ChA as a multisystem neurodegenerative condition.

Parkinsonism may occur in either the early or late stages of ChA, ^{Reference Reilmann43} while the Westphal variant of HD is primarily characterized by parkinsonism and dystonia and typically presents before the age of 20 years. ^{Reference Martino, Stamelou and Bhatia44} A recent study described a case of ChA with early-onset parkinsonism accompanied by dystonia but without chorea. ^{Reference Monfrini, Di Fonzo and Morgante45} Another case involved coexisting VPS13A and PARK2 mutations, suggesting digenic inheritance. ^{Reference Mitchell, Albin, Dauer, Goudreau and Sidiropoulos46} A case report of two ChA patients demonstrated transitioning of symptoms from chorea to parkinsonism, potentially reflecting progressive presynaptic nigrostriatal degeneration, as shown by dopamine transporter single-photon emission CT (SPECT) imaging. ^{Reference Nagy, Noyce, Velayos-Baeza, Lees, Warner and Ling47} Nigral degeneration has been described in some, ^{Reference Hardie, Pullon and Harding21,Reference Rinne, Daniel, Scaravilli, Harding and Marsden48} but not in all, ^{Reference Connolly, Hazrati and Lang49} studies; a study on two ChA cases found no significant nigral neuronal loss but noted striatal substance P-positive neuron degeneration, implying involvement of the striato-pallido-thalamo-cortical pathway in phenotype variation. ^{Reference Connolly, Hazrati and Lang49}

In this study, parkinsonism was observed in two patients. One individual developed parkinsonian features 16 years after the initial onset of chorea, with symptoms persisting despite discontinuation of tetrabenazine, a drug known to cause parkinsonian side effects. The second patient, with a history of epilepsy and long-term treatment with sodium valproate (1000 mg/day for 13 years), presented parkinsonism as the first motor manifestation of ChA at age 37 (confirmed by genetic testing). Although both tetrabenazine and sodium valproate have been associated with drug-induced parkinsonism (DIP), the persistence of parkinsonian symptoms six years after tetrabenazine discontinuation and the emergence of marked parkinsonism after long-term sodium valproate use raise the possibility of an underlying neurodegenerative mechanism rather than a purely pharmacological effect. This pattern may represent a phenotypic shift from hyperkinetic to hypokinetic features, with progression from prominent chorea to bradykinesia and rigidity in later stages of the disease, as reported in late-stage adult-onset HD. ^{Reference Novak and Tabrizi50}

Neuroleptics, tetrabenazine and, to a lesser extent, anticonvulsants are known to induce drug-related movement disorders, including parkinsonism. Symptoms of DIP typically develop within several weeks after treatment initiation. ^{Reference Shin and Chung51,Reference De Faria Sousa and Espinosa52} Also, clinical improvement usually occurs within weeks to months following drug discontinuation or dose reduction, though symptoms may persist or worsen in a subset of patients. ^{Reference Shin and Chung51,Reference De Faria Sousa and Espinosa52} Owing to the study’s cross-sectional design, distinguishing DIP from neurodegenerative parkinsonism was challenging. Although dopamine transporter SPECT imaging may assist in this distinction, ^{Reference Shin and Chung51,Reference De Faria Sousa and Espinosa52} it was not among the primary objectives of the present study.

Beyond the two patients with overt parkinsonism, nine individuals (39.1%) exhibited minimal parkinsonian signs (score of 1 across the predefined motor items). However, due to prolonged disease duration in this subgroup (8.66 ± 3.93 years) and chronic exposure to anticonvulsant and/or neuroleptic medications (Supplementary Table 2), these patients were not classified as parkinsonism patients.

We acknowledge several important limitations. The extreme rarity of ChA resulted in a small sample size, limiting statistical power and generalizability. Given the exploratory design and the number of correlation analyses performed, we controlled for type I error using FDR correction; however, replication in larger cohorts is warranted. Furthermore, some participants were from the same families, which may have inflated correlation estimates due to clustering. Nevertheless, the one-per-family sensitivity analysis yielded results comparable to the primary findings. As our clinic is located within a tertiary referral center, cases may have been more complex or severe than those in the general population, introducing potential referral bias. Five of the 28 invited patients did not complete the assessments; their exclusion may have resulted in bias if they differed systematically from the participants. Additionally, recruiting controls from hospital staff may have introduced selection bias, potentially overestimating case–control differences, as controls were likely to have higher educational or socioeconomic status – factors that may influence olfactory performance and the distribution of risk factors for olfactory dysfunction, such as smoking. Although patients with cognitive impairment were excluded from olfactory testing, residual cognitive influences on OD and OI performance cannot be entirely ruled out and should be considered when interpreting the olfactory findings. Moreover, the MMSE may underestimate cognitive impairment in ChA because of its limited sensitivity to subcortical and executive dysfunction. Finally, a substantial proportion of participants were treated with neuroleptic agents, anticonvulsants and/or tetrabenazine, which may have confounded the interpretation of motor, behavioral and cognitive findings. The cross-sectional design precluded causal inference and assessment of disease progression. These limitations underscore the need for future multicenter studies with larger cohorts and prespecified subgroup analyses to better characterize disease-related manifestations and longitudinal trajectories.