Dear Editor,

The importance of precision medicine in Parkinson’s disease (PD) has been highlighted. We report the case of a female who has a novel heterozygous SLC9A6 mutation (Met453del) that met the Movement Disorders Society (MDS) diagnostic criteria for clinically established PD [1] and underwent deep brain stimulation (DBS) [2]. We now report the patient’s responsiveness to DBS.

The Japanese female first noted bradykinesia on her left side at the age of 44 and visited our hospital at the age of 46. Neurological examinations revealed bradykinesia and rigidity on her left side. Brain magnetic resonance imaging revealed no remarkable findings. Dopamine transporter single-photon emission computed tomography demonstrated bilateral striatal uptake reduction, which was more pronounced on the right, and 123I-metaiodobenzylguanidine myocardial scintigraphy revealed normal myocardial uptake (Supplementary Fig. 1A-C in the online-only Data Supplement). Mild olfactory dysfunction was detected, as indicated by a score of 7/12 on the odor stick identification test for Japanese. Her symptoms improved significantly after starting antiparkinsonian medication, and no red flag signs were observed. On the basis of these findings, the patient was diagnosed with clinically established PD [1]. Four to five years after the initiation of antiparkinsonian treatment, she gradually developed noticeable wearing-off phenomena and dyskinesia, leading to insufficient symptom control. At the age of 51, subcutaneous apomorphine injection was introduced as a rescue treatment for off periods, but motor complications were uncontrollable. In a levodopa challenge test (LCT) at the age of 54, the patient achieved a 40% improvement in the MDS-Unified Parkinson Disease Rating Scale Part III score (Table 1), and DBS surgery was performed. Owing to troublesome dyskinesia, a slight decline in cognitive function, and positive pareidolia (Supplementary Table 1 in the online-only Data Supplement), the globus pallidus internus (GPi) was selected as a target, as GPi-DBS is known to have a direct effect on reducing dyskinesia and a lower risk of worsening cognitive function than subthalamic nucleus-DBS.

Post-DBS improvements in motor symptoms, including dyskinesia, were observed, but the patient’s parkinsonism gradually worsened 3 months later. Despite various adjustments to the DBS settings, the effect of DBS in this case was limited compared with that of levodopa intake, which was suggested by the four-condition (on/off medication and stimulation) test (Table 1, Supplementary Table 2 in the online-only Data Supplement). To investigate the cause of her uncommon clinical course, genetic testing was performed, revealing a heterozygous mutation in SLC9A6 (Met453del). 18F-Florzolotau positron emission tomography revealed tau deposition in the striatum. The patient experienced traumatic subarachnoid hemorrhage due to frequent falls, which resulted in a significant decline in activities of daily living. Despite continued nutritional management via gastrostomy, she gradually developed malnutrition and repeated aspiration pneumonia over the course of 1 year and died at the age of 56.

The SLC9A6 gene is known as the causative gene of Christianson syndrome in males, but heterozygous SLC9A6 mutations in female carriers have recently been implicated in parkinsonism [2,3]. In our clinically diagnosed PD patient with SLC9A6 mutation, despite levodopa responsiveness, GPi-DBS led to only transient improvement in motor symptoms, resulting in worsening of motor control, balance, and speech in the short term. While LCT is considered an effective tool for predicting the postoperative efficacy of DBS in PD patients, the efficacy of DBS has also been reported to vary depending on the type of genetic mutation (e.g., PRKN mutation or GBA carrier) [4]. Our case also raises an important question, i.e., which PD-associated mutations are suitable for DBS [4,5].

We observed tau accumulation in the striatum in all three SLC9A6-associated patients in our earlier study, irrespective of the characteristics of parkinsonism. Although the mechanistic link between SLC9A6 mutations and tau accumulation remains unknown, SLC9A6 mutations may affect endolysosomal trafficking and/or acidification via loss of function of Na+/H+ exchanger 6, leading to altered protein homeostasis and potentially promoting abnormal tau phosphorylation and aggregation [6]. In multiple system atrophy characterized by α-synuclein deposition in the striatum and in progressive supranuclear palsy associated with tau deposition in the brainstem, motor symptom improvement is generally not achieved with DBS [2,7,8]. It remains unclear whether the lack of the anticipated effects of DBS in the present patient was due to the impact of the genetic mutation or the influence of the striatum’s tau burden. This case follows our previous report of SLC9A6-related parkinsonism with striatal tau accumulation [2]. While that study described the imaging and clinical phenotypes, the current report expands on the postoperative course after DBS, highlighting the limited long-term efficacy of DBS. To our knowledge, this is the first report focusing on DBS outcomes in this context.

During this review process, the phenotype associated with the heterozygous SLC9A6 mutation was registered in the Online Mendelian Inheritance in Man (OMIM^®) database (https://omim.org/entry/301142) as a new disorder: NEURODEGENERATIVE DISORDER, X-LINKED, FEMALE-RESTRICTED, WITH PARKINSONISM AND COGNITIVE IMPAIRMENT; NDPACX (#301142). This classification reinforces the clinical relevance of the findings reported here.

In summary, our case provides the first description of DBS for parkinsonism associated with SLC9A6 mutation, and it highlights the need for caution when adapting DBS for genetic mutations or tauopathy, even in parkinsonism patients meeting PD diagnostic criteria and exhibiting responsiveness to levodopa.

Supplementary Materials

Notes

Ethics Statement

Ethical approval for this study was obtained from the Institutional Review Board of the National Institutes for Quantum Science and Technology (approval number #20110262), and informed consent was obtained from this participant.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

Makoto Higuchi received research funding partly from Japan Agency for Medical Research and Development under grant numbers 24wm0625304h0001.

Acknowledgments

The authors thank the patient and his family members who were involved in this research. None of the study participants received financial incentives.

Author Contributions

Conceptualization: Shohei Okusa, Toshiki Tezuka, Morinobu Seki. Data curation: Shohei Okusa. Formal analysis: Shohei Okusa. Funding acquisition: Makoto Higuchi. Investigation: Shohei Okusa. Methodology: Shohei Okusa, Toshiki Tezuka, Morinobu Seki. Project administration: Shohei Okusa, Kenzo Kosugi, Yasuharu Yamamoto, Keisuke Takahata, Takenori Akiyama, Masahito Kobayashi. Resources: Shohei Okusa, Yasuharu Yamamoto, Keisuke Takahata, Makoto Higuchi. Software: Shohei Okusa. Supervision: Makoto Higuchi, Masahiro Toda, Daisuke Ito, Jin Nakahara, Morinobu Seki. Validation: Toshiki Tezuka, Daisuke Ito, Morinobu Seki. Visualization: Shohei Okusa. Writing—original draft: Shohei Okusa. Writing—review & editing: Toshiki Tezuka, Daisuke Ito, Morinobu Seki.

REFERENCES

• 1. Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 2015;30:1591–1601.ArticlePubMed
• 2. Yamamoto Y, Takahata K, Seki M, Okusa S, Tatebe H, Ueda R, et al. SLC9A6-linked parkinson syndrome in female heterozygotes is associated with PET-detectable tau pathology. Neurol Genet 2025;11:e200235.ArticlePubMedPMC
• 3. Nan H, Kim YJ, Tsuchiya M, Ishida A, Haro H, Hiraide M, et al. Novel SLC9A6 variation in female carriers with intellectual disability and atypical parkinsonism. Neurol Genet 2022;8:e651. ArticlePubMedPMC
• 4. Kuusimäki T, Korpela J, Pekkonen E, Martikainen MH, Antonini A, Kaasinen V. Deep brain stimulation for monogenic Parkinson’s disease: a systematic review. J Neurol 2020;267:883–897.ArticlePubMedPMCPDF
• 5. Artusi CA, Lopiano L. Should we offer deep brain stimulation to Parkinson’s disease patients with GBA mutations? Front Neurol 2023;14:1158977.ArticlePubMedPMC
• 6. Fernandez MA, Bah F, Ma L, Lee Y, Schmidt M, Welch E, et al. Loss of endosomal exchanger NHE6 leads to pathological changes in tau in human neurons. Stem Cell Reports 2022;17:2111–2126.ArticlePubMedPMC
• 7. Artusi CA, Rinaldi D, Balestrino R, Lopiano L. Deep brain stimulation for atypical parkinsonism: A systematic review on efficacy and safety. Parkinsonism Relat Disord 2022;96:109–118.ArticlePubMed
• 8. Badihian N, Jackson LM, Klassen BT, Hassan A, Low PA, Singer W, et al. The effects of deep brain stimulation in patients with multiple system atrophy. J Parkinsons Dis 2022;12:2595–2600.ArticlePubMedPMC

Figure & Data

References

Citations

Citations to this article as recorded by  

• NDPACX: a newly defined X-linked Parkinsonian syndrome associated with SLC9A6 hemizygote mutation
  Ryotaro Okochi, Yoshihiro Nihei, Daisuke Ito
  Brain Communications.2025;[Epub]     CrossRef
• Deep brain stimulation and magnetic resonance-guided focused ultrasound in Parkinsonism and related disorders: State-of-the-Art and future prospects
  Tsung-Lin Lee, Ming-Kuei Lu
  Journal of the Formosan Medical Association.2025;[Epub]     CrossRef

Comments on this article