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Letter to the editor
Joubert Syndrome Presenting With Levodopa-Responsive Parkinsonism
Jin Hwangbo1orcid, Ki-Seok Park1orcid, Hyun Sung Kim2orcid, Jae-Hwan Choi1,3orcid, Jae-Hyeok Lee1,3corresp_iconorcid
> Epub ahead of print
DOI: https://doi.org/10.14802/jmd.23275
Published online: March 27, 2024

1Department of Neurology, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Korea

2Department of Neurology, Gyeongsang National University Changwon Hospital, Gyeongsang National University School of Medicine, Changwon, Korea

3Department of Neurology, Pusan National University School of Medicine, Yangsan, Korea

Corresponding author: Jae-Hyeok Lee, MD, PhD Department of Neurology, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan 50612, Korea / Tel: +82-55-360-2453 / Fax: +82-55-360-2152 / E-mail: jhlee.neuro@pusan.ac.kr
• Received: December 29, 2023   • Revised: February 23, 2024   • Accepted: March 27, 2024

Copyright © 2024 The Korean Movement Disorder Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Dear Editor,
Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by a distinctive cerebellar vermis hypoplasia and brainstem malformation termed the “molar tooth sign” on magnetic resonance imaging (MRI). To date, pathogenic variants in 34 genes are known to cause JS. Clinical features include hypotonia in infancy and subsequent development of ataxia and intellectual disability/developmental delay, with additional features including oculomotor apraxia and abnormal respiratory patterns [1]. Parkinsonism is rarely reported in JS patients [2]. Here, we report a male patient with JS who presented with levodopa-responsive parkinsonism.
A 47-year-old man presented with a 2-year history of progressive gait disturbance. Since early childhood, he has exhibited developmental delay in speech accompanied by intellectual disability. He was born as a twin; however, his brother died shortly after birth. There was no other significant family history.
At the age of 47, neurological examination revealed parkinsonism manifesting as a masked face, marked bradykinesia, rigidity, action tremors in the hands, and gait disturbance. The patient also exhibited oculomotor apraxia, manifesting as severe difficulties in initiating voluntary ocular movements upon command or when following targets, and dysarthria. He was unable to stand or walk independently without assistance (Supplementary Video 1 in the online-only Data Supplement). His Mini-Mental State Examination and Montreal Cognitive Assessment scores were 17 and 7 points, respectively.
Three-dimensional video-oculography of the patient’s eye movements exhibited intermittent cyclotorsional pendular nystagmus with low frequency in both eyes. During horizontal reflexive saccades with a fixed target, hypometric saccades were observed with delayed latency in some trials; however, most saccades seemed to be nontargeted and unrelated to the stimulus. Horizontal smooth pursuit was also impaired, and the eye position did not match the target position (Figure 1A). An ophthalmologist discovered no evidence of retinal dysfunction or optic nerve abnormality. The head-up tilt test revealed orthostatic hypotension. Routine blood test results were within the normal ranges, except for mildly elevated liver enzymes (aspartate aminotransferase 76 IU/L [normal range: 0–50 IU/L] and alanine aminotransferase 159 IU/L [normal range: 0–50 IU/L]). The liver FibroScan revealed moderate scarring. Electroencephalography findings were normal. Polysomnography revealed mild obstructive sleep apnea with periodic limb movement during sleep. MRI revealed a “molar tooth sign” in the midbrain due to cerebellar vermis hypoplasia and superior cerebellar peduncular thickening (Figure 1B, C). [18F] N-(3-fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane positron emission tomography (PET) revealed markedly decreased dopamine transporter binding in the posterior putamen, which was more prominent on the left side. Correspondingly, bradykinesia in the right limb was more severe (Figure 1D).
Whole-exome sequencing confirmed the presence of known compound heterozygous mutations (c.244C>T, p.Pro82Ser; c.2758delT, p.Tyr920fs) in the transmembrane protein 67 (TMEM67) gene (NM_153704.5), as listed in ClinVar (rs762543032; rs777993921) [3]. No other genetic variations that might underlie parkinsonism as a co-occurrence unrelated to JS were detected.
After receiving 25/100 mg carbidopa/levodopa three times daily, the patient was able to walk independently (Supplementary Video 1 in the online-only Data Supplement). During the on phase, the Unified Parkinson’s Disease Rating Scale motor score improved from 57 to 33 (42.1%), and the modified Hoehn and Yahr stage improved from 4 to 2.5. Levodopa partially improved oculomotor apraxia at the bedside exam. The follow-up overall saccadic task and smooth pursuit performances were better than those before treatment, although hypometric saccades and saccadic smooth pursuit were still observed (Figure 1A).
JS is characterized by genetic heterogeneity, with 34 identified genes implicated in the production of proteins crucial for ciliary function. There are also genotype‒phenotype variations within the causative genes. The TMEM67 gene mutation found in our patient is a well-known gene that contributes to JS with liver involvement [1]. Interestingly, in our patient, we observed adult-onset parkinsonism accompanied by presynaptic dopaminergic deficits and a dramatic response to levodopa. In addition, levodopa enhanced performance in the saccadic and pursuit tasks. This result could be attributed to the beneficial effects of levodopa on the frontostriatal pathomechanism of oculomotor dysfunction [4].
Movement disorders other than ataxia, which is attributed to cerebellar hypoplasia, are rarely reported in patients with JS. Various movement disorders such as tremor, dystonia, and myoclonus have been described [5]. However, levodopa-responsive parkinsonism associated with dopaminergic deficits has rarely been reported in JS patients. One JS patient with extrapyramidal signs exhibited increased raclopride binding with normal fluorodopa uptake on PET. The levodopa trials were ineffective, but mild subjective improvement in tremors was observed with pramipexole treatment [2].
The roles of primary cilia and specific ciliary signaling pathways in Parkinson’s disease have been previously described [6]. However, whether ciliopathy in JS is directly associated with dopaminergic degeneration remains unclear. In a postmortem study of patients with JS, two cases of abnormalities in the substantia nigra, including a small substantia nigra and a lightly pigmented substantia nigra, were reported, but these findings did not demonstrate dopaminergic neuronal defects [7]. In mouse ciliopathy models, the loss of primary cilia reduced the number of midbrain dopaminergic neurons during development [8]. It is possible that JS may result in dopaminergic neuronal loss in adulthood due to the accumulation of cilia dysfunction with aging. Nevertheless, the incidental co-occurrence of JS and parkinsonism cannot be excluded.
This case report expands the clinical spectrum of JS. Parkinsonism due to ciliopathy can also be observed in patients with JS at middle and late ages. Since the aforementioned symptoms may respond to medication, they should be considered when evaluating patients with JS.
The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.23275.
Video 1.
Before and after levodopa treatment. Segment 1: Before taking levodopa, the patient exhibited marked bradykinesia and tremor in both hands. He was unable to stand or walk without assistance. Segment 2: In the on phase while receiving 100 mg of levodopa three times daily, the severity of bradykinesia improved substantially, and the symptoms were more severe on the right side. He became able to rise from a chair and walk independently.

Ethics Statement

This study was approved by the Institutional Review Board of the Pusan National University Yangsan Hospital (No. 55-2023-011), and informed consent was obtained in accordance with the recommendations of the Declaration of Helsinki.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

This study was supported by the 2023 Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, and a grant of the Korea Health Technology R&D Project through the Korean Healthy Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (RS-2023-00265377).

Author Contributions

Conceptualization: Jae-Hyeok Lee. Data curation: all authors. Funding acquisition: Jae-Hyeok Lee. Supervision: Jae-Hyeok Lee. Visualization: Jin Hwangbo, Hyun Sung Kim, Jae-Hwan Choi. Writing—original draft: Jin Hwangbo, Ki-Seok Park, Hyun Sung Kim. Writing—review & editing: Jae-Hwan Choi, Jae-Hyeok Lee.

We are grateful to the patient and his family for their cooperation.
Figure 1.
Video-oculography, brain magnetic resonance imaging, FP-CIT PET of the patient. A: Video-oculography demonstrated hypometric saccades, nontargeted saccades to the stimulus, and impaired horizontal smooth pursuit during pretreatment. After treatment with levodopa, overall saccade task performance and smooth pursuit performance improved. B: Axial T2-weighted image showing the molar tooth sign and thickened superior cerebellar peduncles. C: Mid-sagittal T1-weighted image showing hypoplasia of the cerebellar vermis. D: FP-CIT PET revealed markedly reduced dopaminergic uptake, which was more prominent on the left side. FP-CIP, [18F] N-(3-fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane; PET, positron emission tomography.
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