Levodopa‐Responsive Dystonia Secondary to <scp> <i>CTNNB1</i> </scp> Neurodevelopmental Disorder

CTNNB1 neurodevelopmental disorder (CTNNB1-NND) is associated with heterozygous loss-of-function mutation of CTNNB1 gene (OMIM116806), which causes dopaminergic neurogenesis dysfunction1, 2 and leads to a wide range of neurological, behavioral, and ocular manifestations, including limb predominant spasticity, dystonia, truncal hypotonia, cognitive impairment, autism spectrum disorder (ASD), speech impairment, behavioral challenges, microcephaly, familial exudative vitreoretinopathy and lens/vitreous opacities, refractive errors, and strabismus.3, 4 Currently, there is no curative treatment for this condition. Trials using levodopa (l-dopa) to treat CTNNB1-NND-related dystonia yielded variable clinical response. Pipo-Deveza and colleagues reported a case with improved hypertonia and neurodevelopmental outcomes after the initiation of l-dopa.2 However, this medication provided only mild or no clinical improvement for CTNNB1-NND patients reported in another case series.5 We report on 5 patients with CTNNB1-NND-associated dystonia who were treated with l-dopa/carbidopa and outline their treatment response. Table S1 summarizes their demographic data, clinical features, molecular diagnosis, and neuroimaging findings. Clinically, they shared some common features that were previously reported in other CTNNB1-NND cases, which are presented in Table S2. This table presents pooled patient's data on the clinical response of dystonia to l-dopa, highlighting common characteristics, such as early-onset global developmental delay, microcephaly, truncal hypotonia, progressive lower-limb spasticity and hyperreflexia, dystonia, and anxiety/emotional lability.1, 3, 4 Two patients had facial dysmorphisms, which were consistent with the findings in previously reported cases.3, 4 Tethered spinal cord was another feature of CTNNB1-NND,4 which was found in 1 of our patients, whereas 3 patients had a fatty filum terminale, which could also be an early sign of tethered cord. Only 1 patient underwent cerebrospinal fluid analysis, which revealed normal levels of 5-hydroxyindoleacetic acid, homovanillic acid, 3-O-methyldopa, tetrahydrobiopterin, neopterin, and pyridoxal-5-phosphate. The average improvement in the Six-Minute Walking Test (6MWT) in our patients was 117.5 m. The individual 6MWT improvement in all patients exceeded the reported minimum clinically important difference in the 6MWT for children with motor impairment.6 Gait analysis for the patient requiring walking support is presented in Table S3, demonstrating objective improvements in step length and walking efficiency. In our cohort, we employed a similar l-dopa–carbidopa treatment regimen. All children commenced treatment at a starting dose of 1 mg/kg/day, divided into 3 doses, which was gradually titrated to 5 to 10 mg/kg/day based on clinical response. Close monitoring was maintained throughout the dose escalation, which occurred over several weeks, although 1 child required a significantly higher dose. Particularly, the symptoms did not improve immediately and typically was observed after a few weeks to a few months of treatment, as demonstrated in Videos 1 and 2. Younger children were treated using compounded formulations, whereas older children were able to take the tablet form. A comparable timeline of clinical improvement has been reported in a previous case.2 Currently, no specific treatment has been recommended for dystonia in CTNNB1-NND, and dystonia may remain undetected when overshadowed by spasticity unless specifically assessed. Initiation of l-dopa for our patients led to improvements in dystonia, motor function, speech, behavioral abnormalities, and cognition. The use of l-dopa in CTNNB1-NND patients with dystonia and developmental delay is supported by studies that highlighted the roles of β-catenin in the development of dopaminergic neurons and maintenance of the integrity of the N-cadherin protein complex, which is essential for cell adhesion and polarity in neurogenic niche progenitor cells.7 Additionally, β-catenin regulates the stability of radial glia cells, influencing their differentiation into dopaminergic neurons and their migration.8, 9 β-Catenin signaling also contributes to the expansion of dopaminergic neurons from progenitor cells.7 These findings underscore the potential importance of early l-dopa treatment in optimizing developmental windows for dopaminergic neuron development. In our study, we observed significant improvement in dystonic symptoms among our pediatric patients compared to the adult participants. The exact pathophysiology underlying the response to l-dopa remains unclear; however, we hypothesize that these processes may contribute to the delayed therapeutic effect. Furthermore, we identified various pathogenic variants in the CTNNB1 gene. Although it remains unclear whether l-dopa responsiveness is specifically linked to certain CTNNB1 variants; we observed a positive response to l-dopa treatment in our cohort. Although genotype–phenotype correlations have been previously described, particularly regarding the severity of manifestations, the relationship between different variants and l-dopa responsiveness has not yet been addressed.10 Larger studies are needed to validate this hypothesis and further investigate the mechanisms involved. Nonmotor manifestations, particularly the behavioral aspects, of this disorder significantly impact the quality of life for affected children and their families. Behavioral challenges such as severe temper tantrum, depression, ASD, and attention deficit hyperactivity disorder were observed in our patients.3, 4 Interestingly, all our patients subjectively reported improvements in behavioral concerns after l-dopa treatment, including reduction in temper tantrum, improved attention, impulse control, and decreased emotional liability, which can be hypothetically explained by the role of the dopaminergic system in mood regulation and emotional response. Our cases highlighted that early treatment with l-dopa holds promise for improving dystonia and neurodevelopmental delay and addressing behavioral aspects in affected patients. This expands the existing data on l-dopa treatment for CTNNB1-NND patients with dystonia and developmental delay. However, the absence of standardized dystonia and spasticity rating scales—such as the Burke–Fahn–Marsden Dystonia Rating Scale—is a limitation, primarily due to the challenges in applying these tools in young children with intellectual disability. Larger multicenter studies are warranted to better elucidate the role of l-dopa in this rare condition and its impact within the critical window of brain development. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical analysis: A. Design, B. Execution, C. Review and critique; (3) Manuscript: A. Writing of the first draft, B. Review and critique. H.A.: 1A, 2A, 3A W.K.L.: 1B, 2B, 2C D.C.: 1C, 2C, 3B I.T.: 2C, 3B A.F.: 2C, 3B C.G.: 2C, 3B Ethical Compliance Statement: This study was approved by the Institutional Review Board of the Hospital for Sick Children with assigned reference number 1000080711. Informed consent was obtained from all participants or their respective caregivers. We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: No specific funding was received for this work, and the authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: AF has stock ownership in Inbrain Pharma and has received payments as consultant and/or speaker from Abbvie, Abbott, Boston Scientific, Ceregate, Dompé Farmaceutici, Inbrain Neuroelectronics, Ipsen, Medtronic, Iota, Syneos Health, Merz, Sunovion, Paladin Labs, UCB, Sunovion. He has received research support from Abbvie, Boston Scientific, Medtronic, Praxis, ES and receives royalties from Springer, unrelated to this work.CG has acted as a paid consultant to Medtronic Inc, Ipsen Inc. and Acadia She has served on the Advisory Board of Medtronic Inc, unrelated to this work. Acknowledgments: We extend our sincere gratitude to the patients and their families for their participation and for generously contributing to this research. The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1. Clinical summary of our patients with CTNNB1-NND (CTNNB1 neurodevelopmental disorder). Table S2. Pooled patient's data on the clinical response of dystonia to levodopa. Table S3. Gait analysis parameters for the adult patient using Zeno Walkway. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.