Study of L-dopa Treatment in Patients With a Neurodevelopmental Disorder (CTNNB1 Gene)

Official title

Prospective Pilot Study of L-dopa Treatment in Patients With a Neurodevelopmental Disorder Related to a Pathogenic Variant of the CTNNB1 Gene

Overview

Neurodevelopmental disorders (NDD) encompass conditions that impair cognitive and/or emotional development in children, significantly impacting school, social, and family life. They are often linked to genetic causes and, in most cases, lack curative treatment. Among these disorders, monoallelic variations in the CTNNB1 gene cause a rare syndrome known as NEDSDV (Neurodevelopmental disorder with spastic diplegia and visual defects, OMIM: 615075). About twenty patients are reported in France. This syndrome is characterized by global developmental delay, intellectual disability, axial hypotonia, autistic traits, microcephaly, and sometimes ocular anomalies. The clinical profile resembles that of cerebral palsy, and CTNNB1 syndrome is considered a genetic form of this condition, accounting for roughly 4% of cases where a gene has been identified. Motor impairment is a core feature, with a wide range of movement disorders. Research remains limited, except for a recent publication. Dystonic hypertonia of the lower limbs is frequently described, more pronounced distally than proximally, without pyramidal signs. Spasticity is less common. Gait has been poorly studied: it may be absent or, when acquired, unstable, often tiptoe, and sometimes broad-based, resembling ataxia despite the absence of cerebellar signs. These motor features are difficult to detect before one year of age. To date, no longitudinal studies exist on motor or cognitive progression in CTNNB1 patients; available data are cross-sectional and do not suggest cognitive decline. From a pathophysiological perspective, the CTNNB1 gene encodes β-catenin, a key protein in cell adhesion and Wnt signaling, involved in cell differentiation and tissue homeostasis. It plays an essential role in embryonic brain development, particularly neuritogenesis and synaptic organization, with a specific impact on dopaminergic structures in the midbrain. Knock-out animal models show severe reduction in dopaminergic neurogenesis. These findings suggest that CTNNB1 anomalies lead to secondary dopaminergic deficits, contributing to clinical signs. The hypothesis is that this deficit could be partially corrected by dopamine supplementation. Regarding treatment, L-dopa (levodopa), used in dopaminergic disorders, has shown beneficial effects in a CTNNB1 patient. In our neuropediatrics department, two patients treated with L-dopa exhibited notable improvements in alertness, language, and motor skills within two months. These observations support the hypothesis that L-dopa may improve certain motor and non-motor symptoms in these patients. In summary, CTNNB1 syndrome is a rare form of NDD, clinically similar to cerebral palsy, with complex motor disorders and a probable dopaminergic deficit. Current evidence calls for further research, including longitudinal studies and therapeutic trials targeting the dopaminergic pathway.

Interventions

• Drug L-Dopa
  Treatment with L-dopa combined with a peripheral decarboxylase inhibitor (carbidopa) will be introduced gradually over a period of one year from the start of treatment. Motor, cognitive, quality of life and tolerance assessments will be carried out before treatment and at 6 and 12 months.

Primary outcome measures

• Assessment of motor skills [Time frame: Baseline and 6 month follow-up visit]

Secondary outcome measures (10)

• Assessment of motor skills [Time frame: 6 month follow-up visit and end-of-study visit at 12 months]
• Assessment of motor skills [Time frame: Baseline, 6 month follow-up visit and end-of-study visit at 12 months]
• Cognitive assessment [Time frame: Baseline and end-of-study visit at 12 months]
• Cognitive assessment [Time frame: Baseline and end-of-study visit at 12 months]
• Cognitve assessment [Time frame: Baseline and end-of-study visit at 12 months]
• Quality of life assessment [Time frame: Baseline, 6 month follow-up visit and end-of-study visit at 12 months]
• Quality of life assessment [Time frame: Baseline, 6 month follow-up ans end-of-study visit at 12 months]
• Assessment of tolerance [Time frame: From baseline to the end-of-study visit at 12 months (continuous assessment throughout the study period)]
• Assessment of tolerance [Time frame: From baseline to the end-of-study visit at 12 months (continuous assessment throughout the study period)]
• Assessment of tolerance [Time frame: From baseline to the end-of-study visit at 12 months (continuous assessment throughout the study period)]

Eligibility criteria

Inclusion criteria

• Aged between 1 and 15 years inclusive,
• Carrier of a pathogenic variant of CTNNB1,
• Patient with dystonia,
• Patient willing to comply with the contraception requirements detailed in the protocol.

Exclusion criteria

• Contraindication to treatment with L-dopa and carbidopa or any of its excipients,
• Current treatment with L-dopa, dopamine agonist, or dopamine blocker,
• Patients with peptic ulcer disease,
• Patients with open-angle glaucoma,
• Patients with orthostatic hypotension,
• Failure to obtain informed consent signed by both parents or legal guardians and the child's assent, if possible,
• Patients not affiliated with or not covered by a social security scheme,
• Individuals participating in another study with an exclusion period still in progress,
• Individuals who are pregnant or wish to become pregnant within 12 months of inclusion.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

France · 1 center

• CHU de Montpellier — Montpellier

Publications

• Yu X, Malenka RC. Beta-catenin is critical for dendritic morphogenesis. Nat Neurosci. 2003 Nov;6(11):1169-77. doi: 10.1038/nn1132. Epub 2003 Oct 5. PMID 14528308
• Wang H, Zhao Y, Yang L, Han S, Qi M. Identification of a novel splice mutation in CTNNB1 gene in a Chinese family with both severe intellectual disability and serious visual defects. Neurol Sci. 2019 Aug;40(8):1701-1704. doi: 10.1007/s10072-019-03823-5. Epub 2019 Mar 30. PMID 30929091
• Tucci V, Kleefstra T, Hardy A, Heise I, Maggi S, Willemsen MH, Hilton H, Esapa C, Simon M, Buenavista MT, McGuffin LJ, Vizor L, Dodero L, Tsaftaris S, Romero R, Nillesen WN, Vissers LE, Kempers MJ, Vulto-van Silfhout AT, Iqbal Z, Orlando M, Maccione A, Lassi G, Farisello P, Contestabile A, Tinarelli F, Nieus T, Raimondi A, Greco B, Cantatore D, Gasparini L, Berdondini L, Bifone A, Gozzi A, Wells S PMID 24614104
• Tang M, Miyamoto Y, Huang EJ. Multiple roles of beta-catenin in controlling the neurogenic niche for midbrain dopamine neurons. Development. 2009 Jun;136(12):2027-38. doi: 10.1242/dev.034330. Epub 2009 May 13. PMID 19439492
• Tan WH, Bird LM, Sadhwani A, Barbieri-Welge RL, Skinner SA, Horowitz LT, Bacino CA, Noll LM, Fu C, Hundley RJ, Wink LK, Erickson CA, Barnes GN, Slavotinek A, Jeremy R, Rotenberg A, Kothare SV, Olson HE, Poduri A, Nespeca MP, Chu HC, Willen JM, Haas KF, Weeber EJ, Rufo PA. A randomized controlled trial of levodopa in patients with Angelman syndrome. Am J Med Genet A. 2018 May;176(5):1099-1107. doi: PMID 28944563
• Roubertie A, Roze E, Bahi-Buisson N, Payet C, Echenne B, Doummar D. [Treatment of childhood dystonia]. Arch Pediatr. 2010 May;17(5):540-53. doi: 10.1016/j.arcped.2010.02.016. Epub 2010 Apr 1. French. PMID 20362421
• Pipo-Deveza J, Fehlings D, Chitayat D, Yoon G, Sroka H, Tein I. Rationale for dopa-responsive CTNNB1/ss-catenin deficient dystonia. Mov Disord. 2018 Apr;33(4):656-657. doi: 10.1002/mds.27320. Epub 2018 Feb 13. No abstract available. PMID 29436745
• Nouri N, Patel MJ, Joksimovic M, Poulin JF, Anderegg A, Taketo MM, Ma YC, Awatramani R. Excessive Wnt/beta-catenin signaling promotes midbrain floor plate neurogenesis, but results in vacillating dopamine progenitors. Mol Cell Neurosci. 2015 Sep;68:131-42. doi: 10.1016/j.mcn.2015.07.002. Epub 2015 Jul 9. PMID 26164566

Identifiers

NCT: NCT07614126 · RECMPL23_0426

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗