Clinical Response of Levodopa in CTNNB1-Related Dystonia

Abstract

β-catenin, which is encoded by the CTNNB1 gene, is essential for the development and functioning of the brain. There are a few documented cases of dystonia related to CTNNB1. Here, we report the case of an 11-year-old Spanish boy referred for movement disorders and gait disturbance. He had motor developmental delay and achieved unassisted walking at 3 years, with a tiptoe gait and valgus foot posture requiring ankle-foot orthoses. Blood tests showed elevated creatine kinase levels (1684 U/L, normal range 62–235). Molecular analysis revealed a deletion in exons 3-9 of the DMD gene, leading to the diagnosis of Becker muscular dystrophy. By age 8, he presents frequent falls due to a dystonic posture of the feet and abnormal movements in the upper and lower limbs. Whole-exome sequencing revealed a novel heterozygous, de novo pathogenic frameshift variant in the CTNNB1 gene (NM_001098209.1):p.Thr297fs/ c.889dupA. Treatment with levodopa/carbidopa (5.3 mg/kg/day) led to a partial clinical improvement, including a decrease in dystonia, measured by the Burke-Fahn-Marsden Dystonia Rating Scale, and choreic movements in all four limbs. We suggest that levodopa contributes to motor improvement in patients with CTNNB1-related dystonia, supporting its inclusion in the differential diagnosis of childhood dopa-responsive dystonia.

Keywords

CTNNB1 - levodopa - dystonia - intellectual disability - Becker muscular dystrophy

Authors' Contributions

Research project: A. Conception, B. Organization, C. Execution;

Statistical Analysis: A. Design, B. Execution, C. Review and Critique;

Manuscript: A. Writing of the first draft, B. Review and Critique.

A.R.B., 1C, 3A

L.M., 1C, 3B

J.A., 1C, 3B

C.B., 1C, 3B

L.C., 1C, 3B

A.N., 1C, 3B

J.D.O.-E., 1A, 1B, 1C, 3B

Ethical Approval

The legal guardians gave their written consent to the recording of the patient for publication, and the study received ethical approval by the Ethics Committee (ART-03-23). 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.

Publikationsverlauf

Eingereicht: 20. März 2024

Angenommen: 27. April 2024

Artikel online veröffentlicht:
03. Juni 2024

• References

• 1 Tucci V, Kleefstra T, Hardy A. et al. Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features. J Clin Invest 2014; 124 (04) 1468-1482
• 2 Yan D, Sun Y, Xu N, Yu Y, Zhan Y. Mainland Chinese League of NEDSDV Rare Disease. Genetic and clinical characteristics of 24 mainland Chinese patients with CTNNB1 loss-of-function variants. Mol Genet Genomic Med 2022; 10 (11) e2067
• 3 Wickham RJ, Alexander JM, Eden LW. et al. Learning impairments and molecular changes in the brain caused by β-catenin loss. Hum Mol Genet 2019; 28 (17) 2965-2975
• 4 de Ligt J, Willemsen MH, van Bon BWM. et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 2012; 367 (20) 1921-1929
• 5 Ho S, Tsang MHY, Fung JLF. et al. CTNNB1-related neurodevelopmental disorder in a Chinese population: a case series. Am J Med Genet A 2022; 188 (01) 130-137
• 6 Rossetti LZ, Bekheirnia MR, Lewis AM. et al; Undiagnosed Diseases Network. Missense variants in CTNNB1 can be associated with vitreoretinopathy-Seven new cases of CTNNB1-associated neurodevelopmental disorder including a previously unreported retinal phenotype. Mol Genet Genomic Med 2021; 9 (01) e1542
• 7 Kharbanda M, Pilz DT, Tomkins S. et al; DDD Study. Clinical features associated with CTNNB1 de novo loss of function mutations in ten individuals. Eur J Med Genet 2017; 60 (02) 130-135
• 8 Wirth T, Tranchant C, Drouot N. et al. Increased diagnostic yield in complex dystonia through exome sequencing. Parkinsonism Relat Disord 2020; 74 (74) 50-56
• 9 Kwong AKY, Tsang MHY, Fung JLF. et al. Exome sequencing in paediatric patients with movement disorders. Orphanet J Rare Dis 2021; 16 (01) 32
• 10 Thomsen M, Lange LM, Zech M, Lohmann K. Genetics and pathogenesis of dystonia. Annu Rev Pathol 2024; 19: 99-131
• 11 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; 33 (04) 656-657
• 12 Takeuchi H, Mori Y, Tsutsumi Y. Pathophysiology, prognosis and treatment of tardive dyskinesia. Ther Adv Psychopharmacol 2022; 12 (January): 20 451253221117313
• 13 Sudnawa KK, Garber A, Cohen R. et al. Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder. Clin Genet 2024; 105 (05) 523-532
• 14 Lee WW, Jeon B, Kim R. Expanding the spectrum of dopa-responsive dystonia (DRD) and proposal for new definition: DRD, DRD-plus, and DRD look-alike. J Korean Med Sci 2018; 33 (28) e184
• 15 Wijemanne S, Jankovic J. Dopa-responsive dystonia–clinical and genetic heterogeneity. Nat Rev Neurol 2015; 11 (07) 414-424
• 16 Nunes MB, Martinez ARM, Rezende TJR. et al. Dystonia in Machado-Joseph disease: clinical profile, therapy and anatomical basis. Parkinsonism Relat Disord 2015; 21 (12) 1441-1447
• 17 Ikezawa J, Shimazaki R, Tobisawa S, Sugaya K, Takahashi K. Dopa-responsive dystonia in spinocerebellar ataxia 6: a case report. Clin Neurol Neurosurg 2023; 229 (March): 107721
• 18 Salles PA, Terán-Jimenez M, Vidal-Santoro A, Chaná-Cuevas P, Kauffman M, Espay AJ. Recognizing atypical dopa-responsive dystonia and its mimics. Neurol Clin Pract 2021; 11 (06) e876-e884