Rationale for dopa‐responsive <i>CTNNB1/ß</i>‐catenin deficient dystonia

Pipo-Deveza, Judy R.; Chitayat, David; Yoon, Grace; Sroka, Hana; Tein, Ingrid

doi:10.1002/mds.27320

Cited by 13 publications

(11 citation statements)

References 7 publications

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“…Previous studies in patients with spastic paraplegia 11 (SPG11) demonstrated neurotransmitter abnormalities in dopamine and tetrahydrobiopterin pathways [8]. In that study, all patients responded partially to L-dopa/carbidopa and sapropterin treatment and they suggested a trial of L-dopa/carbidopa and sapropterin treatment for (1) CTNNB1: L-dopa treatment [12] (2) COL1A1: Treatment to prevent bone fracture resulted from osteogenesis imperfecta Dopa treatment was offered but has not started yet Genetic finding explained the phenotypes of blue sclera and bone fractures in that patient who has been referred to the endocrinologist for further management 17 Dystonia, Choreoathetosis with status dystonicus GNAO1…”

Section: Potential Genotype-targeted Treatment Implicationsmentioning

confidence: 84%

“…Phenotypic diagnosis only has limitations as many symptoms may have more than one underlying etiology and any particular pathophysiology can result in a complex combination of symptoms [6]]. Genetic diagnosis allows a comprehensive understanding of the underlying pathophysiology and provides specific treatment options [7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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Exome sequencing in paediatric patients with movement disorders

Kwong

Tsang

Fung

et al. 2021

Orphanet J Rare Dis

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Background Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. Results We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. Conclusions A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

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Section: Potential Genotype-targeted Treatment Implicationsmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Exome sequencing in paediatric patients with movement disorders

Kwong

Tsang

Fung

et al. 2021

Orphanet J Rare Dis

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“…However, Patient 30 with SPG11 did not show any response to L-dopa despite the presence of secondary neurotransmitter de ciency in homovanillic acid. For CTNNB1 mutation, a recent case study reported a signi cant response to L-dopa treatment in a dystonic patient with a normal CSF neurotransmitter pro le (12). This response was possibly related to synaptic dopamine increase as a previous study suggested the role of beta-catenin in dopamine neurons development (25).…”

Section: Potential Genotype-targeted Treatment Implicationsmentioning

confidence: 90%

“…All of the authors reviewed and approved the nal manuscript. Tables Dystonia CTNNB1 and COL1A1 (1) CTNNB1: L-dopa treatment (12) (2) COL1A1: Treatment to prevent bone fracture resulted from osteogenesis imperfecta Dopa treatment was offered but has not started yet.…”

Section: Consent For Publicationmentioning

confidence: 99%

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Exome Sequencing in Paediatric Patients with Movement Disorders with Treatment Possibilities

Kwong

Tsang

Fung

et al. 2020

Preprint

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Background: Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. Results: We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential targeted treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. Conclusion: A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management using targeted therapies. The study highlights the potential of implementing precision medicine in the patients.

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Childhood‐onset progressive dystonia associated with pathogenic truncating variants in CHD8

Doummar

Treven

Qebibo³

et al. 2021

Ann Clin Transl Neurol

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Originally described as a risk factor for autism, CHD8 loss-of-function variants have recently been associated with a wider spectrum of neurodevelopmental abnormalities. We further expand the CHD8-related phenotype with the description of two unrelated patients who presented with childhood-onset progressive dystonia. Whole-exome sequencing conducted in two independent laboratories revealed a CHD8 nonsense variant in one patient and a frameshift variant in the second. The patients had strongly overlapping phenotypes characterized by generalized dystonia with mild-to-moderate neurodevelopmental comorbidity. Deep brain stimulation led to clinical improvement in both cases. We suggest that CHD8 should be added to the growing list of neurodevelopmental disorder-associated genes whose mutations can also result in dystoniadominant phenotypes.

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Rationale for dopa‐responsive CTNNB1/ß‐catenin deficient dystonia

Cited by 13 publications

References 7 publications

Exome sequencing in paediatric patients with movement disorders

Exome sequencing in paediatric patients with movement disorders

Exome Sequencing in Paediatric Patients with Movement Disorders with Treatment Possibilities

Childhood‐onset progressive dystonia associated with pathogenic truncating variants in CHD8

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