Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology

Giacomo Garone¹, Alice Innocenti², Melissa Grasso³, Alessandra Mandarino⁴, Alessandro Capuano⁵, Gessica Della Bella⁶, Flaminia Frascarelli⁷, Daria Diodato⁸, Roberta Onesimo⁹, Giuseppe Zampino¹⁰, Antonio Novelli¹¹, Maria Cristina Digilio¹², Andrea Bartuli¹², Maria Lisa Dentici¹², Pasquale Parisi¹³, Serena Galosi¹⁴, Davide Tonduti¹⁵, Enrico Bertini¹⁶, Lorenzo Sinibaldi¹², Nicola Specchio¹⁷

Affiliations

¹ Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies, EpiCARE, Rome, Italy; Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sant' Andrea Hospital, Sapienza University of Rome, Rome, Italy. Electronic address: giacomo.garone@opbg.net.
² Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies, EpiCARE, Rome, Italy; Unit of Child Neurology and Psychiatry, Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy.
³ Neurological and Neurosurgical Diseases Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁴ Child and Adolescent Neuropsychiatry Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁵ Cerebral Palsy Center - Neuropsychiatric Unit - ASL Viterbo, Viterbo, Italy.
⁶ Management and Diagnostic Innovations & Clinical Pathways Research Area, Neurorehabilitation and Adapted Physical Activity Day Hospital, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁷ Functional Rehabilitation Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁸ Unit of Muscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁹ Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A, Gemelli IRCCS, Full Member of European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders, ITHACA, Rome, Italy.
¹⁰ Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A, Gemelli IRCCS, Full Member of European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders, ITHACA, Rome, Italy; Università Cattolica Del Sacro Cuore, Rome, Italy.
¹¹ Translational Cytogenomics Research Unit, Laboratory of Medical Genetics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹² Rare Diseases and Medical Genetics Unit, IRCCS Bambino Gesù Children Hospital, Rome, Italy.
¹³ Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sant' Andrea Hospital, Sapienza University of Rome, Rome, Italy.
¹⁴ Unit of Child Neurology and Psychiatry, Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy.
¹⁵ Unit of Pediatric Neurology, C.O.A.L.A (Center for Diagnosis and Treatment of Leukodystrophies), Buzzi Children's Hospital, Milano, 20154, Italy; Department of Biomedical and Clinical Sciences, Università Degli Studi di Milano, Milano, 20157, Italy.
¹⁶ Research Unit of Muscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹⁷ Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies, EpiCARE, Rome, Italy.

PMID: 39067319
DOI: 10.1016/j.parkreldis.2024.107057

Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology

Giacomo Garone et al. Parkinsonism Relat Disord. 2024 Sep.

. 2024 Sep:126:107057.

doi: 10.1016/j.parkreldis.2024.107057. Epub 2024 Jul 9.

Authors

Affiliations

¹ Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies, EpiCARE, Rome, Italy; Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sant' Andrea Hospital, Sapienza University of Rome, Rome, Italy. Electronic address: giacomo.garone@opbg.net.
² Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies, EpiCARE, Rome, Italy; Unit of Child Neurology and Psychiatry, Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy.
³ Neurological and Neurosurgical Diseases Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁴ Child and Adolescent Neuropsychiatry Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁵ Cerebral Palsy Center - Neuropsychiatric Unit - ASL Viterbo, Viterbo, Italy.
⁶ Management and Diagnostic Innovations & Clinical Pathways Research Area, Neurorehabilitation and Adapted Physical Activity Day Hospital, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁷ Functional Rehabilitation Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁸ Unit of Muscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁹ Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A, Gemelli IRCCS, Full Member of European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders, ITHACA, Rome, Italy.
¹⁰ Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A, Gemelli IRCCS, Full Member of European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders, ITHACA, Rome, Italy; Università Cattolica Del Sacro Cuore, Rome, Italy.
¹¹ Translational Cytogenomics Research Unit, Laboratory of Medical Genetics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹² Rare Diseases and Medical Genetics Unit, IRCCS Bambino Gesù Children Hospital, Rome, Italy.
¹³ Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sant' Andrea Hospital, Sapienza University of Rome, Rome, Italy.
¹⁴ Unit of Child Neurology and Psychiatry, Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy.
¹⁵ Unit of Pediatric Neurology, C.O.A.L.A (Center for Diagnosis and Treatment of Leukodystrophies), Buzzi Children's Hospital, Milano, 20154, Italy; Department of Biomedical and Clinical Sciences, Università Degli Studi di Milano, Milano, 20157, Italy.
¹⁶ Research Unit of Muscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹⁷ Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies, EpiCARE, Rome, Italy.

PMID: 39067319
DOI: 10.1016/j.parkreldis.2024.107057

Abstract

Introduction: CTNNB1 gene loss-of-function variants cause Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV, OMIM 615075). Although motor impairment represents a core feature of this condition, the motor phenotype remains poorly described. We systematically assessed a cohort of 14 patients with disease-causing CTNNB1 variants to better characterize the movement disorder phenotype.

Methods: patients were enrolled at Bambino Gesù Children's Hospital in Rome, Italy, between January 2019 and February 2024. 14 participants were included and underwent extensive genetic and neurologic examination. Clinical features, neuroimaging and neurophysiological investigations were retrospectively analyzed from medical charts and video recordings.

Results: 13 out of 14 patients showed motor disorders (one only showing mild coordination difficulties). 12 presented abnormal gait (11 patients with broad-based gait, one with narrow-based in-toeing gait, one with broad-based gait with unilateral intoeing). One did not achieve walking ability. 13 patients presented progressive lower limbs hypertonia without overt pyramidal signs. Five patients reported exaggerated startle, three developed upper body (prominently cervical) dystonia in the second decade, with or without bradykinesia (2/13). Treatment efficacy was variable: botulinum toxin was (at least partially) effective in 5/6, levodopa in 1 of 4 treated patients.

Conclusions: CTNNB1-syndrome is associated with a peculiar, but recognizable movement disorder phenotype, encompassing complex gait disorders with progressive lower limb hypertonia, exaggerated startle, and possible occurrence in the second decade of life of upper body dystonia with or without bradykinesia.

Keywords: Bradykinesia; CTNNB1; Dystonia; Movement disorders; Spastic diplegia.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nicola Specchio reports financial support was provided by Italian Ministry of Health. Nicola Specchio reports financial support was provided by Italian Ministry of Education and Merit. Nicola Specchio reports a relationship with BioMarin Pharmaceutical Inc that includes: consulting or advisory and travel reimbursement. Nicola Specchio reports a relationship with Jazz Pharmaceuticals Inc that includes: consulting or advisory and travel reimbursement. Nicola Specchio reports a relationship with UCB that includes: consulting or advisory. Nicola Specchio reports a relationship with Takeda that includes: consulting or advisory. Nicola Specchio reports a relationship with Angeun that includes: consulting or advisory. Nicola Specchio reports a relationship with Zogenix that includes: consulting or advisory. Enrico Bertini reports a relationship with Roche that includes: consulting or advisory. Enrico Bertini reports a relationship with Pfizer that includes: consulting or advisory. Enrico Bertini reports a relationship with Biogen that includes: consulting or advisory and travel reimbursement. Enrico Bertini reports a relationship with PTC that includes: consulting or advisory. Enrico Bertini reports a relationship with Sarepta that includes: consulting or advisory. Enrico Bertini reports a relationship with Italian Ministry of Health that includes: funding grants. Nicola Specchio reports a relationship with Italian Ministry of Health that includes: funding grants. Roberta Onesimo reports a relationship with Biomarin that includes: consulting or advisory and speaking and lecture fees. Roberta Onesimo reports a relationship with Roche that includes: speaking and lecture fees. Roberta Onesimo reports a relationship with QED that includes: funding grants. Roberta Onesimo reports a relationship with Sanofi that includes: funding grants. Giuseppe Zampino reports a relationship with Biomarin that includes: consulting or advisory and travel reimbursement. Giuseppe Zampino reports a relationship with MSD that includes: funding grants. Giuseppe Zampino reports a relationship with Pfizer that includes: funding grants. Giuseppe Zampino reports a relationship with Novo Nordisk that includes: funding grants. Giuseppe Zampino reports a relationship with Gedeon Richter that includes: funding grants. Giuseppe Zampino reports a relationship with Theracon that includes: funding grants. Giuseppe Zampino reports a relationship with Italian Ministry of Health that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology

Affiliations

Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

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