Buchumschlag

KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation

Fuente: arXiv

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Bibliographische Detailangaben
Hauptverfasser:	Cif, L, Demailly, D, Lin, JP, Barwick, KE, Sa, M, Abela, L, Malhotra, S, Chong, WK, Steel, D, Sanchis-Juan, A, Ngoh, A, Trump, N, Meyer, E, Vasques, X, Rankin, J, Allain, MW, Applegate, CD, Isfahani, S Attaripour, Baleine, J, Balint, B, Bassetti, JA, Baple, EL, Bhatia, KP, Blanchet, C, Burglen, L, Cambonie, G, Seng, EC, Bastaraud, SC, Cyprien, F, Coubes, C, d'Hardemare, V, Study, Deciphering Developmental Disorders, Doja, A, Dorison, N, Doummar, D, Dy-Hollins, ME, Farrelly, E, Fitzpatrick, DR, Fearon, C, Fieg, EL, Fogel, BL, Forman, EB, Fox, RG, Consortium, Genomics England Research, Gahl, WA, Galosi, S, Gonzalez, V, Graves, TD, Gregory, A, Hallett, M, Hasegawa, H, Hayflick, SJ, Hamosh, A, Hully, M, Jansen, S, Jeong, SY, Krier, JB, Krystal, S, Kumar, KR, Laurencin, C, Lee, H, Lesca, G, François, LL, Lynch, T, Mahant, N, Martinez-Agosto, JA, Milesi, C, Mills, KA, Mondain, M, Morales-Briceno, H, BioResource, NIHR, Ostergaard, JR, Pal, S, Pallais, JC, Pavillard, F, Perrigault, PF, Petersen, AK, Polo, G, Poulen, G, Rinne, T, Roujeau, T, Rogers, C, Roubertie, A, Sahagian, M, Schaefer, E, Selim, L, Selway, R, Sharma, N, Signer, R, Soldatos, AG, Stevenson, DA, Stewart, F, Tchan, M, Network, Undiagnosed Diseases, Verma, IC, de Vries, BBA, Wilson, JL, Wong, DA, Zaitoun, R, Zhen, D, Znaczko, A, Dale, RC, de Gusmão, CM, Friedman, J, Fung, VSC, King, MD, Mohammad, SS, Rohena, L, Waugh, JL, Toro, C, Raymond, FL, Topf, M, Coubes, P, Gorman, KM, Kurian, MA
Format:	Preprint
Veröffentlicht:	2025
Schlagworte:	Neurons and Cognition
Online-Zugang:	Acceder al recurso
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_version_	1866915144614805504
author	Cif, L Demailly, D Lin, JP Barwick, KE Sa, M Abela, L Malhotra, S Chong, WK Steel, D Sanchis-Juan, A Ngoh, A Trump, N Meyer, E Vasques, X Rankin, J Allain, MW Applegate, CD Isfahani, S Attaripour Baleine, J Balint, B Bassetti, JA Baple, EL Bhatia, KP Blanchet, C Burglen, L Cambonie, G Seng, EC Bastaraud, SC Cyprien, F Coubes, C d'Hardemare, V Study, Deciphering Developmental Disorders Doja, A Dorison, N Doummar, D Dy-Hollins, ME Farrelly, E Fitzpatrick, DR Fearon, C Fieg, EL Fogel, BL Forman, EB Fox, RG Consortium, Genomics England Research Gahl, WA Galosi, S Gonzalez, V Graves, TD Gregory, A Hallett, M Hasegawa, H Hayflick, SJ Hamosh, A Hully, M Jansen, S Jeong, SY Krier, JB Krystal, S Kumar, KR Laurencin, C Lee, H Lesca, G François, LL Lynch, T Mahant, N Martinez-Agosto, JA Milesi, C Mills, KA Mondain, M Morales-Briceno, H BioResource, NIHR Ostergaard, JR Pal, S Pallais, JC Pavillard, F Perrigault, PF Petersen, AK Polo, G Poulen, G Rinne, T Roujeau, T Rogers, C Roubertie, A Sahagian, M Schaefer, E Selim, L Selway, R Sharma, N Signer, R Soldatos, AG Stevenson, DA Stewart, F Tchan, M Network, Undiagnosed Diseases Verma, IC de Vries, BBA Wilson, JL Wong, DA Zaitoun, R Zhen, D Znaczko, A Dale, RC de Gusmão, CM Friedman, J Fung, VSC King, MD Mohammad, SS Rohena, L Waugh, JL Toro, C Raymond, FL Topf, M Coubes, P Gorman, KM Kurian, MA
author_facet	Cif, L Demailly, D Lin, JP Barwick, KE Sa, M Abela, L Malhotra, S Chong, WK Steel, D Sanchis-Juan, A Ngoh, A Trump, N Meyer, E Vasques, X Rankin, J Allain, MW Applegate, CD Isfahani, S Attaripour Baleine, J Balint, B Bassetti, JA Baple, EL Bhatia, KP Blanchet, C Burglen, L Cambonie, G Seng, EC Bastaraud, SC Cyprien, F Coubes, C d'Hardemare, V Study, Deciphering Developmental Disorders Doja, A Dorison, N Doummar, D Dy-Hollins, ME Farrelly, E Fitzpatrick, DR Fearon, C Fieg, EL Fogel, BL Forman, EB Fox, RG Consortium, Genomics England Research Gahl, WA Galosi, S Gonzalez, V Graves, TD Gregory, A Hallett, M Hasegawa, H Hayflick, SJ Hamosh, A Hully, M Jansen, S Jeong, SY Krier, JB Krystal, S Kumar, KR Laurencin, C Lee, H Lesca, G François, LL Lynch, T Mahant, N Martinez-Agosto, JA Milesi, C Mills, KA Mondain, M Morales-Briceno, H BioResource, NIHR Ostergaard, JR Pal, S Pallais, JC Pavillard, F Perrigault, PF Petersen, AK Polo, G Poulen, G Rinne, T Roujeau, T Rogers, C Roubertie, A Sahagian, M Schaefer, E Selim, L Selway, R Sharma, N Signer, R Soldatos, AG Stevenson, DA Stewart, F Tchan, M Network, Undiagnosed Diseases Verma, IC de Vries, BBA Wilson, JL Wong, DA Zaitoun, R Zhen, D Znaczko, A Dale, RC de Gusmão, CM Friedman, J Fung, VSC King, MD Mohammad, SS Rohena, L Waugh, JL Toro, C Raymond, FL Topf, M Coubes, P Gorman, KM Kurian, MA
contents	Heterozygous mutations in KMT2B are associated with an early-onset, progressive, and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal, and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein-truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5 to 37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke-Fahn-Marsden Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year, and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002, and P = 0.012).
format	Preprint
id	arxiv_https___arxiv_org_abs_2502_06320
institution	arXiv
publishDate	2025
record_format	arxiv
spellingShingle	KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation Cif, L Demailly, D Lin, JP Barwick, KE Sa, M Abela, L Malhotra, S Chong, WK Steel, D Sanchis-Juan, A Ngoh, A Trump, N Meyer, E Vasques, X Rankin, J Allain, MW Applegate, CD Isfahani, S Attaripour Baleine, J Balint, B Bassetti, JA Baple, EL Bhatia, KP Blanchet, C Burglen, L Cambonie, G Seng, EC Bastaraud, SC Cyprien, F Coubes, C d'Hardemare, V Study, Deciphering Developmental Disorders Doja, A Dorison, N Doummar, D Dy-Hollins, ME Farrelly, E Fitzpatrick, DR Fearon, C Fieg, EL Fogel, BL Forman, EB Fox, RG Consortium, Genomics England Research Gahl, WA Galosi, S Gonzalez, V Graves, TD Gregory, A Hallett, M Hasegawa, H Hayflick, SJ Hamosh, A Hully, M Jansen, S Jeong, SY Krier, JB Krystal, S Kumar, KR Laurencin, C Lee, H Lesca, G François, LL Lynch, T Mahant, N Martinez-Agosto, JA Milesi, C Mills, KA Mondain, M Morales-Briceno, H BioResource, NIHR Ostergaard, JR Pal, S Pallais, JC Pavillard, F Perrigault, PF Petersen, AK Polo, G Poulen, G Rinne, T Roujeau, T Rogers, C Roubertie, A Sahagian, M Schaefer, E Selim, L Selway, R Sharma, N Signer, R Soldatos, AG Stevenson, DA Stewart, F Tchan, M Network, Undiagnosed Diseases Verma, IC de Vries, BBA Wilson, JL Wong, DA Zaitoun, R Zhen, D Znaczko, A Dale, RC de Gusmão, CM Friedman, J Fung, VSC King, MD Mohammad, SS Rohena, L Waugh, JL Toro, C Raymond, FL Topf, M Coubes, P Gorman, KM Kurian, MA Neurons and Cognition Heterozygous mutations in KMT2B are associated with an early-onset, progressive, and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal, and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein-truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5 to 37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke-Fahn-Marsden Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year, and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002, and P = 0.012).
title	KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation
topic	Neurons and Cognition
url	https://arxiv.org/abs/2502.06320