Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single‐center cohort study
Background Childhood‐onset dystonia is often genetically determined. Recently, KMT2B variants have been recognized as an important cause of childhood‐onset dystonia. Objective To define the frequency of KMT2B mutations in a cohort of dystonic patients aged <18 years at onset, the associated clini...
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Published in | Movement disorders Vol. 34; no. 10; pp. 1516 - 1527 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Hoboken, USA
John Wiley & Sons, Inc
01.10.2019
Wiley Subscription Services, Inc |
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Abstract | Background
Childhood‐onset dystonia is often genetically determined. Recently, KMT2B variants have been recognized as an important cause of childhood‐onset dystonia.
Objective
To define the frequency of KMT2B mutations in a cohort of dystonic patients aged <18 years at onset, the associated clinical and radiological phenotype, and the natural history of disease.
Methods
Whole‐exome sequencing or customized gene panels were used to screen a cohort of 65 patients who had previously tested negative for all other known dystonia‐associated genes.
Results
We identified 14 patients (21.5%) carrying KMT2B variants, of which 1 was classified as a variant of unknown significance. We also identified 2 additional patients carrying pathogenic mutations in GNAO1 and ATM. Overall, we established a definitive genetic diagnosis in 23% of cases. We observed a spectrum of clinical manifestations in KMT2B variant carriers, ranging from generalized dystonia to short stature or intellectual disability alone, even within the same family. In 78.5% of cases, dystonia involved the lower limbs at onset, with later caudocranial generalization. Eight patients underwent pallidal DBS with a median decrease of Burke‐Fahn‐Marsden Dystonia Rating Scale‐Motor score of 38.5% in the long term. We also report on 4 asymptomatic carriers, suggesting that some KMT2B mutations may be associated with incomplete disease penetrance.
Conclusions
KMT2B mutations are frequent in childhood‐onset dystonia and cause a complex neurodevelopmental syndrome, often featuring growth retardation and intellectual disability as additional phenotypic features. A dramatic and long‐lasting response to DBS is characteristic of DYT‐KMT2B dystonia. © 2019 International Parkinson and Movement Disorder Society |
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AbstractList | Childhood-onset dystonia is often genetically determined. Recently, KMT2B variants have been recognized as an important cause of childhood-onset dystonia.
To define the frequency of KMT2B mutations in a cohort of dystonic patients aged <18 years at onset, the associated clinical and radiological phenotype, and the natural history of disease.
Whole-exome sequencing or customized gene panels were used to screen a cohort of 65 patients who had previously tested negative for all other known dystonia-associated genes.
We identified 14 patients (21.5%) carrying KMT2B variants, of which 1 was classified as a variant of unknown significance. We also identified 2 additional patients carrying pathogenic mutations in GNAO1 and ATM. Overall, we established a definitive genetic diagnosis in 23% of cases. We observed a spectrum of clinical manifestations in KMT2B variant carriers, ranging from generalized dystonia to short stature or intellectual disability alone, even within the same family. In 78.5% of cases, dystonia involved the lower limbs at onset, with later caudocranial generalization. Eight patients underwent pallidal DBS with a median decrease of Burke-Fahn-Marsden Dystonia Rating Scale-Motor score of 38.5% in the long term. We also report on 4 asymptomatic carriers, suggesting that some KMT2B mutations may be associated with incomplete disease penetrance.
KMT2B mutations are frequent in childhood-onset dystonia and cause a complex neurodevelopmental syndrome, often featuring growth retardation and intellectual disability as additional phenotypic features. A dramatic and long-lasting response to DBS is characteristic of DYT-KMT2B dystonia. © 2019 International Parkinson and Movement Disorder Society. Background Childhood‐onset dystonia is often genetically determined. Recently, KMT2B variants have been recognized as an important cause of childhood‐onset dystonia. Objective To define the frequency of KMT2B mutations in a cohort of dystonic patients aged <18 years at onset, the associated clinical and radiological phenotype, and the natural history of disease. Methods Whole‐exome sequencing or customized gene panels were used to screen a cohort of 65 patients who had previously tested negative for all other known dystonia‐associated genes. Results We identified 14 patients (21.5%) carrying KMT2B variants, of which 1 was classified as a variant of unknown significance. We also identified 2 additional patients carrying pathogenic mutations in GNAO1 and ATM. Overall, we established a definitive genetic diagnosis in 23% of cases. We observed a spectrum of clinical manifestations in KMT2B variant carriers, ranging from generalized dystonia to short stature or intellectual disability alone, even within the same family. In 78.5% of cases, dystonia involved the lower limbs at onset, with later caudocranial generalization. Eight patients underwent pallidal DBS with a median decrease of Burke‐Fahn‐Marsden Dystonia Rating Scale‐Motor score of 38.5% in the long term. We also report on 4 asymptomatic carriers, suggesting that some KMT2B mutations may be associated with incomplete disease penetrance. Conclusions KMT2B mutations are frequent in childhood‐onset dystonia and cause a complex neurodevelopmental syndrome, often featuring growth retardation and intellectual disability as additional phenotypic features. A dramatic and long‐lasting response to DBS is characteristic of DYT‐KMT2B dystonia. © 2019 International Parkinson and Movement Disorder Society BackgroundChildhood‐onset dystonia is often genetically determined. Recently, KMT2B variants have been recognized as an important cause of childhood‐onset dystonia.ObjectiveTo define the frequency of KMT2B mutations in a cohort of dystonic patients aged <18 years at onset, the associated clinical and radiological phenotype, and the natural history of disease.MethodsWhole‐exome sequencing or customized gene panels were used to screen a cohort of 65 patients who had previously tested negative for all other known dystonia‐associated genes.ResultsWe identified 14 patients (21.5%) carrying KMT2B variants, of which 1 was classified as a variant of unknown significance. We also identified 2 additional patients carrying pathogenic mutations in GNAO1 and ATM. Overall, we established a definitive genetic diagnosis in 23% of cases. We observed a spectrum of clinical manifestations in KMT2B variant carriers, ranging from generalized dystonia to short stature or intellectual disability alone, even within the same family. In 78.5% of cases, dystonia involved the lower limbs at onset, with later caudocranial generalization. Eight patients underwent pallidal DBS with a median decrease of Burke‐Fahn‐Marsden Dystonia Rating Scale‐Motor score of 38.5% in the long term. We also report on 4 asymptomatic carriers, suggesting that some KMT2B mutations may be associated with incomplete disease penetrance.ConclusionsKMT2B mutations are frequent in childhood‐onset dystonia and cause a complex neurodevelopmental syndrome, often featuring growth retardation and intellectual disability as additional phenotypic features. A dramatic and long‐lasting response to DBS is characteristic of DYT‐KMT2B dystonia. © 2019 International Parkinson and Movement Disorder Society BACKGROUNDChildhood-onset dystonia is often genetically determined. Recently, KMT2B variants have been recognized as an important cause of childhood-onset dystonia. OBJECTIVETo define the frequency of KMT2B mutations in a cohort of dystonic patients aged <18 years at onset, the associated clinical and radiological phenotype, and the natural history of disease. METHODSWhole-exome sequencing or customized gene panels were used to screen a cohort of 65 patients who had previously tested negative for all other known dystonia-associated genes. RESULTSWe identified 14 patients (21.5%) carrying KMT2B variants, of which 1 was classified as a variant of unknown significance. We also identified 2 additional patients carrying pathogenic mutations in GNAO1 and ATM. Overall, we established a definitive genetic diagnosis in 23% of cases. We observed a spectrum of clinical manifestations in KMT2B variant carriers, ranging from generalized dystonia to short stature or intellectual disability alone, even within the same family. In 78.5% of cases, dystonia involved the lower limbs at onset, with later caudocranial generalization. Eight patients underwent pallidal DBS with a median decrease of Burke-Fahn-Marsden Dystonia Rating Scale-Motor score of 38.5% in the long term. We also report on 4 asymptomatic carriers, suggesting that some KMT2B mutations may be associated with incomplete disease penetrance. CONCLUSIONSKMT2B mutations are frequent in childhood-onset dystonia and cause a complex neurodevelopmental syndrome, often featuring growth retardation and intellectual disability as additional phenotypic features. A dramatic and long-lasting response to DBS is characteristic of DYT-KMT2B dystonia. © 2019 International Parkinson and Movement Disorder Society. |
Author | Carecchio, Miryam Joseph, Agnel P. Topf, Maya Invernizzi, Federica Bentivoglio, Anna Rita Panteghini, Celeste Zorzi, Giovanna Galosi, Serena Reale, Chiara Romito, Luigi Kurian, Manju A. Piano, Carla Mencacci, Niccolò E. Zibordi, Federica Lubbe, Steven J. Gonzàlez‐Latapi, Paulina Garavaglia, Barbara Leuzzi, Vincenzo Girotti, Floriano Nardocci, Nardo Morana, Paolo Morana, Benedetto |
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BackLink | https://www.ncbi.nlm.nih.gov/pubmed/31216378$$D View this record in MEDLINE/PubMed |
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Childhood‐onset dystonia is often genetically determined. Recently, KMT2B variants have been recognized as an important cause of childhood‐onset... Childhood-onset dystonia is often genetically determined. Recently, KMT2B variants have been recognized as an important cause of childhood-onset dystonia. To... BackgroundChildhood‐onset dystonia is often genetically determined. Recently, KMT2B variants have been recognized as an important cause of childhood‐onset... BACKGROUNDChildhood-onset dystonia is often genetically determined. Recently, KMT2B variants have been recognized as an important cause of childhood-onset... |
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SubjectTerms | Adolescent Adult Aged Child Childhood Children Cohort analysis Cohort Studies DBS Deep Brain Stimulation - methods Dystonia Dystonic Disorders - genetics Female Genetic screening Growth rate Histone-Lysine N-Methyltransferase - genetics Humans Intellectual disabilities Intellectual Disability - genetics KMT2B Male Middle Aged Movement disorders Mutation Mutation - genetics Neurodevelopmental disorders Phenotype Phenotypes WES Young Adult |
Title | Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single‐center cohort study |
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