Abstract Details

Title Frequency and Phenotypic Spectrum of KMT2B Mutations in Childhood-Onset Dystonia: Results from a Single-Center Cohort Study

Topic Movement Disorders

Presentation(s) N1 - Neuroscience in the Clinic: Child Neurology: Emerging Understanding of the Epilepsy-Movement Disorder Spectrum Across the Lifespan (4:45 PM-5:00 PM)

Poster/Presentation
Number 001

Background Dystonia is a heterogeneous clinical and genetic entity. Knowledge about the molecular pathogenesis of dystonia has expanded since DYT1 (TOR1A) was discovered, with a significant boost due to the use of Next Generation Sequencing techniques. KMT2B, coding for a lysine-specific histone methyl-transferase, is the latest gene associated with childhood-onset dystonia. The frequency of KMT2B mutations in childhood-onset dystonia has not been systematically assessed and the delineation of the phenotypic spectrum and natural history of the disease is limited.

Objective Identify and clinically characterize carriers of pathogenic mutations in KMT2B in a cohort of genetically undefined childhood-onset dystonia.

Design/Methods Sixty-five subjects (30 females, 35 males) with childhood-onset dystonia were enrolled at a tertiary referral center in Milan, Italy. They were followed over 30 years. Video recordings were obtained in all cases. Genetic analyses was performed by whole exome sequencing or customized gene panel. Copy Number Variations were analyzed using EXCAVATOR tool. In silico homology modeling studies were performed to characterize missense variants.

Results We identified fourteen patients carrying KMT2B heterozygous variants, twelve of which were novel. Three patients carried frameshift mutations causing a premature stop codon. One patient had an in-frame deletion causing a partially truncated protein. Nine patients carried missense variants. One patient had a heterozygous deletion over KMT2B. This corresponds to an overall mutational frequency of 21%. Clinical manifestations ranged from isolated generalized dystonia to isolated short stature or intellectual disability. In 85% of cases, dystonia involved the lower limbs at onset, with caudo-cranial spreading. Brain MRI was normal in all mutated patients.

Conclusions KMT2B mutations are a frequent cause of disease in dystonia patients seen in a single tertiary center for pediatric movement disorders. KMT2B mutations are responsible for a complex neurodevelopmental syndrome, featuring dystonia as the distinctive core characteristic.

Authors/Disclosures
Paulina Gonzalez Latapi, MD (Northwestern University) PRESENTER	The institution of Dr. Gonzalez Latapi has received research support from Michael J Fox Foundation.
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Serena Galosi, MD (Sapienza University of Rome/ UCSD and Rady Children'S Hispital)	No disclosure on file
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Anna R. Bentivoglio, MD	No disclosure on file
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Paolo Morana	No disclosure on file
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Manju Kurian, PhD (University College London)	No disclosure on file
Barbara Garavaglia	No disclosure on file
Niccolò Mencacci	No disclosure on file
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