Objective: Clarifying clinical phenotype, molecular genetic features and evolution with deep brain stimulation (DBS) of KMT2B related disease.

Background: Heterozygous mutations in KMT2B are associated with an early-onset, progressive, often complex generalized dystonia with prominent oromandibular, laryngeal and axial involvement. Much remains to be understood about the full spectrum of this disease.

Method: Through multicentric collaboration, 51 patients with disease associated KMT2B mutations were included in the study. Dystonia evolution with DBS (n=18) was monitored and reported using the Burke Fahn Marsden’s dystonia rating scale (BFMDRS).

Results: New disease presentations with atypical patterns of dystonia evolution and non-dystonic neurodevelopmental phenotype as well as co-morbidities, including status dystonicus, intra-uterine growth retardation and endocrinopathies were identified. Analysis of this study cohort (n=51) in tandem with published cases (n=79) revealed that patients with chromosomal deletions and protein truncating variants (PTV) had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants.
 18/51 subjects had DBS for medically refractory dystonia, at a mean age of 17 years. Follow-up after DBS ranged from 0.25 to 22 years. Significant improvement of motor function and disability (BFMDRS-M & BFMDRS-D) was evident at 6 months, 1 year and last follow-up At one-year post-DBS, 50% of subjects showed BFMDRS-M & BFMDRS-D improvements of >30%. In the long-term DBS group (DBS > 5 years, n=8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for truncal and cervical dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait decreased from one year to last assessment.

Conclusion: KM2TB-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, DBS provides significant improvement and protracted clinical benefit according to symptoms distribution.

References: Coubes P, Echenne B, Roubertie A, Vayssière N, Tuffery S, Humbertclaude V, et al. [Treatment of early-onset generalized dystonia by chronic bilateral stimulation of the internal globus pallidus. Apropos of a case]. Neurochirurgie 1999;45(2):139‑44. Meyer E, Carss KJ, Rankin J, Nichols JME, Grozeva D, Joseph AP, et al. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nat Genet 2017;49(2):223‑37. Zech M, Boesch S, Maier EM, Borggraefe I, Vill K, Laccone F, et al. Haploinsufficiency of KMT2B, Encoding the Lysine-Specific Histone Methyltransferase 2B, Results in Early-Onset Generalized Dystonia. Am J Hum Genet 2016;99(6):1377‑87. Gorman KM, Meyer E, Kurian MA. Review of the phenotype of early-onset generalised ; progressive dystonia due to mutations in KMT2B. Review. Eur J Paediatr Neurol 2018; 22(2):245‑56. Carecchio M, Invernizzi F, Gonzàlez-Latapi P, Panteghini C, Zorzi G, Romito L, et al. Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single-center cohort study. Mov Disord 2019: 34(10):1516-1527.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/kmt2b-related-disorders-expansion-of-the-phenotypic-spectrum-and-long-term-efficacy-of-deep-brain-stimulation/