ORCID Profile
0000-0001-6677-869X
Current Organisation
Oregon Health & Science University
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Publisher: Wiley
Date: 09-06-2020
DOI: 10.1002/ANA.25757
Abstract: Genome sequencing (GS) is promising for unsolved leukodystrophies, but its efficacy has not been prospectively studied. A prospective time‐delayed crossover design trial of GS to assess the efficacy of GS as a first‐line diagnostic tool for genetic white matter disorders took place between December 1, 2015 and September 27, 2017. Patients were randomized to receive GS immediately with concurrent standard of care (SoC) testing, or to receive SoC testing for 4 months followed by GS. Thirty‐four in iduals were assessed at interim review. The genetic origin of 2 patient's leukoencephalopathy was resolved before randomization. Nine patients were stratified to the immediate intervention group and 23 patients to the delayed‐GS arm. The efficacy of GS was significant relative to SoC in the immediate (5/9 [56%] vs 0/9 [0%] Wild–Seber, p 0.005) and delayed (control) arms (14/23 [61%] vs 5/23 [22%] Wild–Seber, p 0.005). The time to diagnosis was significantly shorter in the immediate‐GS group (log‐rank test, p = 0.04). The overall diagnostic efficacy of combined GS and SoC approaches was 26 of 34 (76.5%, 95% confidence interval = 58.8–89.3%) in months, greater than historical norms of % over 5 years. Owing to loss of clinical equipoise, the trial design was altered to a single‐arm observational study. In this study, first‐line GS provided earlier and greater diagnostic efficacy in white matter disorders. We provide an evidence‐based diagnostic testing algorithm to enable appropriate clinical GS utilization in this population. ANN NEUROL 2020 :264–273.
Publisher: Oxford University Press (OUP)
Date: 11-2020
Abstract: 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 in iduals 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: 4.5–37.0 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’s 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). At 1 year post-deep brain stimulation, & % of subjects showed BFMDRS-M and BFMDRS-D improvements of & %. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for & years, n = 8), improvement of & % 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 trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.
Location: United States of America
No related grants have been discovered for Jenny Wilson.