Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders.

OBJECTIVE: Genome sequencing (GS) is promising for unsolved leukodystrophies, but its efficacy has not been prospectively studied. METHODS: 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. RESULTS: Thirty-four individuals 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 <4 months, greater than historical norms of <50% over 5 years. Owing to loss of clinical equipoise, the trial design was altered to a single-arm observational study. INTERPRETATION: 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;88:264-273.

A survey-based study identifies common but unrecognized symptoms in a large series of juvenile Huntington's disease.

AIM: The symptoms of Huntington's disease are well known, yet the symptoms of juvenile Huntington's disease (JHD) are less established due to its rarity. The study examined a cluster of symptoms considered to be common, but under-recognized in JHD: pain, itching, sleeping difficulties, psychosis and tics. MATERIALS & METHODS: A symptom survey was constructed using the online tool Qualtrics and dispersed to JHD caregivers through websites. RESULTS: A total of 33 surveys were completed. Disrupted sleep was the most prevalent symptom (87%), followed by tics (78%), pain (69%), itching (60%) and psychosis (39%). CONCLUSION: Despite limitations, the study supports that there are symptoms in the JHD population that are not considered classic, however, are common and significant for patients and caregivers.