Citations

AbstractTo examine the length of a hexanucleotide expansion in C9orf72, which represents the most frequent genetic cause of frontotemporal lobar degeneration and motor neuron disease, we employed a targeted amplification-free long-read sequencing technology: No-Amp sequencing. In our cross-sectional study, we assessed cerebellar tissue from 28 well-characterized C9orf72 expansion carriers. We obtained 3507 on-target circular consensus sequencing reads, of which 814 bridged the C9orf72 repeat expansion (23%). Importantly, we observed a significant correlation between expansion sizes obtained using No-Amp sequencing and Southern blotting (P = 5.0 × 10−4). Interestingly, we also detected a significant survival advantage for individuals with smaller expansions (P = 0.004). Additionally, we uncovered that smaller expansions were significantly associated with higher levels of C9orf72 transcripts containing intron 1b (P = 0.003), poly(GP) proteins (P = 1.3 × 10− 5), and poly(GA) proteins (P = 0.005). Thorough examination of the composition of the expansion revealed that its GC content was extremely high (median: 100%) and that it was mainly composed of GGGGCC repeats (median: 96%), suggesting that expanded C9orf72 repeats are quite pure. Taken together, our findings demonstrate that No-Amp sequencing is a powerful tool that enables the discovery of relevant clinicopathological associations, highlighting the important role played by the cerebellar size of the expanded repeat in C9orf72-linked diseases.

Plasma neurofilament light is a reliable, uniform marker to estimate neuroaxonal injury and forecast all-cause mortality across major stroke types.

AbstractIntroductionWe conducted an open‐label study to examine the effects of the flavonoid (−)‐epicatechin in seven ambulatory adult patients with Becker muscular dystrophy (BMD).MethodsSeven participants received (−)‐epicatechin 50 mg twice per day for 8 weeks. Pre‐ and postprocedures included biceps brachii biopsy to assess muscle structure and growth‐relevant endpoints by western blotting, mitochondria volume measurement, and cristae abundance by electron microscopy, graded exercise testing, and muscle strength and function tests.ResultsWestern blotting showed significantly increased levels of enzymes modulating cellular bioenergetics (liver kinase B1 and 5′‐adenosine monophosphate–activated protein kinase). Peroxisome proliferator‐activated receptor gamma coactivator‐1alpha, a transcriptional coactivator of genes involved in mitochondrial biogenesis and cristae‐associated mitofilin levels, increased as did cristae abundance. Muscle and plasma follistatin increased significantly while myostatin decreased. Markers of skeletal muscle regeneration myogenin, myogenic regulatory factor‐5, myoblast determination protein 1, myocyte enhancer factor‐2, and structure‐associated proteins, including dysferlin, utrophin, and intracellular creatine kinase, also increased. Exercise testing demonstrated decreased heart rate, maximal oxygen consumption per kilogram, and plasma lactate levels at defined workloads. Tissue saturation index improved in resting and postexercise states.Discussion(−)‐Epicatechin, an exercise mimetic, appears to have short‐term positive effects on tissue biomarkers indicative of mitochondrial biogenesis and muscle regeneration, and produced improvements in graded exercise testing parameters in patients with BMD.

PolyQ ATXN3 is a pharmacodynamic marker for SCA3, and a SNP associated with the expanded allele may serve to specifically target mutant ATXN3 .

Introduction: Nusinersen antisense oligonucleotide infusions have been shown to be effective in the treatment spinal muscular atrophy. The majority of the evidence has been collected in young type 1 and type 2 patients, and evidence of efficacy in adult patients is limited. Case Report: A 48-year-old woman with spinal muscular atrophy type 3 who has received the loading dose and 8 maintenance infusions over an 8-month period. Grip and pinch strength, measured by hand-held dynamometry measured at baseline and in 6 to 12 months interval improved over a 24-month period. She also reported multiple other subjective improvements in function. Conclusions: This is the first published case of nusinersen in a middle-aged adult with spinal muscular atrophy. Sustained clinically meaningful improvement may be possible with nusinersen initiation in mid adulthood.

G 4 C 2 repeat–derived poly(GR) plays a key role in mediating TDP-43 mislocalization and aggregation in vitro and in vivo.

AbstractIntroductionRadiologically inserted gastrostomy (RIG) placement in patients with amyotrophic lateral sclerosis (ALS) carries risks related to periprocedural sedation and analgesia. To minimize these risks, we used a paravertebral block (PVB) technique for RIG placement.MethodsWe retrospectively reviewed patients with ALS undergoing RIG placement under PVB between 2013 and 2017.ResultsNinety‐nine patients with ALS underwent RIG placement under PVB. Median (range) age was 66 (28 to 86) years, ALS Functional Rating Scale—Revised score was 27 (6 to 45), and forced vital capacity was 47% (8%–79%) at time of RIG placement. Eighty‐five (85.9%) patients underwent RIG placement as outpatients, with a mean postanesthesia care unit stay of 2.3 hours. The readmission rate was 4% at both 1 and 30 days postprocedure.DiscussionPVB for RIG placement has a low rate of adverse events and provides effective periprocedural analgesia in patients with ALS, the majority of whom can be treated as outpatients.