Extended haplotype with rs41524547-G defines the ancestral origin of SCA10.

Spinocerebellar ataxia type 10 (SCA10) is a rare autosomal dominant ataxia caused by a large expansion of the (ATTCT)n repeat in ATXN10. SCA10 was described in Native American and Asian individuals which prompted a search for an expanded haplotype to confirm a common ancestral origin for the expansion event. All patients with SCA10 expansions in our cohort share a single haplotype defined at the 5'-end by the minor allele of rs41524547, located ~35 kb upstream of the SCA10 expansion. Intriguingly, rs41524547 is located within the miRNA gene, MIR4762, within its DROSHA cleavage site and just outside the seed sequence for mir4792-5p. The world-wide frequency of rs41524547-G is less than 5% and found almost exclusively in the Americas and East Asia-a geographic distribution that mirrors reported SCA10 cases. We identified rs41524547-G(+) DNA from the 1000 Genomes/International Genome Sample Resource and our own general population samples and identified SCA10 repeat expansions in up to 25% of these samples. The reduced penetrance of these SCA10 expansions may be explained by a young (pre-onset) age at sample collection, a small repeat size, purity of repeat units, or the disruption of miR4762-5p function. We conclude that rs41524547-G is the most robust at-risk SNP allele for SCA10, is useful for screening of SCA10 expansions in population genetics studies and provides the most compelling evidence to date for a single, prehistoric origin of SCA10 expansions sometime prior to or during the migration of individuals across the Bering Land Bridge into the Americas.

Longitudinal patient-reported outcomes and survival among early-stage non-small cell lung cancer patients receiving stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: The study objective was to determine whether longitudinal changes in patient-reported outcomes (PROs) were associated with survival among early-stage, non-small cell lung cancer (NSCLC) patients undergoing stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS: Data were obtained from January 2015 through March 2020. We ran a joint probability model to assess the relationship between time-to-death, and longitudinal PRO measurements. PROs were measured through the Edmonton Symptom Assessment Scale (ESAS). We controlled for other covariates likely to affect symptom burden and survival including stage, tumor diameter, comorbidities, gender, race/ethnicity, relationship status, age, and smoking status. RESULTS: The sample included 510 early-stage NSCLC patients undergoing SBRT. The median age was 73.8 (range: 46.3-94.6). The survival component of the joint model demonstrates that longitudinal changes in ESAS scores are significantly associated with worse survival (HR: 1.04; 95% CI: 1.02-1.05). This finding suggests a one-unit increase in ESAS score increased probability of death by 4%. Other factors significantly associated with worse survival included older age (HR: 1.04; 95% CI: 1.03-1.05), larger tumor diameter (HR: 1.21; 95% CI: 1.01-1.46), male gender (HR: 1.87; 95% CI: 1.36-2.57), and current smoking status (HR: 2.39; 95% CI: 1.25-4.56). CONCLUSION: PROs are increasingly being collected as a part of routine care delivery to improve symptom management. Healthcare systems can integrate these data with other real-world data to predict patient outcomes, such as survival. Capturing longitudinal PROs-in addition to PROs at diagnosis-may add prognostic value for estimating survival among early-stage NSCLC patients undergoing SBRT.

Abnormal nuclear aggregation and myotube degeneration in myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is caused by CTG nucleotide repeat expansions in the 3'-untranslated region (3'-UTR) of the dystrophia myotonica protein kinase (DMPK) gene. The expanded CTG repeats encode toxic CUG RNAs that cause disease, largely through RNA gain-of-function. DM1 is a fatal disease characterized by progressive muscle wasting, which has no cure. Regenerative medicine has emerged as a promising therapeutic modality for DM1, especially with the advancement of induced pluripotent stem (iPS) cell technology and therapeutic genome editing. However, there is an unmet need to identify in vitro outcome measures to demonstrate the therapeutic effects prior to in vivo clinical trials. In this study, we examined the muscle regeneration (myotube formation) in normal and DM1 myoblasts in vitro to establish outcome measures for therapeutic monitoring. We found normal proliferation of DM1 myoblasts, but abnormal nuclear aggregation during the early stage myotube formation, as well as myotube degeneration during the late stage of myotube formation. We concluded that early abnormal nuclear aggregation and late myotube degeneration offer easy and sensitive outcome measures to monitor therapeutic effects in vitro.

Genome Therapy of Myotonic Dystrophy Type 1 iPS Cells for Development of Autologous Stem Cell Therapy.

Myotonic dystrophy type 1 (DM1) is caused by expanded Cytosine-Thymine-Guanine (CTG) repeats in the 3'-untranslated region (3' UTR) of the Dystrophia myotonica protein kinase (DMPK) gene, for which there is no effective therapy. The objective of this study is to develop genome therapy in human DM1 induced pluripotent stem (iPS) cells to eliminate mutant transcripts and reverse the phenotypes for developing autologous stem cell therapy. The general approach involves targeted insertion of polyA signals (PASs) upstream of DMPK CTG repeats, which will lead to premature termination of transcription and elimination of toxic mutant transcripts. Insertion of PASs was mediated by homologous recombination triggered by site-specific transcription activator-like effector nuclease (TALEN)-induced double-strand break. We found genome-treated DM1 iPS cells continue to maintain pluripotency. The insertion of PASs led to elimination of mutant transcripts and complete disappearance of nuclear RNA foci and reversal of aberrant splicing in linear-differentiated neural stem cells, cardiomyocytes, and teratoma tissues. In conclusion, genome therapy by insertion of PASs upstream of the expanded DMPK CTG repeats prevented the production of toxic mutant transcripts and reversal of phenotypes in DM1 iPS cells and their progeny. These genetically-treated iPS cells will have broad clinical application in developing autologous stem cell therapy for DM1.

Spinocerebellar ataxia type 10 in Chinese Han.

Spinocerebellar ataxia type 10 (SCA10; OMIM #603516) is an autosomal dominant cerebellar ataxia with variably associated extracerebellar signs.(1,2) SCA10 is caused by an expanded noncoding pentanucleotide repeat in ATXN10, which normally ranges from 9 to 32 repeats(3,4); pathogenic alleles have as many as 4,500 repeats.(4) To date, SCA10 has been found exclusively on American continents. In this report, we describe a Chinese Han family with autosomal dominant cerebellar ataxia caused by an SCA10 expansion.

Repeat interruptions in spinocerebellar ataxia type 10 expansions are strongly associated with epileptic seizures.

Spinocerebellar ataxia type 10 (SCA10), an autosomal dominant neurodegenerative disorder, is the result of a non-coding, pentanucleotide repeat expansion within intron 9 of the Ataxin 10 gene. SCA10 patients present with pure cerebellar ataxia; yet, some families also have a high incidence of epilepsy. SCA10 expansions containing penta- and heptanucleotide interruption motifs, termed "ATCCT interruptions," experience large contractions during germline transmission, particularly in paternal lineages. At the same time, these alleles confer an earlier age at onset which contradicts traditional rules of genetic anticipation in repeat expansions. Previously, ATCCT interruptions have been associated with a higher prevalence of epileptic seizures in one Mexican-American SCA10 family. In a large cohort of SCA10 families, we analyzed whether ATCCT interruptions confer a greater risk for developing seizures in these families. Notably, we find that the presence of repeat interruptions within the SCA10 expansion confers a 6.3-fold increase in the risk of an SCA10 patient developing epilepsy (6.2-fold when considering patients of Mexican ancestry only) and a 13.7-fold increase in having a positive family history of epilepsy (10.5-fold when considering patients of Mexican ancestry only). We conclude that the presence of repeat interruptions in SCA10 repeat expansion indicates a significant risk for the epilepsy phenotype and should be considered during genetic counseling.