Number Of CAG Repeats Research Articles

The number of androgen receptor CAG repeats and mortality in men

Introduction The androgen receptor (AR) mediates peripheral effects of testosterone. Evidence suggests that the number of CAG repeats in exon-1 of the AR gene negatively correlates with AR transcriptional activity. The aim of this analysis was to determine the association between CAG repeat number and mortality in men. Methods Men aged 40–79 years were recruited from primary care for participation in the UK arm of the European Male Aging Study between 2003 and 2005. Cox proportional hazards modelling was used to determine the association between CAG repeat number/mortality. Results were expressed as hazard ratios(HR)/95% confidence intervals (CI). Results 312 men were followed up. The mean baseline age was 59.5 years. At follow up, 85/312(27%) men had died. CAG repeat length ranged from 14 to 39, with the highest proportion of CAG repeat number at 21 repeats(16.4%). In a multivariable model, using men with CAG repeat numbers of 22-23 as the reference, men with a lower number of CAG repeats(<22) showed a trend for a higher mortality in the follow-up period (HR 1.46 (0.75, 2.81)) as did men with higher number of repeats (>23) (1.37 (0.65, 2.91)). Conclusion Our data suggest that CAG repeat number may partially influence the risk of mortality in men. Further larger studies are required to quantify the effect.

Hypothalamic Atrophy, Expanded CAG Repeat, and Low Body Mass Index in Spinocerebellar Ataxia Type 3.

Spinocerebellar ataxia type 3 (SCA3) is an inherited motor disorder that is characterized by low body mass index (BMI). Considering the role of the hypothalamus in regulating appetitive behaviors and metabolism, low BMI may result from hypothalamic degeneration. To examine hypothalamic volume changes in SCA3 by comparing patients and matched healthy controls and to identify potential mediating effects of hypothalamic pathology on CAG repeats for BMI. Magnetic resonance imaging datasets of hypothalamic volumes from 41 SCA3 patients and 49 matched controls were analyzed. Relationships among CAG repeat number, hypothalamic volumes, and BMI were assessed using correlation and mediation analyses. SCA3 patients exhibited significant hypothalamic atrophy. Tubular hypothalamic volume was significantly associated with BMI. Mediation analysis revealed an indirect effect of CAG repeat number on BMI via tubular hypothalamic atrophy. Low BMI in SCA3 is related to neurodegeneration within the tubular hypothalamus, providing a potential target for energy-based treatment. © 2022 International Parkinson and Movement Disorder Society.

Spinocerebellar Ataxia Type 3 (SCA3): Clinical and genetic aspects in Mali

The SCA3 is an autosomal dominant heterogeneous neurodegenerative disorder characterized with gait ataxia, dysarthria and parkinsonism. Is the most common SCA worldwide, however only few cases were reported in Africa. To clinically characterize families with SCA3 and identify the underlying genetic defect. Patients with ataxia were examined in our Neurogenetics Clinic. DNA was collected from probands for genetic analysis. Brain imaging and blood chemistries were performed to exclude common causes. 287 families with a wide range of neurodegenerative were enrolled, and 177 patients presented with autosomal dominant ataxia. The gene panel testing showed CAG repeats in the ATXN3 gene in 4 probands. The mean age of onset was 29 years ranging from 10 to 59, anticipation has been noted in all families. The mean age at diagnosis was 43 years. For the genetic testing the average of CAG was 73 repeats, the four probands had cerebellar atrophy on the brain imaging. We found a positive correlation between age of onset and CAG repeat numbers. Studying families with high number of affected sibs will allow refine or consolidate the natural history of these diseases. The haplotype studies may establish the origin of these mutations. We identified a penetrance in the different families, a very few cases (2) of non-penetrance are known, the MJD is considered fully penetrant. We identified three families with SCA3; confirming that this disease is not uncommon in sub-Saharan Africa. Studying families with high number of affected sibs will allow refine or consolidate the natural history of these diseases. This study was funded by the NIH through H3Africa project. There was no conflict of interest in this study.

CAG Repeats Within the Non-pathological Range in the HTT Gene Influence Personality Traits in Patients With Subjective Cognitive Decline: A 13-Year Follow-Up Study.

Objective:HTT is a gene containing a key region of CAG repeats. When expanded beyond 39 repeats, Huntington disease (HD) develops. HTT genes with <35 repeats are not associated with HD. The biological function of CAG repeat expansion below the non-pathological threshold is not well understood. In fact higher number of repeats in HTT confer advantageous changes in brain structure and general intelligence, but several studies focused on establishing the association between CAG expansions and susceptibility to psychiatric disturbances and to other neurodegenerative disease than HD. We hypothesized that HTT CAG repeat length below the pathological threshold might influence mood and personality traits in a longitudinal sample of individuals with Subjective Cognitive Decline.MethodsWe included 54 patients with SCD. All patients underwent an extensive neuropsychological battery at baseline, APOE genotyping and analysis of HTT alleles. We used the Big Five Factors Questionnaire (BFFQ) and Hamilton Depression Rating Scale (HDRS), respectively, to assess personality traits of patients and depression at baseline. Patients who did not progress to Mild Cognitive Impairment (MCI) had at least 5-year follow-up time.ResultsIn the whole sample, CAG repeat number in the shorter HTT allele was inversely correlated with conscientiousness (Pearson = −0.364, p = 0.007). There was no correlation between HDRS and CAG repeats. During the follow-up, 14 patients [25.93% (95% C.I. = 14.24–37.61)] progressed to MCI (MCI+) and 40 [74.07% (95% C.I. = 62.39–85.76)] did not (MCI−). When we performed the same analysis in the MCI+ group we found that: CAG repeat length on the shorter allele was inversely correlated with energy (Pearson = 0.639, p = 0.014) and conscientiousness (Pearson = −0.695, p = 0.006). CAG repeat length on the longer allele was inversely correlated with conscientiousness (Pearson = −0.901, p < 0.001) and directly correlated with emotional stability (Pearson = 0.639, p = 0.014). These associations were confirmed also by multivariate analysis. We found no correlations between BFFQ parameters and CAG repeats in the MCI− group.DiscussionPersonality traits and CAG repeat length in the intermediate range have been associated with progression of cognitive decline and neuropathological findings consistent with AD. We showed that CAG repeat lengths in the HTT gene within the non-pathological range influence personality traits.

The association between educational attainment and SCA 3 age of onset and disease course

BackgroundThe number of trinucleotide CAG repeats is inversely correlated with the age at onset (AAO) of motor symptoms in individuals with Spinocerebellar Ataxia type 3 (SCA 3) and may be responsible for 50%–60% of the variability in AAO. Drawing from a social determinants of health model, we sought to determine if educational attainment further contributes to the AAO and motor symptom progression of SCA 3. MethodsWe performed a retrospective chart review in which twenty individuals met criteria for inclusion and had been seen by an ataxia specialist at our hospital between January 2005 and July 2019. AAO of motor symptoms and Scale for Assessment and Rating of Ataxia (SARA) scores were used as primary outcome measures. ResultsUsing a linear regression, we found that having greater CAG repeat length and greater than 16 years of education results in an earlier AAO. The importance of the CAG repeat length on AAO, however, is greater amongst individuals with lower education. Using a linear mixed model evaluating SARA score over time with AAO, we found that less than 16 years of education is associated with faster progression of the disease. ConclusionIn our group of SCA 3 patients, level of education correlated with both the AAO and SARA scores. Though our findings need to be confirmed with a larger cohort, our study suggests that level of education can have a strong influence on health outcomes in SCA 3 and possibly other groups of patients with ataxia.

Associations between prognostic index scores and plasma neurofilament light in Huntington's disease

IntroductionThe inclusion of premanifest Huntington's Disease (Pre-HD) subjects in clinical trials necessitates selecting those who are near transition to manifest Huntington's disease (Man-HD). We previously determined that plasma neurofilament light (NfL) levels are significantly correlated with predicted years to Man-HD onset, using established formulae. Recently, a new normalized prognostic index (PIN) score for predicting Pre-HD disease progression has been validated. Our objective was to determine whether plasma NfL levels are similarly associated with PIN score and PIN score-derived years to Man-HD onset (PIN-YTO). Method112 individuals (46 Pre-HD, 66 Man-HD) underwent blood sample collection and clinical assessment, inclusive of the Symbol Digit Modalities Test and Unified Huntington's Disease Rating Scale Total Motor Score. Plasma NfL levels were measured using a Meso Scale Discovery assay. ResultsPre-HD and Man-HD cohorts differed by age (p < .0001), and CAG repeat number (p = .004), but not education level or gender. Plasma NfL levels were significantly correlated with PIN scores (r = 0.69, p < .0001) and PIN-YTO (r = −0.69, p < .0001). Plasma NfL levels were similarly correlated with predicted years to onset scores determined using Langbehn and colleague's formula (r = −0.68, p < .0001). All significant correlations endured corrections for age and CAG repeat number. A plasma NfL cut-point of <45.0 pg/ml distinguished Pre-HD participants >10 predicted years from Man-HD onset, compared to those ≤10 predicted years. ConclusionsWe have extensively shown that plasma NfL levels are associated with predicted years to manifest HD onset in Pre-HD participants, and present a plasma NfL cut-point that may help exclude far-from-onset Pre-HD patients from clinical trials.

A selective inhibitor of the NLRP3 inflammasome as a potential therapeutic approach for neuroprotection in a transgenic mouse model of Huntington\u2019s disease

BackgroundHuntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of the CAG repeat in the huntingtin (HTT) gene. When the number of CAG repeats exceeds 36, the translated expanded polyglutamine-containing HTT protein (mutant HTT [mHTT]) interferes with the normal functions of many cellular proteins and subsequently jeopardizes important cellular machineries in major types of brain cells, including neurons, astrocytes, and microglia. The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome, which comprises NLRP3, ASC, and caspase-1, is involved in the activation of IL-1β and IL-18 and has been implicated in various biological functions. Although the existence of the NLRP3 inflammasome in the brain has been documented, the roles of the NLRP3 inflammasome in HD remain largely uncharacterized. MCC950 is a highly selective and potent small-molecule inhibitor of NLRP3 that has been used for the treatment of several diseases such as Alzheimer’s disease. However, whether MCC950 is also beneficial in HD remains unknown. Therefore, we hypothesized that MCC950 exerts beneficial effects in a transgenic mouse model of HD.MethodsTo evaluate the effects of MCC950 in HD, we used the R6/2 (B6CBA-Tg[HDexon1]62Gpb/1J) transgenic mouse model of HD, which expresses exon 1 of the human HTT gene carrying 120 ± 5 CAG repeats. Male transgenic R6/2 mice were treated daily with MCC950 (10 mg/kg of body weight; oral administration) or water for 5 weeks from the age of 7 weeks. We examined neuronal density, neuroinflammation, and mHTT aggregation in the striatum of R6/2 mice vs. their wild-type littermates. We also evaluated the motor function, body weight, and lifespan of R6/2 mice.ResultsSystematic administration of MCC950 to R6/2 mice suppressed the NLRP3 inflammasome, decreased IL-1β and reactive oxygen species production, and reduced neuronal toxicity, as assessed based on increased neuronal density and upregulation of the NeuN and PSD-95 proteins. Most importantly, oral administration of MCC950 increased neuronal survival, reduced neuroinflammation, extended lifespan, and improved motor dysfunction in R6/2 mice.ConclusionsCollectively, our findings indicate that MCC950 exerts beneficial effects in a transgenic mouse model of HD and has therapeutic potential for treatment of this devastating neurodegenerative disease.

Advances in Modeling Polyglutamine Diseases Using Genome Editing Tools.

Polyglutamine (polyQ) diseases, including Huntington’s disease, are a group of late-onset progressive neurological disorders caused by CAG repeat expansions. Although recently, many studies have investigated the pathological features and development of polyQ diseases, many questions remain unanswered. The advancement of new gene-editing technologies, especially the CRISPR-Cas9 technique, has undeniable value for the generation of relevant polyQ models, which substantially support the research process. Here, we review how these tools have been used to correct disease-causing mutations or create isogenic cell lines with different numbers of CAG repeats. We characterize various cellular models such as HEK 293 cells, patient-derived fibroblasts, human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs) and animal models generated with the use of genome-editing technology.

The Relationship of Steroid Hormones, Genes Related to Testosterone Metabolism and Behavior in Boys With Autism in Slovakia.

ObjectivePurpose of the study was to identify the relationship among actual plasmatic levels of steroid hormones and behavioral manifestations in boys with autism and to assess the genetic contribution to these manifestations. Methods172 boys with autism under 10 years of age and 135 neurotypical boys attended the study. ADI-R and ADOS-2 were used to evaluate the core symptom severities. Problem behavior was assessed using BPI-01 questionnaire. Levels of testosterone, estradiol, dehydroepiandrosterone, dehydroepiandrosterone-sulfate and sex hormone binding globulin (SHBG) were measured in plasma of autistic boys. Three SNPs (in ESR1, SHBG, SRD5A2 genes) and one STR in AR gene (number of CAG repeats in first exon) were assessed. Hormonal levels and number of CAG repeats in AR gene were used for correlation analysis with behavioral measures. Genotype and allelic frequencies were compared among autistic and neurotypical boys. ResultsWe found negative relationship among SHBG levels and restricted, repetitive behaviors (measured by ADOS-2) and positive relationship among actual testosterone levels and frequency of stereotyped behavior (measured by BPI-01). ConclusionActual levels of SHBG and testosterone are related to severities of restricted and repetitive behaviors in boys with autism. Mechanisms of action of these hormones in brain require further investigation.

Association of trinucleotide repeat polymorphisms CAG and GGC in exon 1 of the androgen receptor gene with male infertility: a cross-sectional study.

: Infertility is a global problem that brings about serious sexual and social consequences that strain the health sector and society. The expansion of CAG and GGC repeats in androgen receptor (AR) gene (Ensembl number ENSG00000169083) may lead to reduced fertility. Our objective was to determine the association of CAG and GGC repeats with altered sperm parameters in male infertile subjects. This was a cross-sectional study conducted at Aga Khan University, Karachi, Pakistan. A total of 376 males were recruited, out of which group A (N = 208) and group B (N = 168) were comprised of subjects with normal and altered sperm parameters, respectively, from 18 to 60 years. The numbers of CAG and GGC repeats were determined by using PCR amplification and sequence analysis using the Molecular Evolutionary Genetic Analysis (MEGA) software version 6.0. Statistical analysis was performed using the SPSS version 20 and the P-value of <0.05 was considered significant. The mean androgen receptor gene CAG repeats were significantly longer in males with altered sperm parameters as compared to male subjects with normal sperm parameters (P < 0.001). There was no significant difference found for GGC repeats for subjects with altered sperm parameters. Longer CAG length corresponded to greater severity of spermatogenic defect and may lead to subfertility recommendations.

Influence of gonadal steroids on cortical surface area in infancy.

Sex differences in the human brain emerge as early as mid-gestation and have been linked to sex hormones, particularly testosterone. Here, we analyzed the influence of markers of early sex hormone exposure (polygenic risk score (PRS) for testosterone, salivary testosterone, number of CAG repeats, digit ratios, and PRS for estradiol) on the growth pattern of cortical surface area in a longitudinal cohort of 722 infants. We found PRS for testosterone and right-hand digit ratio to be significantly associated with surface area, but only in females. PRS for testosterone at the most stringent P value threshold was positively associated with surface area development over time. Higher right-hand digit ratio, which is indicative of low prenatal testosterone levels, was negatively related to surface area in females. The current work suggests that variation in testosterone levels during both the prenatal and postnatal period may contribute to cortical surface area development in female infants.

Huntington's Disease Gene Hunters: An Expanding Tale.

Huntington's Disease Gene Hunters: An Expanding Tale.

Size Matters: The CAG Repeat Length of the Androgen Receptor Gene, Testosterone, and Male Adolescent Depression Severity.

There is a distinct increase in the prevalence of depression with the onset of puberty. The role of peripubertal testosterone levels in boys in this context is insufficiently understood and may be modulated by a functional polymorphism of the androgen receptor gene (AR), a variable number of CAG repeats. Moreover, there is preliminary evidence that the relationship between testosterone, CAG repeat length, and the severity of depressive symptoms may differ between subclinical and overt depression, but this has neither been studied in a clinical sample of adolescents with depression nor compared between subclinical and overt depression in an adequately powered study. To investigate the relationship between free testosterone, CAG repeat length of the AR, depression status (subclinical vs. overt), and the severity of depressive symptoms, 118 boys treated as in- or daycare patients at a single psychiatric hospital were studied. Of these, 73 boys had at least mild depressive symptoms according to the Beck Depression Inventory-II (BDI-II > 13). Higher-order moderation analysis in the multiple regression framework revealed a constant relationship between free testosterone and depression severity irrespective of the number of CAG repeats in adolescents with a BDI-II score ≤ 13. In adolescents with a BDI-II score > 13, however, there was a significant negative relationship between free testosterone and BDI-II score in patients with <19 CAG repeats and a significant positive relationship regarding free testosterone and BDI-II score in those with more than 28 CAG repeats, even when considering important covariates. These results suggest that the effects of testosterone on mood in male adolescents with depression depend on the genetic make-up of the AR as well as on depression status. This complex relationship should be considered by future studies addressing mental health issues against an endocrine background and may, moreover, contribute to tailored treatment concepts in psychiatric medicine, especially in adults.

Age of Onset of Huntington's Disease in Carriers of Reduced Penetrance Alleles.

Age of manifest Huntington's disease (HD) onset correlates with number of CAG repeats in the huntingtin gene. Little is known about onset with 36 to 39 repeats, the "reduced penetrance" (RP) range. We provide allele-specific estimates of HD penetrance (diagnostic confidence level of 4) for RP allele carriers. We analyzed 431 pre-manifest RP allele carriers from Enroll-HD, the largest prospective observational HD study. Cumulative penetrance (CP) was estimated from Kaplan-Meier curves. No one with 36 repeats (n=25) phenoconverted. CP for 38 repeats (n=120) was 32% (95% confidence interval [CI] 0%-55%) and 51% (CI, 10%-73%) by ages 70 and 75, respectively, and 68% (CI, 46%-81%) and 81% (CI, 58%-92%) by ages 70 and 75 for 39 repeats (n=253). CP was not estimable at those ages for 37 repeats (n=33). Differences by RP-range repeat length did not reach significance with a 3-year median follow-up duration among censored individuals. © 2021 International Parkinson and Movement Disorder Society.

CAG polymorphism of the Androgen Receptor gene and semen parameters in pathozoospermic patients with and without Y chromosome microdeletions, and in normozoospermic men

Introduction. The effect of polymorphic variants of the androgen receptor gene (AR) on spermatogenesis and semen parameters in men with different genotypes for other loci has not been sufficiently studied.The aim of this work was to study the effect of the (CAG)n polymorphism of the AR gene on semen parameters in men with impaired fertility, with and without partial deletions of the AZFс region from the Y chromosome.Materials and methods. The study included 988 unrelated Russian patients with pathozoospermia, including 591 patients without Y chromosome microdeletions and 397 patients with partial deletions of the AZFc region of the Y chromosome. The control group consisted of 131 normozoospermic men. All men who participated in the study underwent semen analysis and genetic testing. Genomic DNA was isolated from peripheral venous blood lymphocytes and ejaculate. The analysis of the polymorphism of (GAG)n repeat in exon 1 of the AR gene was performed using a polymerase chain reaction by the amplified fragment length polymorphism method.Results. Three groups were studied: patients with pathozoospermia with (n = 32) and without (n = 541) Y chromosome microdeletions, and normozoospermic men (control, n = 131). The median and quartiles of the number of CAG repeats in the groups were 22 and 20-25, respectively. According to the number of trinucleotide repeats of the AR gene, all patients were divided into subgroups: carriers of short ((GAG)n ≤18), medium ((GAG)n = 19-25) and long ((GAG)n ≥26) alleles. Medium alleles prevailed in all groups; in men without AZFc deletions and with microdeletions, their frequency was 79.3 and 81.4 %, respectively, in controls - 81.7 %.Conclusion. No correlation was found in examined cohort for semen parameters (sperm concentration and total number, number of live, progressively motile and morphologically normal spermatozoa) from the number of trinucleotide repeats. However, a statistically significant difference (p ≤0.045; FDR correction) was found in concentration and total number, number of live, progressively motile and morphologically normal spermatozoa when comparing men with nomrozoospermia (control) with patients with pathozoospermia with and without partial AZFc deletions in subgroups of carriers of short, medium and long alleles.

Movement Disorders P-MD001. Evaluation of gait in spinocerebellar ataxia type 12 (SCA-12)

Introduction . SCA12 an autosomal dominant ataxia, is characterized by tremor in hands at onset followed by gait ataxia and other cortical features during the course of illness. The aim of the study was to identify and quantify spatiotemporal parameters of gait in a group of SCA12 patients and to compare it with healthy subjects. Methods . Genetically confirmed SCA12 patients (n = 25) with mean age of 55.7 ± 10.2 years and age matched healthy individuals (n = 25) with 55.2 ± 10.1 years were studied. A walkway system (by Teckscan, USA) was used to evaluate spatiotemporal parameters of gait in both groups. All the participants were instructed to walk bare foot within comfortable normal speed on sensor plates of walkway system for 30 seconds. The two sampled t test was used with the level of significance p value <0.05. Results . All spatial and temporal parameter mean values were significantly different from the control group, except for single support time and swing time. Most significant findings in spatial and temporal parameters concerned stride length (106.8 ± 7.4cm in control group vs 79.0 ± 19.4 cm in patients, p = 0.000), step width (7.8 ± 1.7 cm in control group vs 13.8 ± 2.8 cm in patients, p = 0.000), double support time (0.35 ± 0.6 sec in control group vs 0.61 ± 0.30 sec in patients, p=0.005) and gait velocity (83.5 ± 14.5 cm/sec in control group vs 48.86 ± 21.6 cm/s in patients, p = 0.000). Ten patients with normal gait had mean duration of illness 4.4 ± 1.2 year and mean CAG repeat number 55.7 ± 5.4. Mean duration of illness and mean CAG repeat number of 15 patients having abnormal gait was 6.8 ± 5.4 years and 53.8 ± 7.3. Conclusion . Gait ataxia in SCA12 patients was a late feature and developed after around 5 years of illness. Gait showed significant reduction in stride length, step length, gait velocity with mark increase in step width and double support time.

The Effect of CAG Repeats within the Non-Pathological Range in the HTT Gene on Cognitive Functions in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment

The Huntingtin gene (HTT) is within a class of genes containing a key region of CAG repeats. When expanded beyond 39 repeats, Huntington disease (HD) develops. Individuals with less than 35 repeats are not associated with HD. Increasing evidence has suggested that CAG repeats play a role in modulating brain development and brain function. However, very few studies have investigated the effect of CAG repeats in the non-pathological range on cognitive performances in non-demented individuals. In this study, we aimed to test how CAG repeats’ length influences neuropsychological scores in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). We included 75 patients (46 SCD and 29 MCI). All patients underwent an extensive neuropsychological battery and analysis of HTT alleles to quantify the number of CAG repeats. Results: CAG repeat number was positively correlated with scores of tests assessing for executive function, visual–spatial ability, and memory in SCD patients, while in MCI patients, it was inversely correlated with scores of visual–spatial ability and premorbid intelligence. When we performed a multiple regression analysis, we found that these relationships still remained, also when adjusting for possible confounding factors. Interestingly, logarithmic models better described the associations between CAG repeats and neuropsychological scores. CAG repeats in the HTT gene within the non-pathological range influenced neuropsychological performances depending on global cognitive status. The logarithmic model suggested that the positive effect of CAG repeats in SCD patients decreases as the number of repeats grows.

Identifying androgen receptor (AR) and genomic characteristics that define populations of patients with mHSPC who benefit from early PARP inhibition therapy with talazoparib.

TPS5097 Background: A minority of men with mCRPC, those with DNA repair mutations, can benefit from PARP inhibitor therapy. In addition to DNA repair, PARP is used by cancer cells to interact with other cellular mechanisms including androgen receptors (AR). The next generation PARP inhibitor talazoparib can, in addition to inhibiting DNA repair, trap PARP, preventing it from carrying out its other functions. As progression in mHSPC is based on AR escape mechanisms, we predict that early exposure to PARP inhibition will delay progression. In addition, AR characteristics and function vary by ethnic populations. AR expression is inversely related with the number of polymorphic CAG repeats. As African American (AfrAm) men commonly have shorter CAG repeats in their AR, they may experience different response duration, but have been under-represented in clinical trials. Furthermore, CAG repeats may be associated with greater signaling through pathways such as wnt and Myc, which is associated with aggressive disease. Thus, studying intensified up-front therapy in a diverse prostate cancer population is a critical unmet need. Methods: 70 subjects will be treated with ADT + abiraterone + talazoparib. Outreach by our Division of Health Equities and accrual at community satellites located near diverse populations will be enlisted to accrue a target of 30% African American. Talazoparib will be dosed at 1mg daily (0.75 mg in renal insufficiency). LHRH and abiraterone formulations will be left to physician’s choice. PSA and safety labs will be checked every 4 weeks for the first 12 weeks. Imaging will be performed every 12 weeks for the first year then every 24 weeks if PSA is decreasing, or 12 weeks if rising. Data safety monitoring for toxicity after every 10 subjects have been accrued. Diversity of accrual will be evaluated after 30 subjects are enrolled; amendments will be made if the diversity goal is not achieved. Tissue genomics and ctDNA will be measured at baseline; ctDNA will be repeated after 4 weeks and at castration resistance. Endpoints: Primary: PSA nadir at 7 months has been found to be associated with overall survival and is achieved by 55% of men with mHSPC with ADT + abiraterone. With 70 subjects there is 97% power to confirm improved nadir rate of 75%, and 83% power to determine a nadir rate &gt;70%. Secondary endpoints include objective response by RECIST 1.1 for subjects with measurable disease. radiographic progression free survival. Correlative objectives include comparing outcomes in subsets of men with high vs low number of AR CAG repeats, men with genomic alterations, and the change in ctDNA alteration fractions from baseline to 4 weeks and at progression. Progress: The trial is open to accrual as of Feb 2021. Sponsor: Pfizer/ Prostate Cancer Foundation RFP Clinical trial information: NCT04734730.

Genetic testing and prenatal diagnosis of two pedigrees affected with Huntington disease

To explore the genetic basis for two Chinese pedigrees affected with Huntington disease and provide prenatal diagnosis for them. Peripheral venous blood samples were collected from the probands. PCR and capillary gel electrophoresis were used to determine the number of CAG repeats in their IT15 gene. Pre-symptomatic testing was offered to their children and relatives, and prenatal diagnosis was provided to three pregnant women from the two pedigrees. The two probands, in addition with three asymptomatic members, were found to have a (CAG)n repeat number greater than 40. Upon prenatal diagnosis, the numbers of CAG repeats in two fetuses from pedigree 1 were determined as (16, 19) and (18, 19), both were within the normal range. A fetus from pedigree 2 was found to have a CAG repeat number of (15, 41), which exceeded the normal range. Genetic testing can facilitate the diagnosis of Huntington disease and avoid further birth of affected children.

A series of cases with Huntington-like phenotype and intermediate repeats in HTT

BackgroundIntermediate Alleles (IAs) are expansions of CAG repeats in the HTT gene between 27 and 35 repeats which pathogenic meaning remains controversial. They are present in the general population but there is an increasing number of cases with Huntington-like phenotype reported. MethodsWe reviewed the medical records of cases in our centre where the neurologist suspected Huntington's disease (HD) as one of the feasible diagnoses and genetic testing showed the number of CAG repeats was in the “intermediate range”. We gathered the type of symptoms in all cases and the main neuroimaging findings when available. ResultsWe found 14 cases, 8 males and 6 females, with average age at onset at 64 years old. Most cases exhibited some type of extrapyramidal symptoms. Cognitive and/or behavioral symptoms were also present in most cases (being depression, anxiety and cognitive impairment the most frequent ones). In one case we found deposits of iron in the basal ganglia in the MRI, and in another case we found diffuse cortical hypometabolism with predominantly frontal bilateral involvement and bilateral focal deficit of both caudate and thalamus in the FDG-PET. ConclusionThe clinical and neuroimaging findings of some cases with IA in this series are compatible with the clinical picture of HD but also with several other alternative diagnoses. Therefore we can not establish association between IA and HD. Larger series with more comprehensive diagnostic workout and neuropathological studies are needed to confirm or rule out whether IAs in the HTT gene may cause HD.