Number Of Trinucleotide Repeats Research Articles

Clinical and genetic analysis of a patient with Neuronal intranuclear inclusion body disease characterized by cortical enhancement in the posterior brain region

To explore the clinical, imaging, and genetic characteristics of an adult patient with sporadic Neuronal intranuclear inclusion disease (NIID). A patient who had visited the First People's Hospital of Chenzhou on August 6, 2023 was selected as the study subject. Results of clinical examination, neuroimaging, and genetic testing were retrospectively analyzed along with a literature review. The number of GGC trinucleotide repeats in the 5'-untranslated region of the NOTCH2NLC gene was determined by GC-PCR. The patient had presented with episodic encephalopathy, with enhanced magnetic resonance imaging showing enhancement features of the posterior cerebral cortex during the period of acute episode. Genetic testing revealed an increased number of GGC repeats (n = 97) in the 5'- untranslated region of the NOTCH2NLC gene, which confirmed the diagnosis of NIID. Clinical attention should be paid to the enhanced MRI findings of patients with adult-onset NIID, for whom posterior cortical enhancement may be characteristic manifestation during the acute phase of encephalopathy-like episode.

Change in Visual Acuity of Patients With Fuchs Endothelial Corneal Dystrophy Over 1 Year.

To determine whether the clinical and paraclinical course of Fuchs endothelial corneal dystrophy (FECD) over 1 year is related to the extent of triplet repetition in the transcription factor 4 (TCF4) gene. A prospective study with a 1-year follow-up was conducted. A total of 104 patients (160 eyes) with FECD and an equivalent number of age- and sex-matched control subjects without FECD were included. At inclusion, the corneas were graded using the modified Krachmer grade (KG) and patients were genotyped for the number of trinucleotide repeats (TNRs) in the TCF4 gene by the short tandem repeat assay. Visual acuity, Scheimpflug tomographic features, and the Visual Function and Corneal Health Status using a visual disability instrument were measured on 2 visits at 1-year intervals. KGs ranged from 1 to 6, and 46% of eyes had grades 1 to 4. 71% of the patients harbored TNR expansion (>40) versus 13% in control subjects ( P < 0.001). Severity at inclusion was higher in the presence of TNR expansion when considering eyes independently (mean grade ±SD, 4.08 ± 1.42) without TNR expansion and 4.66 ± 1.27 with TNR expansion ( P = 0.024). In 1 year, the ETDRS score significantly decreased by -2.97 (95% confidence interval -4.69 to -1.26, P = 0.001) and the ETDRS score with glare by -4.25 (95% confidence interval -6.22 to -2.27, P < 10 -5 ). There was no relationship between the rate of decline and TNR expansion or KG. Central corneal thickness and Visual Function and Corneal Health Status scores did not significantly vary. It is possible to measure a subtle progression of FECD over a period as short as 1 year. We did not find a relationship between the presence of TNR expansion and the speed of deterioration over 1 year. This work should facilitate the design of future clinical trials on FECD.

Behavioural, psychiatric, and cognitive phenotypes associated with numbers of repeats of the FRAXE allele on the FMR2 gene

Background The FRAXE site on the X-chromosome has a variable number of trinucleotide repeats. The rare condition Fragile XE has &gt;200 repeats, but most X chromosomes have &lt;60 such repeats, with evidence of a bimodal distribution. It is known that when the number of repeats is &lt;60, the repeat number can increase from mother to son, which raises the question as to whether there is an evolutionary advantage in the size of these repeats. This paper investigates whether the higher of the &lt;60 repeats are associated with neurocognitive differences among boys in a general population. We hypothesised that although there was previous evidence of a link between higher numbers of repeats in the boys in this population with maternal grandmothers with schizophrenia, there may be cognitive or behavioural advantages to their grandsons of increased levels of repeats. Methods We compared 1951 behavioural, psychiatric, and cognitive outcomes of 5060 boys from the Avon Longitudinal Study of Parents and Children (ALSPAC) using a phenome scan. Results We found that boys with relatively high levels of repeats (&gt;24) had a higher risk of certain neurocognitive outcomes (P&lt;0.01). Boys with &gt;24 repeats were more likely to report: (a) psychosis-like experiences; (b) increased ability to recognise facial signs of anger; (c) increased risk of eating disorders; (d) increased likelihood of smoking cigarettes and using illicit drugs during adolescence than would be expected by chance. There was no sign of associations with cognitive abilities. Conclusions We concluded that there was little evidence that higher levels of the normal range of FRAXE repeats were associated with a difference in cognitive abilities, but there was evidence of increased reports of psychotic-like experiences and other behaviour problems in this group. There was no evidence of evolutionary neurocognitive advantage.

Nanopore sequencing method for CTG18.1 expansion in TCF4 in late-onset Fuchs endothelial corneal dystrophy and a comparison of the structural features of cornea with first-degree relatives.

To evaluate the relationship between the number of trinucleotide repeats (TNR) in late-onset Fuchs corneal endothelial dystrophy (FCED) and to compare the endothelial properties of FCED, first-degree relatives, and controls. Blood samples were collected from FCEDs to determine TNR number. The FCED patients, first-degree relatives, and controls were examined with specular microscopy for central corneal thickness (CCT), endothelial cell density (ECD), pleomorphism and polymegatism, and with corneal topography for specific indicators such as (i) displacement of thinnest point of cornea, (ii) loss of isopachs, (iii) focal posterior surface depression towards anterior chamber. This study included 92 patients with FCED, 92 first-degree relatives, and 96 controls. CCT was thickest in FCEDs (558.0 μm) (p < 0.05) while there was no difference between relatives (533.0 μm) and controls (530.4 μm) (p = 0.845). ECD was decreased in both FCED (2069.2 mm2) and relatives (2171.4 mm2) than controls (2822.9 mm2) (p < 0.05 in both). The presence of pleomorphism and polymegatism was significant in patients with FCED (93.4% and 93.4%, respectively), relatives (86.9% and 86.04%, respectively), and controls (8.33% and 1.04%, respectively) (p < 0.05). Specific topographic indicators differed among the groups (p < 0.05). The mean repeat number of the FCED patients was 17.48 ± 4.54 (12-25) times. The TNR number of FCED cases correlated with the relative CCT (p < 0.05, R = 0.615) and cell density (p = 0.009, R = -0.499). A strong association between the corneal endothelium in relatives and TNR number of FCEDs was defined. Relatives tended to have fewer corneal endothelial cells, even though they did not have clinical findings.

Heterogenous Genetic, Clinical, and Imaging Features in Patients with Neuronal Intranuclear Inclusion Disease Carrying NOTCH2NLC Repeat Expansion.

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that is caused by the abnormal expansion of non-coding trinucleotide GGC repeats in NOTCH2NLC. NIID is clinically characterized by a broad spectrum of clinical presentations. To date, the relationship between expanded repeat lengths and clinical phenotype in patients with NIID remains unclear. Thus, we aimed to clarify the genetic and clinical spectrum and their association in patients with NIID. For this purpose, we genetically analyzed Japanese patients with adult-onset NIID with characteristic clinical and neuroimaging findings. Trinucleotide repeat expansions of NOTCH2NLC were examined by repeat-primed and amplicon-length PCR. In addition, long-read sequencing was performed to determine repeat size and sequence. The expanded GGC repeats ranging from 94 to 361 in NOTCH2NLC were found in all 15 patients. Two patients carried biallelic repeat expansions. There were marked heterogenous clinical and imaging features in NIID patients. Patients presenting with cerebellar ataxia or urinary dysfunction had a significantly larger GGC repeat size than those without. This significant association disappeared when these parameters were compared with the total trinucleotide repeat number. ARWMC score was significantly higher in patients who had a non-glycine-type trinucleotide interruption within expanded poly-glycine motifs than in those with a pure poly-glycine expansion. These results suggested that the repeat length and sequence in NOTCH2NLC may partly modify some clinical and imaging features of NIID.

The Role of Alleles with Intermediate Numbers of Trinucleotide Repeats in Parkinson’s Disease and Other Neurodegenerative Diseases

The Role of Alleles with Intermediate Numbers of Trinucleotide Repeats in Parkinson’s Disease and Other Neurodegenerative Diseases

The role of alleles with an intermediate number of trinucleotide repeats in Parkinson's disease and other neurodegenerative disorders

Genetic factors underlie the pathological processes that cause the manifestation of a wide range of neurodegenerative diseases. The pathological expansion of unstable trinucleotide repeats is known to lead monogenic neurological diseases such as Huntington's disease, Kennedy's disease, spinocerebellar ataxia, and others. However, the latest data suggests individuals with intermediate allele (IA) repeat length have a risk of developing common neurological phenotype, for example, Parkinson's disease, Alzheimer's disease. In this study, we review the current knowledge on intermediate alleles of HTT gene for pathogenesis and clinical features of neurodegenerative diseases, with the focus on Parkinson's disease. Early diagnosis of neurodegenerative disease and genetic counselling of the family can be improved via the implementation of specific management strategies of IA carriers by team of highly experienced professionals in the fields of neurology and genetics.

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.

Differential Gene Expression in Post-Finasteride Syndrome Patients

BackgroundAn organic etiology underpinning post-finasteride syndrome, a constellation of persistent sexual, neuropsychiatric, and somatic symptoms reported by men exposed to 5-alpha-reductase inhibitors (5ARIs), is debated. Persistent changes in neurosteroid levels or androgen receptor expression have been implicated. AimTo determine whether differences in gene expression, especially in relevant biologic pathways, exist between patients reporting post-finasteride syndrome symptoms and healthy controls. MethodsThis was a single center, prospective case-control study taking place between March 2013 and September 2018. Men 18 years and older being evaluated for sexual dysfunction (study) or circumcision (control) were eligible for inclusion. Twenty-six men with a history of 5ARI use reporting symptoms consistent with post-finasteride syndrome were included in the patient group. Twenty-six men consented to inclusion in the control group. OutcomesThe primary outcome measure is gene expression data for genes affecting neurosteroid levels and androgen receptor activity from penile skin cells. ResultsGene expression of cells from penile skin samples from twenty-six men of median age 38 years (IQR, 33-42) in the study group was compared with that from twenty-six men of median age 41 years (IQR, 35-62) in the control group (P = .13), with 1,446 genes significantly over-expressed and 2,318 genes significantly under-expressed in study patients. Androgen receptor expression was significantly higher in study patients compared to controls (9.961 vs 9.494, adjusted P value = .01). Serum levels of androgen receptor activity markers 5α-androstanediol (0.950 ng/mL [0.749-1.587] vs 0.949 [0.817-1.337], P = .34) or 3α-androstanedione (3.1 ng/mL [1.925-5.475] vs 6.7 [3.375-11.4], P = .31) revealed no significant differences. No significant differences were found between the number of trinucleotide repeats (21.5 [20-23.75], 22 [19-25], P = .94). Clinical ImplicationsIn this study we present evidence of gene expression correlating with observed biologic differences in patients with post-finasteride syndrome; providers who prescribe 5ARIs should be aware and advise their patients accordingly. Strengths & LimitationsStrengths of this study include the evaluation of multiple proposed etiologies for post-finasteride syndrome. The study is also strengthened by the fact that not all data matched the initial hypotheses, qualifying the argument for the existence of PFS. Limitations include potential selection bias arising from more severe phenotypes seeking care; lack of gene expression data prior to 5ARI exposure; lack of non-penile tissue samples supposedly involved; and a lack of mechanistic data to imply causality. ConclusionThis study is the first to consider and demonstrate gene expression differences in patients with PFS as a potential etiology of sexual dysfunction. Howell S, Song W, Pastuszak A, et al. Differential Gene Expression in Post-Finasteride Syndrome Patients. J Sex Med 2021;18:1479–1490.

Serum neurofilament light chain as a severity marker for spinocerebellar ataxia

Since the serum neurofilament light (NfL) chain is known as a promising biomarker in neurodegenerative diseases, we aimed to evaluate serum NfL as a biomarker indicating neuronal damage in autosomal-dominant (AD) spinocerebellar ataxia (SCA). We reviewed patients diagnosed with AD SCA in the outpatient clinic of Seoul National University Hospital’s (SNUH) Department of Neurology between May and August of 2019. We reviewed the demographic data, clinical characteristics, Scale for the Assessment and Rating of Ataxia (SARA) score, and brain magnetic resonance imaging (MRI) scans. The serum NfL was measured by electrochemiluminescence (ECL) immunoassay. Forty-nine patients with AD SCA were reviewed and their serum NfL level was determined. The median serum NfL level (109.5 pg/mL) was higher than control (41.1 pg/mL) (p-value < 0.001). Among the AD SCA patients, there was a positive correlation between the serum NfL level and the trinucleotide repeat number (r = 0.47, p-value = 0.001), disease duration (r = 0.35, p-value = 0.019), disease duration/age × trinucleotide repeat number (r = 0.330, p-value = 0.021), and SARA score (n = 33; r = 0.37, p-value = 0.033). This study shows that serum NfL is elevated in AD SCA patients and correlates with clinical severity.

Unexpected Associations between the Number of FRAXE Repeats in Boys and Evidence of Diabetes in Their Mothers and Maternal Grandmothers.

The FRAXE section of the FMR2 gene, located on the X chromosome, contains varying numbers of trinucleotide repeats; boys with over 200 repeats tend to have mild cognitive impairments, though this is rare. Little is known, however, concerning the phenotypes of individuals with smaller numbers of repeats. Here we answer the research question as to whether the health of ancestors of boys from whom the relevant X chromosome was inherited differed in any way according to the number of FRAXE repeats. Numbers of FRAXE repeats in 5057 boys from the Avon Longitudinal Study of Parents and Children (ALSPAC) were assessed. The distribution was bimodal, with the second smaller distribution starting at 22 repeats. We tested whether possession of 22+ repeats was associated with differences in the health of mothers (who share the X chromosome) and maternal grandmothers (half of whom share it).Female ancestors of boys with >21 repeats compared with <22 showed that maternal grandmothers (MGM) and mothers (M) had an increased risk of diabetes: MGM Type I odds ratio (OR) 2.40 [95%CI: 1.07,5.38]; MGM Type II OR 1.61 [0.96,2.70]; M OR 1.95 [0.96,3.94] using self-reported questionnaire measures. These results were confirmed from maternal medical records which revealed an increased level of diabetes [OR 2.40 (1.16,4.96)] and an increased risk of repeated glycosuria during pregnancy [OR 1.60 (1.08,2.36)]. We tested numbers of FRAXA repeats and showed no such associations, indicating that the findings were not associated with triploid repeats in general. If these findings are replicated elsewhere, there are at least three possible interpretations: (i) maternal diabetes/prediabetes results in an increased number of FRAXE repeats; (ii) women with high numbers of FRAXE repeats are at increased risk of diabetes; or (iii) some common factor, e.g. genomic instability, results in both diabetes and increased repeats.

Label-free Electrochemical Detection of CGG Repeats on Inkjet Printable 2D Layers of MoS2.

Flexible and ultrasensitive biosensing platforms capable of detecting a large number of trinucleotide repeats (TNRs) are crucial for future technology development needed to combat a variety of genetic disorders. For example, trinucleotide CGG repeat expansions in the FMR1 gene can cause Fragile X syndrome (FXS) and Fragile X-associated tremor/ataxia syndrome (FXTAS). Current state-of-the-art technologies to detect repeat sequences are expensive, while relying on complicated procedures, and prone to false negatives. We reasoned that two-dimensional (2D) molybdenum sulfide (MoS2) surfaces may be useful for label-free electrochemical detection of CGG repeats due to its high affinity for guanine bases. Here, we developed a low-cost and sensitive wax-on-plastic electrochemical sensor using 2D MoS2 ink for the detection of CGG repeats. The ink containing few-layered MoS2 nanosheets was prepared and characterized using optical, electrical, electrochemical, and electron microscopic methods. The devices were characterized by electron microscopic and electrochemical methods. Repetitive CGG DNA was adsorbed on a MoS2 surface in a high cationic strength environment and the electrocatalytic current of the CGG/MoS2 interface was recorded using a soluble Fe(CN)6-3/-4 redox probe by differential pulse voltammetry (DPV). The dynamic range for the detection of prehybridized duplexes ranged from 1 aM to 100 nM with a 3.0 aM limit of detection. A detection range of 100 fM to 1 nM was recorded for surface hybridization events. Using this method, we were able to observe selectivity of MoS2 for CGG repeats and distinguish nonpathogenic from disease-associated repeat lengths. The detection of CGG repeat sequences on inkjet printable 2D MoS2 surfaces is a forward step toward developing chip-based rapid and label-free sensors for the detection of repeat expansion sequences.

The FRAXA and FRAXE allele repeat size of boys from the Avon Longitudinal Study of Parents and Children (ALSPAC).

The FRAXA and FRAXE alleles of the FMR1 and FMR2 genes located on the X chromosome contain varying numbers of trinucleotide repeats. Large numbers of repeats at FRAXA (full mutations) manifest as Fragile X syndrome, associated with mental impairment that affects males more severely. In this paper, we present the dataset of frequencies of FRAXA and FRAXE repeat size extracted from DNA samples collected from boys enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). DNA data were extracted from samples collected in ALSPAC clinics from several types of samples: cord blood, venepuncture blood taken at 43 months, 61 months, seven years or nine years. The DNA was amplified at FRAXA and FRAXE using fluorescent PCR in the Wessex Regional Genetics Laboratory, Salisbury District Hospital. The mean repeat size for FRAXA is 28.92 (S.D. 5.44), the median 30 and the range 8 to 68. There were particularly high numbers of boys with repeat sizes of 20 (10.67%) and 23 (7.35%). The mean repeat size for FRAXE is 17.41 (S.D. 3.94), with median of 16 and range of 0 to 61. There is a relatively high degree of variation of the FRAXA repeat size particularly and we suggest the extensive data available from the ALSPAC study opens up areas of research into understanding phenotypes associated with relatively unexplored repeat sizes. This could be particularly interesting for the lower repeat sizes occurring with high frequency at FRAXA in this population. As the data can be linked to exposures and phenotypes, it will provide a resource for researchers worldwide.

The FRAXA and FRAXE allele repeat size of boys from the Avon Longitudinal Study of Parents and Children (ALSPAC)

The FRAXA and FRAXE alleles of the FMR1 and FMR2 genes located on the X chromosome contain varying numbers of trinucleotide repeats. Large numbers of repeats at FRAXA (full mutations) manifest as Fragile X syndrome, associated with mental impairment that affects males more severely. In this paper, we present the dataset of frequencies of FRAXA and FRAXE repeat size extracted from DNA samples collected from boys enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). DNA data were extracted from samples collected in ALSPAC clinics from several types of samples: cord blood, venepuncture blood taken at 43 months, 61 months, seven years or nine years. The DNA was amplified at FRAXA and FRAXE using fluorescent PCR in the Wessex Regional Genetics Laboratory, Salisbury District Hospital. The mean repeat size for FRAXA is 28.92 (S.D. 5.44), the median 30 and the range 8 to 68. There were particularly high numbers of boys with repeat sizes of 20 (10.67%) and 23 (7.35%). The mean repeat size for FRAXE is 17.41 (S.D. 3.94), with median of 16 and range of 0 to 61. There is a relatively high degree of variation of the FRAXA repeat size particularly and we suggest the extensive data available from the ALSPAC study opens up areas of research into understanding phenotypes associated with relatively unexplored repeat sizes. This could be particularly interesting for the lower repeat sizes occurring with high frequency at FRAXA in this population. As the data can be linked to exposures and phenotypes, it will provide a resource for researchers worldwide.

A bioinformatical approach to the pathogenesis of Fragile X premutation carriers

Aim: The common cause of hereditary mental retardation is Fragile X Syndrome (FXS). This disease occurs when the trinucleotide repeat number (CGG)n in the promoter region of the Fragile X mental retardation 1 (FMR1) gene located in Xq27.3 is increased. Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disease caused by CGG repeat increase to 55-200 in the FMR1 gene. Although regulation disorders or mutations in FMR1 seem to be responsible for the pathogenesis of FXS and FXTAS, the broad phenotypic spectrum suggests that there should be some other potential genes involved. In this study, it was aimed to determine the differentially expressed genes of FMR1 premutation carriers and healthy controls by using bioinformatics techniques.Material and Methods: Gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) database, which were analyzed using the Principal Component Analysis (PCA)-based unsupervised feature extraction (FE).Results: The set of 14 genes were identified that could successfully discriminate fragile X premutation carriers and healthy controls, and the majority of these genes were long non-coding RNAs (lncRNA). Conclusion: Although the results of our study should be supported by extended experimental researches, these genes have the potential to be used as biomarkers and therapeutic targets.

Sensitivity to androgens: beyond the well-known facts

Gonadal and extragonadal effects of testosterone in males have been extensively investigated in recent years. To date, there is no doubt that testosterone deficiency in males is associated with increased risk of obesity, type 2 diabetes mellitus, hypertension, and atherosclerosis. Sensitivity to androgens determined by the length of CAG-repeats in the androgen receptor gene is one of the underlying mechanisms of testosterone action. Increase in the number of CAG-repeats reduces activity of androgen receptors, which manifests in the form of low sensitivity to testosterone. On the contrary, decrease in the number of trinucleotide repeats is accompanied by increased sensitivity of the receptors to androgens. This review discusses the effect of androgen receptor gene polymorphism on embryogenesis and sex differentiation, regulation of spermatogenesis, progression of cancer and benign prostatic hyperplasia, symptoms of hypogonadism, control of carbohydrate and lipid metabolism, bone mineral density, vascular endothelium, response to replacement therapy with testosterone, as well as on the psychosocial aspects of personality in males. Implementation of the study of androgen receptor gene polymorphism into clinical practice will enable not only predicting male fertility or the risk of developing prostate cancer, but also selecting an individual therapy for testosterone deficiency.

Study of patterns of inheritance of premature ovarian failure syndrome carrying maternal and paternal premutations

BackgroundPremature ovarian failure / primary ovarian insufficiency (POF/POI) associated with the mutations of the FMR1 (Fragile-X Mental Retardation 1) gene belongs to the group of the so-called trinucleotide expansion diseases. Our aim was to analyse the relationship between the paternally inherited premutation (PIP) and the maternally inherited premutation (MIP) by the examination of the family members of women with POF, carrying the premutation allele confirmed by molecular genetic testing.MethodsMolecular genetic testing was performed in the patients of the 1st Department of Obstetrics and Gynecology with suspected premature ovarian failure. First we performed the southern blot analyses and for the certified premutation cases we used the Repeat Primed PCR.ResultsDue to POF/POI, a total of 125 patients underwent genetic testing. The FMR1 gene trinucleotide repeat number was examined in the DNA samples of the patients, and in 15 cases (12%) deviations (CGG repeat number corresponding to premutation or gray zone) were detected. In 6 cases out of the 15 cases the CGG repeat number fell within the range of the so-called gray zone (41–54 CGG repeat) (4.8%, 6/125), and the FMR1 premutation (55–200 CGG repeat) ratio was 7.2% (9/125). In 4 out of the 15 cases we found differences in both alleles, one was a premutation allele, and the other allele showed a repeat number belonging to the gray zone. Out of 15 cases, only maternal inheritance (MIP) was detected in 2 cases, in one case the premutation allele (91 CGG repeat number), while in the other case an allele belonging to the gray zone (41 CGG repeat number) were inherited from their mothers. In 10 out of 15 cases, the patient inherited the premutation allele only from the father (PIP). In 5 out of the 10 cases (50%) the premutation allele was inherited from the father, and the repeat number ranged from 55 to 133. Out of 125 cases, 9 patients had detectable cytogenetic abnormalities (7.2%).ConclusionsThe RP-PCR method can be used to define the smaller premutations and the exact CGG number. Due to the quantitative nature of the RP-PCR, it is possible to detect the mosaicism as well.

102 Influence of Genetic Variation in the Androgen Receptor on the Risk of Cardiovascular Disease in Aging Men

Controversy still exists regarding the effect of hypogonadism on cardiovascular (CV) health and the safety of testosterone replacement therapy (TRT). We hypothesized that differences in androgen sensitivity, a function of the number of trinucleotide repeats on the androgen receptor (AR) gene, may result in greater reactivity to age-related testosterone changes and increased risk of CV disease. Participants were men from the Vietnam Era Twin Study of Aging (N=696). Mean age was 56.4 years (range:51-60). Average waking, salivary free-testosterone level was acquired on 3 non-consecutive days. Low testosterone (low-T) was defined as being ≥ 1 SD below the mean. The AR gene CAG repeat length was derived using polymerase chain reaction (PCR) fragment analysis and Sanger sequencing. Average repeat length was 22 (range:8-37). CV disease was assessed by self-report and medication data. We tested the interaction between low testosterone (low-T) and CAG repeat length while controlling for age, ethnicity, smoking status, BMI, hypertension, diabetes, and the correlated nature of the twin data.

Quantitative sonographic assessment of myotonia.

This study explores ultrasound imaging for qualitative and quantitative assessment of myotonia. Sixteen patients with myotonia and 16 controls underwent sonographic evaluation of the thenar eminence muscles to assess the relaxation time after muscle percussion. The mean time for complete muscle relaxation in patients with myotonia was longer than that of controls. A cutoff of > 0.9 s for myotonia detection had a sensitivity of 88% and a specificity of 100%. The interrater reliability was moderate for qualitative assessment but was high for quantitative assessment. The relaxation time did not correlate with the number of trinucleotide repeats in patients with myotonic dystrophy. Sonographic evaluation for the presence of myotonia is feasible, sensitive, and specific but does not correlate with disease severity in myotonic dystrophy. Muscle Nerve 57: 146-149, 2018.

MP91-13 THE ASSOCIATION BETWEEN TESTOSTERONE AND VITALITY: THE ROLE OF GENETIC VARIATION IN THE ANDROGEN RECEPTOR

You have accessJournal of UrologySexual Function/Dysfunction: Medical, Hormonal & Non-surgical Therapy I1 Apr 2017MP91-13 THE ASSOCIATION BETWEEN TESTOSTERONE AND VITALITY: THE ROLE OF GENETIC VARIATION IN THE ANDROGEN RECEPTOR Matthew Panizzon, Tung-Chin Hsieh, Franz Carol, Richard Hauger, and William Kremen Matthew PanizzonMatthew Panizzon More articles by this author , Tung-Chin HsiehTung-Chin Hsieh More articles by this author , Franz CarolFranz Carol More articles by this author , Richard HaugerRichard Hauger More articles by this author , and William KremenWilliam Kremen More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2853AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Controversy still exists regarding the efficacy of testosterone replacement therapy (TRT) for symptomatic hypogonadism. A recent multi-site randomized controlled study of men undergoing TRT failed to show an improvement in several symptom domains, among them is vitality. We hypothesized that differences in androgen sensitivity would obscure symptom improvement for a subset of individuals. Androgen sensitivity is related to the number of trinucleotide (CAG) repeats on exon 1 of the androgen receptor (AR) gene. We sought to examine the regulatory role of this genetic polymorphism on the relationship between testosterone and vitality in middle-aged men METHODS Participants were men from the Vietnam Era Twin Study of Aging (N=696). Average waking, salivary free-testosterone level was acquired on 3 non-consecutive days. The AR gene CAG repeat length was derived using a combination of PCR fragment analysis and Sanger sequencing. Vitality was evaluated with the SF-36Vitality scale. We tested the interaction between low testosterone (low-T) and CAG repeat length while controlling for age, ethnicity, smoking status, BMI, heart disease, hypertension, diabetes, and the correlated nature of the twin data. Low-T was defined as being = 1 SD below the mean for the 3-day average value RESULTS Mean age of the participants was 56.4 years (SD = 2.6) with average CAG repeat length of 22 (range: 8-37). We observed a significant interaction effect between low-T and AR CAG repeat length. In men with a short variant of the AR gene (< 21 repeats), representing greater androgen sensitivity, there was a significant effect of low-T on vitality (p < 0.01). Men with low-T and the short AR gene were on average 10 points lower on the Vitality scale relative to men with normal T and the same genotype. This effect was not observed in men with either medium (21-23 repeats) or long (= 24 repeats) variants of the AR gene. Without the interaction effect in the model, neither low-T nor the AR gene had a significant effect on vitality CONCLUSIONS These results demonstrate that the relationship between low-T and vitality is regulated, in part, by variation in the AR gene. The effect of low-T on vitality was observed only when the genetically-determined sensitivity of the androgen receptor is at its greatest. Variations in the AR gene, bestowing differential androgen sensitivity, are potential targets for personalized therapy of hypogonadism. Future studies are needed to determine how genetic information can be used to improve the efficacy of TRT © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1223 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Matthew Panizzon More articles by this author Tung-Chin Hsieh More articles by this author Franz Carol More articles by this author Richard Hauger More articles by this author William Kremen More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...