Identification of Genetic Mutations in TYR and OCA2 Genes in Congenital Families with Oculocutaneous Albinism (OCA)

Aim: The objective of the present study was to recruit congenital families of oculocutaneous albinism (OCA) and mutations in TYR and OCA2 genes are identified, which is further expanding the mutation spectrum in this population. Methods: Two consanguineous families with OCA were recruited and whole blood was collected. Clinical examination was carried out to determine the visual acuity and related eye, skin and hair examinations. Genomic DNA was extracted by standard phenol-chloroform method. Targeted exome sequencing by TruSight one sequencing panel sequencing was carried out. Sanger sequencing was performed for mutation detection in tyrosinase (TYR) and the OCA2 genes and co-segregation in OCA families. Results: Clinically, the affected individuals of two OCA families showed clinical characteristics including white to pale skin, white or blonde hairs, irritant to light, nystagmus and reduced vision. DNA sequencing showed the genetic mutation of TYR and OCA2 genes in two OCA families. In family 1, the nucleotide variant (c.1255G>A; p.Gly419Arg) was detected inTYR gene, while in another family, the splice-site variant c.1045-15T>G was identified in OCA2. Conclusion: This study concluded that identification of TYR and OCA2 mutations in OCA disease are commonly associated with the population where the consanguinity is persistent. These findings expanded the molecular basis of oculocutaneous albinism in Pakistani families and established the mode of genetic counselling and for diagnostic outcome. Keywords: Consanguineous families; Oculocutaneous albinism (OCA); mutations; tyrosinase (TYR); OCA2 gene.

789 HIGH RESOLUTION ESOPHAGEAL MOTILITY: VARIABLE GEOGRAPHIC DISTRIBUTION IN A LARGE MEXICAN COHORT

High resolution esophageal manometry (HREM) has been in use for about a decade. However, there is no available information regarding geographical or regional differences in diagnostic outcome. Aim Characterize the indications, demographics and diagnostic outcome of HREM in a diverse population of Mexico. Methods Data was collected from four major referral centers representing diverse geographical areas of Mexico: central—Mexico City (two centers, years 2016-2020), south (Veracruz, years 2015-2020) and north (Monterrey, years 2013—2020). All consecutive cases referred for HREM were entered into a data base and analyzed using Chicago 3 classification. Data was evaluated using chi-square to compare frequencies among groups. Results 2,932 patients included: Central n = 877(29.9), North n = 1003(34.2), South n = 1052(35.9). Mean age 47.9(11-93), women 1,795(61.2), men 1,137(38.8). Nationwide, the most common indications for testing were: GERD n = 1677(57.2), followed by dysphagia 587(20), atypical GERD 244(8.3), post-operative GERD 230(7.9), chest pain 114(3.9), and post-operative dysphagia 78(2.8). HREM was normal in 1,468(49.9) patients. Table shows the diagnostic distribution among centers: Central-Mexico had more abnormal cases 531(60.5) (p < 0.0.001) vs 407(40.6) North and 532(50.6) South. Achalasia was more commonly diagnosed in the South n = 104(19.5) whereas outlet obstruction 39(967) p < 0.001 and spastic disorders were more common in the North 47(11.8) p = 0.002. Weak peristaltic disorders were more common in Central-Mexico 369(78.8) p < 0.001. Conclusion This study represents the first large comparative multicenter HREM data base project in Mexico. In this cohort, most patients receiving HREM are women and those whose indication was GERD. These findings indicate variable regional geographical distribution of HERM diagnosis. Our study suggests that further investigation into the causes and epidemiological distribution of motility disorders is warranted.

788 VARIABLE GEOGRAPHICAL DIFFERENCES OF AMBULATORY ESOPHAGEAL REFLUX MONITORING IN MEXICO

Ambulatory esophageal reflux monitoring (AEpH) is useful in evaluating persistent or refractory esophageal symptoms despite adequate pharmacologic and/or surgical therapy. There is limited information whether there are geographical or regional differences in the diagnostic outcome of this test. Aim Characterize the diagnostic outcome of AEpH in a diverse population of Mexico. Analyze whether there is regional geographical diagnostic variability. Methods Data was collected from four major referral centers representing diverse geographical areas of Mexico: Mexico City-Central (two centers, years 2016-2020), Veracruz-South (years 2015-2020) and Monterrey-North (years 2013-2020). Consecutive patients undergoing AEpH with persistent GERD symptoms despite PPI therapy and negative upper endoscopy (no erosive disease >C or D LA classification) were entered into a data base and analyzed. Patients were classified as: NERD (acid exposure time (AET > 6.0%); hypersensitive esophagus (normal AET and positive symptom index (SI) or positive symptom association probability [SAP]); functional heartburn (NL AET, neg SI/SAP). Statistics: ANOVA, Chi-square and descriptive methods were used to compare variables among groups. Results 969 cases met inclusion criteria: 311 (32.1%) Central, 430 (44.3%) South, and 228 (23.5%) North. The results are summarized in the table. There were more women 618(63.8%) than men 351(36.2%); p < 0.001 with a mean age 47.7 ± 14.3. Patients were older in Central-Mexico 49.3 ± 13.6 years vs South 47.5 ± 15 and North 46.1 ± 13.6; p = 0.033. Functional heartburn was the most common diagnosis overall and more prevalent in Central-Mexico 171(55%) vs North 97(42.5%) and South 160(37.2%); p < 0.001. NERD was more predominant in the South 171(39.8%) vs North 72(31.6%) and Central-Mexico 98(31.5%); p = 0.029. Hypersensitive esophagus was more frequent in the North 59(25.9%) vs South 99(23%), and Central 42(13.5%); p < 0.001. Conclusion This is the first large data base study to evaluate the outcome of ambulatory esophageal reflux pH testing in Mexico. Our findings indicate a geographical variability of GERD phenotypes and suggest that further investigations are warranted to determine the causes of this distribution.

A Critical Review of the Differential Diagnosis of Root Fracture Line in CBCT scans

The objective of this critical review of literature is to discuss relevant clinical factors associated with root fractures (RF) visualized by using a new CBCT software. RF constitutes a common occurrence and a challenge in clinical practice, in which the diagnosis becomes essential for the definition of rapid and precise decision-making. The characterization of RF may involve different aspects, such as orientation of the fracture line (horizontal, vertical, oblique), root position of the fracture (cervical, middle, apical third), fracture's coronal-radicular position (coronary, coronal-radicular, radicular), continuity of the fracture (crack, incomplete fracture, complete), bone extension of the fracture (supraosseous, bone level, infraosseous fracture). Imaging examinations have been routinely used to aid in the RF diagnosis. Even with high-resolution cone-beam computed tomography (CBCT) scans, many doubts often remain about the diagnostic outcome. Many interferences in the analysis of image quality to determine the diagnosis are identified, such as the sharpness, the noise, light and dark artifacts, among others. The professional's knowledge is essential for identifying the different patterns of fracture lines and their repercussions on adjacent bone tissues, as well as for the analysis of artifacts that may hide or show similarities to fracture lines. Fractures lines and root fractures that may be associated with phantom conditions that mimic fractures should be carefully analyzed. CBCT is the exam indicated to identify a root fracture. It is also added to the success of the diagnosis that the professional has scientific knowledge, training and mastery of advanced CBCT software.

AAA screening in adults with ASD: a retrospective cohort study

Purpose The Adult Asperger Assessment (AAA), comprising the Autism Questionnaire, the Empathy Quiotient and the Relatives Questionnaire is a commonly used screening tool designed to identify adults who may benefit from a further clinical assessment for autism spectrum disorder. The purpose of this paper is to investigate the usefulness of this screening measure in a clinical setting. Design/methodology/approach This retrospective cohort study comprised of 192 service users referred for diagnostic assessment of Autism by a specialist service of the National Health Service. The authors evaluated the diagnostic accuracy of the AAA by investigating if the Autism Questionnaire, the Empathy Quiotient and the Relatives Questionnaire were able to predict the diagnostic outcome of Autism in a clinical setting. Findings Scores from the Relatives Questionnaire can accurately predict diagnostic outcome. No evidence of accuracy for the Autism Questionnaire or the Empathy Quotient was apparent. Based on the findings, the authors recommend clinicians are cautious when interpreting results of the AAA. Research limitations/implications It should be acknowledged that the results may not be generalisable to whole populations. Also, the authors used the full item versions of the scales; therefore, the findings are most applicable to studies which did similar. Originality/value This study highlights the need for investigation into the lack of validation of commonly used screening measures in autistic populations.

Maternal and neonatal canine cortisol measurement in multiple matrices during the perinatal period: A pilot study

Stress exposure during perinatal period may lead to maternal cortisol increase that negatively affects the offspring development. In recent years, the interest on non-invasive sampling methods to measure cortisol as a marker of stress is increasing in both humans and animals. Indeed, discomfort due to blood collection may compromise the diagnostic outcome, mainly in uncooperative patients. So far, some alternative matrices but not milk have been explored in adult dogs, while no data are available on the neonate and paediatric live pups. This study aimed to measure cortisol concentration in different biological substrates in both dams (blood, saliva, hair and milk) and pups (saliva and hair) at established times from proestrus up to two months after parturition. For this purpose, five female German shepherd bitches and their 22 pups were enrolled. Cortisol concentration was assessed using the enzyme immunoassay kit (Salivary Cortisol ELISA kit, Salimetrics) after matrices appropriate preparation if required. Cortisol was measurable in all the substrates, except some milk samples below the detection limit. Maternal cortisol concentrations differed among the matrices (P <0.0001) with the highest values recorded in plasma (median 0.596 μg/dL) compared to saliva (median 0.159 μg/dL), hair (median 0.083 μg/dL) and milk (median 0.045 μg/dL). Cortisol in dams did not vary within the same matrix over time. In pups, salivary (median 0.295 μg/dL) cortisol was always higher than hair (median 0.049 μg/dL; P <0.0001). At birth (P = 0.01) and two months later (P = 0.05), neonatal salivary cortisol was higher compared to other samplings. The present study demonstrates the suitability of these innovative substrates for cortisol measurement, suggesting them as potential diagnostic support in canine neonatology and welfare.

Altered Gray-White Matter Boundary Contrast in Toddlers at Risk for Autism Relates to Later Diagnosis of Autism Spectrum Disorder

BackgroundRecent neuroimaging studies have highlighted differences in cerebral maturation in individuals with autism spectrum disorder (ASD) in comparison to typical development. For instance, the contrast of the gray-white matter boundary is decreased in adults with ASD. To determine how gray-white matter boundary integrity relates to early ASD phenotypes, we used a regional structural MRI index of gray-white matter contrast (GWC) on a sample of toddlers with a hereditary high risk for ASD.Materials and MethodsWe used a surface-based approach to compute vertex-wise GWC in a longitudinal cohort of toddlers at high-risk for ASD imaged twice between 12 and 24 months (n = 20). A full clinical assessment of ASD-related symptoms was performed in conjunction with imaging and again at 3 years of age for diagnostic outcome. Three outcome groups were defined (ASD, n = 9; typical development, n = 8; non-typical development, n = 3).ResultsASD diagnostic outcome at age 3 was associated with widespread increases in GWC between age 12 and 24 months. Many cortical regions were affected, including regions implicated in social processing and language acquisition. In parallel, we found that early onset of ASD symptoms (i.e., prior to 18-months) was specifically associated with slower GWC rates of change during the second year of life. These alterations were found in areas mainly belonging to the central executive network.LimitationsOur study is the first to measure maturational changes in GWC in toddlers who developed autism, but given the limited size of our sample results should be considered exploratory and warrant further replication in independent and larger samples.ConclusionThese preliminary results suggest that ASD is linked to early alterations of the gray-white matter boundary in widespread brain regions. Early onset of ASD diagnosis constitutes an independent clinical parameter associated with a specific corresponding neurobiological developmental trajectory. Altered neural migration and/or altered myelination processes potentially explain these findings.

Altered Gray-White Matter Boundary Contrast in Toddlers at Risk for Autism Relates to Later Diagnosis of Autism Spectrum Disorder.

Background: Recent neuroimaging studies have highlighted differences in cerebral maturation in individuals with autism spectrum disorder (ASD) in comparison to typical development. For instance, the contrast of the gray-white matter boundary is decreased in adults with ASD. To determine how gray-white matter boundary integrity relates to early ASD phenotypes, we used a regional structural MRI index of gray-white matter contrast (GWC) on a sample of toddlers with a hereditary high risk for ASD. Methods: We used a surface-based approach to compute vertex-wise GWC in a longitudinal cohort of toddlers at high-risk for ASD imaged twice between 12 and 24 months (n=20). A full clinical assessment of ASD-related symptoms was performed in conjunction with imaging and again at three years of age for diagnostic outcome. Three outcome groups were defined (ASD, n=9; typical development, n=8; non-typical development, n=3).Results: ASD diagnostic outcome at age 3 was associated with widespread increases in GWC between age 12 and 24 months. Many cortical regions were affected, including regions implicated in social processing and language acquisition. In parallel, we found that early onset of ASD symptoms (i.e. prior to 18-months) was specifically associated with slower GWC rates of change during the second year of life. These alterations were found in areas mainly belonging to the central executive network.Limitations: Our study is the first to measure maturational changes in GWC in toddlers who developed autism, but given the limited size of our sample results should be considered exploratory and warrant further replication in independent and larger samples. Conclusion: These preliminary results suggest that ASD is linked to early alterations of the gray-white matter boundary in widespread brain regions. Early onset of ASD diagnosis constitutes an independent clinical parameter associated with a specific corresponding neurobiological developmental trajectory. Altered neural migration and/or altered myelination processes potentially explain these findings.

The presence of symptons and symptom-rhythm correlation in patients with Implantable loop recorders

Funding Acknowledgements Type of funding sources: None. INTRODUCTION Implantable loop recorders (ILR) are a powerful diagnostic tool for heart rhythm diseases, and particularly useful when symptoms are infrequent or when long-term data are required. The main indication is for study of syncope/presyncope due to suspected cardioinhibitory etiology. OBJECTIVE To evaluate the diagnostic profitability of ILR in patient (P) with syncope/ presyncope and to evaluate the effect of symptons on follow-up. METHODS Included P undergoing ILR implantation in 6 consecutive years, to study syncope/presyncope. Information was collected on P characteristics, indication, diagnostic outcome and subsequent management and complications. A follow-up (FU) of 1 year and 3 years were done. Diagnostic outcome was based in symptom-rhythm correlation. Symptons and correlation to ECG during the FU and management after the diagnosis were assessed. RESULTS 99 P were selected. Evaluation of syncope in 91.9% (n = 91) and presyncope in 8.1% (n = 8). 54.5% female, median age 59.4 ± 17.4 years. 55.8% (n = 53) completed the 3 years FU and 84.2% (n = 80) completed the 1 year FU. Death occurred in 4% (n = 4) during the FU. ILR results led to device implantation in 35% of the P (22 pacemakers and 1 ICD) in 1 year FU, with a median time to implantation of 11.6 months after ILR, and the majority of ILR motivated by syncope (87%). If we consider only P that finished the 3 years of FU, in 47.2% P were implanted a device. The most common arrhythmic finding were AV block (47.8%), followed by sinus pauses / asystole (43.5%), AF with slow ventricular rate (4.3%) and VT (4.3%). 4.9% of P experienced a complication related to the device (2 infection and 3 non-infectious pain), that resulted in explantation. 60.9% of the P were symptomatic during the FU, with 24.1% achieving symptom-rhythm correlation and 36.8% who did not. Device implantation was associated with the presence of symptons in FU (82.6% vs 17.4%, p = 0.012) and symptom-rhythm correlation (95% vs 5%,p = 0.001). 38.7% (n = 27) of the P finished the 3 years of FU without a diagnostic outcome or detectable event, with 44.4% being assymptomatic and 55.6% presenting symptoms without ECG correlation. Compared to the P that implanted a device, this type of P was frequently of female sex (57.6% vs 30.4%, p = 0.045), younger age (54.8 ± 18.1 vs 65.8 ± 12.8 years, p = 0.014), with less cardiovascular risk factors like dyslipidemia (37.0% vs 78.3%, p = 0.003) and arterial hypertension (48.1% vs 73.9%, p = 0.05), AF (0% vs 19%, p = 0.025), previous history of myocardial infarction and percutaneous coronary intervention (3.2% vs 17.4%, p = 0.05; 3.0% vs 21.7%, p = 0.028) and more frequently with history of depression (51.9% vs 22.7%, p = 0.037). CONCLUSION In this study, ILR monitoring led to a device implantation in 47.2% of the P that finished the 3 years FU. The presence of symptons and symptom-rhythm correlation during FU was associated with device implantation.