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Background: Xylazine is an âº2 adrenergic receptor agonist and a veterinary sedative that can cause severe health complications yet interventions to detect and treat human exposure remain underdeveloped. Community-based drug checking services (DCS) involve the testing of small amounts of drugs to increase community knowledge of unregulated supplies and decrease harms. This study characterized xylazine awareness, desire, use and exposure among people who use drugs (PWUD) in Rhode Island, US. Methods: We analyzed data from an ongoing PWUD cohort study. In 2023, 125 PWUD were enrolled and surveyed. Using point-of-care Fourier Transform infrared spectroscopy (FTIR-S), we tested a drug sample from each participant onsite and confirmed the results offsite at a laboratory. Results were conveyed in real-time, along with harm reduction education, referrals to resources and care. Results: Virtually all participants (99.2 %) wanted to avoid xylazine exposure. Half (51.2 %) knew what xylazine was, and a quarter (26.1 %) suspected previous exposure. Xylazine exposure was primarily surmised through sedating (45.2 %) and ulcerative (29.0 %) effects. Only 8.8 % of participants submitted a sample that they expected to contain xylazine. Xylazine was detected in 14.5 % of samples using FTIR-S and in 21.4 % of samples using a dual laboratory approach of gas chromatography mass spectrometry (GC-MS) and liquid chromatography quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS). Participants thought that these xylazine-positive samples were fentanyl (78.3 %), heroin (13.0 %), or Percocet® (8.7 %). Conclusion: Implementing point-of-care DCS at harm reduction organizations could be useful in rapidly increasing xylazine awareness and engaging at-risk individuals in prevention, harm reduction, treatment, and rapid care for xylazine-related wounds.
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BACKGROUND: Federal, state, and municipal governments in the United States have been reluctant to authorize overdose prevention centers (OPCs), which are evidence-based approaches for preventing overdose deaths and blood-borne pathogen transmission. METHODS: From July 2022 to February 2023, we explored how stigma manifests in OPC policymaking by conducting in-depth interviews with 17 advocates, legislators, service providers, and researchers involved with OPC advocacy and policymaking in Rhode Island, California, Pennsylvania, and New York. RESULTS: We found that although jurisdictions differed in their OPC policymaking experiences, stigma manifested throughout the process, from planning to authorization. Participants described OPCs as a tool for destigmatizing overdose and substance use, yet confronted institutionalized stigma and discriminatory attitudes toward people who use drugs (PWUD) and harm reduction from multiple sources (eg, politicians, media, and members of the public). Opposition toward OPCs and harm reduction approaches more broadly intersected with public discourse on crime, homelessness, and public disorder. Employed stigma-mitigation strategies included humanizing PWUD, publicizing the benefits of OPCs to the wider community, and strategically engaging media. CONCLUSION: These findings illustrate the importance of understanding stigma at different stages of the policymaking process to better facilitate authorization and eventual implementation of OPCs in the United States.
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Background: Xylazine is a sedative found increasingly in the illicit fentanyl supply that can cause hypotension, bradycardia, necrosis and death. This pilot examined the real-world performance of BTNX xylazine test strips (XTS) in drug residue samples. Methods: This study was nested within a drug checking service in Rhode Island. We tested unmeasured drug residue dissolved in 5 mL of distilled water using XTS and Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry (LC-QTOF-MS). Analyses compared XTS and LC-QTOF-MS results to calculate XTS detection of xylazine in residue. Results: Among 41 residue samples, xylazine was detected in 11% by the XTS and 44 % by the laboratory. The LC-QTOF-MS detected xylazine in 18 samples: 4 major, 9 minor, 5 trace by volume relative to the whole sample. The XTS disagreed with the LC-QTOF-MS by indicating a negative result in 77.8 % (N=14) of the samples but never indicated a positive when the LC-QTOF-MS reported xylazine's absence. The XTS correctly detected xylazine 22 % of the time, however, this increased to 100 % of the time if xylazine was a major active component. Conclusions: In this study, the BTNX XTS often disagreed with LC-QTOF-MS by indicating a negative result, likely due to the dilution levels used and sample composition. The XTS may not be accurate in detecting residual amounts of xylazine, especially if xylazine is not a dominant component of the tested sample. Given the novelty of BTNX's XTS products, we recommend XTS only be used in conjunction with other advanced drug checking modalities for residue testing.
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BACKGROUND: Overdose prevention centers (OPCs), also known as supervised injection facilities and safe consumption sites, are evidenced-based interventions for preventing overdose deaths and drug-related morbidities. The pathways to legalizing OPCs in the USA have confronted multiple social, political, and legal obstacles. We conducted a multi-site, qualitative study to explore heterogeneities in these pathways in four jurisdictions, as well as to understand stakeholder perspectives on valuable strategies for galvanizing political and public support for OPCs. METHODS: From July 2022 to February 2023, we conducted 17 semi-structured, in-depth interviews with OPC policymakers, service providers, advocates, and researchers from California, New York City, Philadelphia, and Rhode Island, where efforts have been undertaken to authorize OPCs. Using inductive thematic analysis, we identified and compared contextually relevant, salient approaches for increasing support for OPCs. RESULTS: Participants described several strategies clustering around five distinct domains: (1) embedding OPC advocacy into broader overdose prevention coalitions to shape policy dialogs; (2) building rapport with a plurality of powerbrokers (e.g., lawmakers, health departments, law enforcement) who could amplify the impact of OPC advocacy; (3) emphasizing specific benefits of OPCs to different audiences in different contexts; (4) leveraging relationships with frontline workers (e.g., emergency medicine and substance use treatment providers) to challenge OPC opposition, including 'NIMBY-ism,' and misinformation; and (5) prioritizing transparency in OPC decision-making to foster public trust. CONCLUSION: While tailored to the specific socio-political context of each locality, multiple OPC advocacy strategies have been deployed to cultivate support for OPCs in the USA. Advocacy strategies that are multi-pronged, leverage partnerships with stakeholders at multiple levels, and tailor communications to different audiences and settings could yield the greatest impact in increasing support for, and diffusing opposition to, future OPC implementation.
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Sobredosis de Droga , Trastornos Relacionados con Sustancias , Humanos , Estados Unidos , Sobredosis de Droga/prevención & control , Aplicación de la Ley , Investigación Cualitativa , Ciudad de Nueva YorkRESUMEN
Policy and research on the implementation of services for people who inhale drugs lag behind similar efforts for people who inject drugs, limiting access to adequate harm reduction resources for people who inhale drugs. This commentary considers why supervised inhalation sites (SIS) are needed, highlights operational characteristics of four existing services, and advocates for future SIS research. Our hope is to encourage the expansion of SIS worldwide for overdose prevention and reduction of health inequities. Given the limited literature regarding SIS, more extensive study of these programs is warranted to incorporate inhalation into the implementation of supervised consumption sites to provide fair opportunities for all people who use drugs to do so safely without fear of stigma and overdose.
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Sobredosis de Droga , Abuso de Sustancias por Vía Intravenosa , Humanos , Programas de Intercambio de Agujas , Sobredosis de Droga/prevención & control , Reducción del Daño , Administración por InhalaciónRESUMEN
BACKGROUND: Drug checking is a harm reduction strategy that provides greater awareness and information about the drug supply to the community. While fentanyl test strips are low-cost and available in most parts of the U.S., community-based organizations are considering using more sophisticated technologies, such as Fourier-transform infrared (FTIR) spectroscopy to test drugs. FTIR can detect multiple substances in a non-destructive manner that can be rapidly communicated to the program client by a trained technician, however implementation costs in community-based settings have not been assessed. METHODS: We conducted a costing analysis of a new pilot drug checking service that employed an FTIR spectrometer, fentanyl test strips and confirmatory testing in Rhode Island from January 2023-May 2023. We used microcosting methods to determine the overall cost during this period and cost per drug checked, reflecting realistic service capacity. RESULTS: Among 101 drug samples that were voluntarily submitted and tested, 53% tested positive for fentanyl, 39% for cocaine, 9% for methamphetamine and 13% for xylazine, a powerful sedative. The total cost during this period was $71,044 and the cost per drug checked was $474, though sensitivity analyses indicated that the cost would rise to $78,058 - $83,058 or $544 - $593 for programs needing to pay for specialized training. CONCLUSIONS: These findings demonstrate feasibility and inform the resources needed to scale-up drug checking services to reduce overdose risk.
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Analgésicos Opioides , Sobredosis de Droga , Humanos , Analgésicos Opioides/análisis , Rhode Island , Sistemas de Atención de Punto , Fentanilo/análisis , Reducción del DañoRESUMEN
BACKGROUND: Drug overdose deaths have reached record-breaking levels in North America. Drug checking services (DCS) provide localized information on the contents of drugs to individuals and communities. Depending on the design, individuals can submit drug samples for onsite "real-time" testing or offsite testing. The results can shed light on emerging drugs in the community and support ongoing prevention and surveillance efforts. We sought to describe and report aggregate outcomes of DCS operating in North America. METHODS: The North American Drug Checking Survey was launched in 2022 to characterize and monitor DCS operating in the region. Sixteen organizations from the US (n = 9), Canada (n = 5), and Mexico (n = 2) responded to the survey. Each organization reported on their program's operations and provided service delivery outcomes (site- or program-level) in the aggregate. RESULTS: Participating organizations reported testing a total of 49,786 drug samples between 2014 and 2022. DCS were run by community-led organizations (44%), health departments (25%), universities (19%), or clinical/private laboratories (19%). The types of samples tested differed between programs (e.g., solids vs. liquids, drug paraphernalia accepted). While most organizations tested onsite using fentanyl test strips (88%) and Fourier-transform infrared (FTIR) spectroscopy (63%), many sent samples offsite for confirmatory testing (63%), most often with mass spectrometry. Common facilitators of operating a DCS included: interest of clients (69%), interest of service providers (63%), and receiving external technical assistance (63%). Barriers included: the lack of funding (81%) or staff (50%), gaps in technical expertise (38%), as well as laws banning the possession and/or distribution of illicit drug samples, drug paraphernalia, or drug checking equipment (38%). CONCLUSION: DCS are scaling up in North America. Given the evolving and localized nature of illicit drug supplies, supporting the establishment and operations of DCS could enhance the public's understanding of local drug supplies to reduce drug-related harms over time.
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Sobredosis de Droga , Drogas Ilícitas , Humanos , Fentanilo/análisis , Sobredosis de Droga/epidemiología , Drogas Ilícitas/análisis , Canadá , América del Norte , Analgésicos Opioides/análisisRESUMEN
The population of the Saguenay-Lac-Saint-Jean (SLSJ) region, located in the province of Quebec, Canada, is recognized as a founder population, where some rare autosomal recessive diseases show a high prevalence. Through the clinical and molecular study of 82 affected individuals from 60 families, this study outlines 12 diseases identified as recurrent in SLSJ. Their carrier frequency was estimated with the contribution of 1059 healthy individuals, increasing the number of autosomal recessive diseases with known carrier frequency in this region from 14 to 25. We review the main clinical and molecular features previously reported for these disorders. Five of the studied diseases have a potential lethal effect and three are associated with intellectual deficiency. Therefore, we believe that the provincial program for carrier screening should be extended to include these eight disorders. The high-carrier frequency, together with the absence of consanguinity in most of these unrelated families, suggest a founder effect and genetic drift for the 12 recurrent variants. We recommend further studies to validate this hypothesis, as well as to extend the present study to other regions in the province of Quebec, since some of these disorders could also be present in other French-Canadian families.
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Patrón de Herencia , Humanos , Canadá/epidemiología , Quebec/epidemiología , Consanguinidad , Genes RecesivosRESUMEN
Drug overdoses were a leading cause of injury and death in the United States in 2021. Solitary drug use and solitary overdose deaths have remained persistent challenges warranting additional attention throughout the overdose epidemic. The goal of this narrative review is to describe recent global innovations in overdose detection technologies (ODT) enabling rapid responses to overdose events, especially for people who use drugs alone. We found that only a small number of technologies designed to assist in overdose detection and response are currently commercially available, though several are in the early stages of development. Research, development, and scale-up of practical, cost-effective ODTs remains a public health imperative. Equipping places where people live, learn, work, worship, and play with the necessary tools to detect and prevent overdose deaths could complement ongoing overdose prevention efforts.
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Sobredosis de Droga , Epidemias , Trastornos Relacionados con Sustancias , Humanos , Estados Unidos , Sobredosis de Droga/prevención & control , Sobredosis de Droga/epidemiología , Trastornos Relacionados con Sustancias/epidemiología , Salud Pública , Análisis de Costo-Efectividad , Analgésicos OpioidesRESUMEN
As a result of a founder effect, a Leigh syndrome variant called Leigh syndrome, French-Canadian type (LSFC, MIM / 220,111) is more frequent in Saguenay-Lac-Saint-Jean (SLSJ), a geographically isolated region on northeastern Quebec, Canada. LSFC is a rare autosomal recessive mitochondrial neurodegenerative disorder due to damage in mitochondrial energy production. LSFC is caused by pathogenic variants in the nuclear gene leucine-rich pentatricopeptide repeat-containing (LRPPRC). Despite progress understanding the molecular mode of action of LRPPRC gene, there is no treatment for this disease. The present study aims to identify the biological pathways altered in the LSFC disorder through microarray-based transcriptomic profile analysis of twelve LSFC cell lines compared to twelve healthy ones, followed by gene ontology (GO) and pathway analyses. A set of 84 significantly differentially expressed genes were obtained (p ≥ 0.05; Fold change (Flc) ≥ 1.5). 45 genes were more expressed (53.57%) in LSFC cell lines compared to controls and 39 (46.43%) had lower expression levels. Gene ontology analysis highlighted altered expression of genes involved in the mitochondrial respiratory chain and energy production, glucose and lipids metabolism, oncogenesis, inflammation and immune response, cell growth and apoptosis, transcription, and signal transduction. Considering the metabolic nature of LSFC disease, genes included in the mitochondrial respiratory chain and energy production cluster stood out as the most important ones to be involved in LSFC mitochondrial disorder. In addition, the protein-protein interaction network indicated a strong interaction between the genes included in this cluster. The mitochondrial gene NDUFA4L2 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2), with higher expression in LSFC cells, represents a target for functional studies to explain the role of this gene in LSFC disease. This work provides, for the first time, the LSFC gene expression profile in fibroblasts isolated from affected individuals. This represents a valuable resource to understand the pathogenic basis and consequences of LRPPRC dysfunction.
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The French-Canadian population of Saguenay-Lac-Saint-Jean is known for its homogenous genetic background. The hereditary causes of hearing loss were previously unexplored in this population. Individuals with hearing loss were referred from the otorhinolaryngology, pediatrics and family physicians' clinics to the medical genetics service at the Centre intégré universitaire de santé et de services sociaux du Saguenay-Lac-Saint-Jean between June 2015 and March 2021. A regional clinical evaluation strategy was developed. Samples from 63 individuals belonging to 41 families were sent independently to different molecular clinical laboratories and index cases were analyzed through comprehensive multigene panels, with a diagnostic rate of 54%. Sixteen hearing loss causal variants were identified in 12 genes, with eight of these variants not been previously reported in the literature. Recurrent variants were present in four genes, suggesting a possible founder effect, while GJB2 gene variants were scarce. A comprehensive multigene panel approach as part of the proposed clinical evaluation strategy offers a high diagnostic yield for this population.
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Sordera , Pérdida Auditiva , Canadá/epidemiología , Niño , Efecto Fundador , Pérdida Auditiva/genética , Humanos , Quebec/epidemiologíaRESUMEN
The Campbell-Robson chart is a highly popular figure used in psychophysics and visual perception textbooks to illustrate the Contrast Sensitivity Function (CSF). The chart depicts a grating which varies logarithmically in spatial frequency (SF) from left to right and in contrast from bottom to top. Campbell and Robson's (1964) intuition was that the boundary between the grating and the homogeneous gray area (below threshold) would trace the shape of the observer's own CSF. In this paper, we tested this intuition. A total of 170 participants (96 adults and 74 children) adjusted the four parameters of a truncated log-parabola directly onto a Campbell-Robson chart rendition and completed a gold-standard CSF evaluation. We hoped that this procedure which requires a mere three clicks on the computer mouse, would speed up the measurement of the CSF to under a minute. Unfortunately, the only parameter of the truncated log-parabola fitted to the gold-standard CSF data that could be predicted from the Campbell-Robson chart data was the peak sensitivity for the adult participants. We conclude that the curve visible on the Campbell-Robson chart cannot be used practically to measure the CSF.
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PURPOSE: Biallelic variants in TBC1D24, which encodes a protein that regulates vesicular transport, are frequently identified in patients with DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability [previously referred to as mental retardation], and seizures) syndrome. The aim of the study was to identify a genetic cause in families with DOORS syndrome and without a TBC1D24 variant. METHODS: Exome or Sanger sequencing was performed in individuals with a clinical diagnosis of DOORS syndrome without TBC1D24 variants. RESULTS: We identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome. This variant was already reported in individuals with dominant deafness onychodystrophy (DDOD) syndrome. Deafness was present in all individuals, along with onychodystrophy and abnormal fingers and/or toes. All families but one had developmental delay or intellectual disability and five individuals had epilepsy. We also describe two additional families with DDOD syndrome in whom the same variant was found. CONCLUSION: We expand the phenotype associated with ATP6V1B2 and propose another causal gene for DOORS syndrome. This finding suggests that DDOD and DOORS syndromes might lie on a spectrum of clinically and molecularly related conditions.
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Epilepsia , Discapacidad Intelectual , Uñas Malformadas , ATPasas de Translocación de Protón Vacuolares , Epilepsia/genética , Exoma , Proteínas Activadoras de GTPasa , Humanos , Discapacidad Intelectual/genética , Uñas Malformadas/genética , Fenotipo , ATPasas de Translocación de Protón Vacuolares/genéticaRESUMEN
Objective: A large number of children report fear and distress when undergoing blood work and intravenous placement. In pediatric departments, Child Life interventions are considered to be the gold standard in nonmedical pain management techniques. Virtual reality (VR) has also been identified as an effective tool for pain distraction in children undergoing painful medical procedures. The aim of this study was to document the efficacy of VR as a mode of distraction during a medical procedure compared with two comparison conditions: watching television (TV, minimal control condition) and distraction provided by the Child Life (CL, gold standard control condition) program. Materials and Methods: A total of 59 children aged 8-17 years (35% female) were recruited through the emergency department (ED) of the Children's Hospital of Eastern Ontario and randomly assigned to one of the three conditions. The key outcome measures were visual analog scale ratings of pain intensity and fear of pain, administrated before and right after the procedure. Patient satisfaction was also measured after the intervention. Results: A significant reduction in fear of pain and pain intensity was reported in all three conditions. A larger and statistically significant reduction in fear of pain was observed among children who used VR distraction compared with the CL and TV conditions, but this effect was not observed for pain intensity. The children's satisfaction with the VR procedure was significantly higher than for TV and comparable to CL. Discussion: The advantages of using VR in the ED to manage pain in children are discussed.
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Manejo del Dolor/normas , Flebotomía/métodos , Realidad Virtual , Adolescente , Análisis de Varianza , Niño , Servicio de Urgencia en Hospital/organización & administración , Servicio de Urgencia en Hospital/estadística & datos numéricos , Miedo/psicología , Femenino , Humanos , Masculino , Ontario , Manejo del Dolor/métodos , Manejo del Dolor/estadística & datos numéricos , Flebotomía/psicología , Flebotomía/normasRESUMEN
Leigh syndrome French Canadian type (LSFC) is a mitochondrial disease caused by mutations in the leucine-rich pentatricopeptide repeat-containing (LRPPRC) gene leading to a reduction of cytochrome-c oxidase (COX) expression reaching 50% in skin fibroblasts. We have shown that under basal conditions, LSFC and control cells display similar ATP levels. We hypothesized that this occurs through upregulation of mechanistic target of rapamycin (mTOR)-mediated metabolic reprogramming. Our results showed that compared with controls, LSFC cells exhibited an upregulation of the mTOR complex 1 (mTORC1)/p70 ribosomal S6 kinase pathway and higher levels of hypoxia-inducible factor 1α (HIF-1α) and its downstream target pyruvate dehydrogenase kinase 1 (PDHK1), a regulator of mitochondrial pyruvate dehydrogenase 1 (PDH1). Consistent with these signaling alterations, LSFC cells displayed a 40-61% increase in [U-13C6]glucose contribution to pyruvate, lactate, and alanine formation, as well as higher levels of the phosphorylated and inactive form of PDH1-α. Interestingly, inhibition of mTOR with rapamycin did not alter HIF-1α or PDHK1 protein levels in LSFC fibroblasts. However, this treatment increased PDH1-α phosphorylation in control and LSFC cells and reduced ATP levels in control cells. Rapamycin also decreased LRPPRC expression by 41 and 11% in LSFC and control cells, respectively, and selectively reduced COX subunit IV expression in LSFC fibroblasts. Taken together, our data demonstrate the importance of mTORC1, independent of the HIF-1α/PDHK1 axis, in maintaining LRPPRC and COX expression in LSFC cells.
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Deficiencia de Citocromo-c Oxidasa/enzimología , Complejo IV de Transporte de Electrones/metabolismo , Fibroblastos/enzimología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Enfermedad de Leigh/enzimología , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Proteínas de Neoplasias/metabolismo , Piel/enzimología , Adenosina Trifosfato/metabolismo , Células Cultivadas , Niño , Deficiencia de Citocromo-c Oxidasa/genética , Deficiencia de Citocromo-c Oxidasa/patología , Complejo IV de Transporte de Electrones/genética , Metabolismo Energético , Femenino , Fibroblastos/patología , Regulación Enzimológica de la Expresión Génica , Glucosa/metabolismo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Enfermedad de Leigh/genética , Enfermedad de Leigh/patología , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Mitocondrias/enzimología , Mitocondrias/patología , Proteínas de Neoplasias/genética , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/genética , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo , Complejo Piruvato Deshidrogenasa/genética , Complejo Piruvato Deshidrogenasa/metabolismo , Quebec , Transducción de Señal , Piel/patologíaRESUMEN
Face-recognition abilities differ largely in the neurologically typical population. We examined how the use of information varies with face-recognition ability from developmental prosopagnosics to super-recognizers. Specifically, we investigated the use of facial features at different spatial scales in 112 individuals, including 5 developmental prosopagnosics and 8 super-recognizers, during an online famous-face-identification task using the bubbles method. We discovered that viewing of the eyes and mouth to identify faces at relatively high spatial frequencies is strongly correlated with face-recognition ability, evaluated from two independent measures. We also showed that the abilities of developmental prosopagnosics and super-recognizers are explained by a model that predicts face-recognition ability from the use of information built solely from participants with intermediate face-recognition abilities ( n = 99). This supports the hypothesis that the use of information varies quantitatively from developmental prosopagnosics to super-recognizers as a function of face-recognition ability.
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Discapacidades del Desarrollo/fisiopatología , Reconocimiento Facial/fisiología , Individualidad , Prosopagnosia/fisiopatología , Adulto , Femenino , Humanos , Masculino , Percepción SocialRESUMEN
Interest in using individual differences in face recognition ability to better understand the perceptual and cognitive mechanisms supporting face processing has grown substantially in recent years. The goal of this study was to determine how varying levels of face recognition ability are linked to changes in visual information extraction strategies in an identity recognition task. To address this question, fifty participants completed six tasks measuring face and object processing abilities. Using the Bubbles method (Gosselin & Schyns, 2001), we also measured each individual's use of visual information in face recognition. At the group level, our results replicate previous findings demonstrating the importance of the eye region for face identification. More importantly, we show that face processing ability is related to a systematic increase in the use of the eye area, especially the left eye from the observer's perspective. Indeed, our results suggest that the use of this region accounts for approximately 20% of the variance in face processing ability. These results support the idea that individual differences in face processing are at least partially related to the perceptual extraction strategy used during face identification.
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Reconocimiento Facial , Reconocimiento en Psicología , Adolescente , Adulto , Ojo , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
A pilot population-based carrier screening program started in 2010 in the Saguenay-Lac-Saint-Jean region of Quebec, Canada, for four recessive diseases with local founder effects (tyrosinemia type I, autosomal recessive spastic ataxia of Charlevoix-Saguenay, congenital lactic acidosis, and Andermann syndrome). OBJECTIVES: The objective of this study was to describe the experience of carrier couples identified through this program. METHODS: Semi-structured interviews were performed with carrier couples. Thematic analysis of interview transcripts was performed to identify emerging themes. RESULTS: Interviews were performed with 15 carrier couples (56% response rate). Carrier couples had little knowledge about the target diseases before being identified as carriers, despite pre-test education sessions. The main motivation for screening was a recommendation by a peer who had been screened, even for those with a positive family history of one of the target conditions. Couples perceived themselves at low risk of being a carrier couple, whatever their family history. Being found to be a carrier couple was initially a shock, illustrating how ill prepared they were for such a result, but carrier couples appreciated knowing their status. CONCLUSION: Our results emphasize the informational needs of couples to make informed decisions and the importance of post-test counseling for those with positive results. Our findings can inform counseling procedures in expanded carrier screening. © 2017 John Wiley & Sons, Ltd.
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Agenesia del Cuerpo Calloso/diagnóstico , Deficiencia de Citocromo-c Oxidasa/diagnóstico , Tamización de Portadores Genéticos , Enfermedad de Leigh/diagnóstico , Espasticidad Muscular/diagnóstico , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Ataxias Espinocerebelosas/congénito , Tirosinemias/diagnóstico , Adulto , Femenino , Efecto Fundador , Heterocigoto , Humanos , Masculino , Proyectos Piloto , Ataxias Espinocerebelosas/diagnóstico , Adulto JovenRESUMEN
Approximately one in every 200 mammalian proteins is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. These proteins play important roles notably in neurological development and function. To date, more than 20 genes have been implicated in the biogenesis of GPI-anchored proteins. GPAA1 (glycosylphosphatidylinositol anchor attachment 1) is an essential component of the transamidase complex along with PIGK, PIGS, PIGT, and PIGU (phosphatidylinositol-glycan biosynthesis classes K, S, T, and U, respectively). This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum. Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families. Using whole-exome sequencing, we identified two frameshift mutations (c.981_993del [p.Gln327Hisfs∗102] and c.920delG [p.Gly307Alafs∗11]), one intronic splicing mutation (c.1164+5C>T), and six missense mutations (c.152C>T [p.Ser51Leu], c.160_161delinsAA [p.Ala54Asn], c.527G>C [p.Trp176Ser], c.869T>C [p.Leu290Pro], c.872T>C [p.Leu291Pro], and c.1165G>C [p.Ala389Pro]). Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia. The splicing mutation was found to decrease GPAA1 mRNA. Moreover, flow-cytometry analysis of five available individual samples showed that several GPI-anchored proteins had decreased cell-surface abundance in leukocytes (FLAER, CD16, and CD59) or fibroblasts (CD73 and CD109). Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the deficiency of GPI-anchored proteins. These findings highlight the role of the transamidase complex in the development and function of the cerebellum and the skeletal system.