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Ornithine transcarbamylase (OTC) deficiency can present during the neonatal period, infancy, or adulthood. Late‐onset phenotypes are influenced by residual enzyme activity and OTC gene expression. The objective of this study was to assess the pathogenicity of a rare promoter region variant, c.‐106C>A. We reviewed three independent pedigrees harboring the c.‐106C>A variant. Retrospective chart reviews were conducted for 16 affected males to evaluate biochemical and clinical features. Functional OTC enzyme data were obtained from the liver biopsy of three affected males. The median age of diagnosis for symptomatic males was 15 years (range: 0.08–55). All 21 heterozygous females have been asymptomatic to date. Of the 16 hemizygous males, seven have experienced at least one episode of hyperammonemia, and eight have remained asymptomatic. The proband from Family A presented at age 55, with a peak ammonia level of 694 μmol/L. His OTC activity was 8.2 μmol/g liver/min (control: 94.9 μmol/g liver/min). The proband from Family B presented at age 15 with an ammonia level of 1568 μmol/L and later died from cerebral edema. His OTC activity was 2.2 μmol/g liver/min (control: 73.2 μmol/g liver/min). The proband from Family C presented at age 24 with hyperammonemia and later died following withdrawal of care. His liver punch biopsy OTC enzyme activity was measured to be 0 μmol/g liver/min (control range: 25–31.7 μmol/g liver/min). For most affected males, ammonia scavenger therapy has successfully prevented recurrent decompensation. The combined biochemical, clinical, and enzymatic data strongly support the pathogenicity of the c.‐106C>A OTC promoter region variant in late‐onset OTC deficiency. Key Points This study highlights a rare promoter region variant in the OTC gene (c.‐106C>A) that is associated with late‐onset ornithine transcarbamylase deficiency across three independent pedigrees. Affected hemizygous males demonstrated marked clinical and biochemical heterogeneity, ranging from asymptomatic status to fatal hyperammonemic crises. Liver biopsy data showed severely reduced or absent OTC enzyme activity, supporting a functional impact of the c.‐106C>A promoter variant on gene expression. Our findings emphasize the importance of sequencing regulatory regions of the OTC gene in suspected cases when coding‐region analysis is initially unrevealing.

Purpose and scopeThe aim of this position statement is to provide recommendations aimed at Canadian reproductive care clinicians and genetics professionals regarding the use of reproductive carrier screening for autosomal recessive and X-linked recessive conditions.Methods of statement developmentA multidisciplinary expert group was assembled to review the existing literature on reproductive carrier screening for autosomal recessive and X-linked recessive conditions and make recommendations relevant to the Canadian context. The statement was circulated for comment to the membership of the Canadian College of Medical Geneticists (CCMG) and Canadian Association of Genetic Counsellors (CAGC), and multiple family physician reviewers. Feedback from these groups was incorporated, and the final position statement was approved by the CCMG Board of Directors on 5 December 2024 and the CAGC Board of Directors on 14 April 2025.Results and conclusionsRoutinely offered pan-ethnic reproductive carrier screening via a provincial or territorial programme is recommended for a limited panel of relatively common and severe childhood onset genetic conditions, based on Canadian experience with ethnicity-based testing: cystic fibrosis, fragile X syndrome, spinal muscular atrophy, haemoglobinopathies and founder mutations for Tay-Sachs disease, Canavan disease and familial dysautonomia. Provincial/territorial programmes must be developed to provide oversight, ensure appropriate resourcing and manage education and roll-out. Maintaining regional ethnicity-based screening programmes is also recommended, where relevant. Publicly funded population-level expanded carrier screening is not recommended at this time.

Autosomal recessive tyrosine kinase 2 (TYK2) deficiency is characterized by susceptibility to mycobacterial and viral infections. Here, we report a 4-year-old female with severe respiratory viral infections, EBV-driven Burkitt-like lymphoma, and infection with the neurotropic Jamestown Canyon virus. A novel, homozygous c.745C > T (p.R249*) variant was found in TYK2. The deleterious effects of the TYK2 lesion were confirmed by immunoblotting; by evaluating functional responses to IFN-α/β, IL-10, and IL-23; and by assessing its scaffolding effect on the cell surface expression of cytokine receptor subunits. The effects of the mutation could not be pharmacologically circumvented in vitro, suggesting that alternative modalities, such as hematopoietic stem cell transplantation or gene therapy, may be needed. We characterize the first patient from Canada with a novel homozygous mutation in TYK2.

Background Generating rigorous evidence to inform care for rare diseases requires reliable, sustainable, and longitudinal measurement of priority outcomes. Having developed a core outcome set for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, we aimed to assess the feasibility of prospective measurement of these core outcomes during routine metabolic clinic visits. Methods We used existing cohort data abstracted from charts of 124 children diagnosed with MCAD deficiency who participated in a Canadian study which collected data from birth to a maximum of 11 years of age to investigate the frequency of clinic visits and quality of metabolic chart data for selected outcomes. We recorded all opportunities to collect outcomes from the medical chart as a function of visit rate to the metabolic clinic, by treatment centre and by child age. We applied a data quality framework to evaluate data based on completeness, conformance, and plausibility for four core MCAD outcomes: emergency department use, fasting time, metabolic decompensation, and death. Results The frequency of metabolic clinic visits decreased with increasing age, from a rate of 2.8 visits per child per year (95% confidence interval, 2.3–3.3) among infants 2 to 6 months, to 1.0 visit per child per year (95% confidence interval, 0.9–1.2) among those ≥ 5 years of age. Rates of emergency department visits followed anticipated trends by child age. Supplemental findings suggested that some emergency visits occur outside of the metabolic care treatment centre but are not captured. Recommended fasting times were updated relatively infrequently in patients’ metabolic charts. Episodes of metabolic decompensation were identifiable but required an operational definition based on acute manifestations most commonly recorded in the metabolic chart. Deaths occurred rarely in these patients and quality of mortality data was not evaluated. Conclusions Opportunities to record core outcomes at the metabolic clinic occur at least annually for children with MCAD deficiency. Methods to comprehensively capture emergency care received at outside institutions are needed. To reduce substantial heterogeneous recording of core outcome across treatment centres, improved documentation standards are required for recording of recommended fasting times and a consensus definition for metabolic decompensations needs to be developed and implemented.

Background The Canadian Inherited Metabolic Diseases Research Network (CIMDRN) is a pan-Canadian practice-based research network of 14 Hereditary Metabolic Disease Treatment Centres and over 50 investigators. CIMDRN aims to develop evidence to improve health outcomes for children with inherited metabolic diseases (IMD). We describe the development of our clinical data collection platform, discuss our data quality management plan, and present the findings to date from our data quality assessment, highlighting key lessons that can serve as a resource for future clinical research initiatives relating to rare diseases. Methods At participating centres, children born from 2006 to 2015 who were diagnosed with one of 31 targeted IMD were eligible to participate in CIMDRN’s clinical research stream. For all participants, we collected a minimum data set that includes information about demographics and diagnosis. For children with five prioritized IMD, we collected longitudinal data including interventions, clinical outcomes, and indicators of disease management. The data quality management plan included: design of user-friendly and intuitive clinical data collection forms; validation measures at point of data entry, designed to minimize data entry errors; regular communications with each CIMDRN site; and routine review of aggregate data. Results As of June 2019, CIMDRN has enrolled 798 participants of whom 764 (96%) have complete minimum data set information. Results from our data quality assessment revealed that potential data quality issues were related to interpretation of definitions of some variables, participants who transferred care across institutions, and the organization of information within the patient charts (e.g., neuropsychological test results). Little information was missing regarding disease ascertainment and diagnosis (e.g., ascertainment method – 0% missing). Discussion Using several data quality management strategies, we have established a comprehensive clinical database that provides information about care and outcomes for Canadian children affected by IMD. We describe quality issues and lessons for consideration in future clinical research initiatives for rare diseases, including accurately accommodating different clinic workflows and balancing comprehensiveness of data collection with available resources. Integrating data collection within clinical care, leveraging electronic medical records, and implementing core outcome sets will be essential for achieving sustainability.

Methylation of cytosine is a DNA modification associated with gene repression. Recently, a novel cytosine modification, 5-hydroxymethylcytosine （5-hmC） has been discovered. Here we examine 5-hmC distribution during mammalian development and in cellular systems, and show that the developmental dynamics of 5-hmC are different from those of 5-methylcytosine （5-mC）; in particular 5-hmC is enriched in embryonic contexts compared to adult tissues. A detectable 5-hmC signal appears in pre-implantation development starting at the zygote stage, where the paternal genome is subjected to a genome-wide hydroxylation of 5-mC, which precisely coincides with the loss of the 5-mC signal in the paternal pronucleus. Levels of 5-hmC are high in cells of the inner cell mass in blastocysts, and the modification colocalises with nestin-expressing cell populations in mouse post-implantation embryos. Compared to other adult mammalian organs, 5-hmC is strongly enriched in bone marrow and brain, wherein high 5-hmC content is a feature of both neuronal progenitors and post-mitotic neurons. We show that high levels of 5-hmC are not only present in mouse and human embryonic stem cells （ESCs） and lost during differentiation, as has been reported previously, but also reappear during the generation of induced pluripotent stem cells; thus 5-hmC enrichment cor- relates with a pluripotent cell state. Our findings suggest that apart from the cells of neuronal lineages, high levels of genomic 5-hmC are an epigenetic feature of embryonic cell populations and cellular pluri- and multi-lineage potency. To our knowledge, 5-hmC represents the first epigenetie modification of DNA discovered whose enrichment is so cell- type specific.

Photonic devices rarely provide both elaborate spatial control and sharp spectral control over an incoming wavefront. In optical metasurfaces, for example, the localized modes of individual meta-units govern the wavefront shape over a broad bandwidth, while nonlocal lattice modes extended over many unit cells support high quality-factor resonances. Here, we experimentally demonstrate nonlocal dielectric metasurfaces in the near-infrared that offer both spatial and spectral control of light, realizing metalenses focusing light exclusively over a narrowband resonance while leaving off-resonant frequencies unaffected. Our devices attain this functionality by supporting a quasi-bound state in the continuum encoded with a spatially varying geometric phase. We leverage this capability to experimentally realize a versatile platform for multispectral wavefront shaping where a stack of metasurfaces, each supporting multiple independently controlled quasi-bound states in the continuum, molds the optical wavefront distinctively at multiple wavelengths and yet stay transparent over the rest of the spectrum. Such a platform is scalable to the visible for applications in augmented reality and transparent displays.Nonlocal metasurfaces are demonstrated that offer both spatial and spectral control of light, realizing metalenses focusing light exclusively over a narrowband resonance while leaving off-resonant frequencies unaffected.

Metasurfaces have been rapidly advancing our command over the many degrees of freedom of light; however, so far, they have been mostly limited to manipulating light in free space. Metasurfaces integrated on top of guided-wave photonic systems have been explored to control the scattering of light off-chip with enhanced functionalities—namely, the point-by-point manipulation of amplitude, phase or polarization. However, these efforts have so far been limited to controlling one or two optical degrees of freedom at best, as well as device configurations much more complex compared with conventional grating couplers. Here we introduce leaky-wave metasurfaces, which are based on symmetry-broken photonic crystal slabs that support quasi-bound states in the continuum. This platform has a compact form factor equivalent to the one of grating couplers, but it provides full command over the amplitude, phase and polarization (four optical degrees of freedom) across large apertures. We present devices for phase and amplitude control at a fixed polarization state, and devices controlling all the four optical degrees of freedom for operation at a wavelength of 1.55 μm. Merging the fields of guided and free-space optics through the hybrid nature of quasi-bound states in the continuum, our leaky-wave metasurfaces may find applications in imaging, communications, augmented reality, quantum optics, LIDAR and integrated photonic systems. Based on symmetry-breaking perturbations, leaky-wave metasurfaces with pointwise control of the amplitude, phase and polarization of surface emission offer a universal generalization of grating couplers for integrated photonics.

In this White Paper we present the potential of the Enhanced X-ray Timing and Polarimetry (eXTP) mission for determining the nature of dense matter; neutron star cores host an extreme density regime which cannot be replicated in a terrestrial laboratory. The tightest statistical constraints on the dense matter equation of state will come from pulse profile modelling of accretion-powered pulsars, burst oscillation sources, and rotation-powered pulsars. Additional constraints will derive from spin measurements, burst spectra, and properties of the accretion flows in the vicinity of the neutron star. Under development by an international Consortium led by the Institute of High Energy Physics of the Chinese Academy of Science, the eXTP mission is expected to be launched in the mid 2020s.