High diagnostic rate of trio exome sequencing in consanguineous families with neurogenetic diseases.

Consanguineous marriages have a prevalence rate of 24% in Turkey. These carry an increased risk of autosomal recessive genetic conditions, leading to severe disability or premature death, with a significant health and economic burden. A definitive molecular diagnosis could not be achieved in these children previously, as infrastructures and access to sophisticated diagnostic options were limited. We studied the cause of neurogenetic disease in 246 children from 190 consanguineous families recruited in three Turkish hospitals between 2016 and 2020. All patients underwent deep phenotyping and trio whole exome sequencing, and data were integrated in advanced international bioinformatics platforms. We detected causative variants in 119 known disease genes in 72% of families. Due to overlapping phenotypes 52% of the confirmed genetic diagnoses would have been missed on targeted diagnostic gene panels. Likely pathogenic variants in 27 novel genes in 14% of the families increased the diagnostic yield to 86%. Eighty-two per cent of causative variants (141/172) were homozygous, 11 of which were detected in genes previously only associated with autosomal dominant inheritance. Eight families carried two pathogenic variants in different disease genes. De novo (9.3%), X-linked recessive (5.2%) and compound heterozygous (3.5%) variants were less frequent compared to non-consanguineous populations. This cohort provided a unique opportunity to better understand the genetic characteristics of neurogenetic diseases in a consanguineous population. Contrary to what may be expected, causative variants were often not on the longest run of homozygosity and the diagnostic yield was lower in families with the highest degree of consanguinity, due to the high number of homozygous variants in these patients. Pathway analysis highlighted that protein synthesis/degradation defects and metabolic diseases are the most common pathways underlying paediatric neurogenetic disease. In our cohort 164 families (86%) received a diagnosis, enabling prevention of transmission and targeted treatments in 24 patients (10%). We generated an important body of genomic data with lasting impacts on the health and wellbeing of consanguineous families and economic benefit for the healthcare system in Turkey and elsewhere. We demonstrate that an untargeted next generation sequencing approach is far superior to a more targeted gene panel approach, and can be performed without specialized bioinformatics knowledge by clinicians using established pipelines in populations with high rates of consanguinity.

The RD-Connect Genome-Phenome Analysis Platform: Accelerating diagnosis, research, and gene discovery for rare diseases.

Rare disease patients are more likely to receive a rapid molecular diagnosis nowadays thanks to the wide adoption of next-generation sequencing. However, many cases remain undiagnosed even after exome or genome analysis, because the methods used missed the molecular cause in a known gene, or a novel causative gene could not be identified and/or confirmed. To address these challenges, the RD-Connect Genome-Phenome Analysis Platform (GPAP) facilitates the collation, discovery, sharing, and analysis of standardized genome-phenome data within a collaborative environment. Authorized clinicians and researchers submit pseudonymised phenotypic profiles encoded using the Human Phenotype Ontology, and raw genomic data which is processed through a standardized pipeline. After an optional embargo period, the data are shared with other platform users, with the objective that similar cases in the system and queries from peers may help diagnose the case. Additionally, the platform enables bidirectional discovery of similar cases in other databases from the Matchmaker Exchange network. To facilitate genome-phenome analysis and interpretation by clinical researchers, the RD-Connect GPAP provides a powerful user-friendly interface and leverages tens of information sources. As a result, the resource has already helped diagnose hundreds of rare disease patients and discover new disease causing genes.

Cerebrovascular Effects of Lower Body Negative Pressure at 3T MRI: Implications for Long-Duration Space Travel.

BACKGROUND: Optic disc edema develops in most astronauts during long-duration spaceflight. It is hypothesized to result from weightlessness-induced venous congestion of the head and neck and is an unresolved health risk of space travel. PURPOSE: Determine if short-term application of lower body negative pressure (LBNP) could reduce internal jugular vein (IJV) expansion associated with the supine posture without negatively impacting cerebral perfusion or causing IJV flow stasis. STUDY TYPE: Prospective. SUBJECTS: Nine healthy volunteers (six women). FIELD STRENGTH/SEQUENCE: 3T/cine two-dimensional phase-contrast gradient echo; pseudo-continuous arterial spin labeling single-shot gradient echo echo-planar. ASSESSMENT: The study was performed with two sequential conditions in randomized order: supine posture and supine posture with 25 mmHg LBNP (LBNP25 ). LBNP was achieved by enclosing the lower extremities in a semi-airtight acrylic chamber connected to a vacuum. Heart rate, bulk cerebrovasculature flow, IJV cross-sectional area, fractional IJV outflow relative to arterial inflow, and cerebral perfusion were assessed in each condition. STATISTICAL TESTS: Paired t-tests were used to compare measurement means across conditions. Significance was defined as P < 0.05. RESULTS: LBNP25 significantly increased heart rate from 64 ± 9 to 71 ± 8 beats per minute and significantly decreased IJV cross-sectional area, IJV outflow fraction, cerebral arterial flow rate, and cerebral arterial stroke volume from 1.28 ± 0.64 to 0.56 ± 0.31 cm2 , 0.75 ± 0.20 to 0.66 ± 0.28, 780 ± 154 to 708 ± 137 mL/min and 12.2 ± 2.8 to 9.7 ± 1.7 mL/cycle, respectively. During LBNP25 , there was no significant change in gray or white matter cerebral perfusion (P = 0.26 and P = 0.24 respectively) and IJV absolute mean peak flow velocity remained ≥4 cm/sec in all subjects. DATA CONCLUSION: Short-term application of LBNP25 reduced IJV expansion without decreasing cerebral perfusion or inducing IJV flow stasis. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1.

Lower transfer factor of the lung for carbon monoxide in women with a patent foramen ovale.

NEW FINDINGS: What is the central question of this study? Do individuals with a patent foramen ovale (PFO+ ) have a lower lung transfer factor for carbon monoxide than those without (PFO- )? What is the main finding and its importance? We found a lower rate constant for carbon monoxide uptake in PFO+ compared with PFO- women, which was physiologically relevant (≥0.5 z-score difference), but not for PFO+ versus PFO- men. This suggests that factors independent of the PFO are responsible for our findings, possibly inherent structural differences in the lung. ABSTRACT: The transfer factor of the lung for carbon monoxide (TLCO ) measure assumes that all cardiac output flows through the pulmonary circuit. However, right-to-left blood flow through a shunt can result in a lower transfer factor than predicted. A patent foramen ovale (PFO) is a potential source of right-to-left shunt that is present in ∼35% of the population, but the effect of PFO on TLCO is unknown. We sought to determine the effect of PFO on the TLCO . We conducted a retrospective analysis of TLCO data from 239 (101 women) participants. Anthropometrics and lung function, including spirometry, plethysmography and TLCO , were compiled from our previously published work. Women, but not men, with a PFO had a significantly lower TLCO and rate constant for carbon monoxide uptake (KCO ) (percentage of predicted and z-score) than women without a PFO. Women and men with a PFO had normal alveolar volumes that did not differ from those without a PFO. Correcting the data for haemoglobin in a subset of subjects did not change the results (n = 58; 25 women). The lower KCO in women with versus without a PFO was physiologically relevant (≥0.5 z-score difference). There was no effect of PFO in men. This suggests that factors independent of the PFO are responsible for our findings, possibly inherent structural differences in the lung.

No effect of patent foramen ovale on acute mountain sickness and pulmonary pressure in normobaric hypoxia.

NEW FINDINGS: What is the central question to this study? Is there a relationship between a patent foramen ovale and the development of acute mountain sickness and an exaggerated increase in pulmonary pressure in response to 7-10 h of normobaric hypoxia? What is the main finding and its importance? Patent foramen ovale presence did not increase susceptibility to acute mountain sickness or result in an exaggerated increase in pulmonary artery systolic pressure with normobaric hypoxia. This suggests hypobaric hypoxia is integral to the increased susceptibility to acute mountain sickness previously reported in those with patent foramen ovale, and patent foramen ovale presence alone does not contribute to the hypoxic pulmonary pressor response. ABSTRACT: Acute mountain sickness (AMS) develops following rapid ascent to altitude, but its exact causes remain unknown. A patent foramen ovale (PFO) is a right-to-left intracardiac shunt present in ∼30% of the population that has been shown to increase AMS susceptibility with high altitude hypoxia. Additionally, high altitude pulmonary oedema (HAPE) is a severe type of altitude illness characterized by an exaggerated pulmonary pressure response, and there is a greater prevalence of PFO in those with a history of HAPE. However, whether hypoxia per se is causing the increased incidence of AMS in those with a PFO and whether a PFO is associated with an exaggerated increase in pulmonary pressure in those without a history of HAPE is unknown. Participants (n = 36) matched for biological sex (18 female) and the presence or absence of a PFO (18 PFO+) were exposed to 7-10 h of normobaric hypoxia equivalent to 4755 m. Presence and severity of AMS was determined using the Lake Louise AMS scoring system. Pulmonary artery systolic pressure, cardiac output and total pulmonary resistance were measured using ultrasound. We found no significant association of PFO with incidence or severity of AMS and no association of PFO with arterial oxygen saturation. Additionally, there was no effect of a PFO on pulmonary pressure, cardiac output or total pulmonary resistance. These data suggest that hypobaric hypoxia is necessary for those with a PFO to have increased incidence of AMS and that presence of PFO is not associated with an exaggerated pulmonary pressor response.

Unchanged cerebrovascular CO2 reactivity and hypercapnic ventilatory response during strict head-down tilt bed rest in a mild hypercapnic environment.

KEY POINTS: Carbon dioxide levels are mildly elevated on the International Space Station and it is unknown whether this chronic exposure causes physiological changes to astronauts. We combined ∼4 mmHg ambient PCO2 with the strict head-down tilt bed rest model of spaceflight and this led to the development of optic disc oedema in one-half of the subjects. We demonstrate no change in arterialized PCO2 , cerebrovascular reactivity to CO2 or the hypercapnic ventilatory response. Our data suggest that the mild hypercapnic environment does not contribute to the development of spaceflight associated neuro-ocular syndrome. ABSTRACT: Chronically elevated carbon dioxide (CO2 ) levels can occur in confined spaces such as the International Space Station. Using the spaceflight analogue 30 days of strict 6° head-down tilt bed rest (HDTBR) in a mild hypercapnic environment ( PCO2 = ∼4 mmHg), we investigated arterialized PCO2 , cerebrovascular reactivity and the hypercapnic ventilatory response in 11 healthy subjects (five females) before, on days 1, 9, 15 and 30 of bed rest (BR), and 6 and 13 days after HDTBR. During all HDTBR time points, arterialized PCO2 was not significantly different from the pre-HDTBR measured in the 6° HDT posture, with a mean (95% confidence interval) increase of 1.2 mmHg (-0.2 to 2.5 mmHg, P = 0.122) on day 30 of HDTBR. Respiratory acidosis was never detected, although a mild metabolic alkalosis developed on day 30 of HDTBR by a mean (95% confidence interval) pH change of 0.032 (0.022-0.043; P < 0.001), which remained elevated by 0.021 (0.011-0.031; P < 0.001) 6 days after HDTBR. Arterialized pH returned to pre-HDTBR levels 13 days after BR with a change of -0.001 (-0.009 to 0.007; P = 0.991). Compared to pre-HDTBR, cerebrovascular reactivity during and after HDTBR did not change. Baseline ventilation, ventilatory recruitment threshold and the slope of the ventilatory response were similar between pre-HDTBR and all other time points. Taken together, these data suggest that the mildly increased ambient PCO2 combined with 30 days of strict 6° HDTBR did not change arterialized PCO2 levels. Therefore, the experimental conditions were not sufficient to elicit a detectable physiological response.

Intracranial Effects of Microgravity: A Prospective Longitudinal MRI Study.

Background Astronauts on long-duration spaceflight missions may develop changes in ocular structure and function, which can persist for years after the return to normal gravity. Chronic exposure to elevated intracranial pressure during spaceflight is hypothesized to be a contributing factor, however, the etiologic causes remain unknown. Purpose To investigate the intracranial effects of microgravity by measuring combined changes in intracranial volumetric parameters, pituitary morphologic structure, and aqueductal cerebrospinal fluid (CSF) hydrodynamics relative to spaceflight and to establish a comprehensive model of recovery after return to Earth. Materials and Methods This prospective longitudinal MRI study enrolled astronauts with planned long-duration spaceflight. Measures were conducted before spaceflight followed by 1, 30, 90, 180, and 360 days after landing. Intracranial volumetry and aqueductal CSF hydrodynamics (CSF peak-to-peak velocity amplitude and aqueductal stroke volume) were quantified for each phase. Qualitative and quantitative changes in pre- to postflight (day 1) pituitary morphologic structure were determined. Statistical analysis included separate mixed-effects models per dependent variable with repeated observations over time. Results Eleven astronauts (mean age, 45 years ± 5 [standard deviation]; 10 men) showed increased mean volumes in the brain (28 mL; P < .001), white matter (26 mL; P < .001), mean lateral ventricles (2.2 mL; P < .001), and mean summated brain and CSF (33 mL; P < .001) at postflight day 1 with corresponding increases in mean aqueductal stroke volume (14.6 µL; P = .045) and mean CSF peak-to-peak velocity magnitude (2.2 cm/sec; P = .01). Summated mean brain and CSF volumes remained increased at 360 days after spaceflight (28 mL; P < .001). Qualitatively, six of 11 (55%) astronauts developed or showed exacerbated pituitary dome depression compared with baseline. Average midline pituitary height decreased from 5.9 to 5.3 mm (P < .001). Conclusion Long-duration spaceflight was associated with increased pituitary deformation, augmented aqueductal cerebrospinal fluid (CSF) hydrodynamics, and expansion of summated brain and CSF volumes. Summated brain and CSF volumetric expansion persisted up to 1 year into recovery, suggesting permanent alteration. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Lev in this issue.

Expanding the phenotype of Wiedemann-Steiner syndrome: Craniovertebral junction anomalies.

Wiedemann-Steiner syndrome (WDSTS) is a rare autosomal dominant condition caused by heterozygous loss of function variants in the KMT2A (MLL) gene, encoding a lysine N-methyltransferase that mediates a histone methylation pattern specific for epigenetic transcriptional activation. WDSTS is characterized by a distinctive facial phenotype, hypertrichosis, short stature, developmental delay, intellectual disability, congenital malformations, and skeletal anomalies. Recently, a few patients have been reported having abnormal skeletal development of the cervical spine. Here we describe 11 such individuals, all with KMT2A de novo loss-of-function variants: 10 showed craniovertebral junction anomalies, while an 11th patient had a cervical abnormality in C7. By evaluating clinical and diagnostic imaging data we characterized these anomalies, which consist primarily of fused cervical vertebrae, C1 and C2 abnormalities, small foramen magnum and Chiari malformation type I. Craniovertebral anomalies in WDSTS patients have been largely disregarded so far, but the increasing number of reports suggests that they may be an intrinsic feature of this syndrome. Specific investigation strategies should be considered for early identification and prevention of craniovertebral junction complications in WDSTS patients.

Impaired pulmonary gas exchange efficiency, but normal pulmonary artery pressure increases, with hypoxia in men and women with a patent foramen ovale.

NEW FINDINGS: What is the central question of this study? Do individuals with a patent foramen ovale (PFO+ ) have a larger alveolar-to-arterial difference in PO2 ( A-aDO2 ) than those without (PFO- ) and/or an exaggerated increase in pulmonary artery systolic pressure (PASP) in response to hypoxia? What is the main finding and its importance? PFO+ had a greater A-aDO2 while breathing air, 16% and 14% O2 , but not 12% or 10% O2 . PASP increased equally in hypoxia between PFO+ and PFO- . These data suggest that PFO+ may not have an exaggerated acute increase in PASP in response to hypoxia. ABSTRACT: Patent foramen ovale (PFO) is present in 30-40% of the population and is a potential source of right-to-left shunt. Accordingly, those with a PFO (PFO+ ) may have a larger alveolar-to-arterial difference in PO2 ( A-aDO2 ) than those without (PFO- ) in normoxia and with mild hypoxia. Likewise, PFO is associated with high-altitude pulmonary oedema, a condition known to have an exaggerated pulmonary pressure response to hypoxia. Thus, PFO+ may also have exaggerated pulmonary pressure increases in response to hypoxia. Therefore, the purposes of the present study were to systematically determine whether or not: (1) the A-aDO2 was greater in PFO+ than in PFO- in normoxia and mild to severe hypoxia and (2) the increase in pulmonary artery systolic pressure (PASP) in response to hypoxia was greater in PFO+ than in PFO- . We measured arterial blood gases and PASP via ultrasound in healthy PFO+ (n = 15) and PFO- (n = 15) humans breathing air and 30 min after breathing four levels of hypoxia (16%, 14%, 12%, 10% O2 , randomized and balanced order) at rest. The A-aDO2 was significantly greater in PFO+ compared to PFO- while breathing air (2.1 ± 0.7 vs. 0.4 ± 0.3 Torr), 16% O2 (1.8 ± 1.2 vs. 0.7 ± 0.8 Torr) and 14% O2 (2.3 ± 1.2 vs. 0.7 ± 0.6 Torr), but not 12% or 10% O2 . We found no effect of PFO on PASP at any level of hypoxia. We conclude that PFO influences pulmonary gas exchange efficiency with mild hypoxia, but not the acute increase in PASP in response to hypoxia.

Recessive variants of MuSK are associated with late onset CMS and predominant limb girdle weakness.

Congenital myasthenic syndrome (CMS) is a heterogeneous disorder that causes fatigable muscle weakness. CMS has been associated with variants in the MuSK gene and, to date, 16 patients have been reported. MuSK-CMS patients present a different phenotypic pattern of limb girdle weakness. Here, we describe four additional patients and discuss the phenotypic and clinical relationship with those previously reported. Two novel damaging missense variants are described: c.1742T > A; p.I581N found in homozygosis, and c.1634T > C; p.L545P found in compound heterozygosis with p.R166*. The reported patients had predominant limb girdle weakness with symptom onset at 12, 17, 18, and 30 years of age, and the majority exhibited a good clinical response to Salbutamol therapy, but not to esterase inhibitors. Meta-analysis including previously reported variants revealed an increased likelihood of a severe, respiratory phenotype with null alleles. Missense variants exclusively affecting the kinase domain, but not the catalytic site, are associated with late onset. These data refine the phenotype associated with MuSK-related CMS.

PRKG1 and genetic diagnosis of early-onset thoracic aortic disease.

BACKGROUND: The 20% of thoracic aortic aneurysms and dissections independent from the main connective tissue syndromes and expected to be familial has gained importance over the past years. The more frequent pattern of inheritance of these nonsyndromic cases is autosomal dominant with incomplete penetrance and variable expression. Although many candidate genes exist, unresolved familial cases suggest still unravelled genetic variation. The main purpose of this study was to establish the genetic diagnosis of one of those. MATERIALS AND METHODS: To begin with, we applied a candidate gene approach based on both traditional and a customized massive parallel sequencing panel, followed by Illumina HiSeq 2000 whole exome sequencing of four family members affected by early-onset thoracic aortic disease and two unaffected relatives. We prioritized whole exome sequencing results based on variant location, type and frequency in general population databases and performed segregation analysis in 14 family members using traditional sequencing. RESULTS: After the negative results we obtained with candidate gene approaches, the analysis and prioritization of whole exome sequencing results brought out the heterozygote c.530G>A:p.Arg177Gln PRKG1 variant (NM_001098512), located in one of the aortic smooth muscle cell contractile apparatus genes. This candidate variant segregated with thoracic aortic disease, as it was present in seven affected and absent in five unaffected family members, further supporting its causality. CONCLUSIONS: This was the second time PRKG1 was associated with thoracic aortic disease, highlighting and reaffirming it as a strong candidate for gene-based diagnosis of nonsyndromic early-onset cases.

Increased Diagnostic Yield by Reanalysis of Whole Exome Sequencing Data in Mitochondrial Disease.

Background: The genetic diagnosis of mitochondrial disorders is complicated by its genetic and phenotypic complexity. Next generation sequencing techniques have much improved the diagnostic yield for these conditions. A cohort of individuals with multiple respiratory chain deficiencies, reported in the literature 10 years ago, had a diagnostic rate of 60% by whole exome sequencing (WES) but 40% remained undiagnosed. Objective: We aimed to identify a genetic diagnosis by reanalysis of the WES data for the undiagnosed arm of this 10-year-old cohort of patients with suspected mitochondrial disorders. Methods: The WES data was transferred and processed by the RD-Connect Genome-Phenome Analysis Platform (GPAP) using their standardized pipeline. Variant prioritisation was carried out on the RD-Connect GPAP. Results: Singleton WES data from 14 individuals was reanalysed. We identified a possible or likely genetic diagnosis in 8 patients (8/14, 57%). The variants identified were in a combination of mitochondrial DNA (n = 1, MT-TN), nuclear encoded mitochondrial genes (n = 2, PDHA1, and SUCLA2) and nuclear genes associated with nonmitochondrial disorders (n = 5, PNPLA2, CDC40, NBAS and SLC7A7). Variants in both the NBAS and CDC40 genes were established as disease causing after the original cohort was published. We increased the diagnostic yield for the original cohort by 15% without generating any further genomic data. Conclusions: In the era of multiomics we highlight that reanalysis of existing WES data is a valid tool for generating additional diagnosis in patients with suspected mitochondrial disease, particularly when more time has passed to allow for new bioinformatic pipelines to emerge, for the development of new tools in variant interpretation aiding in reclassification of variants and the expansion of scientific knowledge on additional genes.

Jugular venous flow dynamics during acute weightlessness.

During spaceflight, fluids shift headward, causing internal jugular vein (IJV) distension and altered hemodynamics, including stasis and retrograde flow, that may increase the risk of thrombosis. This study's purpose was to determine the effects of acute exposure to weightlessness (0-G) on IJV dimensions and flow dynamics. We used two-dimensional (2-D) ultrasound to measure IJV cross-sectional area (CSA) and Doppler ultrasound to characterize venous blood flow patterns in the right and left IJV in 13 healthy participants (6 females) while 1) seated and supine on the ground, 2) supine during 0-G parabolic flight, and 3) supine during level flight (at 1-G). On Earth, in 1-G, moving from seated to supine posture increased CSA in both left (+62 [95% CI: +42 to 81] mm2, P < 0.0001) and right (+86 [95% CI: +58 to 113] mm2, P < 0.00012) IJV. Entry into 0-G further increased IJV CSA in both left (+27 [95% CI: +5 to 48] mm2, P = 0.02) and right (+30 [95% CI: +0.3 to 61] mm2, P = 0.02) relative to supine in 1-G. We observed stagnant flow in the left IJV of one participant during 0-G parabolic flight that remained during level flight but was not present during any imaging during preflight measures in the seated or supine postures; normal venous flow patterns were observed in the right IJV during all conditions in all participants. Alterations to cerebral outflow dynamics in the left IJV can occur during acute exposure to weightlessness and thus, may increase the risk of venous thrombosis during any duration of spaceflight.NEW & NOTEWORTHY The absence of hydrostatic pressure gradients in the vascular system and loss of tissue weight during weightlessness results in altered flow dynamics in the left internal jugular vein in some astronauts that may contribute to an increased risk of thromboembolism during spaceflight. Here, we report that the internal jugular veins distend bilaterally in healthy participants and that flow stasis can occur in the left internal jugular vein during acute weightlessness produced by parabolic flight.

Structural variant calling and clinical interpretation in 6224 unsolved rare disease exomes.

Structural variants (SVs), including large deletions, duplications, inversions, translocations, and more complex events have the potential to disrupt gene function resulting in rare disease. Nevertheless, current pipelines and clinical decision support systems for exome sequencing (ES) tend to focus on small alterations such as single nucleotide variants (SNVs) and insertions-deletions shorter than 50 base pairs (indels). Additionally, detection and interpretation of large copy-number variants (CNVs) are frequently performed. However, detection of other types of SVs in ES data is hampered by the difficulty of identifying breakpoints in off-target (intergenic or intronic) regions, which makes robust identification of SVs challenging. In this paper, we demonstrate the utility of SV calling in ES resulting in a diagnostic yield of 0.4% (23 out of 5825 probands) for a large cohort of unsolved patients collected by the Solve-RD consortium. Remarkably, 8 out of 23 pathogenic SV were not found by comprehensive read-depth-based CNV analysis, resulting in a 0.13% increased diagnostic value.

Development of optic disc edema during 30 days of hypercapnic head-down tilt bed rest is associated with short sleep duration and blunted temperature amplitude.

Sleep and circadian temperature disturbances occur with spaceflight and may, in part, result from the chronically elevated carbon dioxide (CO2) levels on the international space station. Impaired sleep may contribute to decreased glymphatic clearance and, when combined with the chronic headward fluid shift during actual spaceflight or the spaceflight analog head-down tilt bed rest (HDTBR), may contribute to the development of optic disc edema. We determined if strict HDTBR combined with mildly elevated CO2 levels influenced sleep and core temperature and was associated with the development of optic disc edema. Healthy participants (5 females) aged 25-50 yr, underwent 30 days of strict 6° HDTBR with ambient Pco2 = 4 mmHg. Measures of sleep, 24-h core temperature, overnight transcutaneous CO2, and Frisén grade edema were made pre-HDTBR, on HDTBR days 4, 17, 28, and post-HDTBR days 4 and 10. During all HDTBR time points, sleep, core temperature, and overnight transcutaneous CO2 were not different than the pre-HDTBR measurements. However, independent of the HDTBR intervention, the odds ratios {mean [95% confidence interval (CI)]} for developing Frisén grade optic disc edema were statistically significant for each hour below the mean total sleep time (2.2 [1.1-4.4]) and stage 2 nonrapid eye movement (NREM) sleep (4.8 [1.3-18.6]), and above the mean for wake after sleep onset (3.6 [1.2-10.6]) and for each 0.1°C decrease in core temperature amplitude below the mean (4.0 [1.4-11.7]). These data suggest that optic disc edema occurring during HDTBR was more likely to occur in those with short sleep duration and/or blunted temperature amplitude.NEW & NOTEWORTHY We determined that sleep and 24-h core body temperature were unaltered by 30 days exposure to the spaceflight analog strict 6° head-down tilt bed rest (HDTBR) in a 0.5% CO2 environment. However, shorter sleep duration, greater wake after sleep onset, and lower core temperature amplitude present throughout the study were associated with the development of optic disc edema, a key finding of spaceflight-associated neuro-ocular syndrome.

Rare disease research workflow using multilayer networks elucidates the molecular determinants of severity in Congenital Myasthenic Syndromes.

Exploring the molecular basis of disease severity in rare disease scenarios is a challenging task provided the limitations on data availability. Causative genes have been described for Congenital Myasthenic Syndromes (CMS), a group of diverse minority neuromuscular junction (NMJ) disorders; yet a molecular explanation for the phenotypic severity differences remains unclear. Here, we present a workflow to explore the functional relationships between CMS causal genes and altered genes from each patient, based on multilayer network community detection analysis of complementary biomedical information provided by relevant data sources, namely protein-protein interactions, pathways and metabolomics. Our results show that CMS severity can be ascribed to the personalized impairment of extracellular matrix components and postsynaptic modulators of acetylcholine receptor (AChR) clustering. This work showcases how coupling multilayer network analysis with personalized -omics information provides molecular explanations to the varying severity of rare diseases; paving the way for sorting out similar cases in other rare diseases.

Advancing the Understanding of Vesicle-Associated Membrane Protein 1-Related Congenital Myasthenic Syndrome: Phenotypic Insights, Favorable Response to 3,4-Diaminopyridine, and Clinical Characterization of Five New Cases.

BACKGROUND: Congenital myasthenic syndromes (CMS) are a group of inherited neuromuscular junction (NMJ) disorders arising from gene variants encoding diverse NMJ proteins. Recently, the VAMP1 gene, responsible for encoding the vesicle-associated membrane protein 1 (VAMP1), has been associated with CMS. METHODS: This study presents a characterization of five new individuals with VAMP1-related CMS, providing insights into the phenotype. RESULTS: The individuals with VAMP1-related CMS exhibited early disease onset, presenting symptoms prenatally or during the neonatal period, alongside severe respiratory involvement and feeding difficulties. Generalized weakness at birth was a common feature, and none of the individuals achieved independent walking ability. Notably, all cases exhibited scoliosis. The clinical course remained stable, without typical exacerbations seen in other CMS types. The response to anticholinesterase inhibitors and salbutamol was only partial, but the addition of 3,4-diaminopyridine (3,4-DAP) led to significant and substantial improvements, suggesting therapeutic benefits of 3,4-DAP for managing VAMP1-related CMS symptoms. Noteworthy is the identification of the VAMP1 (NM_014231.5): c.340delA; p.Ile114SerfsTer72 as a founder variant in the Iberian Peninsula and Latin America. CONCLUSIONS: This study contributes valuable insights into VAMP1-related CMS, emphasizing their early onset, arthrogryposis, facial and generalized weakness, respiratory involvement, and feeding difficulties. Furthermore, the potential efficacy of 3,4-DAP as a useful therapeutic option warrants further exploration. The findings have implications for clinical management and genetic counseling in affected individuals. Additional research is necessary to elucidate the long-term outcomes of VAMP1-related CMS.