Novel Genetic Microvascular Dysplasia Causing Hypoperfusion of Cardiac, Renal, and Cerebral Circulation
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ABSTRACT:
SUBMITTER: Frustaci A
PROVIDER: S-EPMC10672279 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:BackgroundSpondyloepiphyseal dysplasia congenita (SEDC) is an extremely rare inherited chondrodysplasia characterized by abnormal epiphyses, short stature, and flattened vertebral bodies. We investigate the phenotypes and the disease-associated variants of SEDC in two unrelated Chinese families.MethodsWe identified disease-associated variants in two nonconsanguineous families with SEDC using targeted next-generation sequencing and confirmed the variants using Sanger sequencing. We investigated the phenotypes of the patients, including clinical manifestations, bone turnover biomarkers, bone mineral density and skeletal radiographic features.ResultsTwo probands were diagnosed as SEDC according to the phenotypes of disproportionately short-trunk stature, kyphosis, lumbar lordosis and adduction deformity of hips. Radiographs revealed kyphosis and lumbar lordosis, flattened vertebral bodies, compressed femoral heads and shortening of the femurs. Bone mineral density of the probands was lower than that of age- and gender-matched normal children, but bone turnover biomarker levels were within normal range. Two novel heterozygous missense variants (NM_001844.5: c.1654 G>A, NP_001835.3: p.Gly552Arg; NM_001844.5: c.3518G>T, NP_001835.3: p.Gly1173Val) in collagen type II alpha 1 chain (COL2A1) were detected in the two families, which would impair the formation of stable triple-helical type II collagen.ConclusionsWe identified two novel disease-associated variants in COL2A1, which led to severe SEDC. Our findings expanded the gene variant spectrum and phenotypic spectrum of extremely rare type II collagenopathies.
| S-EPMC7057085 | biostudies-literature
Project description:Abnormalities in small renal vessels may increase the risk of developing impaired renal function, but methods to assess these vessels are extremely limited. We hypothesized that the presence of small vessel disease in the brain, which manifests as silent cerebral infarction (SCI), may predict the progression of kidney disease in patients with type 2 diabetes. We recruited 608 patients with type 2 diabetes without apparent cerebrovascular or cardiovascular disease or overt nephropathy and followed them for a mean of 7.5 years. At baseline, 177 of 608 patients had SCI, diagnosed by cerebral magnetic resonance imaging. The risk for the primary outcome of ESRD or death was significantly higher for patients with SCI than for patients without SCI [hazard ratio, 2.44; 95% confidence interval (CI) 1.36 to 4.38]. The risk for the secondary renal end point of any dialysis or doubling of the serum creatinine concentration was also significantly higher for patients with SCI (hazard ratio, 4.79; 95% CI 2.72 to 8.46). The estimated GFR declined more in patients with SCI than in those without SCI; however, the presence of SCI did not increase the risk for progression of albuminuria. In conclusion, independent of microalbuminuria, cerebral microvascular disease predicted renal morbidity among patients with type 2 diabetes.
| S-EPMC2831864 | biostudies-other
Project description:RNF213 is a susceptibility gene for moyamoya disease, yet its exact functions remain unclear. To evaluate the role of RNF213 in adaptation of cerebral blood flow (CBF) under cerebral hypoperfusion, we performed bilateral common carotid artery stenosis surgery using external microcoils on Rnf213 knockout (KO) and vascular endothelial cell-specific Rnf213 mutant (human p.R4810K orthologue) transgenic (EC-Tg) mice. Temporal CBF changes were measured by arterial spin-labelling magnetic resonance imaging. In the cortical area, no significant difference in CBF was found before surgery between the genotypes. Three of eight (37.5%) KO mice died after surgery but all wild-type and EC-Tg mice survived hypoperfusion. KO mice had a significantly more severe reduction in CBF on day 7 than wild-type mice (KO, 29.7% of baseline level; wild-type, 49.3%; p?=?0.038), while CBF restoration on day 28 was significantly impaired in both KO (50.0%) and EC-Tg (56.1%) mice compared with wild-type mice (69.5%; p?=?0.031 and 0.037, respectively). Changes in the subcortical area also showed the same tendency as the cortical area. Additionally, histological analysis demonstrated that angiogenesis was impaired in both EC-Tg and KO mice. These results are indicative of the essential role of RNF213 in the maintenance of CBF.
| S-EPMC5827518 | biostudies-literature
Project description:Cortical microinfarcts (CMIs) observed in brains of patients with Alzheimer's disease tend to be located close to vessels afflicted with cerebral amyloid angiopathy (CAA). CMIs in Alzheimer's disease are preferentially distributed in the arterial borderzone, an area most vulnerable to hypoperfusion. However, the causal association between CAA and CMIs remains to be elucidated. This study consists of two parts: (1) an observational study using postmortem human brains (n = 31) to determine the association between CAA and CMIs, and (2) an experimental study to determine whether hypoperfusion worsens CAA and induces CMIs in a CAA mouse model. In postmortem human brains, the density of CMIs was 0.113/cm(2) in mild, 0.584/cm(2) in moderate, and 4.370/cm(2) in severe CAA groups with a positive linear correlation (r = 0.6736, p < 0.0001). Multivariate analysis revealed that, among seven variables (age, disease, senile plaques, neurofibrillary tangles, CAA, atherosclerosis and white matter damage), only the severity of CAA was a significant multivariate predictor of CMIs (p = 0.0022). Consistent with the data from human brains, CAA model mice following chronic cerebral hypoperfusion due to bilateral common carotid artery stenosis induced with 0.18-mm diameter microcoils showed accelerated deposition of leptomeningeal amyloid β (Aβ) with a subset of them developing microinfarcts. In contrast, the CAA mice without hypoperfusion exhibited very few leptomeningeal Aβ depositions and no microinfarcts by 32 weeks of age. Following 12 weeks of hypoperfusion, cerebral blood flow decreased by 26% in CAA mice and by 15% in wild-type mice, suggesting impaired microvascular function due to perivascular Aβ accumulation after hypoperfusion. Our results suggest that cerebral hypoperfusion accelerates CAA, and thus promotes CMIs.
| S-EPMC3282897 | biostudies-literature
Project description:Congenital abnormalities of the kidney and urinary tract are frequently observed in children and represent a significant cause of morbidity and mortality. These conditions are phenotypically variable, often affecting several segments of the urinary tract simultaneously, making clinical classification and diagnosis difficult. Renal agenesis/hypoplasia and dysplasia account for a significant portion of these anomalies, and a genetic contribution to its cause is being increasingly recognized. Nevertheless, overlap between diseases and challenges in clinical diagnosis complicate studies attempting to discover new genes underlying this anomaly. Most of the insights in kidney development derive from studies in mouse models or from rare, syndromic forms of human developmental disorders of the kidney and urinary tract. The genes implicated have been shown to regulate the reciprocal induction between the ureteric bud and the metanephric mesenchyme. Strategies to find genes causing renal agenesis/hypoplasia and dysplasia vary depending on the characteristics of the study population available. The approaches range from candidate gene association or resequencing studies to traditional linkage studies, using outbred pedigrees or genetic isolates, to search for structural variation in the genome. Each of these strategies has advantages and pitfalls and some have led to significant discoveries in human disease. However, renal agenesis/hypoplasia and dysplasia still represents a challenge, both for the clinicians who attempt a precise diagnosis and for the geneticist who tries to unravel the genetic basis, and a better classification requires molecular definition to be retrospectively improved. The goal appears to be feasible with the large multicentric collaborative groups that share the same objectives and resources.
| S-EPMC1994209 | biostudies-literature
Project description:PURPOSE:Ipsilateral thalamic diaschisis (ITD) refers to the phenomenon of thalamic hypoperfusion or hypometabolism due to a distant cerebral injury. To further investigate the characteristics and spectrum of ITD, we analyzed quantitative measurements of thalamic hypoperfusion in acute anterior circulation stroke. METHODS:We selected consecutive patients with large-vessel occlusion (LVO) anterior circulation stroke and available CT perfusion (CTP) examination on admission who underwent endovascular thrombectomy. Thalamic perfusion parameters on CTP were tested between ipsi- and contralesional thalamus and ischemic territory. Values were compared with thresholds from CTP analysis software. Associations of thalamic perfusion parameters with acute imaging and clinical data were determined in uni- and multivariate logistic regression analyses. RESULTS:Ninety-nine patients were included. All perfusion parameters indicated significant non-ischemic hypoperfusion of the thalamus, not reaching the levels of ischemia in the middle cerebral artery territory due to LVO (all p < 0.002). Multiple perfusion parameters exhibited significant association with ischemic lesion extent (relative cerebral blood flow [CBF]: ? = - 0.23, p = 0.022; ?time to drain: ? = 0.33, p < 0.001; ?Tmax: ? = - 0.36, p < 0.001) and involvement of the Lentiform Nucleus (?mean transit time: ? = 0.64, p = 0.04; ?time to drain: ? = 0.81, p = 0.01; ?Tmax: ? = - 0.82, p = 0.01). Symptom severity on admission exhibited minor significant association with reduction of thalamic CBF in uncorrected analysis (Odds ratio: 0.05, p = 0.049), but short- and long-term outcomes were unaffected by perfusion status. ITD reached guideline-based software-threshold levels in only one patient. CONCLUSIONS:ITD in acute stroke is a non-binary phenomenon affected by lesion extent and involvement of the lentiform nucleus. We found uncorrected association of ITD with early clinical presentation, but no association with short- or long-term outcome was evident. Relevant misclassification of ITD by guideline-based CTP software was not indicated, which needs further dedicated testing.
| S-EPMC7334597 | biostudies-literature
Project description:BackgroundSpondyloepiphyseal dysplasia congenita is an autosomal dominant cartilaginous dysplasia characterized by short trunk, abnormal epiphysis, and flattened vertebral body. Skeletal features of SEDC are present at birth and evolve over time. Other features of SEDC include myopia and/or retinal degeneration with retinal detachment and cleft palate. A mutation in the COL2A1 gene located in 12q13.11 is considered as one of the important causes of SEDC. In 2016, Barat-Houari et al. reported a large number of COL2A1 mutations. Among them, a non-synonymous mutation in COL2A1 exon 37, c.2437G>A (p. Gly813Arg), has been reported to cause SEDC in only one patient from France so far.MethodsWe followed up a patient with SEDC phenotype and his family members. The clinical manifestations, physical examination and imaging examination, including X-ray, CT and MRI, were recorded. The whole-exome sequencing was used to detect the patients' genes, and the pathogenic genes were screened out by comparing with many databases.ResultsWe report a Chinese patient with SEDC phenotype characterized by short trunk, abnormal epiphysis, flattened vertebral body, narrow intervertebral space, dysplasia of the odontoid process, chicken chest, scoliosis, hip and knee dysplasia, and joint hypertrophy. Gene sequencing analysis showed that the patient had a heterozygous mutation (c.2437G>A; p. Gly813Arg) in the COL2A1 gene. No COL2A1 mutation or SEDC phenotype was observed in his family members. This is the first report of SEDC caused by this mutation in an East Asian family.ConclusionThis report provides typical clinical, imaging, and genetic evidence for SEDC, confirming that a de novo mutation in the COL2A1 gene, c.2437G>A (p. Gly813Arg), causes SEDC in Chinese population.
| S-EPMC8059726 | biostudies-literature
Project description:Chronic cerebral circulation insufficiency (CCCI) is viewed as an alarming state induced by long-term reduction in cerebral perfusion, which is associated with neurological deficits and high risk of stroke occurrence or recurrence. CCCI accounts for a large proportion of both outpatients and inpatients with cerebrovascular diseases, while management of CCCI remains a formidable challenge to clinicians. Normobaric oxygen (NBO) is an adjuvant hyperoxygenation intervention supplied with one atmosphere pressure (1 ATA =101.325 kPa). A plethora of studies have demonstrated the efficacy of NBO on the penumbra in acute stroke. NBO has been shown to increase the oxygen pressure, raise the intracranial blood flow, protect blood-brain barrier and enhance neuroprotective effects. As similar underlying mechanisms are shared by the penumbra in stroke and the ischemic-hypoxic brain tissues in CCCI, we speculate that NBO may serve as a promising therapeutic strategy for attenuating short-term symptoms or improving long-term clinical outcomes among patients with CCCI. Due to the scant research exploring the efficacy and safety of NBO for treating CCCI so far, both experimental and clinical studies are warranted to verify our hypothesis in the future.
| S-EPMC6421875 | biostudies-literature
Project description:Septo-optic dysplasia (SOD) is a developmental phenotype characterized by midline neuroradiological anomalies, optic nerve hypoplasia, and pituitary anomalies, with a high degree of variability and additional systemic anomalies present in some cases. While disruption of several transcription factors has been identified in SOD cohorts, most cases lack a genetic diagnosis, with multifactorial risk factors being thought to play a role. Exome sequencing in a cohort of families with a clinical diagnosis of SOD identified a genetic diagnosis in 3/6 families, de novo variants in SOX2, SHH, and ARID1A, and explored variants of uncertain significance in the remaining three. The outcome of this study suggests that investigation for a genetic etiology is warranted in individuals with SOD, particularly in the presence of additional syndromic anomalies and when born to older, multigravida mothers. The identification of causative variants in SHH and ARID1A further expands the phenotypic spectra associated with these genes and reveals novel pathways to explore in septo-optic dysplasia.
| S-EPMC9320703 | biostudies-literature
Project description:BackgroundWe present a patient who received cerebral oximetry monitoring during targeted temperature management (TTM) post-cardiac arrest and discuss its potential in the early detection of cerebral hypoperfusion and implications on haemodynamics and ventilatory management.Case summaryA 60-year-old Chinese male was admitted for acute pulmonary oedema with Type 2 respiratory failure. He failed an initial trial of non-invasive ventilation and was planned for intubation and mechanical ventilation. However, the patient suffered a pulseless electrical activity cardiac arrest peri-intubation. He was started on our institution's protocolized post-cardiac arrest care bundle, which included cerebral regional oxygen saturation (rSO2) monitoring and TTM. Initial arterial blood gas (ABG) post-return of spontaneous circulation showed severe respiratory acidosis, and the patient was sedated, paralyzed, and ventilator settings optimized. Repeat ABG showed resolution of respiratory acidosis. However, a drop in rSO2 to 35% was subsequently noted. Ventilator settings were quickly adjusted, and dobutamine was started to improve global and cerebral perfusion. These measures improved cerebral rSO2 to more than 50%. Patient was cooled for 24?h and gradually rewarmed. He was later extubated with a cerebral performance category of 1 and is now on outpatient follow-up.DiscussionDuring post-cardiac arrest care, there are many factors which can contribute to a decrease in cerebral blood flow. Therapeutic hypothermia and ventilation strategies, including the use of neuromuscular blocking agents, can both reduce pCO2 which is a major regulator of cerebrovascular tone. Accidental hypocapnia can lead to adverse cerebral vasoconstriction and hypoperfusion. Without cerebral oximetry, cerebral ischaemia may not be detected early and can potentially result in secondary brain injury.
| S-EPMC6764554 | biostudies-literature