Isobutyryl-CoA dehydrogenase deficiency associated with autism in a girl without an alternative genetic diagnosis by trio whole exome sequencing: A case report

Background: Isobutyryl-CoA dehydrogenase (IBD) is a mitochondrial enzyme catalysing the third step in the degradation of the essential branched-chain amino acid valine and is encoded by ACAD8. ACAD8 mutations lead to isobutyryl-CoA dehydrogenase deficiency (IBDD), which is identified by increased C4-acylcarnitine levels. Affected individuals are either asymptomatic or display a variety of symptoms during infancy, including speech delay, cognitive impairment, failure to thrive, hypotonia, and emesis. Methods: Here, we review all previously published IBDD patients and describe a girl diagnosed with IBDD who was presenting with autism as the main disease feature. Results: To assess whether a phenotype-genotype correlation exists that could explain the development or absence of clinical symptoms in IBDD, we compared CADD scores, in silico mutation predictions, LoF tolerance scores and C4-acylcarnitine levels between symptomatic and asymptomatic individuals. Statistical analysis of these parameters did not establish significant differences amongst both groups. Conclusion: As in our proband, tri

Variation in the C-Reactive Protein Gene Is Associated with Serum Levels of CRP in Patients with Acute Ischemic Stroke

Background and Purpose: Elevated levels of C-reactive protein (CRP) are found in up to three quarters of patients with acute ischemic stroke and are associated with poor outcome. We investigated whether haplotypes representing common variations in the CRP gene are associated with levels of CRP in patients with acute ischemic stroke. Methods: We included 185 patients with ischemic stroke in whom CRP was measured within 24 h of symptom onset. Common haplotypes within the CRP gene were determined by 3 genotype-tagging single-nucleotide polymorphisms (SNPs). Results: Four haplotypes with frequencies >5% covered 99.2% of the genetic variation. Haplotype 4 (CCG, frequency 8.3%) was associated with a 20.6 mg/l (95% CI, 9.8-30.4) stronger increase in CRP level as compared with haplotype 1 (CTC, frequency 33.7%). Conclusion: Variation in the CRP gene is associated with levels of CRP in acute ischemic stroke. Copyright (C) 2010 S. Karger AG, Base

Fibrinogen gamma ' levels in patients with intracerebral hemorrhage

Background: The fibrinogen gamma' variant (gamma') has both antithrombotic and prothrombotic properties when compared to normal fibrinogen. It may therefore be of relevance in intracerebral hemorrhage and intraventricular extension of the bleeding. Objective: To study the role of gamma' in intracerebral hemorrhage, and in intraventricular extension of the hemorrhage. Patients/Methods: We performed a case-control study in 156 controls and 55 patients with intracerebral hemorrhage, with and without intraventricular extension. Levels of fibrinogen gamma' and the gamma'/total fibrinogen ratio were measured in all participants. Results: Levels of gamma' were increased in patients with intracerebral hemorrhage when compared with controls (0.40 vs 0.32 g/l, p<0.001). The gamma'/total fibrinogen ratio was similar in patients and controls (0.092 vs 0.096 p=0.42). There was evidence for an unfavorable outcome in patients with fibrinogen levels in the highest tertile compared with the lowest tertile (OR 4.0, 95% CI 1.1-15.2), and a nonsignificant trend toward unfavorable outcome with higher levels of gamma' (p-value for tren Conclusions: Our study shows that absolute levels of fibrinogen gamma' are increased in patients with intracerebral hemorrhage, but relative levels are similar in patients and controls, suggesting that the absolute rise in gamma' is an acute phase response. (C) 2011 Elsevier Ltd. All rights reserved

gamma '/total fibrinogen ratio is associated with short-term outcome in ischaemic stroke

Fibrinogen gamma (gamma) is a natural isoform of fibrinogen, and alters the rate of formation and the properties of clots. It could therefore affect outcome after ischaemic stroke. The prognostic significance of gamma fibrinogen levels is, however, still unclear. It was the objective of this study to assess levels of gamma in ischaemic stroke, and its association with short-term outcome. We included 200 ischaemic stroke patients and 1 56 control persons. Total fibrinogen and gamma levels were measured; outcome at discharge was assessed by means of the modified Rankin Scale score (defined as unfavourable when > 2). We compared levels between patients and controls using multiple linear regression analysis, and logistic regression analysis was used to assess the relationship between levels and outcome. All analyses were adjusted for age and sex. Mean gamma levels were significantly higher in patients with ischaemic stroke than in controls (0.37 vs. 0.32 g/l, p < 0.001), and patients also had a higher gamma/total fibrinogen ratio (0.102 vs. 0.096, p=0.19). The gamma/total fibrinogen ratio is associated with unfavourable outcome in patients with ischaemic stroke (odds ratio per unit increase of gamma/total fibrinogen ratio 1.27, 95% confidence interval 1.09-1.47). Our study shows that patients with ischaemic stroke have increased levels of fibrinogen gamma and suggests a trend towards an increased gamma/total fibrinogen ratio in ischaemic stroke. Increased fibrinogen gamma relative to total fibrinogen levels are associated with unfavourable outcome in the early phase after stroke

Relationship of Von Willebrand Factor with carotid artery and aortic arch calcification in ischemic stroke patients

AbstractBackgroundLarge population studies have revealed that increased von Willebrand Factor (VWF) levels are associated with an increased risk of ischemic stroke. In previous studies VWF was associated with atherosclerosis in healthy individuals. However, it is yet unknown what the association is between atherosclerosis and VWF levels in patients with ischemic stroke.ObjectivesThe aim of our study was to determine the association of atherosclerosis, measured with recent developed techniques, and VWF levels in a large, well characterized, cohort of ischemic stroke patients and to determine the prognostic value.MethodsWe included 925 consecutive patients with transient ischemic attack (TIA) or ischemic stroke. Calcification volumes (mm3) were scored in the aortic arch and both carotid arteries using multidetector computed tomography (CT) angiography. VWF antigen (VWF:Ag) levels were measured using ELISA.ResultsMean VWF:Ag levels were significantly higher in the presence of calcification in either the aortic arch (1.47 vs. 1.37 IU/ml [P = 0.039]) or the carotid arteries (1.49 vs. 1.34 IU/ml [P = 0.001]). Patients with a large artery atherosclerosis ischemic stroke had significantly higher VWF:Ag levels then the other TOAST subtypes (P < 0.0001). High VWF:Ag levels were associated with an unfavorable outcome (modified Rankin Scale >2 vs. ≤2; 1.64 vs. 1.41 IU/ml, [P < 0.0001]).ConclusionOur study showed a strong association between the extent of atherosclerosis in both the aortic arch and the carotid arteries and VWF levels in patients with TIA or ischemic stroke. Higher VWF levels are found in large artery atherosclerosis and are associated with a poor outcome

De novo TRPV4 Leu619Pro variant causes a new channelopathy characterised by giant cell lesions of the jaws and skull, skeletal abnormalities and polyneuropathy

Background Pathogenic germline variants in Transient Receptor Potential Vanilloid 4 Cation Channel (TRPV4) lead to channelopathies, which are phenotypically diverse and heterogeneous disorders grossly divided in neuromuscular disorders and skeletal dysplasia. We recently reported in sporadic giant cell lesions of the jaws (GCLJs) novel, somatic, heterozygous, gain-of-function mutations in TRPV4, at Met713. Methods Here we report two unrelated women with a de novo germline p.Leu619Pro TRPV4 variant and an overlapping systemic disorder affecting all organs individually described in TRPV4 channelopathies. Results From an early age, both patients had several lesions of the nervous system including progressive polyneuropathy, and multiple aggressive giant cell-rich lesions of the jaws and craniofacial/skull bones, and other skeletal lesions. One patient had a relatively milder disease phenotype possibly due to postzygotic somatic mosaicism. Indeed, the TRPV4 p.Leu619Pro variant was present at a lower frequency (variant allele frequency (VAF)=21.6%) than expected for a heterozygous variant as seen in the other proband, and showed variable regional frequency in the GCLJ (VAF ranging from 42% to 10%). In silico structural analysis suggests that the gain-of-function p.Leu619Pro alters the ion channel activity leading to constitutive ion leakage. Conclusion Our findings define a novel polysystemic syndrome due to germline TRPV4 p.Leu619Pro and further extend the spectrum of TRPV4 channelopathies. They further highlight the convergence of TRPV4 mutations on different organ systems leading to complex phenotypes which are further mitigated by possible post-zygotic mosaicism. Treatment of this disorder is challenging, and surgical intervention of the GCLJ worsens the lesions, suggesting the future use of MEK inhibitors and TRPV4 antagonists as therapeutic modalities for unmet clinical needs