Abstract
Background
Bevacizumab—a humanized monoclonal antibody—has been widely used to treat patients with hereditary hemorrhagic telangiectasia (HHT), but no randomized trial has yet been ...conducted.
Methods
This study is a double‐blind multicenter randomized phase 2 trial with a 1:1 active‐treatment‐to‐placebo ratio. We included patients over the age of 18 with a confirmed diagnosis and the need for at least four red blood cell (RBC) units transfused in the 3 months before study enrollment. Bevacizumab was administered at a dose of 5 mg/kg every 14 days with a total of six injections. The primary efficacy criterion was a decrease of at least 50% in the cumulative number of RBC units transfused in a 3‐month period before and after treatment.
Results
A total of 24 patients (12 in each group) were included and randomized at 4 different centers. In intention‐to‐treat analysis, 63.6% of patients (7/11) in the bevacizumab group versus 33.3% of patients (4/12) in the placebo group decreased the number of blood transfusions by at least 50% (
p
= 0.22). Hemoglobin levels significantly improved at 6 months in the bevacizumab versus placebo group (
p
= 0.02). The pharmacokinetics study revealed that patients with high exposure to bevacizumab had a significant decrease in RBC transfusions (
p
= 0.03). Fifty‐nine adverse events were observed, 34 in the placebo arm versus 25 in the bevacizumab arm.
Conclusion
Though the present trial was underpowered, patients with HHT receiving bevacizumab required numerically fewer red blood cell transfusions than those receiving placebo, particularly those with high exposure.
Bardet‐Biedl syndrome (BBS) is an emblematic ciliopathy associated with retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, hypogonadism and renal dysfunction. Before birth, ...enlarged/cystic kidneys as well as polydactyly are the hallmark signs of BBS to consider in absence of familial history. However, these findings are not specific to BBS, raising the problem of differential diagnoses and prognosis. Molecular diagnosis during pregnancies remains a timely challenge for this heterogeneous disease (22 known genes). We report here the largest cohort of BBS fetuses to better characterize the antenatal presentation. Prenatal ultrasound (US) and/or autopsy data from 74 fetuses with putative BBS diagnosis were collected out of which molecular diagnosis was established in 51 cases, mainly in BBS genes (45 cases) following the classical gene distribution, but also in other ciliopathy genes (6 cases). Based on this, an updated diagnostic decision tree is proposed. No genotype/phenotype correlation could be established but postaxial polydactyly (82%) and renal cysts (78%) were the most prevalent symptoms. However, autopsy revealed polydactyly that was missed by prenatal US in 55% of the cases. Polydactyly must be carefully looked for in pregnancies with apparently isolated renal anomalies in fetuses.
A, Fraction of BBS genes involved in our cohort of 45 fetuses with a Bardet‐Biedl syndrome. B, BBS decision tree for the identification of disease‐causing variations in BBS patients.
We read with great interest the recent article published by Yooet al1reporting 4 additional Rett-like (RTT) patients with therecurring A567TGABBR2mutation.2More interestingly, theyshowed, with in ...vitro and in vivo functional studies, that theseverity of the phenotype caused byGABBR2mutations wasdirectly linked to their impact onc-aminobutyric acid (GABA)signaling activity, this latter being more reduced with the 2 mis-sense mutations, S695I and I705N, associated with epilepticencephalopathy (EE).1,3They hypothesized that the position ofvariants in different transmembrane (TM) domains ofGABBR2,TM6 for S695I and I705N, and TM3 for A567T, could deter-mine the phenotypic expression. This hypothesis was recentlyreinforced with the report of a novelGABBR2mutation also inTM6 and associated with infantile epileptic spasms.
Synaptic function is central to brain function. Understanding the synapse is aided by studies of patients lacking individual synaptic proteins. Common neurological diseases are genetically complex. ...Their understanding is likewise simplified by studies of less common monogenic forms. We detail the disease caused by absence of the synaptic protein CNKSR2 in 8 patients ranging from 6 to 62 years old. The disease is characterized by intellectual disability, attention problems, and abrupt lifelong language loss following a brief early childhood epilepsy with continuous spike‐waves in sleep. This study describes the phenotype of CNKSR2 deficiency and its involvement in systems underlying common neurological disorders. Ann Neurol 2014;76:758–764
13q12.3 microdeletion syndrome is a rare cause of syndromic intellectual disability. Identification and genetic characterization of patients with 13q12.3 microdeletion syndrome continues to expand ...the phenotypic spectrum associated with it. Previous studies identified four genes within the approximately 300 Kb minimal critical region including two candidate protein coding genes: KATNAL1 and HMGB1. To date, no patients carrying a sequence‐level variant or a single gene deletion in HMGB1 or KATNAL1 have been described. Here we report six patients with loss‐of‐function variants involving HMGB1 and who had phenotypic features similar to the previously described 13q12.3 microdeletion syndrome cases. Common features included developmental delay, language delay, microcephaly, obesity and dysmorphic features. In silico analyses suggest that HMGB1 is likely to be intolerant to loss‐of‐function, and previous in vitro data are in line with the role of HMGB1 in neurodevelopment. These results strongly suggest that haploinsufficiency of the HMGB1 gene may play a critical role in the pathogenesis of the 13q12.3 microdeletion syndrome.
Background
Patient prognosis in type 1 myotonic dystrophy (DM1) is very poor. Annual 24‐hour holter ECG monitoring is recommended but its relevance is debated. Main objective was to determine whether ...holter ECG parameters could predict global death in DM1 patients and secondarily to assess whether they could predict cardiovascular events and sudden cardiac death, to compare DM1 patients and healthy controls, and to assess their evolution in DM1 over a 5‐year period.
Methods
This retrospective study included genetically confirmed DM1. Primary endpoint was global death. Secondary endpoints were labeled “sudden cardiac death” which was a composite of sudden cardiac death, aborted sudden cardiac death, implantable cardioverter defibrillator therapy, sustained ventricular tachycardia, atrioventricular block grade 3, pause >3 s; and “cardiovascular events” which was a composite of all‐cause mortality, pacemaker or cardioverter defibrillator implantation, sustained ventricular tachycardia, supraventricular tachycardia, hospitalization for acute cardiac cause and heart failure.
Results
Forty‐seven patients (22 women, 40 ± 13 years old) were included. Three (7%) DM1 patients died, 9 (19%) experienced "sudden cardiac death" endpoint and 21 (45%) experienced "cardiovascular event" endpoint during mean follow‐up of 95 ± 22 months. None of holter ECG parameters were discriminant to predict death or secondary endpoints. Compared to healthy controls, DM1 patients had higher SDNN and LF/HF ratio. Finally, heart rate variability parameters remained stable over a mean interval of 61 ± 15 months excepting pNN50 which decreased significantly.
Conclusion
Results suggest that annually‐repeated holter ECG in DM1 is not useful for stratifying risk of sudden death and cardiovascular outcomes.
Mammalian genomes are organized into megabase-scale topologically associated domains (TADs). We demonstrate that disruption of TADs can rewire long-range regulatory architecture and result in ...pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. This rewiring occurred only if the variant disrupted a CTCF-associated boundary domain. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome.
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•Disruptions of TADs lead to de novo enhancer-promoter interactions and misexpression•Misexpression occurs when CTCF-associated TAD boundary elements are disrupted•Structural variations disrupting TAD structures can cause malformation syndromes•Different phenotypes can result from one enhancer acting on different target genes
Disease-associated structural variants, when affecting CTCF-associated boundary elements, cause pathogenicity by disrupting the structure of topologically associated chromatin domains leading to ectopic promoter interactions and altered gene expression.
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