Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome

The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species

Mini-Crush Versus T-Provisional Techniques in Bifurcation Lesions. Clinical and Angiographic Long-Term Outcome After Implantation of Drug-Eluting Stents

Objectives: This retrospective study sought to assess the clinical and angiographic long-term outcome after implanting drug-eluting stents in bifurcation lesions with the T-provisional (T-prov) technique and mini-crush (MC) technique. Background: The best option on the treatment of coronary bifurcation lesions is a subject of considerable debate. However, recent evidence suggests that bifurcation lesions might be treated by drug-eluting stent on both branches using the MC technique with a low rate of major adverse cardiac event and restenosis. Methods: From April 2004 to July 2006, 457 patients were consecutively treated with either MC technique (n = 199) or T-prov technique (n = 258). Of these latter, 170 patients were treated with 1 stent and 88 patients with 2 stents. The 9-month angiographic follow-up was completed in 188 of 229 (82.1%) bifurcation lesions of MC patients and in 207 of 266 lesions (77.8%) of T-prov patients. Results: After a propensity score adjustment, 2-year cumulative major adverse cardiac events were similar between groups (p = 0.16). The MC group compared with the T-prov 1-stent group had significantly lower main and side branches restenosis (hazard ratio [HR]: 0.52, 95% confidence interval [CI]: 0.27 to 0.99; p = 0.047; and HR: 0.41, 95% CI: 0.20 to 0.85; p = 0.016, respectively). However, the MC group compared with the T-prov-only group had significantly lower side branch restenosis (HR: 0.55, 95% CI: 0.37 to 0.82; p = 0.004). Conclusions: Both techniques of bifurcation treatment met high procedural success with low complication rates and similar major adverse cardiac event long-term outcome. However, the MC technique yields a lower restenosis rate at both main and side branches. These results may confirm the advantage of using prescheduled 2-stent technique to give a complete coverage of the side branches' ostium. © 2009 American College of Cardiology Foundation

Prognostic value of exercise myocardial scintigraphy in patients with coronary chronic total occlusions

Objectives: To evaluate the prognostic value of exercise myocardial scintigraphy in patients undergoing incomplete revascularization by means of percutaneous coronary intervention (PCI) with at least a residual chronic total occlusion (CTO) left untreated. Methods: Of 569 consecutive patients with multivessel disease undergoing myocardial scintigraphy after incomplete revascularization by PCI between March 1997 and December 2004, 126 (79% male, 64 ± 10 years) with ≥ 1 residual CTO fulfilled the eligibility criteria and entered in the study. Hard events defined as cardiac death and myocardial infarction, soft events defined as incidence of unstable angina and PCI procedures, and their composite were assessed at a median follow-up period of 44 months. Results: Hard events were observed in six patients (4.8%). All of them had severely abnormal perfusion defects detected by myocardial scintigraphy. Soft events occurred in 0 (0%), 10 (7.9%), and 15 (11.9%) patients with normal, mildly abnormal, and severely abnormal perfusion, respectively. In the Kaplan-Meier analysis, the log-rank test was statistically significant across patients stratified by summed stress score either in terms of hard, soft and hard, or soft events. Univariate and multivariate Cox proportional-hazards showed an incremental significant information when the scintigraphic variables were added to clinical, angiographic, left ventricular ejection fraction, and Duke treadmill score, for prediction of the composite of hard and soft cardiac events (P < 0.006). Conclusions: Among patients with a residual CTO left untreated after PCI, myocardial perfusion imaging provides significant independent information concerning the subsequent risk of cardiac events. (J Interven Cardiol 2010;23:139-148) © 2010, Wiley Periodicals, Inc

A New Splicing Mutation in the L1CAM Gene Responsible for X-Linked Hydrocephalus (HSAS)

X-linked hydrocephalus (XLH) is a genetic disorder leading to a syndrome characterized by mental retardation, bilateral adducted thumbs, and spasticity of upper and lower limbs. In most cases, X-linked mutation leads to a defective activity of the neuronal cell adhesion molecule L1CAM (L1 cell adhesion molecule, OMIM 308840). Depending on mutations of L1CAM, four X-linked neurological syndromes have been described. These syndromes are very different albeit each one possesses marked variability. In the present study, we describe a novel L1CAM mutation in a 33-year-old woman reporting two voluntary terminations of pregnancy due to fetal hydrocephalus. The genetic analysis identified the potential splicing variant c.1267+5delG. When analyzed in vitro, this mutation produces the skipping of exon 10. The same mutation was confirmed in analyzing DNA from amniocytes from the second pregnancy, and ultrasound scan and autopsy confirmed the occurrence of a severe L1 syndrome. These data describe a novel L1 mutation which improves our understanding on genotype-phenotype correlation while confirming the importance of prenatal screening for L1CAM mutations

Identification of Duchenne/Becker muscular dystrophy mosaic carriers through a combined DNA/RNA analysis

The Duchenne/Becker muscular dystrophy (DMD) carrier screening includes the evaluation of mutations in DMD gene, and the most widely used analysis is the multiplex ligation-dependent probe amplification (MLPA) for the DMD deletions/duplications detection. The high frequency of de novo mutations permits to estimate a risk up to 20% of mosaicisms for mothers of sporadic DMD children. The purpose of this study is to evaluate alternative analytical strategy for the detection of mosaics carrier women, in order to improve the recurrence risk estimation

Atypical phenotypes and clinical variability in a large Italian family with DYT1-primary torsion dystonia

The GAG deletion in the DYT1 gene usually causes a typical form of primary torsion dystonia (PTD) with early onset in a limb, rapid generalization, and sparing of cranial-cervical muscles, but atypical phenotypes have often been reported. Here, we describe a large DYT1 Italian family with phenotypically heterogeneous PTD that recapitulates all the atypical features associated with the DYT1 mutation, including late age at onset, focal or segmental phenotypes, onset or spreading of dystonia to the cranial-cervical muscles. Of 38 healthy family members, 15 also carried the DYT1 mutation, with an estimated penetrance of 21%. A literature review of atypical familial cases of DYT1-PTD showed that late onset, cervical involvement, and limited progression of dystonia are features frequently seen in DYT1 families. However, nearly all of these atypical patients fall within at least one of the clinical categories that best predict the DYT1 carrier status, namely, early onset, onset in a limb, and family history positive for early-onset dystonia

Atypical phenotypes and clinical variability in a large Italian family with DYT1-primary torsion dystonia

The GAG deletion in the DYT1 gene usually causes a typical form of primary torsion dystonia (PTD) with early onset in a limb, rapid generalization, and sparing of cranial-cervical muscles, but atypical phenotypes have often been reported. Here, we describe a large DYT1 Italian family with phenotypically heterogeneous PTD that recapitulates all the atypical features associated with the DYT1 mutation, including late age at onset, focal or segmental phenotypes, onset or spreading of dystonia to the cranial-cervical muscles. Of 38 healthy family members, 15 also carried the DYT1 mutation, with an estimated penetrance of 21%. A literature review of atypical familial cases of DYT1-PTD showed that late onset, cervical involvement, and limited progression of dystonia are features frequently seen in DYT1 families. However, nearly all of these atypical patients fall within at least one of the clinical categories that best predict the DYT1 carrier status, namely, early onset, onset in a limb, and family history positive for early-onset dystonia