Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome

Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin‐2 (SYT2), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment. These variants are thought to have a dominant‐negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Here we report seven patients of five families, with biallelic loss of function variants in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings were consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function. This series further establishes SYT2 as a CMS‐disease gene and expands its clinical and genetic spectrum to include recessive loss‐of‐function variants, manifesting as a severe congenital onset presynaptic CMS with potential treatment implications.     

Comparison of body composition, adipocyte size, and glucose and insulin concentrations in Pima Indian and Caucasian children

Pima Indian adults with normal glucose tolerance have higher plasma glucose and insulin concentrations than Caucasian adults. To estimate the age of onset of these differences, and to assess their relationship to abdominal and gluteal adipocyte size, we measured adiposity, adipocyte size, and glucose and insulin concentrations during a glucose tolerance test in lean (less than 20% body fat), prepubertal children from each race. The Pima (n = 13) and Caucasian (n = 10) groups were of similar age, percent body fat, and weight. Pima Indian children had higher fasting glucose (101 +/- 2 v 94 +/- 2 mg/dL, P = .01) and insulin (22 +/- 2 v 15 +/- 2 microU/mL, P less than .01) concentrations and larger abdominal adipocytes (0.49 +/- 0.03 v 0.37 +/- 0.04 microgram lipid/cell, P less than .05) than the Caucasian children. Postprandial glucose and insulin concentrations and gluteal adipocyte size were similar in the two races. The higher plasma glucose and insulin concentrations found in Pima adults are present in lean Pima children, and are associated with increased abdominal adipocyte size. These increases may precede the development of obesity in this racial group.     

B-cell growth factor receptor expression and B-cell growth factor response of leukemic B cell precursors and B lineage lymphoid progenitor cells

The purpose of this study was to analyze the expression of B cell growth factor (BCGF) receptors and to elucidate the biologic effects of biochemically purified natural BCGF at the B cell precursor stage of human B lineage lymphoid differentiation. The specific binding of radioiodinated high-mol-wt BCGF (125I-HMW-BCGF) and low-molecular-wt BCGF (125I-LMW-BCGF) to fresh marrow blasts from B cell precursor acute lymphoblastic leukemia (ALL) patients was initially investigated. The estimated number of radioiodinated BCGF molecules bound per blast ranged from undetectable to 24.3 X 10(3) for HMW-BCGF, and from 11.5 X 10(3) to 457.8 X 10(3) for LMW-BCGF. In 3H-TdR incorporation assays, 75% of cases showed a significant response to LMW-BCGF with a median stimulation index of 9.3. By comparison, only 33% of cases showed a significant response to HMW-BCGF with a median stimulation index of 2.4. Subsequently, B cell precursor colony assays were performed to assess and compare the biologic effects of BCGF on leukemic B lineage lymphoid progenitor cells. Among 28 cases studied, 57% responded to both HMW-BCGF and LMW-BCGF, 21% responded only to LMW-BCGF, and the remaining cases showed no proliferative response to either growth factor. The response patterns of virtually pure populations of FACS- sorted leukemic B cell precursors were essentially identical to the proliferative responses of unsorted leukemic B-cell precursors. Synergistic effects between HMW-BCGF and LMW-BCGF were observed in 80% of the cases that responded to both. The numbers of cell-bound radioiodinated BCGF molecules, the stimulation indices, as well as the number of B cell precursor colonies in BCGF-stimulated cultures showed a marked interpatient variation. Patients with structural chromosomal abnormalities (SCAs) involving 12p11-13 or patients with a Philadelphia chromosome showed a greater HMW-BCGF response at the level of leukemic progenitor cells than did other patients (P = .02). The LMW-BCGF response was significantly greater for patients with SCA than for patients without SCA (P = .04). The response of leukemic progenitor cells to HMW-BCGF or LMW-BCGF did not correlate with sex, age, disease status, FAB morphology, WBC at diagnosis, or immunophenotype. To our knowledge, this study represents the first detailed analyses of BCGF receptor expression and BCGF effects in B cell precursor ALL. The data presented provide direct evidence for the expression of functional receptors for both HMW-BCGF and LMW-BCGF in B cell precursor ALL.     

Local intracoronary administration of antisense oligonucleotide against c-myc for the prevention of in-stent restenosis: results of the randomized investigation by the Thoraxcenter of antisense DNA using local delivery and IVUS after coronary stenting (ITALICS) trial.

OBJECTIVE: This study was designed to determine whether antisense oligodeoxynucleotides (ODN) directed against the nuclear proto-oncogene c-myc could inhibit restenosis when given by local delivery immediately after coronary stent implantation. BACKGROUND: Failure of conventional pharmacologic therapies to reduce the incidence of coronary restenosis after percutaneous revascularization techniques has prompted interest in the use of agents that target intracellular central regulatory mechanisms. METHODS: Eighty-five patients were randomly assigned to receive either 10 mg of phosphorothioate-modified 15-mer antisense ODN or saline vehicle by intracoronary local delivery after coronary stent implantation. The primary end point was percent neointimal volume obstruction measured by computerized analysis of electrocardiogram-gated intravascular ultrasound (IVUS) at six-month follow-up. Secondary end points included clinical outcome and quantitative coronary angiography analysis. RESULTS: Analysis of follow-up IVUS data was performed on 77 patients. In-stent volume obstruction was similar between groups (44 +/- 16% and 46 +/- 14%, placebo vs. ODN; p = 0.57; 95% confidence interval: -1.13 to 0.85). Minimum luminal diameter increased from 0.84 +/- 0.36 and 0.90 +/- 0.45 (p = 0.55) to 2.70 +/- 0.37 and 2.80 +/- 0.37 (p = 0.28) after stent implantation, which decreased to 1.50 +/- 0.61 and 1.50 +/- 0.53 (p = 0.98) by six months, yielding similar loss indexes (placebo vs. ODN, respectively). There were no differences in angiographic restenosis rates (38.5 and 34.2%; p = 0.81; placebo vs. ODN) or clinical outcome. CONCLUSIONS: Treatment with 10 mg of phosphorothioate-modified ODN directed against c-myc does not reduce neointimal volume obstruction or the angiographic restenosis rate in this patient population.     

Coronary restenosis elimination with a sirolimus eluting stent: first European human experience with 6-month angiographic and intravascular ultrasonic follow-up.

AIMS: Coronary stenting is limited by a 10%-60% restenosis rate due to neointimal hyperplasia. Sirolimus is a macrocyclic lactone agent that interacts with cell-cycle regulating proteins and inhibits cell division between phases G1 and S1. The hypothesis tested in this study is that local delivery of sirolimus with an eluting stent can prevent restenosis. METHODS AND RESULTS: Fifteen patients were treated with 18 mm sirolimus eluting BX VELOCITY stents. Quantitative angiography and three-dimensional quantitative intravascular ultrasound were performed at implantation and at the 6 months follow-up. All stent implantations were successful. One patient died on day 2, of cerebral haemorrhage and one patient suffered a subacute stent occlusion due to edge dissection (re-PTCA, CKMB 42). At 9 months no further adverse events had occurred and all patients were angina free. Quantitative coronary angiography revealed no change in minimal lumen diameter and percent diameter stenosis and hence no in-lesion or in-stent restenosis. Quantitative intravascular ultrasound showed that intimal hyperplasia volume and percent obstruction volume at follow-up were negligible at 5.3 mm(3)and 1.8%, respectively. No edge effect was observed in the segments proximal and distal to the stents. CONCLUSION: Implantation of a sirolimus-eluting stent seems to effectively prevent intimal hyperplasia.     

Antenatal diagnosis of deletion chromosome 11(q23-qter) (Jacobsen syndrome)

A case of Jacobsen syndrome, suspected antenatally on the grounds of trigonocephaly and hypoplastic left heart syndrome, is presented. Clinicians are reminded that a hypoplastic left heart should not be assumed to be an isolated malformation and that a careful search for associated malformations can facilitate the recognition of an underlying genetic syndrome.     

Computed Tomography in the Diagnosis of Sacroiliitis

Computed tomography (CT) and conventional radiography of the sacroiliac joint were compared in 43 patients. CT appeared to be far more sensitive and equally specific in the recognition of sacroiliitis. In a number of patients with sacroiliitis diagnosed by both techniques, CT demonstrated abnormalities that were not demonstrated by conventional radiographs. Of those patients with clinical evidence of sacroiliitis and HLA—B27 positivity, 50% had negative or equivocal radiographs compared to 19% who had negative computed tomographic images for sacroiliiti.     

Comparative assessment of relapse and failure between CAD/CAM stainless steel and standard stainless steel fixed retainers in orthodontic retention patients:: A randomized controlled trial

ObjectivesTo compare relapse and failure rates of computer-aided design/computer-aided manufacturing (CAD/CAM) and standard fixed retainers.Materials and MethodsThis single-center, single-blinded, prospective randomized clinical trial included 46 patients who completed active orthodontic treatment and complied with retention visits. The patients were randomly assigned to three groups: CAD/CAM group with multistranded stainless steel wires (CAD/CAM, n = 16), Lab group with the same multistranded wires (lab, n = 16), and control group with stainless steel Ortho-FlexTech wires (traditional, n = 14). Intraoral scans were obtained at placement of fixed retainers (T1), 3-month visit (T2), and 6-month visit (T3) and measured for intercanine width and Little''s Irregularity Index. Failures were recorded.ResultsThe CAD/CAM group experienced less intercanine width decrease than the traditional group at 3 months (mean difference, 0.83 ± 0.16 mm; 95% confidence interval [CI], 0.44–1.22; P < .001) and 6 months (mean difference, 1.23 ± 0.40 mm; 95% CI, 0.19–2.27; P < .05). The CAD/CAM group experienced less increase in Little''s Irregularity Index compared with the lab group within 3 months (mean difference, 0.81 ± 0.27 mm; 95% CI, 0.12–1.49; P < .05). Failures from greatest to least were experienced by the lab group (43.8%), the CAD/CAM group (25%), and the traditional group (14.3%).ConclusionsWithin 6 months of bonding fixed retainers, CAD/CAM fixed retainers showed less relapse than lab-based and traditional chairside retainers and less failures than lab-based retainers.