Update on transcobalamin deficiency: clinical presentation, treatment and outcome.

Transcobalamin (TC) transports cobalamin from blood into cells. TC deficiency is a rare autosomal recessive disorder usually presenting in early infancy with failure to thrive, weakness, diarrhoea, pallor, anemia, and pancytopenia or agammaglobulinemia. It can sometimes resemble neonatal leukemia or severe combined immunodeficiency disease. Diagnosis of TC deficiency is suspected based on megaloblastic anemia, elevation of total plasma homocysteine, and blood or urine methylmalonic acid. It is confirmed by studying the synthesis of TC in cultured fibroblasts, or by molecular analysis of the TCN2 gene. TC deficiency is treatable with supplemental cobalamin, but the optimal type, route and frequency of cobalamin administration and long term patient outcomes are unknown. Here we present a series of 30 patients with TC deficiency, including an update on multiple previously published patients, in order to evaluate the different treatment strategies and provide information about long term outcome. Based on the data presented, current practice appears to favour treatment of individuals with TC deficiency by intramuscular injections of hydroxy- or cyanocobalamin. In most cases presented, at least weekly injections (1 mg IM) were necessary to ensure optimal treatment. Most centres adjusted the treatment regimen based on monitoring CBC, total plasma homocysteine, plasma and urine methylmalonic acid, as well as, clinical status. Finally, continuing IM treatment into adulthood appears to be beneficial.

A systematic approach to assessing the clinical significance of genetic variants.

Molecular genetic testing informs diagnosis, prognosis, and risk assessment for patients and their family members. Recent advances in low-cost, high-throughput DNA sequencing and computing technologies have enabled the rapid expansion of genetic test content, resulting in dramatically increased numbers of DNA variants identified per test. To address this challenge, our laboratory has developed a systematic approach to thorough and efficient assessments of variants for pathogenicity determination. We first search for existing data in publications and databases including internal, collaborative and public resources. We then perform full evidence-based assessments through statistical analyses of observations in the general population and disease cohorts, evaluation of experimental data from in vivo or in vitro studies, and computational predictions of potential impacts of each variant. Finally, we weigh all evidence to reach an overall conclusion on the potential for each variant to be disease causing. In this report, we highlight the principles of variant assessment, address the caveats and pitfalls, and provide examples to illustrate the process. By sharing our experience and providing a framework for variant assessment, including access to a freely available customizable tool, we hope to help move towards standardized and consistent approaches to variant assessment.

[Acquired long QT syndrome: a dominant problem?]. / QT long acquis: un problème envahissant?

QT prolongation is essentially of pharmacologic origin. It is principally linked to a block of the outward potassium current Ikr, with as a consequence a prolongation of the repolarisation causing early after potentials and re-entry. The term "repolarisation reserve" expresses the variable risk of arrhythmia among individuals under the same drug blocking Ikr. This reserve can be altered under various pathologic or genetic conditions. A series of risk factors (bradycar-Torsades de pointes} were described in 1966 by Dessertenne. They are due to a perturbation of ventricular repolarisation causing QT prolongation on surface ECG. Acquired dia, electrolytic disorders, cardiac disease, neurologic disorders, nutrition troubles, female gender) can play a role as well as the metabolic processing of pharmacological agents by Cytochrome P450 and various inhibitors or inductors of this system which can influence the half life of drugs. The list of drugs involved is continuously increasing: antiarrhythmics, antihistamines, psychotropics, anti-infectious are the main categories involved. Risk prediction is difficult particularly for non cardiovascular drugs and a low risk incidence. An other risk is to exclude patients from the benefit of an efficient drug for a serious but not frequent risk, at last an industrial risk for the manufacturer when a drug is withdrawn lately when important quantities of money have already been invested for its development. The diagnosis of torsades is easy on standard ECG although QT measurement and its heart rate variation remain uneasy. The treatment of the arrhythmias is based on heart rate acceleration by Isoprenaline or intravenous pacing and on intravenous administration of magnesium.

[Aneurysm of a saphenous vein bypass graft to coronary artery: a case report discovered as an incidental finding]. / Anévrisme d'un pontage veineux aortocoronarien: a propos d'un cas de découverte fortuite.

We report a case of aortocoronary bypass graft aneurysm revealed by exertional dyspnea and presenting as an anterior mediastinal mass at the unenhanced computed tomography scan. The diagnosis has been established using combined contrast-enhanced CT scan which specified the vascular nature of the mass and coronary angiography which connected it to the aorto-marginal branch saphenous vein graft. This case illustrates the frequently asymptomatic expression of aneurysm and the importance of combined imaging modalities for the diagnosis.