Clinical and genetic findings in a large cohort of patients with congenital myopathies due to mutations in the skeletal muscle ryanodine receptor (RYR1) gene

RYR1 mutations are the most common cause of structural congenital myopathies and may exhibit both dominant and recessive inheritance. Histopathological findings are variable and include central cores, multi-minicores, type 1 predominance/ uniformity, fibre type disproportion, increased internal nucleation and fatty and connective tissue. Until recently, diagnostic RYR1 sequencing was limited to mutational hotspots due to the large size of the gene. Since the introduction of full RYR1 sequencing in 2007 we have detected pathogenic mutations in 77 families: 39 had dominant inheritance and 38 recessive inheritance. In some cases with presumably recessive inheritance, only one heterozygous mutation inherited from an asymptomatic parent was identified. Of 28 dominant mutations, 6 were novel; 37 of the 59 recessive mutations were also novel. Dominant mutations were more frequently in recognized hotspot regions, while recessive mutations were distributed throughout the coding sequence. Dominant mutations were predominantly missense, whereas recessive mutations included many nonsense and splice mutations expected to result in reduced RyR1 protein. There was wide clinical variability in patients with both dominant and recessive inheritance. As a group, those with dominant mutations were generally more mildly affected than those with recessive inheritance, who had earlier onset and were weaker with more functional limitations. Extraocular muscle involvement was almost exclusively observed in the recessive group. Bulbar involvement was also more prominent in this group, resulting in a larger number requiring gastrostomy insertion. In conclusion, genomic sequencing of the entire RYR1 leads to the detection of many novel mutations, but may miss large genetic rearrangements in some cases. Assigning pathogenicity to novel mutations is often difficult and interpretation of genetic results in the context of clinical, histological and, increasingly, muscle MRI findings is essential.

IRM cardiaque dans le suivi des cardiopathies congénitales à l'âge adulte [Cardiac MRI in the follow-up of adult congenital cardiomyopathy patients].

Magnetic resonance imaging is a rapidly developing modality in cardiology. It offers an excellent image definition and a large field of view, allowing a more accurate morphological assessment of cardiac malformations. Due to its unique versatility and its ability to provide myocardial tissue characterization, cardiac magnetic resonance (CMR) is now recognized as a central imaging modality for a wide range of congenital heart diseases, including assessment of post-surgical cardiac anatomy, quantification of valvular disease and detection of myocardial ischemia. CMR provides useful diagnostic information without any radiation exposure, and improves the global management of patients with congenital heart disease.

Could Hyperglycaemia and Troponin I predict outcome in intensive care after congenital heart surgery in children?

Objective: To establish if hyperglycaemia and cardiac Troponin I (cTnI) after congenital heart surgery on cardiopulmonary bypass in children could predict outcome in intensive care unit. Methods: retrospective cohort study including 274 children (mean age 4.6 years; range 0 - 17 years-old). CTnI and glucose values were retrieved from our database. Integrated values (area under the curve (AUC)) were calculated for evaluation of sustained hyperglycaemia and then normalised per hour (48h-Gluc/h). Maximal cTnI, fi rst glucose value (Gluc1) and 48h-Gluc/h were then correlated with duration of mechanical ventilation, ICU stay and mortality using cut-off values. Results: The mean duration of mechanical ventilation was 5.1 ± 7.2 days and ICU stay was 11.0 ± 13.3 days, 11 patients (3.9%) died. Hyperglycaemia (>6.1 mmol/l) was present in 68% of children at admission and was sustained in 85% for 48 hours. The mean value of Gluc1 (7.3 ± 2.7 vs. 11.8 ± 6.4 mmol/l, p < 0.0001), 48h-Gluc/h (7.4 ± 1.4 vs. 9.9 ± 4.6 mmol/l/h, p < 0.0001) and cTnI max (16.7 ± 21.8 vs. 59.2 ± 41.4 mcg/l, p < 0.0001) were signifi cantly lower in survivors vs. non survivors. Cut-off values and odds ratio are summarised in Table 1. Analyses for duration of mechanical ventilation and for length of stay in ICU are depicted in Table 2. Conclusions: Hyperglycaemia is frequent after cardiopulmonary bypass and sustained in the fi rst 48 hours. Admission glycaemia and cTnI max are associated with a high risk of mortality, prolonged duration of mechanical ventilation and prolonged length of stay in ICU.

Development of glycopeptide-intermediate resistance by Staphylococcus aureus leads to attenuated infectivity in a rat model of endocarditis.

Glycopeptide-intermediate resistant Staphylococcus aureus (GISA) are characterized by multiple changes in the cell wall and an altered expression of global virulence regulators. We investigated whether GISA are affected in their infectivity in a rat model of experimental endocarditis. The glycopeptide-susceptible, methicillin-resistant S. aureus M1V2 and its laboratory-derived GISA M1V16 were examined for their ability to (i) adhere to fibrinogen and fibronectin in vitro, (ii) persist in the bloodstream after intravenous inoculation, (iii) colonize aortic vegetations in rats, and (iv) compete for valve colonization by co-inoculation. Both GISA M1V16 and M1V2 adhered similarly to fibrinogen and fibronectin in vitro. In rats, GISA M1V16 was cleared faster from the blood (P < 0.05) and required 100-times more bacteria than parent M1V2 (10(6) versus 10(4)CFU) to infect 90% of vegetations. GISA M1V16 also had 100 to 1000-times lower bacterial densities in vegetations. Moreover, after co-inoculation with GISA M1V16 and M1V2Rif, a rifampin-resistant variant of M1V2 to discriminate them in organ cultures, GISA M1V16 was out-competed by the glycopeptide-susceptible counterpart. Thus, in rats with experimental endocarditis, GISA showed an attenuated virulence, likely due to a faster clearance from the blood and a reduced fitness in cardiac vegetations. The GISA phenotype appeared globally detrimental to infectivity.

Atrial arrhythmias in adults with congenital heart disease.

BACKGROUND: Atrial arrhythmias increase disease burden in the general adult population. Adults with congenital heart lesions constitute a rapidly growing group of patients with cardiovascular disease. We hypothesized that atrial arrhythmias increase with age and impair health outcomes in this population. METHODS AND RESULTS: We conducted a population-based analysis of prevalence, lifetime risk, mortality, and morbidity associated with atrial arrhythmias in adults with congenital heart disease from l983 to 2005. In 38 428 adults with congenital heart disease in 2005, 5812 had atrial arrhythmias. Overall, the 20-year risk of developing atrial arrhythmia was 7% in a 20-year-old subject and 38% in a 50-year-old subject. More than 50% of patients with severe congenital heart disease reaching age 18 years developed atrial arrhythmias by age 65 years. In patients with congenital heart disease, the hazard ratio of any adverse event in those with atrial arrhythmias compared with those without was 2.50 (95% confidence interval, 2.38 to 2.62; P<0.0001), with a near 50% increase in mortality (hazard ratio, 1.47; 95% confidence interval, 1.37 to 1.58; P<0.001), more than double the risk of morbidity (stroke or heart failure) (hazard ratio, 2.21; 95% confidence interval, 2.07 to 2.36; P<0.001), and 3 times the risk of cardiac interventions (hazard ratio, 3.00; 95% confidence interval, 2.81 to 3.20; P<0.001). CONCLUSIONS: Atrial arrhythmias occurred in 15% of adults with congenital heart disease. The lifetime incidence increased steadily with age and was associated with a doubling of the risk of adverse events. An increase in resource allocation should be anticipated to deal with this increasing burden.

Cricotracheal resection for pediatric subglottic stenosis.

Until recently, cricotracheal resection (CTR) has not been commonly accepted as a treatment modality for severe subglottic stenosis in the pediatric age group. The reasons have included the risk of a possible dehiscence at the site of the anastomosis, the likelihood of injury to the recurrent laryngeal nerves, and the interference with normal growth of the larynx. Thirty-eight infants and children with a severe subglottic stenosis underwent a partial cricoid resection with primary thyrotracheal anastomosis. Thirty-three patients were tracheotomy-dependent at the time of surgery and 34 were referred cases; 27 were classified as grade III, and 10 as grade IV stenoses according to new Cotton's classification. Nineteen patients were younger than 3 years of age at the time of surgery. The tracheotomy was resected during the surgical procedure in 21 cases. Decannulation was achieved in 36/38 cases after an open procedure. There is one complete restenosis and one good result awaiting decannulation after further surgery for a Pierre Robin syndrome. The authors experienced no lesion of the recurrent laryngeal nerves and no fatality. Thirty-one patients show no exertional dyspnea, three a slight stridor while exercising, and two patients are not decannulated. The postoperative follow-up in longer than 10 years in eight cases. All patients show a normal growth of the larynx and trachea. Compared to laryngotracheoplasties, CTR gives better results for severe subglottic stenosis. This operation should become the treatment of choice for severe (grade III and IV) subglottic stenosis in infants and children.

The C57BL/6J Mouse Exhibits Sporadic Congenital Portosystemic Shunts.

C57BL/6 mice are the most widely used strain of laboratory mice. Using in vivo proton Magnetic Resonance Spectroscopy ((1)H MRS), we have repeatedly observed an abnormal neurochemical profile in the brains of both wild-type and genetically modified mice derived from the C57BL/6J strain, consisting of a several fold increase in cerebral glutamine and two fold decrease in myo-inositol. This strikingly abnormal neurochemical "phenotype" resembles that observed in chronic liver disease or portosystemic shunting and appeared to be independent of transgene, origin or chow and was not associated with liver failure. As many as 25% of animals displayed the abnormal neurochemical profile, questioning the reliability of this model for neurobiology. We conducted an independent study to determine if this neurochemical profile was associated with portosystemic shunting. Our results showed that 100% of the mice with high brain glutamine displayed portosystemic shunting by concomitant portal angiography while all mice with normal brain glutamine did not. Since portosystemic shunting is known to cause alterations in gene expression in many organs including the brain, we conclude that portosystemic shunting may be the most significant problem associated with C57BL/6J inbreeding both for its effect on the central nervous system and for its systemic repercussions.

Laryngotracheal reconstruction for pediatric glotto-subglottic stenosis.

BACKGROUND: The management of pediatric laryngotracheal stenosis (LTS) can be challenging, and laryngotracheal reconstruction (LTR) with cartilage interposition grafting remains the mainstay of surgical treatment for pediatric LTS in most experienced centers. The purpose of this study was to report the results of this procedure in a center where primary cricotracheal resection is frequently performed. METHODS: A retrospective chart review was performed on 45 patients who underwent LTR in our hospital between October 1997 and July 2012. Demographic characteristics and information on the preoperative status, stenosis, and operation were collected. Primary outcomes were measured as overall (ODR) and operation-specific (OSDR) decannulation rates and secondary outcomes as morbidity, mortality, and postoperative functional results. RESULTS: ODR and OSDR were 86.7% (39/45) and 66.7% (30/45), respectively. Re-stenosis was observed in 11/45 (24%) patients, all of whom were endoscopically or surgically treated. Revision surgery was performed in 10 patients, 6 for re-stenosis and 2 for peristomial tracheomalacia. Two children died of mucous obstruction of tracheostomy tube at 3 and 6 months postoperatively (4.4%). Respiratory, voice, and swallowing functions were excellent or good in 86, 75, and 84% of patients, respectively. CONCLUSIONS: LTR for pediatric LTS has high decannulation rates with acceptable morbidity and mortality in selected patients. Most LTR procedures were double-stage for lower grade subglottic stenoses associated with glottic involvement that required stenting. Careful preoperative evaluation and adequate surgical indications are extremely important to achieve high decannulation rates.

Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: congenital dislocations and vertebral changes as principal diagnostic features.

We recently reported on the deficiency of carbohydrate sulfotransferase 3 (CHST3; chondroitin-6-sulfotransferase) in six subjects diagnosed with recessive Larsen syndrome or humero-spinal dysostosis [Hermanns et al. (2008); Am J Hum Genet 82:1368-1374]. Since then, we have identified 17 additional families with CHST3 mutations and we report here on a series of 24 patients in 23 families. The diagnostic hypothesis prior to molecular analysis had been: Larsen syndrome (15 families), humero-spinal dysostosis (four cases), chondrodysplasia with multiple dislocations (CDMD "Megarbane type"; two cases), Desbuquois syndrome (one case), and spondylo-epiphyseal dysplasia (one case). In spite of the different diagnostic labels, the clinical features in these patients were similar and included dislocation of the knees and/or hips at birth, clubfoot, elbow joint dysplasia with subluxation and limited extension, short stature, and progressive kyphosis developing in late childhood. The most useful radiographic clues were the changes of the lumbar vertebrae. Twenty-four different CHST3 mutations were identified; 16 patients had homozygous mutations. We conclude that CHST3 deficiency presents at birth with congenital dislocations of knees, hips, and elbows, and is often diagnosed initially as Larsen syndrome, humero-spinal dysostosis, or chondrodysplasia with dislocations. The incidence of CHST3 deficiency seems to be higher than assumed so far. The clinical and radiographic pattern (joint dislocations, vertebral changes, normal carpal age, lack of facial flattening, and recessive inheritance) is characteristic and distinguishes CHST3 deficiency from other disorders with congenital dislocations such as filamin B-associated dominant Larsen syndrome and Desbuquois syndrome.

Paper 3: EUROCAT data quality indicators for population-based registries of congenital anomalies.

The European Surveillance of Congenital Anomalies (EUROCAT) network of population-based congenital anomaly registries is an important source of epidemiologic information on congenital anomalies in Europe covering live births, fetal deaths from 20 weeks gestation, and terminations of pregnancy for fetal anomaly. EUROCAT's policy is to strive for high-quality data, while ensuring consistency and transparency across all member registries. A set of 30 data quality indicators (DQIs) was developed to assess five key elements of data quality: completeness of case ascertainment, accuracy of diagnosis, completeness of information on EUROCAT variables, timeliness of data transmission, and availability of population denominator information. This article describes each of the individual DQIs and presents the output for each registry as well as the EUROCAT (unweighted) average, for 29 full member registries for 2004-2008. This information is also available on the EUROCAT website for previous years. The EUROCAT DQIs allow registries to evaluate their performance in relation to other registries and allows appropriate interpretations to be made of the data collected. The DQIs provide direction for improving data collection and ascertainment, and they allow annual assessment for monitoring continuous improvement. The DQI are constantly reviewed and refined to best document registry procedures and processes regarding data collection, to ensure appropriateness of DQI, and to ensure transparency so that the data collected can make a substantial and useful contribution to epidemiologic research on congenital anomalies.

Traitement des sténoses sous-glottiques de l'enfant par résection crico-trachéale [Treatment of subglottis stenosis in children by cricotracheal resection].

Fifty-eight infants and children with a severe subglottic stenosis underwent a partial cricotracheal resection with primary thyrotracheal anastomosis. There were 2 grade II, 40 grade III, and 16 grade IV stenoses according to the Myer-Cotton classification. A 100% subglottic lumen was formed in 34 cases and a better than 80% lumen in 23 cases. Fifty-four of the 58 (93%) patients are presently decannulated; one patient sustained a complete restenosis and three patients with a better than 80% subglottic airway still await decannulation for the following reasons: severe tracheomalacia, bilateral cricoarytenoïd joint fixation and laryngeal malformation with fusion of the vocal cords in each case respectively. Forty-four patients have no exercise intolerance, 8 live fully normally but present a slight exertional dyspnea, one patient with a laryngeal malformation is decannulated but suffers from a severe exertional dyspnea, and 4 patients are still not decannulated. The voice is normal in 20 cases, a slight dysphonia is present in 17, a moderate to severe dysphonia in another 17 and 4 patients are still not decannulated.