Novel COL4A2 variant in a large pedigree: Consequences and dilemmas.

Pathogenic COL4A2 variants cause abnormalities in collagen production and can have serious implications for a range of organ systems, most notably the brain. Herein, we describe a large family of first-degree relatives affected by a novel heterozygous variant in COL4A2 (c.3490G.A). A wide disease spectrum is described, from asymptomatic to symptomatic, including 2 children with porencephaly and co-existing juvenile idiopathic polyarthritis. During a subsequent pregnancy, antenatal testing identified a positive fetus. In view of the literature, we review management and genetic counselling dilemmas.

NAPB - a novel SNARE-associated protein for early-onset epileptic encephalopathy.

Next-generation sequencing has accelerated the identification of disease genes in many rare genetic disorders including early-onset epileptic encephalopathies (EOEEs). While many of these disorders are caused by neuronal channelopathies, the role of synaptic and related neuronal proteins are increasingly being described. Here, we report a 6-year-old girl with unexplained EOEE characterized by multifocal seizures and profound global developmental delay. Recessive inheritance was considered due to parental consanguinity and Irish Traveller descent. Exome sequencing was performed. Variant prioritization identified a homozygous nonsense variant in the N-ethylmaleimide-sensitive factor attachment protein, beta (NAPB) gene resulting in a premature stop codon and 46% loss of the protein. NAPB plays a role in soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE)-complex dissociation and recycling (synaptic vesicle docking). Knockout mouse models of the murine ortholog Napb have been previously reported. These mice develop recurrent post-natal epileptic seizures in the absence of structural brain changes. The identification of a disease-causing variant in NAPB further recognizes the importance of the SNARE complex in the development of epilepsy and suggests that this gene should be considered in patients with unexplained EOEE.

The Bhutani Nomogram Reduces Incidence of Severe Hyperbilirubinaemia in Term and Near Term Infants.

Very high bilirubin levels can have devastating neurodevelopmental effects on infants including hearing loss and cerebral palsy. A previous study in our institution determined the rate of, and factors associated with, bilirubin values above exchange transfusion level. Since this study the Bhutani nomogram was introduced to help identify infants at risk of severe hyperbilirubinaemia. In our study we looked at the initial serum bilirubin taken in infants 36 weeks and 2.5 kgs. Our results show that since this nomogram was introduced there has been a significant reduction in the number of infants reaching exchange transfusion levels. We also showed that the Bhutani nomogram could successfully be used in a population of unknown direct Coombs status.

Is neonatal group B streptococcal infection preventable?

Early onset group B streptococcal (EOGBS) infection causes significant neonatal morbidity and mortality. We determined the incidence of EOGBS at Galway University Hospital (GUH) and examined any "missed opportunities" for preventing neonatal infection between 2004 and 2009. Our obstetric approach is risk-based. The incidence was 0.45/1,000 live-births; one death and one with neurological sequelae. A single mother received IAP; however we could not determine any potential for reducing cases of EOGBS by improving current IAP usage.

Initial assessment of jaundice in otherwise healthy infants--a comparison of methods in two postnatal units.

Transcutaneous bilirubin (TcB) has the potential to reduce total serum bilirubin (TS) sampling. The principal aim of this study was to determine and compare the number of initial TSB samples (TSBs) in two postnatal units (hospitals A & B) whereby hospital A used TcB and hospital B did not. A secondary aim was to determine the clinical factors that led to initial TSBs exceeding exchange transfusion level in both hospitals. Results demonstrated both hospitals had similar populations and patient numbers following selection criteria. 1645 neonates (10.4%) had one or more TSBs performed in hospital A, versus 2373 neonates (15.1%) in hospital B (p < 0.01). Fourteen neonates in hospital A and 3 neonates in hospital B had initial TSBs above exchange transfusion level. For neonates with TSBs above exchange, preventable factors related to earlier testing and follow up. In routine clinical practice, TcB is associated with a significantly reduced number of TSB measurements. TSB levels above exchange transfusion are linked to preventable factors, in otherwise healthy neonates.

Severe hyperbilirubinaemia and kernicterus: more caution is needed in newborn jaundice surveillance.

Since the 1990s, there has been a re-emergence of cases of severe hyperbilirubinaemia and kernicterus. The current UK incidence of bilirubin encephalopathy is 0.9/100,000 with a higher reported incidence in some countries. Three otherwise healthy newborn infants, who presented with severe hyperbilirubinaemia, including one who developed kernicterus, are reported here. Some of the current challenges in newborn jaundice surveillance are highlighted.

Screening for haemoglobinopathy--a comparison of two methods in an Irish maternity unit.

Two-pronged retrospective and prospective studies were carried out to compare opportunistic versus systematic screening for carriers of haemoglobinopathy in an Irish maternity unit. Identification was either performed opportunistically on the basis of ethnicity or systematically on the basis of a low mean corpuscular haemoglobin. A comparison was made between the numbers that were tested for haemoglobinopathy and subsequent detection rates. In the prospective study women were identified again on the basis of either ethnicity or a low MCH and all women identified were tested for haemoglobin variants. A comparison was made between the numbers tested and subsequent detection rates. In both studies systematic screening identified similar rates as opportunistic screening. However, opportunistic screening identified a greater absolute number of carriers. Our retrospective study showed a disappointing uptake of testing of those identified, regardless of the method of screening. Better identification of carriers requires that all those identified as at-risk of haemoglobinopathy carriage should be tested, irrespective of the method of screening.

Relationship between serum quinidine concentration and quinidine dosage.

This retrospective study was designed to identify and assess which patient-specific factors affect the relationship between the steady-state trough serum quinidine concentration (SQC) measured by fluorescence polarization immunoassay and quinidine dosage. Data were obtained from 100 hospitalized patients (72 males, 28 females) receiving quinidine for atrial or ventricular arrhythmias, or both, between ages 24 and 85 years (mean age 63 yrs). Age, lean body weight, creatinine clearance (ClCr), and sex were statistically significant factors affecting this relationship; ejection fraction, total body weight, smoking history, alcohol history, recent myocardial infarction, recent surgery, elevated liver function tests, and sampling time were not statistically significant. The ClCr alone provided the most additional information in predicting SQC, and ClCr and weight provided the most additional information in predicting dosage. Currently in clinical practice, quinidine dosage adjustments are not routinely recommended for patients with renal insufficiency. These data suggest that the calculated ClCr is important in predicting both SQC and dosage when a nonspecific quinidine assay is used. This dosing model must be evaluated prospectively.

Spiculopteragia spiculoptera and S. asymmetrica (Nematoda: Trichostrongyloidea) from red deer (Cervus elaphus) in Texas.

Specimens of Spiculopteragia spiculoptera and S. asymmetrica were recovered from the abomasa of five of ten naturally infected red deer (Cervus elaphus) in Texas (USA). Female specimens of Spiculopteragia were present in all five animals. Male specimens of S. spiculoptera and S. asymmetrica were present in one of five and three of five red deer, respectively. Spiculopteragia spiculoptera has not previously been recognized in the United States and the present report constitutes the first records of Spiculopteragia spp. in red deer from North America. It is likely that species of Spiculopteragia have been introduced to North America with the import of exotic cervids on several occasions. Focal populations of these nematodes have been established in North America; however, distribution of the parasites likely coincides with areas of residence of introduced populations of red deer and fallow deer (Cervus dama) in the Nearctic.

Treatment of digitalis intoxication with emphasis on the clinical use of digoxin immune Fab.

Many studies and cases of digitalis intoxication have been reported since the time of William Withering's first publication in 1785. Recognition and management of digitalis toxicity is challenging. Before digoxin immune Fab was commercially available, treatment consisted of managing the signs and symptoms of toxicity until the digitalis was eliminated. Digoxin immune Fab offers a safe, effective, and specific method of quickly reversing digitalis toxicity. Factors that must be considered with the clinical use of this agent include the dosage calculation, administration technique, postdose monitoring, pharmacokinetics, mechanism of action, interference with commercially available digoxin assays, partial neutralizing dosing, rebound of free digoxin, and indications for use. For severe, life-threatening toxicity, digoxin immune Fab is the treatment of choice.

Clinical and pharmacokinetic profiles of digoxin immune Fab in four patients with renal impairment.

Minimal pharmacokinetic data on digoxin immune Fab are currently available, especially in patients with impaired renal function. The serum concentration-time profiles of total digoxin, free digoxin, and digoxin immune Fab in four patients with moderate to severe renal impairment who received digoxin immune Fab are presented. The calculated elimination half-life of digoxin immune Fab was 25-73 hours. The calculated elimination half-life of total digoxin was 24-72 hours. Free digoxin concentrations rebounded to a peak of 1-2.9 ng/mL 44-97 hours after the administration of digoxin immune Fab. The areas under the curve for digoxin immune Fab were 213-1026 micrograms.h/mL, and total body clearances were 2.3-7.1 mL/min. The total digoxin concentrations peaked at 14-33 times the pre-Fab digoxin concentrations 5-30 hours after digoxin immune Fab administration. In comparing these data with data available from patients with normal renal function, the half-life of digoxin immune Fab and total digoxin was longer, the peak total digoxin concentration occurred later, the ratio of the peak total digoxin concentration to pre-Fab digoxin concentration was larger, and the rebound in free digoxin occurred later in patients with renal impairment. The Fab dose should not be reduced in patients with renal impairment; however, post-Fab monitoring should be extended to compensate for the prolonged half-life of Fab and later rebound of free digoxin.