Genetics of epilepsy: epilepsy research foundation workshop report.

The Sixth Epilepsy Research Foundation workshop, held in Oxford in March 2006, brought together basic scientists, geneticists, epidemiologists, statisticians, pharmacologists and clinicians to consider progress, issues and strategies for harnessing genetics to improve the understanding and treatment of the epilepsies. General principles were considered, including the fundamental importance of clear study design, adequate patient numbers, defi ned phenotypes, robust statistical data handling, and follow-up of genetic discoveries. Topics where some progress had been made were considered including chromosomal abnormalities, neurodevelopment, hippocampal sclerosis, juvenile myoclonic epilepsy, focal cortical dysplasia and pharmacogenetics. The ethical aspects of epilepsy genetics were reviewed. Principles and limitations of collaboration were discussed. Presentations and their matched discussions are produced here. There was optimism that further genetic research in epilepsy was not only feasible, but might lead to improvements in the lives of people with epilepsy.     

Alagille syndrome: family studies.

Alagille syndrome (AGS) is one of the major forms of chronic liver disease in childhood with severe morbidity and a mortality of 10 to 20%. It is characterised by cholestasis of variable severity with paucity of interlobular bile ducts and anomalies of the cardiovascular system, skeleton, eyes, and face. Previous studies suggest a wide variation in the expression of the disease and a high incidence of new mutations. To determine more accurately the rate of new mutations and to develop criteria for detecting the disorder in parents we systematically investigated parents in 14 families with an affected child. Clinical examination was supplemented by liver function tests, echocardiography, radiographic examination of the spine and forearm, ophthalmological assessment, and chromosome analysis. Six parents had typical anomalies in two or more systems pointing to the presence of autosomal dominant inheritance. Systematic screening of parents for the features defined in this study should improve the accuracy of genetic counselling.     

E(f)-current contributes to whole-cell calcium current in low calcium in frog sympathetic neurons

Because Ca(2+) plays diverse roles in intracellular signaling in neurons, several types of calcium channels are employed to control Ca(2+) influx in these cells. Our experiments focus on resolving the paradox of why whole-cell current has not been observed under typical recording conditions for one type of calcium channel that is highly expressed in frog sympathetic neurons. These channels, referred to as E(f)-channels, are present in the membrane at a density greater than the channels that carry approximately 90% of whole-cell current in low Ba(2+); but, E(f)-current has not been detected in low Ba(2+). Using Ca(2+) instead of Ba(2+) as the charge carrier, we recorded a possible E-type current in frog sympathetic neurons. The current was resistant to specific blockers of N-, L-, and P/Q-type calcium channels but was more sensitive to Ni(2+) block than was N- or L-current. Current amplitude in Ca(2+) is slightly greater than that in Ba(2+). In 3 mM Ca(2+), the current contributed approximately 12% of total current at peak voltage and increased at voltages more hyperpolarized to the peak, reaching approximately 40% at -30 mV, where whole-cell current starts to activate. The presence of E(f)-current in 3 mM Ca(2+) suggests a potential role for E(f)-channels in regulating calcium influx into sympathetic neurons.     

The Place of Percutaneous Cholangiography in Managing the Jaundiced Patient

Percutaneous transhepatic cholangiography proved a valuable procedure in managing 40 adults with unexplained jaundice. The procedure aids in identifying the site of extrahepatic biliary obstruction and the state of the biliary tree. It is safe and reliable when done by an experienced radiologist under the proper conditions.     

Management of hepatic coma complicating viral hepatitis

The treatment is described of 17 patients with presumed viral hepatitis who developed hepatic coma unresponsive to standard conservative measures. Five patients were considered for treatment by exchange transfusion. Four were treated, with transient improvement in two, but all died. Nine patients were considered for treatment by heterologous liver perfusion. Six were treated, with transient improvement in two and complete recovery in one. The last patient remains well 12 months later. Dialysis in four patients had no effect on the coma; the addition of albumin to the dialysate did not increase the extraction of bilirubin.The clinical course in most cases was irregular. Complications were common, the most important being cerebral oedema with medullary coning, bleeding, bacterial infection, hypoglycaemia, and pancreatitis.Heterologous liver perfusion was the most efficient method of removing bilirubin. However, it is not yet clear whether it is more effective than exchange transfusion in the treatment of the patient.     

Functional Assessment of TSC2 Variants Identified in Individuals with Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in the TSC1 or TSC2 genes. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 (TORC1). Here, we investigate the effects of 78 TSC2 variants identified in individuals suspected of TSC, on the function of the TSC1–TSC2 complex. According to our functional assessment, 40 variants disrupted the TSC1–TSC2‐dependent inhibition of TORC1. We classified 34 of these as pathogenic, three as probably pathogenic and three as possibly pathogenic. In one case, a likely effect on splicing as well as an effect on function was noted. In 15 cases, our functional assessment did not agree with the predictions of the SIFT amino acid substitution analysis software. Our data support the notion that different, nonterminating TSC2 mutations can have distinct effects on TSC1–TSC2 function, and therefore, on TSC pathology.     

A new Nav1.7 sodium channel mutation I234T in a child with severe pain

Dominant gain‐of‐function mutations that hyperpolarize activation of the Na_v1.7 sodium channel have been linked to inherited erythromelalgia (IEM), a disorder characterized by severe pain and redness in the feet and hands in response to mild warmth. Pharmacotherapy remains largely ineffective for IEM patients with cooling and avoidance of triggers being the most reliable methods to relieve pain. We now report a 5 year old patient with pain precipitated by warmth, together with redness in her hands and feet. Her pain episodes were first reported at 12 months, and by the age of 15–16 months were triggered by sitting as well as heat. Pain has been severe, inducing self‐mutilation, with limited relief from drug treatment. Our analysis of the patient's genomic DNA identified a novel Na_v1.7 mutation which replaces isoleucine 234 by threonine (I234T) within domain I/S4–S5 linker. Whole‐cell voltage‐clamp analysis shows a I234T‐induced shift of −18 mV in the voltage‐dependence of activation, accelerated time‐to‐peak, slowed deactivation and enhanced responses to slow ramp depolarizations, together with a −21 mV shift in the voltage‐dependence of slow‐inactivation. Our data show that I234T induces the largest activation shift for Na_v1.7 mutations reported thus far. Although enhanced slow‐inactivation may attenuate the gain‐of‐function of the I234T mutation, the shift in activation appears to be dominant, and is consistent with the severe pain symptoms reported in this patient.