Congenital indifference to pain (CIP) is a rare condition in which patients have severely impaired pain perception, but are otherwise essentially normal. We identified and collected DNA from individuals from nine families of seven different nationalities in which the affected individuals meet the diagnostic criteria for CIP. Using homozygosity mapping and haplotype sharing methods, we narrowed the CIP locus to chromosome 2q24-q31, a region known to contain a cluster of voltage-gated sodium channel genes. From these prioritized candidate sodium channels, we identified 10 mutations in the SCN9A gene encoding the sodium channel protein Nav1.7. The mutations completely co-segregated with the disease phenotype, and nine of these SCN9A mutations resulted in truncation and loss-of-function of the Nav1.7 channel. These genetic data further support the evidence that Nav1.7 plays an essential role in mediating pain in humans, and that SCN9A mutations identified in multiple different populations underlie CIP.

We describe an outbreak of acute rheumatic fever that occurred in the intermountain area centered in Salt Lake City, Utah. Seventy-four children meeting the modified Jones criteria for the diagnosis of acute rheumatic fever were evaluated by the staff at Primary Children's Medical Center, Salt Lake City, from January 1985 through June 1986. This represents an eightfold increase over the average annual incidence at this hospital during the past decade. Carditis, a dominant feature of the outbreak, was confirmed by auscultation in 53 of the patients (72 percent). An additional 14 patients were found to have mitral regurgitation by Doppler ultrasound examination, raising the total incidence of carditis to 91 percent. The children were predominantly from white (96 percent) middle-class families with above-average incomes and with ready access to medical care. There was no apparent increase in the incidence of streptococcal disease or other explanation for the marked increase in acute rheumatic fever. However, mucoid M type 18 and M type 3 group A streptococcal strains were isolated from several siblings of the patients and from schoolchildren (chosen at random) in the area. We conclude that acute rheumatic fever remains an important health problem in the United States.

A follow-up study of a large Utah family with significant linkage to chromosome 2q24 led us to identify a new febrile seizure (FS) gene, SCN9A encoding Nav1.7. In 21 affected members, we uncovered a potential mutation in a highly conserved amino acid, p.N641Y, in the large cytoplasmic loop between transmembrane domains I and II that was absent from 586 ethnically matched population control chromosomes. To establish a functional role for this mutation in seizure susceptibility, we introduced the orthologous mutation into the murine Scn9a ortholog using targeted homologous recombination. Compared to wild-type mice, homozygous Scn9a N641Y/N641Y knockin mice exhibit significantly reduced thresholds to electrically induced clonic and tonic-clonic seizures, and increased corneal kindling acquisition rates. Together, these data strongly support the SCN9A p.N641Y mutation as disease-causing in this family. To confirm the role of SCN9A in FS, we analyzed a collection of 92 unrelated FS patients and identified additional highly conserved Nav1.7 missense variants in 5% of the patients. After one of these children with FS later developed Dravet syndrome (severe myoclonic epilepsy of infancy), we sequenced the SCN1A gene, a gene known to be associated with Dravet syndrome, and identified a heterozygous frameshift mutation. Subsequent analysis of 109 Dravet syndrome patients yielded nine Nav1.7 missense variants (8% of the patients), all in highly conserved amino acids. Six of these Dravet syndrome patients with SCN9A missense variants also harbored either missense or splice site SCN1A mutations and three had no SCN1A mutations. This study provides evidence for a role of SCN9A in human epilepsies, both as a cause of FS and as a partner with SCN1A mutations.

Febrile seizures are the most common form of childhood seizures, occurring in 2% to 5% of North American children. We report a large Utah family with 21 members affected by febrile seizures inherited as an autosomal dominant trait. All had generalized tonic–clonic seizures with onset associated with fever, consistent with the consensus febrile seizure phenotype, and none had febrile seizures beyond 6 years of age. Eighteen affected individuals had recurrent febrile seizures. Eight individuals developed afebrile seizures between ages 5 and 13 years. Afebrile seizures consisted of generalized tonic–clonic, generalized tonic, generalized atonic, simple partial, and partial complex seizure types and were associated with abnormal electroencephalographic findings in 5 individuals, all of whom were intellectually normal. We undertook linkage analysis in this family, defining the disease phenotype as febrile seizures alone. Linkage analysis in epilepsy candidate gene/loci regions failed to show evidence for linkage to febrile seizures. However, a genomewide scan and subsequent fine mapping revealed significant evidence for a new febrile seizure locus (FEB3) on chromosome 2q23‐24 with linkage to the marker D2S2330 (LOD score 8.08 at θ = 0.001). Haplotype analysis defined a critical 10‐cM region between markers D2S141 and D2S2345 that contains the FEB3 locus.

One hundred and eight survivors of trauma attending a stress clinic were assessed on measures of coping, personality, control expectancies and psychological distress. The psychometric characteristics of these questionnaires are discussed, and the relationships between them investigated using correlational and regression techniques. Although cross-sectional studies can only be indicative, it would appear that most coping strategies, and particularly escape-avoidance, are consistently associated with high psychological distress, with the exception of positive reappraisal and distancing, which are the only strategies associated with better psychological outcome. It may be that deeply distressed survivors cannot find effective ways of obtaining relief, and therefore report many ways of trying to cope.