Joel A. Thompson

A Role of SCN9A in Human Epilepsies, As a Cause of Febrile Seizures and As a Potential Modifier of Dravet Syndrome

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.

A locus for febrile seizures (FEB3) maps to chromosome 2q23-24.

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.

Cerebral Sinovenous Thrombosis in Children: Another Reason to Treat Iron Deficiency Anemia

Iron deficiency anemia is a rare cause of cerebral sinovenous thrombosis in children. We report three cases of cerebral sinovenous thrombosis and iron deficiency anemia treated at Primary Childrens Medical Center in Salt Lake City, Utah, between 1998 and 2001. The children were 9, 19, and 27 months old at the time of admission. Hemoglobin levels ranged from 6.6 to 7.0 g/dL, mean corpuscular volume levels from 45 to 56 fL, and platelet counts from 248,000 to 586,000/μL. Magnetic resonance imaging and magnetic resonance venography revealed thrombosis of the straight sinus and internal cerebral veins in all three children, with the addition of the vein of Galen, left transverse and sigmoid sinuses, and upper left internal jugular vein in one child. Recovery ranged from excellent to poor in 3 months to 3 years of follow-up. Four additional cases, ages 6 to 22 months, were found in the English-language literature. Evaluation for prothrombotic disorders was negative in all children, including the current cases. Treatments have included thrombectomy, corticosteroids, mannitol, heparin, low-molecular-weight heparin, warfarin, aspirin, blood transfusion, and iron supplementation, but there is no consensus regarding therapy, other than to correct the anemia and treat iron deficiency. Iron deficiency anemia, a preventable cause of cerebral sinovenous thrombosis, deserves consideration when cerebral sinovenous thrombosis is detected in young children. (J Child Neurol 2004;19:526—531).

Cardiac arrest during induction of anesthesia in Duchenne muscular dystrophy.

I. McCracken GH, and Mize SG: A controlled study of intrathecal antibiotic therapy in gram-negative enteric meningitis of infancy: Report of the Neonatal Meningitis Cooperative Study Group, J PEtm,rR 89:66, 1976. 2. Gross RJ, Rowe B. and Easton JA: Neonatal meningitis caused by Citrobacter koseri, J Clin Pathol 26:138, 1973. 3. Gwynn CM, and George RH: Neonatal citrobacter meningitis. Arch Dis Child 48:455, 1973. 4. Tamborlane WV. and Soto EV: Citrobaeter diversus meningitii: A case report, Pediatrics 55:739, 1975. 5. ttarris D, and Cone TE: Escherichia freundii meningitis: Report of two cases, J PEt~tATg 56:774, 1960. 6. Sedlak J: Present knowledge and aspects of Citrobacter, Curr Top Microbiol lmmunol 62:41, 1973. 7. Jones SR, Ragsdale AR, Kutscher E, and Sanford JP: Clinical and bacteriologic observations on a recently recognized species of Enterobacteriaceae, Citrobacter diversus, J Infect Dis 128:563, 1973. 8. Madrazo A, Geiger J, and Lauter CB: Citrobacter diversus at Grace Hospital, Detroit, Michigan, Am J Med Sci 270:497, 1975. 9. Cussen LJ, and Ryan GB: Hemorrhagic cerebral necrosis in neonatal infants with cnterbacterial meningitis, J PEDIATR 71:771, 1967. 10. Shortland-Webb WR: Proteus and coliform meningoencephalitis in neonates, J Clin Pathol 21:422, 1968. I1. Rance CP, Roy TE, Donohue WL, Sepp A, Elder R, and Finlayson M: An epidemic of septicemia with meningitis and hemorrhagic encephalitis in premature infants, J PEDIATR 61:24, 1962. 12. Hoffman H J, Hendrick EB, and ttiscox JL: Cerebral abscesses in early infancy, J Neurosurg 33:172, 1970. 13. Eberhard S J: Diagnosis of brain abscesses in infants and children: A retrospective study of twenty-six cases. NC Med J 30:301, 1969. 14. Samson DS, and Clark K: A current review of brain abscess, Am J Med 54:201, 1973.

Source analysis of generalized spike-wave complexes.

SummaryDipole source analysis was carried out in three adults and four children with 3 c/s generalized spike-wave (SW) discharges and absence seizures. Eighty-seven SW complexes were investigated. When one regional source was used the equivalent location was always near the baso-frontal area close to the midline. It explained on the average 89% of the variance in the adults and 82% in the children. When two regional sources were used and initially constrained for symmetry, the residual variance (RV) was reduced to 7% in the adults and 9% in the children. The sources remained in the frontal areas and were on the average 2 cm from the midline. When the mirror source was freed it remained contralateral in 76% of the complexes but moved ipsilaterally to various locations in the rest. To reduce the RV to between 2 and 3% one or two additional regional sources were required. These were located in the temporal or parietal areas in the adults and occasionally one occipital region in the children. The study showed that widespread and repetitive EEG events, like the generalized SW, can lend themselves to spatio-temporal multiple dipole modeling. More precise anatomic correlates may become possible with an expanded electrode array and the verification of their locations against the patients MRI scan.

Infant botulism in the age of botulism immune globulin

Infant botulism causes acute bulbar dysfunction, weakness, and respiratory failure in infants living in endemic regions of the United States. Until Food and Drug Administration approval of botulism immune globulin (BIG) in October 2003, management of infant botulism had changed little since the 1970s. Currently, IV therapy with BIG is advised to shorten the duration and diminish the potential complications of the disorder. This review describes two decades of experience with infant botulism and provides a contemporary perspective on the role and benefit of BIG.

Ischemic Stroke in the Young: Evaluation and Age Comparison of Patients Six Months to Thirty-nine Years

Ischemic stroke in the young is uncommon, but we currently evaluate at least one young stroke patient at our institutions each week. We undertook this chart review of strokes in patients between the ages of 6 months and 39 years to review all conditions associated with, and thus possibly contributory to, the stroke. We also compare younger and older age groups to observe if age-dependent factors exist. Of 100 total ischemic strokes, 22 were in persons 6 months to 18 years and 78 were in persons 19 to 39 years. Seventy-five percent of strokes were associated with a condition known or postulated to increase stroke risk. Some of these conditions are well accepted as causes for stroke, such as some forms of heart disease, whereas others are only postulated, such as the hypercoagulable states. Taken as a whole, associated conditions were approximately equally divided between infectious/inflammatory, structural, and presumed hypercoagulable conditions. Strokes in the first two decades of life were more commonly associated with infectious/inflammatory conditions, whereas strokes in the next two decades more commonly had structural or presumed hypercoagulable associated conditions. Since many strokes remain unexplained, it would be valuable to determine the significance, if any, of conditions less well known as risk factors for stroke. (J Child Neurol 1993;8:266-270).

Favorably skewed X-inactivation accounts for neurological sparing in female carriers of Menkes disease

Desai V, Donsante A, Swoboda KJ, Martensen M, Thompson J, Kaler SG. Favorably skewed X‐inactivation accounts for neurological sparing in female carriers of Menkes disease.

CT scans in Menkes disease

The clinical courses and serial computerized tomography (CT) scans of four patients with Menkes disease are described. Although the initial clinical presentations were similar, head growth and serial CT scans showed striking individual differences. The CT scans varied from showing no abnormalities early in the disease to showing diffuse cortical atrophy, subdural accumulation of fluid, or multifocal areas of ischemic infarction. The pathologic findings in one patient showed only cerebral and cerebellar atrophy, whereas the findings in another patient showed areas of ischemic infarction, probably secondary to abnormal vessels. Menkes disease should be suspected in male infants with psychomotor deterioration and seizures, or when trauma is suspected from subdural hematoma and multiple fractures.

Salicylate Poisoning Complicated by Fluid Retention

We have presented two cases of salicylate poisoning that demonstrate fluid retention in the face of adequate hydration, resembling the syndrome of inappropriate secretion of ADH. These cases necessitated marked alterations from normal fluid therapy. Mannitol was found to be an effective, albeit transient, diuretic for treating the acute symptoms associated with fluid retention, but only strict fluid restriction resulted in a prompt and satisfactory diuresis.