Neonatal pulmonary hypertension--urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function.

BACKGROUND: Endogenous production of nitric oxide is vital for the decrease in pulmonary vascular resistance that normally occurs after birth. The precursor of nitric oxide is arginine, a urea-cycle intermediate. We hypothesized that low concentrations of arginine would correlate with the presence of persistent pulmonary hypertension in newborns and that the supply of this precursor would be affected by a functional polymorphism (the substitution of asparagine for threonine at position 1405 [T1405N]) in carbamoyl-phosphate synthetase, which controls the rate-limiting step of the urea cycle. METHODS: Plasma concentrations of amino acids and genotypes of the carbamoyl-phosphate synthetase variants were determined in 65 near-term neonates with respiratory distress. Plasma nitric oxide metabolites were measured in a subgroup of 10 patients. The results in infants with pulmonary hypertension, as assessed by echocardiography, were compared with those in infants without pulmonary hypertension. The frequencies of the carbamoyl-phosphate synthetase genotypes in the study population were assessed for Hardy-Weinberg equilibrium. RESULTS: As compared with infants without pulmonary hypertension, infants with pulmonary hypertension had lower mean (+/-SD) plasma concentrations of arginine (20.2+/-8.8 vs. 39.8+/-17.0 micromol per liter, P<0.001) and nitric oxide metabolites (18.8+/-12.7 vs. 47.2+/-11.2 micromol per liter, P=0.05). As compared with the general population, the infants in the study had a significantly skewed distribution of the genotypes for the carbamoyl-phosphate synthetase variants at position 1405 (P<0.005). None of the infants with pulmonary hypertension were homozygous for the T1405N polymorphism. CONCLUSIONS: Infants with persistent pulmonary hypertension have low plasma concentrations of arginine and nitric oxide metabolites. The simultaneous presence of diminished concentrations of precursors and breakdown products suggests that inadequate production of nitric oxide is involved in the pathogenesis of neonatal pulmonary hypertension. Our preliminary observations suggest that the genetically predetermined capacity of the urea cycle--in particular, the efficiency of carbamoyl-phosphate synthetase--may contribute to the availability of precursors for nitric oxide synthesis.

Partial and generalized epilepsy with febrile seizures plus and a novel SCN1A mutation.

BACKGROUND: Generalized epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant syndrome characterized by febrile seizures (FS) and a variety of afebrile generalized seizure types. GEFS+ has previously been linked to mutations in two genes encoding the voltage-gated sodium channel alpha-subunit (SCN1A) and beta1-subunit (SCN1B). We studied a large family with FS and partial as well as generalized seizure types. METHODS: All but two living affected family members were interviewed and examined. Information on deceased affected family members was sought. EEG for 11 affected family members and one unaffected family member were obtained. Genetic linkage analysis and mutation screening of SCN1A were performed on blood samples from 16 affected individuals and their first-degree relatives. RESULTS: There were 27 affected family members; 18 were alive at the time of the study. All affected family members had FS; seven had FS only, and 19 also had afebrile seizures. Eleven individuals continued to have FS beyond 6 years of age. FS were complex in 12 family members, usually with prolonged duration. The index patient had right temporal lobe epilepsy and hippocampal sclerosis. Four other patients had strong historical evidence of temporal lobe epilepsy, and three others had nonlocalizing evidence of partial epilepsy. Pedigree analysis indicated autosomal dominant transmission. All affected individuals who were tested and one asymptomatic individual had a sodium channel mutation of SCN1A, an A-->C transversion at nucleotide 3809 resulting in the substitution of lysine 1270 by threonine in the D3/S2 segment (designated as K1270T). CONCLUSIONS: Our findings indicate that partial epilepsy preceded by FS can be associated with sodium channel mutations and may represent a variant of GEFS+.

Association of the apolipoprotein E gene with age-related macular degeneration: possible effect modification by family history, age, and gender.

PURPOSE: Age-related macular degeneration (AMD) is a complex disorder affecting older adults in which genetic factors are likely to play a role. It has been previously suggested that the e4 allele of the apolipoprotein E (APOE) gene may have a protective effect on AMD risk and that the e2 allele may increase disease risk. The purpose of our study was to examine whether an independent data set would support the proposed role of APOE in AMD etiology. METHODS: We compared AMD cases (n=230) to controls (n=372) with respect to APOE genotypes using c2 tests and logistic regression analysis. We also conducted separate analyses for familial (n=129) and sporadic (n=101) AMD cases since these groups may have a different disease etiology. RESULTS: We did not find evidence for the risk-increasing effect attributed to the e2 allele in either familial or sporadic AMD. No evidence for a protective effect of the e4 allele was obtained for sporadic AMD. The age- and sex-adjusted odds ratio (OR) for e4 carriers among familial AMD cases compared to controls was 0.66 (95% confidence interval: 0.38-1.12, p=0.13). In the subgroup of individuals younger than 70 years of age, an OR of 0.24 (95% confidence interval: 0.08-0.72, p=0.004) was obtained. CONCLUSIONS: Our data modestly support a protective effect of the APOE-e4 allele on AMD risk, but emphasize the need to investigate more thoroughly whether the effect could be restricted to cases with a family history of AMD and whether it varies across age and sex groups.

Diet and risk of colon cancer in a large prospective study of older women: an analysis stratified on family history (Iowa, United States).

OBJECTIVE: The purpose was to investigate whether dietary associations with risk of colon cancer in women differ by family history of the disease. METHODS: Data were analyzed from a prospective cohort study of 35,216 Iowa (United States) women aged 55 to 69 years at baseline. Through 31 December 1995, 241 colon cancers were identified through record linkage with the State Health Registry. The cohort was stratified on family history of colon cancer in first-degree relatives; nutrient intakes were divided into tertiles. RESULTS: Analyses using Cox regression revealed that the association of most dietary components with colon cancer incidence were similar for individuals with and without a family history. However, total calcium intake was associated inversely with colon cancer among women with a negative family history (relative risk [RR] = 0.50 for upper cf lower tertile, P < 0.001), but was unrelated to incidence for women with a positive family history (RR = 1.1 for upper cf lower tertile, P = 0.69). Similarly, total vitamin E intake was associated with lower risk among women with a negative family history (RR = 0.67 for upper cf lower tertile, P = 0.04), but not among women with a positive family history (RR = 0.87 for upper cf lower tertile, P = 0.67). High intakes of fiber, fruits, and vegetables were each weakly inversely associated with risk among family-history negative women, but not among family-history positive women. CONCLUSIONS: These data, if corroborated, suggest that dietary factors typically associated with lower risk may be less effective risk-reduction interventions against colon cancer for individuals with a family history of colon cancer.

A complete genomic screen for multiple sclerosis underscores a role for the major histocompatability complex. The Multiple Sclerosis Genetics Group.

Multiple sclerosis (MS), an inflammatory autoimmune demyelinating disorder of the central nervous system, is the most common cause of acquired neurological dysfunction arising in the second to fourth decades of life. A genetic component to MS is indicated by an increased relative risk of 20-40 to siblings compared to the general population (lambda s), and an increased concordance rate in monozygotic compared to dizygotic twins. Association and/or linkage studies to candidate genes have produced many reports of significant genetic effects including those for the major histocompatability complex (MHC; particularly the HLA-DR2 allele), immunoglobulin heavy chain (IgH), T-cell receptor (TCR) and myelin basic protein (MBP) loci. With the exception of the MHC, however, these results have been difficult to replicate and/or apply beyond isolated populations. We have therefore conducted a two-stage, multi-analytical genomic screen to identify genomic regions potentially harbouring MS susceptibility genes. We genotyped 443 markers and 19 such regions were identified. These included the MHC region on 6p, the only region with a consistently reported genetic effect. However, no single locus generated overwhelming evidence of linkage. Our results suggest that a multifactorial aetiology, including both environmental and multiple genetic factors of moderate effect, is more likely than an aetiology consisting of simple mendelian disease gene(s).