Complex segregation analysis of autism.

A complex segregation analysis of autism in 185 Utah families was carried out using the mixed model. The 209 affected individuals in these families represent nearly complete ascertainment of the autistic cases born in Utah between 1965 and 1984. The sibling recurrence risk for autism was 4.5% (95% confidence limits 2.8%-6.2%). Likelihoods were maximized for major-gene models, a polygenic model, a sibling-effect model, and a mixed model consisting of major-gene and shared-sibling effects. The analysis provided no evidence for major-locus inheritance of autism. Subdivision of the sample according to the probands' IQ levels showed that sibling recurrence risk did not vary consistently with IQ level. A segregation analysis of families in which the proband had an IQ less than 50 also failed to provide evidence for a major locus. However, because of the etiologic heterogeneity of this disorder, genetic analysis of other meaningful subsets of families could prove informative.     

Occult pneumococcal bacteraemia and febrile convulsions.

Over two years 29 children had bacteraemia due to Streptococcus pneumoniae at this hospital. In 15 previously healthy children the site of infection could not be identified, and in most of them, bacteraemia was not suspected clinically. All 15 had high total white cell (greater than or equal to 17 x 10(9)/1) and neutrophil (greater than or equal to 11 x 10(9)/1) counts. Twelve children were under 4 years of age, and of these, 10 had been admitted because of a simple febrile convulsion and one had a prolonged febrile convulsion. Occult pneumococcal bacteraemia has been reported in the USA for more than 10 years, but no series has been reported from the United Kingdom. Occult pneumococcal bacteraemia may be an important cause of febrile convulsions. Persisting bacteraemia and the development of focal infections, including pneumococcal meningitis, have been reported. Meningitis did not occur after occult bacteraemia in our patients. Studies to date have been retrospective, and thus the true incidence of the complications and the best treatment are not clear. A prospective study of children with febrile convulsions could provide answers.     

Failure of phenobarbitone to prevent febrile convulsions.

One-hundred-sixty-five children without known neurological disorder who presented with their first febrile convulsion between the ages of six months and three years were assigned to daily phenobarbitone treatment or to a control group and followed up at a special clinic for six months. One-hundred-and-sixty-one-one children completed the trial, and of the 88 children assigned to phenobarbitone treatment 10 had further convulsions during this period compared with 14 of the 73 control children. Only 49 of those assigned to phenobarbitone took the drug regularly throughout the trial, and four of these had further febrile convulsions, a proportion not significantly different from that in the controls. All four had mean plasma phenobarbitone concentrations over 69 mumol/l (16 mug/ml) during the trial and in three the plasma concentration was at or over this figure within eight hours over 69 mumol/l (16 mug/ml) during the trial and in three the plasma concentration was at or over this figure within eight hours of the repeat convulsion. Regular phenobarbitone does not seem to prevent febrile convulsions. Attention should instead be directed to organising emergency services to allow early termination of fevrile convulsions, whether first or subsequent, to prevent irreversible brain damage.     

Genetic aspects of febrile convulsions

Summary A total of 6706 children 3 years of age (3491 boys, 3215 girls) in a particular geographical area in Fuchu (population approximately 182 000), Tokyo, was investigated. Some 654 children (9.8%; 10.5% for male, 9.0% for female) had had at least one convulsion, and the incidence of febrile convulsions was 6.7% (7.2% for male, 6.2% for female). The 450 FC children with febrile convulsions and 620 randomly selected control children were analyzed on the mode of inheritance.The incidence of the disease among siblings was 21.9% (29.7% after age correction), which rose greatly with increasing numbers of affected family members, and the segregation ratio among siblings was higher (36.5%) with one FC parent, and lower (18.5%) if neither parent had had a seizure. The more severe the illness in FC children, the larger the incidence among siblings.Population and family studies indicated that heredity plays an important role in febrile convulsions and that multifactorial inheritance is most likely.     

Complex segregation analysis of hypospadias

Hypospadias, when the urethra opens on the ventral side of the penis, is a common malformation seen in about 3 per 1000 male births. It is considered a complex disorder with both genetic and environmental factors involved in the pathogenesis. Low birth weight is known to be an important risk factor for hypospadias, but several observations speak in favour of genetic factors as well. In order to delineate the relative contribution of the genetic factors behind hypospadias, we performed a complex segregation analysis of 2005 pedigrees in Sweden. The probands were ascertained through the departments of paediatric surgery and departments of plastic surgery and urology in Sweden where boys with hypospadias undergo surgery. In 7% of the ascertained families one or more additional cases of hypospadias were present. The complex segregation analysis showed a heritability of 0.99 and evidence for multifactorial inheritance. The results suggest that hypospadias might be due to monogenic effects in a small proportion of the families, but that there is a multifactorial cause for the majority of the cases.     

Genetic analysis of febrile convulsions: twin and family studies

Summary Thirty-two twin pairs and 673 sibship-cases with febrile convulsions (FC) were studied. Twin study: (1) The pairwise concordance rate for FC was 56% (10/18 pairs) in monozygotic and 14% (2/14 pairs) in dizygotic twins (P<0.05). (2) Intra-pair similarity of clinical symptoms in concordant twin pairs was greater than that in sibship-cases. Sibship-pair study (population): (3) In sibship-pair study a large positive correlation of some clinical symptoms — in particular, age at onset of FC, exogenous factors, and degree of fever (P<0.001 for each) — was indicated. (4) Compared with FC children with no family history, those with such family history had a higher frequency of age at onset between 8 and 19 months, exogenous factors, low degree of fever before onset of convulsions, many recurrences, and recurrence after age 3 (P<0.01–0.001 for each). (5) Morbidity risk among near relatives was highest in first-degree relatives (16%) than in second (4.0%) or third-degree relatives (4.1%). The following differences were found: siblings (24%)>parents (12%), uncles (4.5%)>aunts (3.5%), male cousins (4.4%)>female cousins (3.8%). Segregation ratio, influence by affection of father or mother, and maternal preponderance were analysed. (6) Similar findings were also observed in the clinic study. (7) A multifactorial mode of inheritance for FC receives some support from this study, and the heritability was estimated to be 75% in the population study. The results may be useful for genetic counselling for FC.     

A microwave-hyperthermia model of febrile convulsions

While convulsions associated with fever represent a serious problem in pediatric medicine, conventional animal models of febrile convulsions suffer numerous technical limitations. A microwave-hyperthermia model that eliminates these problems was tested. Microwave energy was used to increase the core temperature of 13- and 17-day-old rats, resulting in convulsions similar to febrile convulsions in human infants. Rats were irradiated for 10 min in circularly polarized waveguides at 918 MHz, CW (average SAR = 9.4 W/kg at 13 days and 18.0 W/kg at 17 days as determined by twin-well calorimetry). Day 17 irradiated rats were less susceptible to convulsions than were day 13 irradiated rats, indicating an age-dependent decline in susceptibility. Contrary to findings of earlier models using infrared or hot-oven heating, convulsions induced with microwave hyperthermia impaired neither brain growth nor subsequent performance during behavioral testing. Simultaneous measurement of brain and rectal temperatures during microwave irradiation revealed differential heating rates that favor thermal homeostasis in brain tissue.     

Complex segregation analysis of diabetes mellitus

Complex segregation analysis was applied to a sample of 12,293 nuclear families each with at least 1 diabetic patient. The families were divided into two groups depending on the proband's treatment: insulin-dependent (IDG) and insulin-independent (IIG). Heterogeneity analysis has revealed a highly significant difference in the IIG group when families were divided into different mating types. The higher recurrence risk was found in the group with affected mothers. Also evidence for a major recessive gene was found in the IGG group, while it was not possible to distinguish between the hypothesis for absence of a major locus and absence of polygenic inheritance in the IDG group. Risks to develop the disease were calculated for a few typical situations.     

Complex segregation analysis of nonsyndromic cleft lip and palate.

This study was undertaken to examine the inheritance pattern of nonsyndromic cleft lip with or without cleft palate (CL/P). Complex segregation analysis using the unified model as in POINTER and the regressive model as in REGD programs were applied to analyze a midwestern U.S. Caucasian population of 79 families ascertained through a proband with CL/F. In REGD, the dominant or codominant Mendelian major locus models of inheritance were the most parsimonious fit. In POINTER, besides the Mendelian major locus model, the multifactorial threshold (MF/T) model and the mixed model were also consistent with the observed data. However, the high heritability parameter of .93 (SD .063) in the MF/T model suggests that any random exogenous factors are unlikely to be the underlying mechanisms, and the mixed model indicates that this high heritability is accounted for by a major dominant locus component. These findings indicate that the best explanation for the etiology of CL/P in this study population is a putative major locus associated with markedly decreased penetrance. Molecular studies may provide further insight into the genetic mechanism underlying CL/P.     

Complex segregation analysis of dental morphological variants

A set of 20 morphological variants of the dental crowns and four characteristics of the jaws are tested for probable mode of inheritance using the complex segregation analysis method of Morton et al. (Am. J. Hum. Genet. 23:602-611, 1971). Models tested include three two-allele single-locus models (dominant, codominant, and recessive) and a model employing the polychotomized normal distribution of liability (an additive polygenic model), with transmissibility estimated via maximum likelihood. Most of the traits studied are observed using ordinal scales with several grades, and many are tested using more than one dichotomy of their scale. These multiple analyses allow for an examination of such factors as trait incidence on the results of the statistical analysis. The results of the analysis yield propositions of major genes for 13 of the 24 traits examined. Two traits give good evidence of being polygenic in origin. The remaining nine characters present methodological problems that do not allow for a definite conclusion on their mode of inheritance at this time. The ability to test varying levels of transmissibility in the polygenic model allows for an estimation of the percentage of trait variance determined by familial factors. Estimates of transmissibility for all characters examined range from 0 to 1, with a mean of 0.36. These findings may suggest a large environmental role in the development of dental crown morphology. However, the possibility exists that difficulties in the ability to classify the expression of certain traits consistently result in overestimates of the environmental influences on the development of those characters.     

Primary immunisation and febrile convulsions in Oxford 1972-5.

A three-year study of febrile convulsions in Oxford with comprehensive notification from general practice and hospitals showed a 3% risk for all children of suffering at least one febrile convulsion by the age of 5 years. Children were most at risk between 6 and 27 months, and febrile convulsions were most likely to be prolonged in children aged 9-15 months. The association between febrile convulsions and primary immunisations in the preceding 28 days was compared in case and control children, matched for age and sex. Results suggested that such association was a chance relationship with age. If association was direct, the febrile convulsion rates per 1000 immunisation doses were estimated as follows: diphtheria, pertussis, tetanus--0-09 per 1000; poliomyelitis--0-6 per 1000; and measles--0-9 per 1000. Hence if any of these vaccines had a secific causal relationship with febrile convulsions, these rates would probably have been much higher.     

Successful prophylaxis against febrile convulsions with valproic acid or phenobarbitone.

A total of 184 six-month periods were analysed during which feverish illnesses occurred in children aged 6-42 months with a history of a febrile convulsion. Fits occurred in 34 out of 100 such periods when no treatment was being given, in six out of 45 periods when the serum phenobarbitone concentration was 69.0 mumol/l (1.6 mg/100 ml) or more, and in five out of 39 periods when the plasma valproic acid concentration was 416.4 mumol/l (6.0 mg/100 ml) or more. Thus in adequate dosage both phenobarbitone and valproic acid were significantly better than no treatment in preventing febrile convulsions (p less than 0.02). The two drugs were of comparable efficacy. It is concluded that with improved compliance valproic acid, which is relatively free from side effects, might be an effective prophylactic agent against febrile convulsions.     

Complex segregation analysis of tongue pigmentation. A search for residual family resemblance

Complex segregation analysis of tongue pigmentation in 493 nuclear families fails to indicate significant evidence for incomplete recessivity, polygenic variation, or an effect of sibship environment, thus establishing simple Mendelian inheritance for the trait.