A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy.

Familial exudative vitreoretinopathy (FEVR) is a hereditary disorder characterized by an abnormality of the peripheral retina. Both autosomal dominant (adFEVR) and X-linked (XLFEVR) forms have been described, but the biochemical defect(s) underlying the symptoms are unknown. Molecular analysis of the Norrie gene locus (NDP) in a four generation FEVR family (shown previously to exhibit linkage to the X-chromosome markers DXS228 and MAOA (Xp11.4-p11.3)) reveals a missense mutation in the highly conserved region of the NDP gene, which caused a neutral amino acid substitution (Leu124Phe), was detected in all of the affected males, but not in the unaffected family members, nor in normal controls. The observations suggest that phenotypes of both XLFEVR and Norrie disease can result from mutations in the same gene.

Large-scale analysis of gene expression changes during acute and chronic exposure to [Delta]9-THC in rats.

Large-scale cDNA microarrays were employed to assess transient changes in gene expression levels following acute and chronic exposure to cannabinoids in rats. A total of 24,456 cDNA clones were randomly selected from a rat brain cDNA library, amplified by PCR, and arrayed at high density to investigate differential gene expression profiles following acute (24 h), intermediate (7 days), and chronic (21 days) exposure to Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the psychoactive ingredient of marijuana. Hippocampal mRNA probes labeled with (33)P obtained from both vehicle and Delta(9)-THC-treated animals were hybridized with identical cDNA microarrays. Results revealed a total of 49 different genes altered by Delta(9)-THC exposure; of these, 28 were identified, 10 had homologies to expressed sequence tags (ESTs), and 11 had no homology to known sequences in the GenBank database. Chronic or acute cannabinoid receptor activation altered expression of several genes (i.e., prostaglandin D synthase, calmodulin) involved in biochemical cascades of cannabinoid synthesis or cannabinoid effector systems. Other genes [i.e., neural cell adhesion molecule (NCAM), myelin basic protein], whose relation to cannabinoid system function was not immediately obvious, were also significantly altered. Verification of the changes obtained with the large-scale screen was determined by RNA dot blots in different groups of animals treated the same as those in the large-scale screen. Results are discussed in terms of the different types of genes affected at different times during chronic Delta(9)-THC exposure.

A five-year prospective study of the health of children in different ethnic groups, with particular reference to the effect of inbreeding.

A 5-year prospective study of 4,934 children of different ethnic groups has demonstrated a 3-fold increase of postneonatal mortality and childhood morbidity in the offspring of consanguineous Pakistani parents. Most of these families contained more than one consanguineous union, resulting in a mean inbreeding coefficient for their children of 0.0686. It is estimated that 60% of the mortality and severe morbidity of this group of children could be eliminated if inbreeding ceased. However consanguinity is much favoured in this minority group, and health education will have to be carefully and sensitively handled.

Population incidence and segregation ratios in the Martin-Bell syndrome.

A clinical and cytogenetic study of children attending schools for the educationally handicapped has been carried out in the City of Coventry. As a result of this an estimate of the population incidence of the Martin-Bell syndrome among schoolchildren has been made. Among school-boys the incidence of mental retardation due to the fra (X) was found to be 0.73 per 1000 and among schoolgirls 0.48 per 1000. The overall prevalence is 0.61 per 1000. Genetic and cytogenetic analysis of 14 families ascertained in an unbiased manner showed that the expected 50% ratio of affected to unaffected relatives was disturbed, the possible result of a segregation distortion.

Uses and limitations of twin studies.

Series of twin pairs selected because one (or both) is ill are prone to biassed ascertainment, and great care has to be taken to avoid this. Such bias is absent if the primary source is a twin registry established at birth. In general, series of twin pairs have no advantage over studies on sibs in assessing the size of genetic contribution to disease. However, individual monozygotic twin pairs who are discordant for single gene or multifactorial conditions offer unique opportunities for investigating postzygotic mutations, for searching for factors that may precipitate disease or influence its course, and for assessing the effect of prophylactic measures.

Race, consanguinity and social features in Birmingham babies: a basis for prospective study.

STUDY OBJECTIVE: The aim of the study was to investigate the influence of consanguinity on children's health. DESIGN: The study is a prospective survey from birth to five years of a cohort of babies born in a multiracial community. This report details the initial findings on consanguinity. SETTING: Participating families live predominantly in three health districts of Birmingham, and were recruited in three local maternity hospitals. PARTICIPANTS: Babies of 2432 European mothers, 509 Afro-Caribbean mothers, 625 Indian mothers, 956 Pakistani mothers, and 216 Bangladeshi mothers have been enrolled in the study. Eighty mothers refused to participate. MEASUREMENTS AND RESULTS: Sociodemographic information was obtained using a structured questionnaire administered at interview. Interview data were supplemented with obstetric information from the medical records. The highest prevalence of parental consanguinity was in Pakistani Muslims (69%), whereas in Muslims from other countries it was 23%, and it was less than 1% in non-Muslims. In the majority of consanguineous Muslim pedigrees the degree of inbreeding was greater than that for first cousin parents. CONCLUSIONS: This prospective study will allow an assessment to be made about any ill health in childhood arising from parental consanguinity, about whether screening programmes are indicated for particular autosomal recessive diseases, and about whether premarital health education might be beneficial. The study has also documented parental ages in different races and this, together with the levels of parental consanguinity in all races, will be useful in genetic methods for assessing the frequency of recessive genes, the possibility of genetic heterogeneity, and whether or not parental age effect exists for new mutations of specific genetic disorders.

Usher syndrome in the city of Birmingham--prevalence and clinical classification.

AIMS: To estimate the prevalence of Usher syndrome in the city of Birmingham, and to establish a database of patients who have been classified into different clinical subtypes essential for future gene mutation analysis. METHODS: Symptomatic cases of Usher syndrome (US) resident in the city of Birmingham in June 1994 were ascertained through multiple sources. Ophthalmic and audiological reassessment together with examination of medical records and patient questionnaires allowed classification of three subtypes, US 1, US 2, and US 3. In addition, family pedigrees were examined and blood was taken from index patients for DNA extraction. RESULTS: In the population aged over 15 years the prevalence was 6.2 per 100 000 population for all US subtypes. The prevalence for US 1 and US 2 was 5.3 per 100 000 population. This is greater than previously reported. In the age group 30-49 years the prevalence approached 1 in 10 000. Clinical classification found 33% US 1, 47% US 2, and 20% US 3. CONCLUSION: This higher prevalence rate and greater frequency of US 2 and US 3 may reflect a more complete ascertainment.

X linked exudative vitreoretinopathy: clinical features and genetic linkage analysis.

A four generation family in which familial exudative vitreoretinopathy is inherited as an X linked condition is described. Essentially the condition is one of abnormal vascularisation and signs at birth are those of a retinopathy superficially resembling retinopathy of prematurity, retinal folds, or, in advanced cases, enophthalmos or even phthisis. Prognosis depends on the progression of the retinal changes. The family members, including seven affected males and five obligate carrier females, have been types for 20 DNA markers, and linkage analysis suggests a gene locus either at Xq21.3 or at Xp11. As the latter region includes the locus for the gene for Norrie disease, it is possible that this and X linked vitreoretinopathy are allelic. We can further speculate that the differences in severity of the clinical manifestations are dependent only upon the timing of the insult.

Clinical and genetic features of ataxia-telangiectasia.

There are several variants of ataxia-telangiectasia (A-T): classical A-T with marked radiation sensitivity; classical A-T with intermediate levels of radiation sensitivity; mild A-T with intermediate levels of radiation sensitivity; A-T without telangiectasia; A-T without oculomotor apraxia; and A-T with microcephaly. These disorders are probably caused by different allelic mutations, because affected sibs resemble the index patients, and because there is an association of certain haplotypes of 11q22-23 with specific phenotypes. The Nijmegen Breakage Syndrome, with its lack of ataxia, seems on clinical grounds to be a different disorder. Although A-T is almost always inherited as an autosomal recessive, there are some unusual features; an unexpectedly low parental consanguinity rate, an incidence in sibs that is < 0.25, and occurrence of disease in many different races and in the offspring of mixed race unions. Moreover, looking at haplotypes from 63 UK patients, there is a remarkably low incidence of homozygosity. An autosomal recessive condition that is deficient in parental consanguinity, and in homozygosity for the region around the gene, can be explained by J. H. Edwards' hypothesis that homozygosity for alleles at a neighbouring locus are lethal early in embryogenesis. Other possible mechanisms to explain the unusual genetic features are discussed.

Large electroencephalographic responses and their relationship to cleido-cranial dysplasia.

We have reported six individuals (five certain heterozygotes for cleido-cranial-dysostosis and one possible heterozygote) who have unusual EEG findings, consisting of very large responses to photic flash stimulation at very low stimulus rates. Such visual responses are extremely rare and have not been seen before in the experience of an EEG department over 12 years and they were not seen in 98 control subjects. It is likely that these responses are an irregular manifestation of the gene for cleido-cranial-dysplasia, and that the responses are independent of skull deformity. One importance of these responses is their demonstration in neurologically normal individuals for previously such large responses have only been reported in association with neurolipidosis. They may have neurophysiological significance in that they may reflect an unusual balance between inhibitory and excitatory mechanisms in the nervous system.

Ten years experience of a genetic eye clinic: 1978-1987.

Over a ten year period of running a joint ophthalmological/genetic clinic, 387 index patients were advised, and a further 260 individuals (relatives of the above) were examined and counselled. Determination of the precise diagnoses and modes of inheritance in the index patients necessitated retinal function tests in 267 (69%) and examination of 84 of their parents and 23 sisters and daughters. Finally, 41% of index patients and 39% of their relatives were given high risks for transmitting an autosomal dominant or X-linked disorder to their children. It is noteworthy that 16% of these high-risk index patients and 66% of these high-risk relatives had no visual symptoms; ophthalmological expertise was required to assess the significance of their minor signs. It was concluded that an active Register is required for contacting relatives outside the nuclear family, and for future recall of children currently too young for carrier tests or genetic counselling.