Norman C. Nevin

The epidemiology of Huntington's disease in Northern Ireland.

A survey of Huntingtons disease (HD) in Northern Ireland, with a population of 1.5 million, has shown a 1991 prevalence rate of 6.4/100,000. Virtually complete ascertainment was achieved, enabling prevalence rate estimates and age statistics to be calculated over the last 20 years. The prevalence rate is similar to the high prevalence rates of HD found in most European populations, suggesting the presence of either one extremely ancient or a number of separate mutational origins, resulting in a uniform European HD prevalence. The ages at diagnosis and duration of the disease are similar to previous studies, suggesting a consistent effect of the HD gene in all families. Estimates of heterozygote frequency (HF), direct and indirect mutation rate, fertility, and genetic fitness (W) were made. Reliable HF estimates gave values between 10 and 11 x 10(-5). The direct and indirect mutation rates were 0.32 x 10(-6) and 1.05 x 10(-6) respectively. W was increased in the affected HD population but decreased in the at risk population. Fertility in HD is not reduced, but it appears that at risk patients have actively limited their family size. Factors responsible include, among others, the fear of developing HD and genetic counselling of families. This is the first published epidemiological survey to include ascertainment data in a population both before and after isolation of the HD gene, and with the diagnosis in virtually all patients confirmed by DNA mutation testing.

Guidelines for follow-up of women at high risk for inherited breast cancer: consensus statement from the Biomed 2 Demonstration Programme on Inherited Breast Cancer.

Protocols for activity aiming at early diagnosis and treatment of inherited breast or breast-ovarian cancer have been reported. Available reports on outcome of such programmes are considered here. It is concluded that the ongoing activities should continue with minor modifications. Direct evidence of a survival benefit from breast and ovarian screening is not yet available. On the basis of expert opinion and preliminary results from intervention programmes indicating good detection rates for early breast cancers and 5-year survival concordant with early diagnosis, we propose that women at high risk for inherited breast cancer be offered genetic counselling, education in ‘breast awareness’ and annual mammography and clinical expert examination from around 30 years of age. Mammography every second year may be sufficient from 60 years on. BRCA1 mutation carriers may benefit from more frequent examinations and cancer risk may be reduced by oophorectomy before 40–50 years of age. We strongly advocate that all activities should be organized as multicentre studies subjected to continuous evaluation to measure the effects of the interventions on long-term mortality, to match management options more precisely to individual risks and to prepare the ground for studies on chemoprevention.

Idiopathic intestinal pseudo-obstruction: A familial visceral neuropathy

Four individuals with idiopathic intestinal pseudo‐obstruction (IIP), a familial visceral neuropathy with autosomal dominant inheritance, are presented. The disorder is characterised by abdominal colic, abdominal distension and diarrhoea, and is of a progressive nature with relapses and remissions. The main feature is a disturbance of motility in the affected intestine, with histological evidence of a neuronal disorder, characterised by hyperplasia and eventual atrophy. Management of the condition is difficult; initially, treatment should be conservative by nasogastric suction with intravenous nutrition. When laparotomy is undertaken to exclude mechanical obstruction, resection of the intestine is inadvisable, and ileocolic anastomosis may be beneficial.

Tumour necrosis factor microsatellites show association with multiple sclerosis

The TNF alpha and beta genes are located between the class I and class III HLA loci and have been implicated in the pathogenesis of multiple sclerosis. We carried out allelic association analysis using four microsatellite markers localised within a 20 kb region around the TNF genes. The study was performed on DNA samples from 189 clinically definite MS patients and 206 normal controls, all of Northern Irish origin. The allele distributions for the TNFa and b markers were significantly different between the MS patients and controls (P = 0.014, df 8 and 0.0019, df 4, respectively). The difference could largely be attributed to increases in the TNFa 118 bp allele and the TNFb 127 bp allele in MS patients, with a conserved MS associated haplotype (130:118:127 TNF d:a:b). Of the 19 patients homozygous for this haplotype, 17 were HLA typed and results suggested that the TNF haplotype association can occur independently of inheritance of DR2. Transmission disequilibrium testing (TDT) also supported the TNFa 118 bp association. These results suggest that in this population TNF is possibly one of the genetic factors contributing to MS susceptibility.

Aglossia-adactylia syndrome.

Aglossia-adactylia is described in two male patients, aged 31 and 21 years old. Including a previous reported case (Nevin, Dodge, and Kernohan, 1970) there are three patients with this syndrome in Northern Ireland. The aetiology is unknown but in spite of the extreme variability of the clinical manifestation, a dominant mutant gene cannot be ruled out.

Phenylketonuria and the peoples of Northern Ireland

Abstract The comparison of regional patterns of recessive disease mutations is a new source of information for studies of population genetics. The analysis of phenylketonuria (PKU) mutations in Northern Ireland shows that most major episodes of immigration have left a record in the modern genepool. The mutation I65T can be traced to the Palaeolithic people of western Europe who, in the Mesolithic period, first colonised Ireland. R408W (on haplotype 1) in contrast, the most common Irish PKU mutation, may have been prevalent in the Neolithic farmers who settled in Ireland after 4500 BC. No mutation was identified that could represent European Celtic populations, supporting the view that the adoption of Celtic culture and language in Ireland did not involve major migration from the continent. Several less common mutations can be traced to the Norwegian Atlantic coast and were probably introduced into Ireland by Vikings. This indicates that PKU has not been brought to Norway from the British Isles, as was previously argued. The rarity in Northern Ireland of IVS12nt1, the most common mutation in Denmark and England, indicates that the English colonialisation of Ireland did not alter the local genepool in a direction that could be described as Anglo-Saxon. Our results show that the culture and language of a population can be independent of its genetic heritage, and give some insight into the history of the peoples of Northern Ireland.

Influence of Social Class on the Risk of Recurrence of Anencephalus and Spina Bifida

This study suggests that social class has an effect on the incidence of anencephalus and spina bifida, the malformations being more frequent in the lower socio‐economic groups. A family study of 226 patients with a CNS malformation suggests that social class also may be important in détérmining the recurrence risk of such malformations: there are higher risks in social classes III, IV and V than in social classes I and II.

Melorheostosis in a family with autosomal dominant osteopoikilosis

We describe a 19-year-old woman with melorheostosis and osteopoikilosis (mixed sclerosing bone dysplasia). Her sister and mother had osteopoikilosis, but no evidence of melorheostosis. Isolated melorheostosis and melorheostosis with osteopoikilosis are sporadic disorders. Osteopoikilosis is an autosomal dominant trait. Mixed sclerosing bone dysplasia in a family with autosomal dominant osteopoikilosis raises the possibility that the two bone disorders may be related. This family and that of Butkus et al. [1997: Am J Med Genet 72:43-46] suggest that the melorheostosis could be due to a second mutation at the same locus as that which causes autosomal dominant osteopoikilosis.

A novel single base deletion in the LDLR gene (211delG): Effect on serum lipid profiles and the influence of other genetic polymorphisms in the ACE, APOE and APOB genes.

A single base deletion (211delG) in the low density lipoprotein receptor (LDLR) gene was shown to cause familial hypercholesterolaemia (FH) in a large family from Northern Ireland. Twenty-four of 52 family members tested had this mutation, 13 of which were newly diagnosed. Mutation-positive individuals had significantly higher mean total-cholesterol (TC) and LDL-cholesterol (LDL-C) than those without 211delG. LDL-C was a more accurate indicator of disease status than TC. When TC levels alone were considered, in individuals over 16 years, a false negative rate (TC < 7.5 mmol/l) of 40% was found; however this fell to 13% based on inclusion of LDL-C levels. Individuals with coronary artery disease (CAD) had significantly higher TC levels than those without CAD and tended to have tendinous xanthomas (TX) and corneal arcus (CA). Generic polymorphisms in the angiotensin converting enzyme (ACE) and apolipoprotein (apo) B genes did not appear to be associated with lipid levels or with the clinical severity of the disease; however, the apo E epsilon4 allele did show a lipid-raising effect in individuals with the mutation.

Ullrich-Turner syndrome : Seven pregnancies in an apparent 45,X woman

A 37-year-old woman was referred for genetic counseling after termination of her probable seventh pregnancy. Ultrasound examination at 13 weeks of gestation had shown a fetus with bilateral cystic hygromas. A transabdominal amniocentesis confirmed 45,X karyotype in the fetus. The patient had marked short stature and a 45,X chromosome constitution in blood lymphocytes. Subsequently she had a hysterectomy and oophorectomy. Tissue of representative sites of the pathological specimen showed a 45,X chromosome constitution. However, molecular analysis of 8 sites from the uterus and ovaries, and of skin fibroblasts with X-chromosome microsatellites showed the presence of only one allele, except for the microsatellite DXS996 which demonstrated 2 alleles (155 bp and 161 bp) in ovarian tissue. The lymphocytes from the mother and her only son demonstrated the same single allele (161 bp). We conclude that molecular analysis of lymphocytes and of tissue is necessary for detecting low-level mosaicism in apparently homogeneous 45,X women.