Genetic aspects of von Hippel-Lindau (VHL) disease were studied in familial and isolated cases. Complex segregation analysis with pointers was performed in 38 kindreds with two or more affected members. Dominant inheritance with almost complete penetrance in the highest age classes (0*96 at 51 to 60 and 0.99 at 61 to 70 years) was confirmed and there was no evidence of heterogeneity between families ascertained through complete and incomplete selection. The point prevalence of heterozygotes in East Anglia was 1-89/100 000 (1/53 000) persons with an estimated birth incidence of 2-73/100 000 (1/36 000) live births. Reproductive fitness was 0-83. Direct and indirect estimates of the mutation rate were 4-4 (95% CI 0-9 to 7-9)x ie/gene/generation and 2*32x 10t6/gene/generation respectively. There was no significant association between parental age or birth order and new mutations for VHL disease.Von Hippel-Lindau disease (McKusick 19330) is an inherited cancer syndrome with variable expression. The most frequent complications are haemangioblastomas of the retina and central nervous system, renal cell carcinoma, phaeochromocytoma, and renal, pancreatic, and epididymal cysts. '-Following early

The familial occurrence and mode of inheritance were analysed in families with migraine without aura (MO) and migraine with aura (MA). The probands were found among 4000 persons from the general population. All persons with MA were included as probands, and an equivalent number of probands with MO was selected as a random sample among those with MO. Spouses and first-degree relatives were blindly interviewed. All interviews were performed by one neurological research fellow. The distinct familial patterns indicate that MO and MA have a different aetiology. Compared with the general population, the first-degree relatives of probands with MO had a 1.9-fold increased risk of MO while spouses had a 1.5-fold increased risk of MO, indicating that both genetic and environmental factors are important in MO. The first-degree relatives of probands with MA had a four-fold increased risk of MA while spouses had no increased risk of MA, indicating that MA is determined largely by genetic factors. The complex segregation analysis indicated that both MO and MA have multifactorial inheritance without generational difference.

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We investigated the familial occurrence of cluster headache in 370 probands with cluster headache, diagnosed according to the operational diagnostic criteria of the international Headache Society. Seven probands belonged to three families. A positive family history of cluster headache was found in 7% (25 of 366) of the families. Compared with the general population, the first- and second-degree relatives of the 370 probands with cluster headache had a 14- and 2-fold increased risk of having cluster headache, after standardization for sex and age. This increased familial risk strongly suggests that cluster headache has a genetic cause. The patterns of segregation were assessed by complex segregation analysis performed with the computer program, POINTER. The segregation analysis suggests that cluster headache has an autosomal dominant gene with a penetrance of 0.30 to 0.34 in males and 0.17 to 0.21 in females. The gene is present in 3% to 4% of males and 7% to 10% of females with cluster headache.