M. Vegter-Van Der Vlis

Hereditary cerebral haemorrhage caused by cortical amyloid angiopathy

This article describes 136 patients with hereditary cerebral haemorrhages; all patients belonged to families (originally) resident in Katwijk (The Netherlands). Cases of hereditary cerebral haemorrhage have also been reported in NW-Iceland, and in the Dutch coastal village of Scheveningen. Katwijk is a Dutch fishing-village, located 20 miles north of Scheveningen. These 136 cases were encompassed in three large pedigrees, and the disorder followed an autosomal dominant mode of inheritance. No connection between the pedigrees from Iceland, Scheveningen and Katwijk has as yet been established. In our series, sclerosis with amyloid deposits could be observed in roughly a quarter of the small arteries and arterioles in the cerebral cortex and the covering arachnoid. The pathological vessels were irregularly distributed in areas and clusters, possibly leading to superficial cerebral infarcts and, secondarily, to haemorrhages. Our findings are identical with those described in patients from Scheveningen, but different from the Icelandic group. In addition to some differences in the age at onset and in the distribution of the angiopathy, it has recently been demonstrated that the amyloid in our patients is constituted by a microprotein which shows a homology to the beta-protein in Alzheimers disease and Downs syndrome, while the amyloid in Icelandic cases is formed by an aggregation of cystatin C (gamma trace). An unexpected finding in most of our patients is the accumulation of senile plaque-like lesions in the cerebral cortex. We did not observe Alzheimers fibrillary tangles in any of our cases.

Duration of illness in Huntington's disease is not related to age at onset.

The age at onset and duration of illness were studied in patients with Huntingtons disease in the Leiden Roster which at 1 July 1990 contained 2787 patients. Of 1106 patients, 800 deceased and 306 alive, the age at onset was known. The median duration was 16.2 (range 2-45) years. In contrast to the current opinion, the median duration was independent of the age of onset. The median duration in juvenile Huntingtons disease was 17.1 years, which is much longer than reported in the literature, and comparable with the categories for the age of onset of 20-34 and 35-49 years. Only in the group where onset was over 50 years of age was the median duration somewhat shorter (15.6 years), which can be ascribed to unrelated causes of death. As age of onset and duration of illness are not related, at least two mechanisms to determine the clinical course have to be postulated: one for age of onset and another for duration of illness. Duration was shorter for males, especially for those with an affected father.

Paradox of a better test for Huntington's disease

OBJECTIVES To describe the consequences of the identification of the Huntingtons disease (HD) mutation on predictive and prenatal testing. METHODS A retrospective study was performed considering the test applicants, procedures, and results before and after the identification of the mutation. 1032 people at risk for Huntingtons disease in The Netherlands were included, of whom 741 applied for the predictive test in the period 1987 to 1997 in Leiden at the Department of Clinical Genetics, and after 1994, also in the other seven clinical genetics departments in The Netherlands. Uptake, sociodemographic variables, and test results, taken before and after the mutation was identified, are described. RESULTS The uptake of the predictive test in the period studied was 24% and for the prenatal test 2%. No differences were noted in numbers and sociodemographic data between the period before and after the mutation was identified. After an initial increase in test applicants, a decrease was seen after 1995. After 1993 a significant increase of 25% at risk test applicants and a significant decrease of prenatal exclusion tests was noticed. Only 7% asked for reassessment by mutation analysis. New problems arose after the identification of the mutation, such as the option of reassessing the risk obtained by linkage analysis, direct mutation testing of 25% at risk persons with a parent who does not wish to know, new choices regarding reproduction, and new uncertainties for carriers of intermediate and reduced penetrance alleles and for their offspring and relatives. CONCLUSIONS Although predictive testing has become reliable and available for every person at risk since the mutation has been identified, the uptake of predictive and prenatal tests fell short of expectation, no change in sociodemographic variables was seen, and a decrease in number of applicants was noted. Furthermore, new uncertainties, psychological problems, and questions arose.

Oculomotor defects in patients with Huntington's disease and their offspring

We recorded saccadic, pursuit and fixation eye movements in patients (n = 5) with moderately advanced Huntingtons disease (HD), offspring of HD patients (n = 22) and control subjects (n = 15), using the scleral sensor coil technique. Saccadic slowing was seen in all patients, no controls and (marginally) in a few at-risk subjects. Fixational stability was lower in patients than in the other groups; a structured background enhanced the difference and revealed decreased stability in a number of at-risk subjects. Smooth pursuit showed large errors in most patients and several controls but none of the at-risk subjects. Sporadic follow-up data show that at least two of the at-risk subjects developed manifest HD within a few years after passing the oculomotor test with entirely normal results. The material as a whole suggests that oculomotor dysfunction does not develop prior to, but concurrently with and as a part of generalized, progressive deterioration of motor control. The implication is that oculomotor screening of clinically healthy at-risk subjects does not reliably contribute to an earlier diagnosis of future HD.

Huntington's Chorea in the Netherlands The problem of genetic heterogeneity

For 1100 patients with Huntingtons Chorea in 102 families from The Netherlands the average age at death per family is presented. This average ranges from 72 to 38 years. An analysis of variance of the data is strongly indicative of genetic heterogeneity. For the patients with the relatively high age at death little or no difference is observed from the age at death of their non‐affected parents and non‐affected sibs. Eleven children who presented with the juvenile form of the disease had all inherited the abnormal gene from their father. These 11 children were found only in families with an average age at death below 57 years. Other factors that might possibly influence the variation of average age at death between families are discussed, but cannot explain the observed differences.

Ages of death of children with Huntington's Chorea and of their affected parents

Bird et al. (1974) noted an interesting ‘anticipation’ phenomenon in Huntingtons Chorea occurring in patients who inherited the gene from their father. More extensive samples from 165 pedigrees in the Low Countries permitted us to show that most of this apparent ‘anticipation’ is an artifact due to sampling biases related to the year of birth categories of the affected parents. When these biases were excluded no differences exist between the ages of death of affected mothers and their affected children, but a small difference of approximately two ymrs remains between affected fathers and their affected children. This is explainable by the observation that juvenile cases of Huntingtons Chorea usually have inherited the abnormality from their father.