Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch).

Human hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), an autosomal dominant form of cerebral amyloid angiopathy (CAA), is characterized by extensive amyloid deposition in the small leptomeningeal arteries and cortical arterioles, which lead to an early death of those afflicted in their fifth or sixth decade. Immunohistochemical and biochemical studies have indicated that the amyloid subunit in HCHWA-D is antigenically related to and homologous in sequence with the amyloid beta protein isolated from brains of patients with Alzheimer's disease and Down syndrome. The amyloid beta protein is encoded by the amyloid beta protein precursor (APP) gene located on chromosome 21. Restriction fragment length polymorphisms detected by the APP gene were used to examine whether this gene is a candidate for the genetic defect in HCHWA-D. The data indicate that the APP gene is tightly linked to HCHWA-D and therefore, in contrast to familial Alzheimer's disease, cannot be excluded as the site of mutation in HCHWA-D.

Predictive testing of 25 percent at-risk individuals for Huntington disease (1987-1997).

Before the mutation causing Huntington disease was identified, predictive testing of 25% at-risk persons with a 50% at-risk parent who did not wish to know his/her genetic status, was only possible by exclusion testing. The exclusion test, using linked markers, ensures the parent's wish not to know because the parent's risk is not changed. When mutation analysis became available in 1993, new testing options for 25% at-risk persons emerged: viz., the exclusion-definitive test and direct mutation analysis. These new tests not only disclose the risk of the test candidate, but may also change the risk of the at-risk parent and siblings. The testing options for 25% at-risk test applicants and their consequences are discussed and the testing procedures and results of testing 64 25% at-risk persons in the period 1987 to 1997 are described. Relatives received unsought information in 56% of the test procedures before and 34% after the mutation was identified. A decision tree and guidelines for predictive testing of 25% at-risk test applicants are proposed. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:662-668, 1999.

Using a roster and haplotyping is useful in risk assessment for persons with intermediate and reduced penetrance alleles in Huntington disease.

The risk of a person having a child with an inherited disorder, caused by an unstable triplet repeat, such as Huntington disease (HD), depends on the expansion of the mutation in that person, which is connected both to the biological nature of the mutation and to the person's relation to the carrier of the full mutation. Once the mutation causing HD was identified, we were able to diagnose sporadic patients. A sporadic patient can sometimes be connected to a known HD pedigree by using a roster. By haplotyping and calculating the posterior identity-by-descent probability, we could establish whether a connection was coincidental or not. Furthermore, we describe the frequency of intermediate and reduced penetrance alleles detected. Using the family history and the roster to search for a connection, we examined whether these alleles were on the HD haplotype of a family. It is important to know the origin of an intermediate or reduced penetrance allele because if it comes from an HD branch of the family or from the non-HD affected side of the pedigree, different risks for relatives and penetrance ensue. In our study, most intermediate alleles came from the non-HD-affected side of the pedigree and had a repeat size in the lower range with a negligible risk for expansion. Intermediate alleles on the HD haplotypes were larger and found in predictive test applicants from known families or relatives from new mutations with a higher risk for expansion. Reduced penetrance alleles in the higher range were mainly found in symptomatic and predictive test applicants from known families, with a considerable risk for penetrance, although at older age. We conclude that a roster, a thorough family history, and haplotyping in persons with intermediate and reduced penetrance alleles are essential in considering the risk of a person having (a child with) HD.

Presymptomatic DNA testing for Huntington disease: identifying the need for psychological intervention.

UNLABELLED: In the Dutch presymptomatic DNA-testing program for Huntington disease (HD), 29 individuals with increased risk and 44 with decreased risk were followed-up 6 months after test results. A prognostic model was built aimed at identifying individuals at risk for psychological maladjustment, as measured by the Impact of Event Scale, the Beck Hopelessness Scale, the General Health Questionnaire, and the Social Support Questionnaire. RESULTS: 1) The more that applicants suffered from intrusive feelings about HD and tried to avoid HD-related situations, prior to the test, the greater the chance that they will experience this 6 months after the test if they proved to be at increased risk; 2) the more that both individuals with increased risk and those with decreased risk who suffered from the threat of having HD tried to avoid HD-related situations prior to the test and the less satisfied they were with available support, the greater the probability that they will show avoidance behavior after the test; 3) the more pessimistic that individuals with increased risk as well as those with decreased risk were about their future prior to the test, the more they avoided HD-related situations and the more dissatisfied they were about their available support (pretest), the greater the probability that they will become depressive and suicidal. Psychological adjustment was also studied as a function of a) intrusion/denial-avoidance pattern over time and b) healthy mental functioning/future expectancies. Most individuals with increased risk (86%) seem to cope well thus far, although this was based largely on strong psychological defenses and dependent on satisfactory relationships.(ABSTRACT TRUNCATED AT 250 WORDS)

Presymptomatic, prenatal, and exclusion testing for Huntington disease using seven closely linked DNA markers.

Presymptomatic, testing, prenatal diagnosis, or exclusion testing are now available for persons at risk for Huntington disease. These tests will reduce uncertainty, assist in life planning, and prevent the birth of potentially affected children. We present the results of presymptomatic tests for 37 applicants including two prenatal and one exclusion test in 23 families. We initially used the markers G8, H5.52, F5.53, and pTV20 (D4S10), p8 (D4S62), and pRB1.6 (D4S81) and extended the informativity of the test at a later stage with the markers pKP1.65, C4H, S1.5 (D4S43), 674 (D4S95), 157.9 (D4S111), and YNZ32 (D4S125). Applicants with an unsuitable family structure were not admitted to the test. Of the 37 applicants, 33 were informative. In our hands the most efficient strategy is first to use the markers H5.52 (D4S10), pRB1.6 (D4S81), 674 (D4S95), pKP1.65 (D4S43), 157.9 (D4S111), YNZ32 (D4S125), and 252.3 (D4S115). The overall informativity in our data set was 84% and in the most recent test we achieved a 90-95% informativity. The other markers are used only when the first set is not informative.

Presymptomatic DNA-testing for Huntington disease: pretest attitudes and expectations of applicants and their partners in the Dutch program.

We studied the baseline attitudes, prior to testing, of 70 applicants at risk for Huntington disease (HD) and their partners in the Dutch presymptomatic DNA-testing program. Two thirds of the applicants were female; 36% already had children. The main reason (60%) for undertaking the test was for family planning. Other reasons were either to reduce uncertainty (43%) or to obtain certainty (38%). Partners of applicants stated that planning for the future was for them the most important reason (76%). Significantly more at-risk females (42%) than males (16%) anticipated an unfavorable test outcome. Quite remarkably, most applicants and partners denied that a positive result might have adverse effects on either personal mood, quality of life, or marriage. Only a few did not expect that a favorable result would induce relief. The eventual outcome of the test was expected to enable applicants to gain control over their future, whatever the results. Hence, we propose that the applicants form a self-selected group, based on their expectation that they will not be emotionally affected by either result.

DNA-testing for Huntington's disease in The Netherlands: a retrospective study on psychosocial effects.

Presymptomatic DNA-testing for Huntington's disease has made it possible to predict whether or not at-risk individuals are gene-carriers with a reliability of about 98%. In our retrospective study of 18 tested individuals, most of the newly identified carriers function apparently well. They use avoidance and repression of affect as psychological defense strategies. However, 8 out of 9 non-carriers do not experience the expected relief about their test results. They experience survivor guilt and emotional numbness and find it difficult to cope with the effects of the test results on the family system. The partners of gene-carriers are at risk of becoming emotionally isolated by putting aside their own feelings for fear of seeming self-centered. Appreciation of these effects on tested individuals is important and professional support is needed to prevent post-traumatic stress disorders. Whatever the test result may be, the working through process may take years rather than months. These findings have important implications for patient care and necessitate an extended period of observation after presymptomatic testing.

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 Alzheimer's disease and Down's 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 Alzheimer's fibrillary tangles in any of our cases.

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 Huntington's 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.

Juvenile Huntington disease in the Netherlands.

Juvenile Huntington disease (JHD) patients are distinguished from adult patients by an age at onset of less than 20 years. Investigating patients in our own database, we examined the proposition derived from studies in world literature that JHD should not be viewed as a separate clinical entity but rather as a manifestation of the rigid variant of the disease. Of 53 patients with JHD recorded in the Leiden Roster for Huntington Disease, relationships between sex, age at onset, duration of illness, maternal or paternal inheritance, motor symptom, first clinical features, and characteristics during the disease course, were obtained from the patients' files, and investigated. Although chorea is present in JHD, patients more often developed rigidity. Paternal inheritance, early dementia, epilepsy/myoclonus, and tremor during the disease course are confined for the most part to the rigid cases. A shorter duration of illness was evident in male patients with rigid JHD who inherited the disease from their father and developed their first disease feature at a younger age. The recognition of JHD as a distinct clinical entity does not appear to be warranted. Therefore, we propose, in accordance with other investigators, that rigid JHD be considered a clinical variant with special features.

[Procedure and initial results of presymptomatic DNA studies in Huntington's chorea]. / Procedure en eerste resultaten van presymptomatisch DNA-onderzoek bij de chorea van Huntington.

The availability of DNA-markers more tightly linked to the Huntington's disease locus made presymptomatic and exclusion testing possible with an accuracy of up to 98%. The testing programme started in Leiden in August 1987. In 56 adults with 25% and 50% risks presymptomatic tests were performed. In 8 persons the risk was increased to 98%, in 17 it was decreased to less than 5%. In two instances the test was not informative. The remaining 29 persons have not yet been tested for different reasons. So far 3 exclusion tests were requested: one showed a decreased risk, one has not yet been performed and one request was rejected. The results and the reactions to the test are discussed.

[Presymptomatic DNA diagnosis in Huntington's chorea: reactions to the certainty of not being a genetic carrier]. / Presymptomatische DNA-diagnostiek bij de chorea van Huntington: reacties op de zekerheid niet-gendrager te zijn.

Presymptomatic DNA diagnostics in Huntington's chorea make it possible to establish with approx. 98% certainty whether an at-risk person is a gene carrier. Sympathy and care are usually shown to those demonstrated to have the gene and so will become affected in the future. Persons shown not to be carriers sometimes do not experience the expected relief. The authors successively discuss the effects of a favourable finding on the family system, such as survivor's guilt and emotional numbing as aspects of a coping process. It is concluded that even a favourable finding needs to be worked through, a process that takes years rather than months.

Parental transmission in Huntington's disease.

There have been reports that juvenile onset Huntington's chorea is almost always inherited from the father, and that late-onset Huntington's chorea is inherited more often from the mother than from the father. In this larger survey of the parental transmission of disease in Huntington chorea 12 of 13 patients whose symptoms began before the age of 10 years had inherited the disease from the father. However, the 205 patients with late-onset disease (those who had lived up to at least the age of 65) were as likely to have inherited their disease from their father as from their mother.

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

For 1100 patients with Huntington's 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 Huntington's 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 years remains between affected fathers and their affected children. This is explainable by the observation that juvenile cases of Huntington's Chorea usually have inherited the abnormality from their father.

Paradox of a better test for Huntington's disease.

OBJECTIVES: To describe the consequences of the identification of the Huntington's 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 Huntington's 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.

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 Huntington's 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 Huntington's 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.

Psychological effects of presymptomatic DNA testing for Huntington's disease in the Dutch program.

This study assessed the 6-month follow-up effects of presymptomatic DNA testing for Huntington's disease (HD) in 73 individuals at 50% prior risk who were identified either as carriers of the HD gene (N = 29) or as noncarriers (N = 44). The subject's knowledge of being a gene carrier was expected to induce intrusive emotions, denial-avoidance behavior, and pessimistic expectancies of the future and adjustment problems. The Impact of Event Scale, the Beck Hopelessness Scale, and the General Health Questionnaire were used as standard measures of psychological distress. At the disclosure of the test results, carriers had a strong increase in pessimistic expectations but showed a decline to baseline levels 6 months later. Noncarriers reported a steep decline in hopelessness compared with their pretest conditions but had increased scores after 6 months. Six months after the disclosure of the test results, both gene carriers and noncarriers reported a significant decrease in unwanted intrusive thoughts about HD. Carriers showed a slight increase in denial-avoidance behavior, whereas noncarriers showed a clear decrease. Our observations might indicate that tested individuals found relief from the prior psychological distress and that they were able to acknowledge the impact of the test result on their future. An unresolved question is how the foreknowledge will affect carriers as they approach the impending onset of the disease. Longer observation periods (> 6 months after disclosure) are required to study changes of the impact of DNA test results over time.