Cohort study of patients with adrenal lesions discovered incidentally.

BACKGROUND: This prospective cohort study investigated the incidence, clinical features and natural history of incidentally discovered adrenal mass lesions (adrenal incidentaloma, AI) in an unselected population undergoing radiological examination. METHODS: During an 18-month period, all patients with AI were reported prospectively from all 19 radiology departments in western Sweden. Inclusion criteria were: incidentally discovered adrenal enlargement or mass lesion in patients without extra-adrenal malignancy on detection. Clinical and biochemical evaluation was performed on inclusion and after 24 months. Computed tomography (CT) of the adrenals was scheduled at 4, 12 and 24 months. Magnetic resonance imaging was performed for lesions larger than 20 mm. The indications for surgical excision were: hormone activity, lesion diameter more than 30 mm, lesion growth or other radiological features suspicious of malignancy. RESULTS: Of 534 patients assessed for eligibility, 226 (mean age 67 years, 62·4 per cent women; mean lesion diameter 23·9 mm, 22·6 per cent bilateral) fulfilled the inclusion criteria. Mean follow-up was 19·0 months. After baseline evaluation, 14 patients had surgery owing to primary hyperaldosteronism (3), catecholamine-producing tumour (1), tumour size (6), size and indication of subclinical hypercortisolism (3) and metastasis (1). No hypersecreting lesions were confirmed during follow-up; one patient underwent adrenalectomy for a suspected phaeochromocytoma (adrenocortical adenoma at histopathology). No primary adrenal malignancy was found. CONCLUSION: In this prospective cohort study 6·6 per cent of patients with an AI had surgery and benign hormone-producing tumours were verified in 3·1 per cent. Repeat CT and hormone evaluation after 2 years did not increase the sensitivity for diagnosis of malignant or hormone-producing tumours.

Familial aggregation of psychotic symptoms in Huntington's disease.

OBJECTIVE: The mutation responsible for Huntington's disease is an elongated and unstable trinucleotide (CAG) repeat on the short arm of chromosome 4. Psychotic symptoms are more common in patients with Huntington's disease than in the general population. This study explored the relationship of psychosis in Huntington's disease patients with the number of CAG repeats and family history of psychosis. METHOD: Forty-four patients with Huntington's disease, 22 with and 22 without psychotic symptoms, were recruited from two university-affiliated medical genetics clinics in Seattle and Vancouver, B.C. Psychiatric assessments of the subjects were made through chart review, and diagnoses were validated by structured interviews in a subset of patients. The demographic and clinical characteristics of the psychotic and nonpsychotic patients were compared. RESULTS: The two groups did not differ in demographic and clinical characteristics, except that subjects with psychosis were significantly more likely than nonpsychotic subjects to have a first-degree relative with psychosis. In eight of nine families in which Huntington's disease probands with psychosis had a first-degree relative with psychosis, the relative's psychosis co-occurred with Huntington's disease. In the Huntington's disease probands with psychosis, the onset of psychosis correlated with the onset of the neurological symptoms of Huntington's disease, and the age at onset of psychosis was lower in probands with a higher number of CAG repeats. CONCLUSIONS: Patients with Huntington's disease and psychotic symptoms may have a familial predisposition to develop psychosis. This finding suggests that other genetic factors may influence susceptibility to a particular phenotype precipitated by CAG expansion in the Huntington's disease gene.

Influence of lamotrigine on progression of early Huntington disease: a randomized clinical trial.

OBJECTIVE: To assess the efficacy of lamotrigine, a novel antiepileptic drug that inhibits glutamate release, to retard disease progression in Huntington disease (HD). BACKGROUND: Excitatory amino acids may cause selective neuronal death in HD, and lamotrigine may inhibit glutamate release in vivo. METHODS: A double-blinded, placebo-controlled study was conducted of 64 patients with motor signs of less than 5 years' duration who were randomly assigned to either placebo or lamotrigine and assessed at 0 (baseline), 12, 24, and 30 months. The primary response variable was total functional capacity (TFC) score. Secondary response variables included the quantified neurological examination and a set of cognitive and motor tests. Repeated fluorodeoxyglucose measurements of regional cerebral metabolism using PET also were included. RESULTS: Fifty-five patients (28 on lamotrigine, 27 on placebo) completed the study. Neither the primary response variable nor any of the secondary response variables differed significantly between the treatment groups. Both the lamotrigine and the placebo group deteriorated significantly on the TFC, in the lamotrigine group by 1.89 and the placebo group by 2.11 points. No effect of CAG size on the rate of deterioration could be detected. CONCLUSIONS: There was no clear evidence that lamotrigine retarded the progression of early Huntington disease over a period of 30 months. However, more patients on lamotrigine reported symptomatic improvement (53.6 versus 14.8%; p = 0.006), and a trend toward decreased chorea was evident in the treated group (p = 0.08). The study also identified various indices of disease progression, including motor tests and PET studies, that were sensitive to deterioration over time.

Reactions to predictive testing in Huntington disease: case reports of coping with a new genetic status.

A predictive testing program for Huntington disease has been available in Stockholm, Sweden since October 1990. Psychosocial assessments were performed throughout the testing program to evaluate the impact of the risk situation itself and the effect of predictive testing, and to identify those individuals who were most vulnerable to severe stress and anxiety reactions. All subjects underwent neurological, neuropsychological, and psychiatric examinations. Individuals undergoing predictive testing were assessed twice by a genetic counsellor before receiving their results, and at 10 days (gene carriers only) and then 2, 6, 12, and 24 months after receiving the results. The process of coping with the test results and the psychological adjustment to knowledge about new genetic status have been shown to vary considerably. In this report, we describe the results obtained from two gene carriers and two noncarriers. The four persons chosen represent different ways of coping with the outcome of the test and of integrating knowledge about their genetic status into everyday life. These cases illustrate common themes and recurrent problems often surfacing during the counselling and testing process. The longitudinal evaluations provide information about the impact, adaptation, and long-term effects of living with a new genetic status.

Familial influence on age of onset among siblings with Huntington disease.

In order to provide data relevant to a search for modifying genes for age of onset in Huntington disease, we examined the relationship between CAG number and age of onset in a total of 370 individuals from 165 siblingships, in two cohorts of siblings with Huntington disease: an American group of 144 individuals from 64 siblingships, and a Canadian population of 255 individuals from 113 siblingships. Using a logarithmic model to regress the age of onset on the number of CAG triplets, we found that CAG number alone accounted for 65%-71% of the variance in age of onset. The siblingship an individual belonged to accounted for 11%-19% of additional variance. This adds to the previous evidence that there are familial modifiers of the age of onset, independent of the CAG number. Such modifiers may consist of additional genes, which could be the target of a linkage study. A linkage study is feasible with the cooperation of a number of major centers and may be made more efficient by concentrating on sibling pairs that are highly discordant for age of onset.

Low frequency of the APP 670/671 mutation in familial Alzheimer's disease in Sweden.

Molecular genetic studies have identified disease-causing mutations at codon 717 of the amyloid protein precursor gene in families with early-onset Alzheimer's disease. Recently, we reported a new mutation at codon 670/671 in a large Swedish family with Alzheimer's disease. The mutation results in two amino acid changes at the N-terminal of the beta-amyloid region. In the present study, we screened for the APP 670/671 mutation in sufferers from 31 other Swedish families with Alzheimer's disease using PCR and restriction enzyme digestion. The mutation was found only in the family previously reported and not in any other family. It is concluded that this mutation is a rare cause of familial Alzheimer's disease in Sweden.

Caudate volume as an outcome measure in clinical trials for Huntington's disease: a pilot study.

Previous research has demonstrated that longitudinal change in caudate volume could be observed over a period of 3 years in subjects with Huntington's disease (HD). The current pilot study was designed to determine whether measurement of caudate change on magnetic resonance imaging (MRI) is a feasible and valid outcome measure in an actual clinical trial situation. We measured caudate volumes on pre- and post-treatment MRI scans from 19 patients at two sites who were participating in CARE-HD (Co-enzyme Q10 and Remacemide: Evaluation in Huntington's Disease), a 30-month clinical trial of remacemide and co-enzyme Q(10) in symptomatic patients with HD. Results from this pilot study indicated that decrease in caudate volume was significant over time. Power analysis indicated that relatively small numbers of subjects would be needed in clinical trials using caudate volume as an outcome measure. Advantages and disadvantages of using MRI caudate volume as an outcome measure are presented. We recommend the adoption of quantitative neuroimaging of caudate volume as an outcome measure in future clinical trials for treatments of HD.

Attitudes towards predictive testing in Huntington's disease--a deep interview study in Sweden.

Ten persons with a 50% risk of inheriting Huntington's disease were interviewed in depth about experiences of the disease with special regard to their attitude to a predictive test. The persons showed great interest, concern and worry about a test: six were generally positive while four were negative or uncertain. Every interview had a very personal character and early life experiences seemed to have a determinative influence on the attitude to the test. Persons who were without symptoms of the disease and had passed the mean age of onset within the family (usually older individuals) were largely enthusiastic about a test, as were those with slight and undetermined symptoms. Younger persons, especially those with a qualitatively good contact with the affected parent, seemed to be less interested. Contradictions during the interview were more common among those positive to testing and an ambivalence among many was reflected in a tendency towards changing opinions over time.

Hypothalamic-pituitary-adrenal response to different tests in type 1 diabetes mellitus.

OBJECTIVE: To determine whether different tests of the adrenocorticotropic hormone (ACTH) reserve are influenced by diabetic state and metabolic control in newly diagnosed type 1 diabetic patients. DESIGN AND METHODS: We evaluated the ACTH reserve in 10 patients with uncomplicated type 1 diabetes during periods of poor and improved metabolic control and in 10 healthy subjects. The ACTH-cortisol secretion was assessed by a diurnal profile, an intravenous corticotropin-releasing hormone (CRH) test and an insulin tolerance test (ITT). RESULTS: The diurnal profiles were similar in all groups. CRH resulted in a diminished ACTH response during poor compared with improved metabolic control (mean+/-SD) (AUC 4950+/-4227 vs. 5847+/-3788 ng/L min, p<0.05). The response in the diabetic patients during improved metabolic control was of the same magnitude as in the control subjects (5934+/-1778 ng/L x min). ITT elicited a similar ACTH and cortisol response in the diabetic patients during poor and improved metabolic control as in the healthy control subjects. CONCLUSIONS: The ITT was uninfluenced by diabetic state and metabolic control and should therefore be considered the method of choice in evaluation of the ACTH reserve in patients with type 1 diabetes.

Growth hormone response to the insulin tolerance and clonidine tests in type 1 diabetes.

The insulin tolerance test (ITT) is regarded the gold standard for assessing growth hormone (GH) release in adult patients with suspected GH deficiency. Some of these patients also have diabetes mellitus. There are contradictory reports regarding the GH response to ITT in type 1 diabetic patients with varying degrees of metabolic control. This is also true for the clonidine test. We studied ten patients with uncomplicated type 1 diabetes mellitus during periods of poor and improved metabolic control and compared them with ten healthy control subjects. The GH secretion was assessed by an ITT with an insulin infusion of 2.5 mU/kg/min and an intravenous clonidine test. The GH response to ITT was similar during poor and improved metabolic control (mean +/- SEM) (AUC 2327 +/- 616 vs. 2649 +/- 508 microg/l x min) and did not differ from the response in control subjects (AUC 2587 +/- 343 microg/1 x min). The clonidine test induced a significantly greater GH response during poor than during improved metabolic control in the diabetic patients (AUC 2598 +/- 492 vs. 1508 +/- 368 microg/l x min, p < 0.05); this response was greater than in the control subjects (670 +/- 226 x microg/l x min, p < 0.005 vs. improved metabolic control). Thus, the GH response to ITT is similar in diabetic patients with varying degrees of metabolic control and healthy subjects, while the GH response to the clonidine test is higher in the type 1 diabetic patients than in healthy controls.

Experimenting with Minnaert's Cigar.

We have studied the seldom-seen halo phenomenon that can arise in divergent light, Minnaert's Cigar, which we produced in laboratory experiments and computer simulation. In the laboratory experiments halos or transections were produced in clouds of alum crystals precipitated in a solution of ethyl alcohol or in alum crystals deposited upon glass plates. The three-dimensional cigar form was less pronounced in our small-scale experiments than when the form was observed over several meters. In our experiments and simulations transections through Minnaert's Cigar include different halo forms that may arise on window panes or windshields covered with halo-active ice crystals or as horizontal halos on glittering frost-covered ground.

Screening of amyloid precursor protein gene mutation (APP 717 Val-->Ile) in Swedish families with Alzheimer's disease.

Screening for the APP 717 Val-->Ile mutation in the amyloid precursor protein (APP) gene in 34 Swedish families with familial Alzheimer's disease (FAD), 16 sporadic cases of Alzheimer's disease and five patients with Down's syndrome (DS) failed to identify further cases of the mutation. These results suggests that the mutation is rare among Swedish families with Alzheimer's disease. In addition, we summarize present reports of the frequency of the mutation.

High incidence rate and absent family histories in one quarter of patients newly diagnosed with Huntington disease in British Columbia.

The advent of the direct mutation test for Huntington disease (HD) has made it possible to identify a previously unrecognized symptomatic population of HD, including those with an atypical presentation or patients without a family history of HD. The present study investigated the uptake of this test in the province of British Columbia (BC), Canada and assessed the incidence rate and rate of identification of new mutations for HD. All symptomatic individuals residing in BC who were referred for the genetic test for HD between 1993 and 2000 (n=205) were analyzed for CAG expansion, baseline demographics and clinical data, and a family history of HD. A total of 141 (or 68.8%) had a CAG expansion > or =36. Of these, almost one-quarter (24.1%) did not have a family history of HD. An extensive chart review revealed that 11 patients (or 7.8%) had reliable information on both parents (who lived well into old age) and therefore possibly could represent new mutations for HD. This indicates a three to four times higher new mutation rate than previously reported. Our findings also show that the yearly incidence rate for HD was 6.9 per million, which is two times higher than previous incidence studies performed prior to the identification of the HD mutation. We also identified five persons with a clinical presentation of HD but without CAG expansion (genocopies) (2.4%).

Psychological consequences and predictors of adverse events in the first 5 years after predictive testing for Huntington's disease.

The promise of genetic medicine is to provide information, based on genotype, to persons not yet sick about their risk of future illness. However, little is known of the long-term psychological effects for asymptomatic persons learning their risk of having a serious disease. Predictive genetic testing for Huntington's disease (HD) has been offered for the longest time for any disease. In the present study, the psychological consequences of predictive testing were assessed prospectively in individuals at risk for HD during seven visits over 5 years. Questionnaires of standard measures of psychological distress (the General Severity Index of the Symptom Check List-90-Revised), depression (the Beck Depression Inventory), and general well-being (the General Well-Being Scale) were administered to the participants. A significant reduction in psychological distress was observed for both result groups throughout 2 years (p < 0.001) and at 5 years (p = 0.002). Despite the overall improvement of the psychological well-being, 6.9% (14 of 202) of the participants experienced an adverse event during the first 2 years after predictive testing that was clinically significant. The frequency of all defined adverse events in the participants was 21.8%, with higher frequency in the increased risk group (p = 0.03) and most occurring within 12 months of receiving results.

The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size.

Prior studies describing the relationship between CAG size and the age at onset of Huntington disease (HD) have focused on affected persons. To further define the relationship between CAG repeat size and age at onset of HD, we now have analyzed a large cohort of affected and asymptomatic at-risk persons with CAG expansion. This cohort numbered 1,049 persons, including 321 at-risk and 728 affected individuals with a CAG size of 29-121 repeats. Kaplan-Meier analysis has provided curves for determining the likelihood of onset at a given age, for each CAG repeat length in the 39-50 range. The curves were significantly different (P < .0005), with relatively narrow 95% confidence intervals (95% CI) (+/-10%). Penetrance of the mutation for HD also was examined. Although complete penetrance of HD was observed for CAG sizes of > or = 42, only a proportion of those with a CAG repeat length of 36-41 showed signs or symptoms of HD within a normal life span. These data provide information concerning the likelihood of being affected, by a specific age, with a particular CAG size, and they may be useful in predictive-testing programs and for the design of clinical trials for persons at increased risk for HD.

The "flap" endonuclease gene FEN1 is excluded as a candidate gene implicated in the CAG repeat expansion underlying Huntington disease.

At least 12 disorders including Huntington disease (HD) are associated with expansion of a trinucleotide repeat (TNR). Factors contributing to the risk of expansion of TNRs and the mechanism of expansion have not been elucidated. Data from Saccharomyces cerevisiae suggest that the flap endonuclease FEN1 plays a role in expansion of repetitive DNA tracts. It has been hypothesized that insufficiency of FEN1 or a mutant FEN1 might contribute to the occurrence of expansion events of long repetitive DNA tracts after polymerase slippage events during lagging strand synthesis. The expression pattern of FEN1 was determined, and ubiquitous tissue expression, including germ cells, suggested that FEN1 has the potential to be involved in HD. Fifteen HD parent/child pairs that demonstrated intergenerational increases in CAG length of greater than 10 repeats were examined for possible mutations or polymorphisms within the FEN1 gene that could underlie the saltatory repeat expansions seen in these individuals. No alterations were observed compared to 50 controls, excluding FEN1 as a trans-acting factor underlying TNR expansion. The identification of a candidate gene(s) in HD or other CAG-expansion disorders implicated in TNR instability will elucidate the mechanism of expansion for this growing family of neurological disorders.

Measurement of mutational flow implies both a high new-mutation rate for Huntington disease and substantial underascertainment of late-onset cases.

We describe a new approach for analysis of the epidemiology of progressive genetic disorders that quantifies the rate of progression of the disease in the population by measuring the mutational flow. The framework is applied to Huntington disease (HD), a dominant neurological disorder caused by the expansion of a CAG-trinucleotide sequence to >35 repeats. The disease is 100% penetrant in individuals with > or = 42 repeats. Measurement of the flow from disease alleles provides a minimum estimate of the flow in the whole population and implies that the new mutation rate for HD in each generation is > or = 10% of currently known cases (95% confidence limits 6%-14%). Analysis of the pattern of flow demonstrates systematic underascertainment for repeat lengths <44. Ascertainment falls to <50% for individuals with 40 repeats and to <5% for individuals with 36-38 repeats. Clinicians should not assume that HD is rare outside known pedigrees or that most cases have onset at age <50 years.

A worldwide assessment of the frequency of suicide, suicide attempts, or psychiatric hospitalization after predictive testing for Huntington disease.

Prior to the implementation of predictive-testing programs for Huntington disease (HD), significant concern was raised concerning the likelihood of catastrophic events (CEs), particularly in those persons receiving an increased-risk result. We have investigated the frequency of CEs-that is, suicide, suicide attempt, and psychiatric hospitalization-after an HD predictive-testing result, through questionnaires sent to predictive-testing centers worldwide. A total of 44 persons (0.97%) in a cohort of 4,527 test participants had a CE: 5 successful suicides, 21 suicide attempts, and 18 hospitalizations for psychiatric reasons. All persons committing suicide had signs of HD, whereas 11 (52.4%) of 21 persons attempting suicide and 8 (44.4%) of 18 who had a psychiatric hospitalization were symptomatic. A total of 11 (84.6%) of 13 asymptomatic persons who experienced a CE during the first year after HD predictive testing received an increased-risk result. Factors associated with an increased risk of a CE included (a) a psychiatric history