Capitate-trapezoid synostosis: analysis of an Early Bronze Age case and review of the literature.

BACKGROUND: Carpal synostoses are congenital defects characterised by complete or incomplete coalition of two or more carpal bones. Although most of these defects are discovered only incidentally, sometimes they become clinically manifest. Among the different types of carpal coalition, the synostosis between capitate and trapezoid bones is quite rare, with only sparse data available in the literature. The aim of this report was to describe a case of capitate-trapezoid synostosis (CTS) observed in an ancient human skeleton, as well as to scrutinise the pertinent literature in order to assess for the characteristics of this type of defect, including its potential relevance to clinical practice. MATERIALS AND METHODS: We studied the skeletal remains of an Early Bronze Age male warrior affected by incomplete CTS. Macroscopic and radiological examination of the defect was carried out. We also performed a comprehensive PubMed search in the Medline and other specialty literature databases to retrieve and analyse data relevant to the subject under consideration. RESULTS AND CONCLUSIONS: The present case is the most ancient CTS ever found. In those literature-reported cases accompanied by careful anatomical description, such as the present one, incomplete coalition invariably occurs between the dorsal surfaces of the two bones, this characteristic emerging as a distinctive morphological trait. Literature analysis further suggests that the true prevalence of CTS is likely to be higher than estimates based on data gathered from radiology series, and that this defect may be associated with pain and carpal bossing more frequently than generally thought.

[Integrated models between hospital and field for patients with heart failure]. / Modelli integrati tra ospedale e territorio per l'assistenza al paziente con scompenso cardiaco.

Chronic heart failure is a major health problem, which is growing parallel to the increasing proportion of elderly in the population. Recurrent hospitalizations occur in about half of the subjects within 6 months after the initial admission. Several co-morbidities usually coexist in these patients and influence resource utilization and outcome. The high re-admission rates and low proportion of patients who are currently enrolled in specific follow-up programs underscore the existing pitfalls in outpatient care, and the lack of co-operation between hospital departments and out-of-hospital clinics or general practitioners. As a consequence, up to half of the hospital admissions may be caused by potentially preventable factors. As worldwide health-care cost-containment escalates, it becomes crucial to develop new cost-effective strategies to improve the quality of care of more severe patients. The implementation of clinic-based heart failure programs showed some evidence of an improvement in functional status and in the frequency of hospital readmissions. However, patients referred to Heart Failure Clinics represent a selected population of patients compared to the overall population of "real-world" elderly patients with incapacitating symptoms, serious co-morbidities and frequent inability to attend an outpatient clinic. Few trials are currently available to verify the efficacy of a clinic-based approach in such patients, with discordant results. Other studies have extended the multidisciplinary program to the patient's home. These strategies might be particularly appropriate and cost-effective if targeted to elderly and higher-risk patients, and appear to be of particular relevance given the phenomenon of progressive aging of the general population. The results of our intensive, nurse-monitored, homecare surveillance on quality of life and hospitalization rate in elderly patients with refractory heart failure who previously failed to reach the goal of clinical stability with a clinic-based program extend the effectiveness of heart failure programs, in terms of quality of life and hospital readmission, to terminally ill subjects with short life expectancy and very high resource utilization.

Benefits of beta-blockers in heart failure: a class specific effect?

There is now compelling evidence in favor of the use of beta-adrenergic antagonists for the treatment of chronic heart failure. In clinically stable patients who remain symptomatic despite the fact that they are already receiving an angiotensin-converting enzyme inhibitor, diuretics and digoxin, the addition of a beta-blocker has been shown to produce further improvements in cardiac function and structure as well as in the quality and quantity of life. However, although such benefits can be achieved with a number of beta-blockers, the relevant differences in the ability of inhibiting the adrenergic drive among the various agents in the same class could translate into quantitatively different clinical effects. At present, the question whether all beta-blockers confer equal benefit or not to heart failure patients remains unanswered, since only few studies have prospectively addressed the issue and overall evidence does not permit to draw a conclusion that one agent has to be preferred to another. A large ongoing trial, designed to compare the effects of metoprolol and carvedilol on all-cause mortality in chronic heart failure, will provide much of the information required.

Incidence and predictors of sudden cardiac death during long-term follow-up in patients with dilated cardiomyopathy on optimal medical therapy.

BACKGROUND: In spite of a total mortality reduction in recent years, sudden cardiac death (SD) remains a major problem in patients with idiopathic dilated cardiomyopathy (IDC) and its occurrence is often unpredictable. Furthermore, the risk of SD may change during follow-up because of the natural history of the disease and the effects of therapeutic interventions. In our study, we evaluated the modifications of the risk of SD during follow-up in a cohort of patients with IDC and analyzed the variables predicting SD not only at enrolment but also at the last examination during optimal medical treatment. METHODS: Since 1978, 343 consecutive patients with IDC were enrolled in the Heart Muscle Disease Registry of Trieste (Italy) and submitted to complete invasive and non-invasive study. Patients were re-evaluated usually at intervals of 12 months. RESULTS: After a mean of 68+/-45 months, 125 events (death, heart transplantation or aborted SD) had occurred. The cumulative risk after 5 years was 30%, while after 10 years it almost doubled (54%). During the first 3 months after enrolment, the incidence of SD was high (3%). A plateau, lasting about 3.5 years, followed. A slow but progressive rise in the risk of mortality then occurred (6% at 5 years, 18% at 10 years). No variables evaluated at enrolment were associated with SD at multivariate analysis. On the other hand, the end-diastolic left ventricular diameter (> or = 38 mm/m2) and ejection fraction (< or = 0.30) were predictive of SD if evaluated within 1 year before the event. Beta-blocker treatment was associated with a non-significant reduction of risk. CONCLUSIONS: In patients with IDC the incidence of SD progressively increased during long-term follow-up, especially in those with persistent severe left ventricular dilation and dysfunction who were not on beta-blocker treatment. Serial clinical evaluation may help to select patients at higher risk for SD.

[Changes in medical treatment of heart failure in the light of large clinical trials]. / Come è cambiata la terapia medica dello scompenso cardiaco alla luce dei grandi trial clinici.

In the last years, the treatment of heart failure has radically changed, as has knowledge of this complex and heterogeneous clinical syndrome. This is largely due to the results of several multicenter clinical trials, which have been undertaken since the late 80's. These trials have not only contributed to the elaboration of present-day treatment protocols, but also to a better understanding of the pathophysiologic mechanisms involved in heart failure. In the past, heart failure was generally interpreted on the basis of pathophysiologic models according to which hemodynamic abnormalities played a very important role in determining the clinical presentation and evolution of the disease. This led to the use of digitalis, diuretics, inotropic drugs and vasodilators for the treatment of heart failure. More recently, improved knowledge of the pathophysiologic mechanisms involved in the progression of this disease has highlighted the central role and the complexity of various neurohormonal mechanisms. Antagonism of these systems has proved to be the only strategy which favorably modifies the natural history of heart failure. The proved effectiveness of ACE-inhibitors and particularly of beta-blockers in patients with heart failure and left ventricular systolic dysfunction was the most convincing demonstration of the validity of this model. However, the evolution and updating of the guidelines on the treatment of heart failure should only be considered as the first step in the development of strategies aimed at extending these principles to daily clinical practice and in particular to the real patient who is different from patients typically enrolled in heart failure trials. Moreover, the development of new effective models for the management of the ever-growing number of patients with heart failure is of utmost urgency.

[Echocardiographic follow-up of patients with heart failure. Which parameters should be measured? How often?]. / Il follow-up ecocardiografico del paziente con scompenso cardiaco. Quali parametri misurare? Con quale frequenza?

The echocardiographic evaluation keeps a relevant place in the evaluation of patients with heart failure and left ventricular systolic dysfunction, not only for its contribution to the diagnosis, prognostic stratification and comprehension of pathogenetic mechanisms, but also for the analysis of the evolution of the disease and the response to optimal medical therapy. On the other hand, the role of echocardiography in the follow-up of patients with diastolic dysfunction is still unclear. In patients with heart failure and left ventricular systolic dysfunction the analysis of changes in left ventricular function and dimension during follow-up is particularly relevant to recognize the potential benefit of optimal medical therapy with ACE-inhibitors and beta-blockers and their prognostic significance. The echo-Doppler hemodynamic evaluation is also of clinical and prognostic value particularly for the recognition of the persistence or (re)appearance of restrictive filling pattern during follow-up. Moreover, in patients with persistent severe left ventricular systolic dysfunction, the evaluation of right ventricular function may allow for the identification of a subset of patients at high risk for cardiovascular events. A practical flow-chart of echocardiographic assessment of patients with heart failure and left ventricular systolic dysfunction includes the following steps: 1) after 3 to 6 months on optimal therapy, to detect the persistence of restrictive filling pattern, if present at diagnosis; 2) after 12 to 24 months, to analyze the response of left ventricular function and dimension to optimal medical treatment; 3) serial examinations, according to the stage of the disease or to the episodes of worsening heart failure, to identify echocardiographic indicators of disease progression, such as worsening of left ventricular and/or right ventricular function or (re)appearance of restrictive filling pattern. The changes in these parameters seem to have a relevant prognostic significance to define the risk profile of patients with heart failure and left ventricular systolic dysfunction.

Family and molecular data for a fine analysis of age at onset in Huntington disease.

We analyzed the data on age at onset and CAG size of 319 patients clinically diagnosed with Huntington disease (HD) and 86 presymptomatic subjects recorded by four Italian Centers over the last 14 years. To overcome the problem of different CAG numbers found in each subject, also in the same family, the data were analyzed in terms of deviations from the average exponential relationship between onset and CAG number. The subject's year of birth was also considered to quantify possible sampling biases. Observations between relatives were compared with those of the whole group. The deviations were equal, on average, in subjects who inherited their HD gene from their fathers or mothers. Overall, our data argue in favor of a greater similarity across the same generation than across successive generations. In particular, an excess of parents with later than expected age of onset was observed, paralleled by a CAG-independent anticipation of onset in parent-child transmissions. These results can be interpreted in terms of a shared environment determining similar departures from the average CAG-onset relationship but also of a systematic effect that differentiates the two generations here examined.

A fine physical map of the CACNA1A gene region on 19p13.1-p13.2 chromosome.

The P/Q-type Ca(2+) channel alpha(1A) subunit gene (CACNA1A) was cloned on the short arm of chromosome 19 between the markers D19S221 and D19S179 and found to be responsible for Episodic Ataxia type 2, Familial Hemiplegic Migraine and Spinocerebellar Ataxia type 6. This region was physically mapped by 11 cosmid contigs spanning about 1. 4Mb, corresponding to less than 70% of the whole region. The cosmid contig used to characterize the CACNA1A gene accounted only for the coding region of the gene lacking, therefore, the promoter and possible regulation regions. The present study improves the physical map around and within the CACNA1A by giving a complete cosmid or BAC contig coverage of the D19S221-D19S179 interval. A number of new STSs, whether polymorphic or not, were characterized and physically mapped within this region. Four ESTs were also assigned to cosmids belonging to specific contigs.

Long-term effects of carvedilol in idiopathic dilated cardiomyopathy with persistent left ventricular dysfunction despite chronic metoprolol. The Heart-Muscle Disease Study Group.

OBJECTIVES: The purpose of this study was to analyze whether long-term treatment with the nonselective beta-adrenergic blocking agent carvedilol may have beneficial effects in patients with dilated cardiomyopathy (DCM), who are poor responders in terms of left ventricular (LV) function and exercise tolerance to chronic treatment with the selective beta-blocker metoprolol. BACKGROUND: Although metoprolol has been proven to be beneficial in the majority of patients with heart failure, a subset of the remaining patients shows long-term survival without satisfactory clinical improvement. METHODS: Thirty consecutive DCM patients with persistent LV dysfunction (ejection fraction < or =40%) and reduced exercise tolerance (peak oxygen consumption <25 ml/kg/min) despite chronic (>1 year) tailored treatment with metoprolol and angiotensin-converting enzyme inhibitors were enrolled in a 12-month, open-label, parallel trial and were randomized either to continue on metoprolol (n = 16, mean dosage 142+/-44 mg/day) or to cross over to maximum tolerated dosage of carvedilol (n = 14, mean dosage 74+/-23 mg/day). RESULTS: At 12 months, patients on carvedilol, compared with those continuing on metoprolol, showed a decrease in LV dimensions (end-diastolic volume -8+/-7 vs. +7+/-6 ml/m2, p = 0.053; end-systolic volume -7+/-5 vs. +6+/-4 ml/m2, p = 0.047), an improvement in LV ejection fraction (+7+/-3% vs. -1+/-2%, p = 0.045), a reduction in ventricular ectopic beats (-12+/-9 vs. +62+/-50 n/h, p = 0.05) and couplets (-0.5+/-0.4 vs. +1.5+/-0.6 n/h, p = 0.048), no significant benefit on symptoms and quality of life and a negative effect on peak oxygen consumption (-0.6+/-0.6 vs. +1.3+/-0.5 ml/kg/min, p = 0.03). CONCLUSIONS: In DCM patients who were poor responders to chronic metoprolol, carvedilol treatment was associated with favorable effects on LV systolic function and remodeling as well as on ventricular arrhythmias, whereas it had a negative effect on peak oxygen consumption.

[Improvement of prognosis in idiopathic dilated cardiomyopathy: role of early diagnosis and optimized medical treatment. Study Group on Heart Muscle Diseases]. / Il miglioramento della prognosi nella cardiomiopatia dilatativa idiopatica: il ruolo della diagnosi precoce e della terapia medica ottimizzata. Gruppo di Studio sulle Malattie del Muscolo Cardiaco.

BACKGROUND: The aim of this study was to assess the extent to which a more widespread use of new effective treatments for heart failure associated with earlier detection of the disease may have contributed to enhancing the prognosis of idiopathic dilated cardiomyopathy (IDC) patients over the past 20 years. METHODS: Heart transplant-free survival curves were analyzed in 343 IDC patients, prospectively enrolled from January 1, 1978 to June 30, 1997 in the Heart Muscle Disease Registry of the Cardiology Department in Trieste (94 enrolled between 1978 and 1987, Group 1; 249 between 1988 and 1997, Group 2). At enrollment, 91 patients had no heart failure symptoms (NoHF), whereas the remaining 252 showed HF of recent (HF < or = 6 months, n = 132) or non-recent (HF > 6 months, n = 120) onset. RESULTS: In comparison to Group 1, Group 2 was treated more frequently with ACE-inhibitors and beta-blockers (p < 0.0001) and showed a better long-term survival (p = 0.0034), resulting from a reduction of death for refractory HF or need for heart transplant (p = 0.011). Conversely, the risk of sudden death did not significantly differ between the two groups. NoHF, HF > 6 months and HF < or = 6 months groups were similarly treated with ACE-inhibitors and beta-blockers. Long-term survival was better in patients without HF than in those with overt HF (p = 0.0015). As compared to Group HF > 6 months, Group HF < or = 6 months had a poorer one-year prognosis (p = 0.045), related to the presence of a subgroup of patients with refractory HF and need for heart transplant, but showed a better survival rate over the following years (p = 0.015). Over the two subsequent decades of enrollment, a significant improvement in patient survival was observed within Groups NoHF (p = 0.03) and HF > 6 months (p = 0.01), but not in Group HF < or = 6 months. CONCLUSIONS: Over the past 20 years, the increasing use of ACE-inhibitors and beta-blockers in IDC was associated with a significant improvement in long-term survival, resulting from a reduction in mortality for refractory heart failure or need for heart transplant. In addition, early diagnosis may have contributed significantly to enhancing the prognosis of IDC, since the benefits of medical therapy were lower in patients identified and treated in advanced stages of the disease. Moreover, early diagnosis was shown to be useful in recognizing patients with recent onset of heart failure who are not responders to aggressive medical treatments and urgently need heart transplant.

The role of the SCA2 trinucleotide repeat expansion in 89 autosomal dominant cerebellar ataxia families. Frequency, clinical and genetic correlates.

The spinocerebellar ataxia type 2 (SCA2) is caused by a trinucleotide (CAG) expansion in the coding region of the ataxin 2 gene on chromosome 12q.89 families with autosomal dominant cerebellar ataxia (ADCA) types I, II and III, and 47 isolated cases with idiopathic late onset cerebellar ataxia (ILOCA), were analysed for this mutation. The identification of the SCA2 mutation in 31 out of 38 families with the ADCA I phenotype, but in none of those with ADCA II, ADCA III or ILOCA confirms the specificity of this mutation. A clinical comparison of the ADCA I patients with the three known mutations (SCA1, -2 or -3) highlights significant differences between the groups; SCA2 patients tended to have a longer disease duration, a higher frequency of slow saccades and depressed tendon reflexes. However, these neurological signs were also seen in an ADCA I family in which the SCA2 mutation was not identified, illustrating the importance of a direct genetic test. The SCA2 families were from different geographical and ethnic backgrounds. However, haplotype analysis failed to show evidence of a founder mutation, even in families from the same geographical origin. The range of normal alleles varied from 17 to 30 CAG repeats and from 35 to 51 repeats for the pathological alleles. Similar to the other diseases caused by unstable trinucleotide repeats, a significant inverse correlation has been found between the number of repeats and age of onset, and there is a significantly higher paternal instability of repeat length on transmission to offspring. The SCA2 mutation is the most frequent amongst ADCA I patients, accounting for 40%, compared with SCA1 and SCA3 which account for 35% and 15%, respectively.

Predictive testing for Huntington's disease: ten years' experience in two Italian centres.

Pre-symptomatic testing for Huntington's disease (HD) has been available as a clinical service in the medical centres of Rome and Genoa since December 1987, initially by DNA-linkage and since mid-1993 by direct mutation analysis. A multidisciplinary approach and a protocol which follows the Ethical Issue Policy Statement on Huntington's Disease Molecular Genetics Predictive Test has been used. In the period under study, 332 subjects requested the test, 288 were enrolled in the protocol and nearly half of these completed it. One hundred and forty-eight people withdrew from the testing procedure for various reasons but most frequently due to a more realistic evaluation of all possible consequences of test results, induced by psychological counselling. Therefore, 140 people completed the test. The overall gene-carrier/non-carrier ratio was 0.46:1. None of the identified gene carriers had catastrophic reactions such as suicide, suicide attempts or major psychiatric disorders. All appear to have had a similar pattern of reactions to an adverse result and none expressed regret for undergoing the test. In conclusion, presymptomatic testing for HD can be considered a safe procedure without adverse consequences when framed in an integrated protocol at qualified genetic centres.

Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p.

Point mutations of the CACNA1A gene coding for the alpha 1A voltage-dependent calcium channel subunit are responsible for familial hemiplegic migraine (FHM) and episodic ataxia type 2 (EA2). In addition, expansions of the CAG repeat motif at the 3' end of the gene, smaller than those responsible for dynamic mutation disorders, were found in patients with a progressive spinocerebellar ataxia, named SCA6. In the present work, the analysis of two new families with small CAG expansions of the CACNA1A gene is presented. In one family, with a clinical diagnosis of EA2, a CAG23 repeat allele segregated in patients showing different interictal symptoms, ranging from nystagmus only to severe progressive cerebellar ataxia. No additional mutations in coding and intron-exon junction sequences in disequilibrium with the CAG expansion were found. In the second family, initially classified as autosomal dominant cerebellar ataxia of unknown type, an inter-generational allele size change showed that a CAG20 allele was associated with an EA2 phenotype and a CAG25 allele with progressive cerebellar ataxia. These results show that EA2 and SCA6 are the same disorder with a high phenotypic variability, at least partly related to the number of repeats, and suggest that the small expansions may not be as stable as previously reported. A refinement of the coding and intron-exon junction sequences of the CACNA1A gene is also provided.

[Effectiveness of the Palmaz Schatz stent in elderly patients with unstable angina: factors predictive of short-term and long-term events]. / Efficacia dello stent di Palmaz Schatz nel paziente anziano con angina instabile: fattori predittivi di eventi a breve e lungo termine.

INTRODUCTION: To evaluate clinical, procedural and therapeutical predictors of in- and out-hospital events in the elderly, we analyzed 69 consecutive patients (age: 74, range: 70-87) with unstable angina who successfully underwent Palmaz Schatz coronary stenting. METHODS: Between March 1991 and March 1994, after the stenting procedure, a cohort of 38 patients (AC) was treated with iv heparin for 48 hours, warfarin (dosage titrated on INR) and dipiridamole (75 mg tid) for 3 months, aspirin (325 mg a day) chronically; between April 1994 and April 1995, after 48 hours of iv heparin, a second cohort of 31 patients (NO AC) received subcutaneous low molecular weight heparin (4000 U a day) for a week, ticlopidine (250 bid) for 1 month, and aspirin (100 mg a day) chronically. NO AC patients showed, by protocol, a higher postdilatation pressure (14 +/- 2 vs 9 +/- 3 atm, p < 0.0001). RESULTS: The 2 cohorts of patients were similar with respect to baseline clinical and angiographic findings. A shorter hospital stay (5 +/- 2 vs 10 +/- 6 days, p < 0.0001) and a lower incidence of in-hospital events were seen in the NO AC group (3.2 vs 24%, p = 0.028), both by a reduction of ischaemic events (3.2 vs 10.5%, p = ns) and hemorrhagic events (0 vs 13.2%, p = 0.03). During a mean follow-up of 21 +/- 13 months, NO AC patients did not show a significant lower rate of out-hospital events (1 year event-free survival respectively 94.7% in NO AC cohort vs 85.7% in AC cohort, p = ns). At logistic regression model, anticoagulant therapy (OR 10.89, Cl 1.39-85.28, p < 0.05) and refractory angina (Braunwald C3) (OR 5.70, Cl 1.12-29.03, p < 0.05) were significantly related to the incidence of acute events, while refractory angina (OR 5.76, Cl 1.27-26.00, p = 0.02) and multivessel disease (OR 3.31, Cl 0.89-12.20, p = 0.07) to the occurrence of late cardiac events, particularly for a higher risk of non-target site new revascularizations. Stent implantation on saphenous vein graft was also associated to a higher risk of repeating a revascularization of non-treated sites (20 vs 4%, p = 0.021). CONCLUSIONS: In elderly with unstable angina treated with Palmaz Schatz stenting, NO AC patients showed a significant reduction of in-hospital events without a subsequent higher risk of late events. In addition, refractory angina, multivessel disease and stent implantation on saphenous vein graft were the other main clinical variables predictive of out-hospital events particularly for higher risk of non-target site new revascularizations.

Acetazolamide-responsive episodic ataxia in an Italian family refines gene mapping on chromosome 19p13.

Episodic ataxia type 2 is an autosomal dominant disorder with attacks of vertigo and ataxia which respond to acetazolamide treatment. The gene, distinct from the KCNA1 responsible for episodic ataxia type 1, has been mapped on chromosome 19p13 in a 11-12 cM region. A large Italian kindred affected with acetazolamide-responsive episodic ataxia is reported, with onset in adulthood, a strong vestibular component during attacks and a high frequency of cerebellar vermis degeneration. The genetic analysis (i) showed strong linkage between the disease and the 19p13 microsatellite markers in a region which widely overlaps that previously reported and (ii) set a new distal boundary of the gene-containing region. Combining present and previous mapping data, the gene of episodic etaxia type 2 is most probably located in an interval approximately 1.5 Mb between markers D19S221 and D19S226.

Analysis of (CAG)n size heterogeneity in somatic and sperm cell DNA from intermediate and expanded Huntington disease gene carriers.

The length of the CAG repeat responsible for Huntington disease has been analysed by two PCR methods in blood and sperm DNA of 13 expansion carriers, two carriers of intermediate alleles, and four normal subjects. The two methods consistently confirmed size heterogeneity, more pronounced in sperm and confined to the CAG stretch. Based on densitometric scanning of films, four indexes addressed to different features of the PCR pattern were used to quantitate mosaicism. These revealed strong correlations with CAG size and intergenerational instability. However, mosaicism did not show a greater similarity in sibs who shared the same HD chromosome, nor was correlated with instability in the proband's pedigree. Our data do not support the hypothesis that cis-acting factors play a major role in the instability and leave the CAG size per se as the major determinant of sperm cell CAG instability.

Genetic fitness in Huntington's Disease and Spinocerebellar Ataxia 1: a population genetics model for CAG repeat expansions.

An analysis of genetic fitness was performed in Huntington's Disease (HD) and Spinocerebellar Ataxia 1 (SCA1) families. Two partially overlapping samples were used: clinically defined HD and SCA1 patients from families ascertained in definite geographical areas, and molecularly typed carriers of HD and SCA1 mutations (CAG trinucleotide expansions). In both cases, a control group of normal relatives was used. HD and SCA1 patients born before 1915-20 had more children than normal controls. Carriers of HD and SCA1 mutations, all in the low/medium expansion range (37-49 and 47-54 CAG repeats respectively), had a higher number of children than controls up to more recent times (1935-1950). The reproduction of heterozygotes for large expansions could be analysed only in subjects born after 1950 and provided indirect evidence of a lower than normal number of children. The above results fit a model based on a differential fitness according to the degree of expansion. Such a model predicts that 1) up to relatively recently the frequency of alleles in the low/medium range has been maintained or even increased by the increased fitness of their carriers, as well as by new mutations, and 2) the frequency of large expansions, part of which are lost at each generation, is maintained through further expansions of alleles in the low/medium expansion range. The implications of such a model on linkage disequilibrium and the possible spread of these diseases in future generations are discussed.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Clinical, neuroimaging, pathological and genetic study of a large Italian family.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a rare hereditary stroke disease. The gene has been recently mapped, in two French families, on chromosome 19q12 between two highly polymorphic genetic markers. We report on a new large Italian family affected with this disease, which is characterized by recurrent stroke episodes, focal neurological deficits progressing to pseudo-bulbar palsy, and dementia. Multiple deep infarcts and diffuse leucoencephalopathy were revealed by MRI and brain histopathology showed abnormalities of arterial media. A genetic study performed with microsatellite markers from region 19q12 showed that the disease locus lies in an interval largely overlapping that already described and is closely linked to two microsatellite markers, D19S212 and D19S222. A joint analysis of genotypic and phenotypic data shows that diffuse leucoencephalopathy is a reliable sign of the disease in otherwise normal 50%-risk subjects over the age 30 years and that penetrance of stroke episodes or dementia is most likely complete around age 60 years.

Polymorphism analysis of the huntingtin gene in Italian families affected with Huntington disease.

Two sources of variation in the huntingtin gene, the length of the CCG-rich segment downstream to the (CAG)n stretch undergoing expansion in Huntington disease (HD) and the deletion of 3 bp at codon positions 2642-2645 (delta 2642), were analysed on the normal and HD chromosomes of 80 Italian families affected with HD. No instances of meiotic instability of the CCG-rich segment were detected. A strong linkage disequilibrium was found between the HD mutation and alleles at both polymorphic regions: CCG-rich length alleles different from 176 bp are underrepresented while delta 2642 is overrepresented on HD chromosomes. The presence of such alleles on HD chromosomes does not affect age at onset of the disease. Normal chromosomes displayed a non-random association, shorter (CAG)n segments being preferentially followed by longer CCG-rich segments. Finally, the finding, among normal subjects, of carriers of variants on both chromosomes denotes that variation at either of the two polymorphisms does not impair the function of the huntingtin gene product.