Rare diseases in the elderly: a new perspective for the specialist in geriatrics

Rare diseases (RD) encompass a broad spectrum of highly heterogeneous illnesses characterized by a prevalence lower than 1: 2000 in general population. Although relatively uncommon, when considered as a whole, these pathologies represent a relevant public health problem. In light of their usual early onset and high severity and mortality, RD have been traditionally regarded as affecting mainly childhood or young adulthood, and considered to be excluded from filed of interest of geriatric specialists. However, more recent epidemiological studies, suggest that demographic changes, sometimes joined with advances in diagnostic and therapeutic strategies, are permitting longer survival of some persons affected by these conditions, thus making RD compatible with geriatric age. Hence, in the next future, specialists in geriatrics will be referred to by an increasing number of elderly subjects with RD seeking medical care. Geriatricians should be aware about the high management complexity of elderly patients with RD, characterized by considerable frailty status, related to both the primary RD and to the ageing-related condition

Mutation study of Spanish patients with hereditary hemorrhagic telangiectasia and expression analysis of Endoglin and ALK1

10 páginas, 2 figuras, 1 tabla -- PAGS nro. 295Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant and age-dependent vascular disorder originated by mutations in Endoglin (ENG) or activin receptor-like kinase-1 (ALK1, ACVRL1) genes. The first large series HHT analysis in Spanish population has identified mutations in 17 unrelated families. Ten different mutations in ALK1 and six in ENG genes were found. Six unrelated families had a mutation in ENG gene, four representing new mutations, p.Y258fs, pV323fs, p.F279fs (c.834_837del CTTC), and p.F279fsdupC. Eleven unrelated families harboured mutations in ALK1; ten were new mutations identified as p.H328P, p.R145fs, p.G68C, p.A377T, p.H297R, p.M376T, p.C36Y, p.H328P, p.T82del and p.R47P. Overall, ALK1 mutations (HHT2) were predominant over ENG mutations (HHT1), in agreement with data reported for other Mediterranean countries (France, Italy), but at variance with Northern Europe or North America. Endoglin expression in HHT1 or HHT2 activated monocytes and blood outgrowth endothelial cells (BOECs) from older patients was well below the theoretical 50% level expected from the HHT1 haploinsufficiency model, suggesting that the pathogenic endoglin haploinsufficiency leading to the HHT phenotype is age-dependent. Interestingly, ALK1 protein levels of HHT BOECs in some missense ALK1 mutants were similar to controls. In vitro expression of these ALK1 constructs suggests that, in addition to the haploinsufficiency model, certain ALK1 mutants may inhibit the function of the wild type alleleAuthors are indebted to Drs. Michelle Letarte and Ursula Cymerman for suggestions on methods of HHT patient sequencing, Dr. Kohei Miyazono for ALK1 constructs, Carmen Langa for technical assistance, Prof. Ginevra Guanti for hosting in her lab to A.F-L. and L.M.B., and to all the volunteers and HHT patients for their collaboration. A.F-L is a predoctoral fellow of I3P Program from Ministerio de Educación y Ciencia, SpainPeer reviewe

Liver involvement in a large cohort of patients with hereditary hemorrhagic telangiectasia: Echo-color-Doppler vs multislice computed tomography study

Background/Aims: Hepatic arterio-venous malformations (HAVMs) have been found in 74% of hereditary hemorrhagic telangiectasia (HHT) patients with multislice CT (MSCT). This single-blind study aimed to compare the diagnostic accuracy of echo-color-Doppler with MSCT and identify the most sensitive ultrasound criteria indicating hepatic shunts. Methods: One hundred and fifty-three HHT patients were systematically screened for HAVMs by biological tests, abdominal MSCT and echo-color-Doppler. Twenty-five normal subjects and 15 cirrhotic patients were also included as control groups. Both intrahepatic ("color spots" and hypervascularization) and extrahepatic parameters (diameter, flow velocity and tortuosity of hepatic artery and diameter and flow velocity of portal/hepatic vein) were utilized. "Color-spots" are defined as subcapsular vascular spots with a high-velocity arterial blood flow and low resistivity index and can identify extremely small HAVMs. Results: CT was positive in 128/153 (84%) patients and Doppler color spots were found in 131/153 (86%) patients. The sensitivity, specificity and diagnostic accuracy of "color spots" compared to MSCT were 95.3%, 68.0% and 91.8%, respectively. The "color-spot" showed a greater correlation to CT (V-index = 0.655; p < 0.0001) than extrahepatic criteria (V = 0.317). In 20/29 (69%) subjects, echo-color-Doppler, confirmed by CT, identified the third criterion for definite HHT diagnosis. Conclusions: Intrahepatic criteria was superior to extrahepatic criteria for identification of HAVMs. A new Doppler parameter ("color-spots") with an optimal accuracy for detecting HAVMs is proposed for easy periodic screening of HHT patients. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved

A long diagnostic delay in patients with Hereditary Haemorrhagic Telangiectasia: a questionnaire-based retrospective study

<p>Abstract</p> <p>Background</p> <p>The difficulty in establishing a timely correct diagnosis is a relevant matter of concern for several rare diseases. Many rare-disease-affected patients suffer from considerable diagnostic delay, mainly due to their poor knowledge among healthcare professionals, insufficient disease awareness among patients’ families, and lack of promptly available diagnostic tools. Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal-dominantly inherited vascular dysplasia, affecting 1:5,000-10,000 patients. HHT is characterized by high variability of clinical manifestations, which show remarkable overlapping with several common diseases.</p> <p>Aim</p> <p>To perform a detailed analysis concerning the diagnostic time lag occurring in patients with HHT, defined as the time period spanning from the first clinical manifestation to the attainment of a definite, correct diagnosis.</p> <p>Methods</p> <p>A questionnaire was administered to the HHT patients previously recruited from 2000 and 2009. Clinical onset, first referral to a physician for disease manifestations, and first correct diagnosis of definite HHT were collected. Eventual misdiagnosis at first referral and serious complications occurring throughout the time elapsing between disease onset and definite diagnosis were also addressed.</p> <p>Results</p> <p>In the 233 respondents, the clinical onset of disease occurred at an age of 14.1 yrs, while the age of first referral and the age of first definite diagnosis of HHT were 29.2 yrs and 40.1 yrs, respectively. Only 88/233 patients received a correct diagnosis at first counseling. Thus, the diagnostic time lag, represented by the time elapsing from disease onset and first definite diagnosis of HHT, proved to be 25.7 yrs. Twenty-two patients suffered from severe complications during this time interval. The diagnostic delay was significantly longer (p < 0.001) in index patients (first patients who attained definite HHT diagnosis in a given family) than in non-index patients (relative of index patients). The diagnostic time lag was also significantly associated with education grade (p < 0.001).</p> <p>Conclusions</p> <p>Our data report for the first time a systematic inquiry of diagnostic delay in HHT showing that patients receive a definite diagnosis only after nearly three decades from disease onset. Concerted efforts are still to be made to increase awareness of this disease among both families and physicians.</p

Safety of reduced or absent antithrombotic therapy after left atrial appendage closure in patients affected by hereditary hemorrhagic telangiectasia and atrial fibrillation

Left atrial appendage (LAA) closure represents a novel therapeutic chance for patients with contraindications to long-term anticoagulation therapy, such as those affected by hereditary hemorrhagic telangiectasia (HHT) and atrial fibrillation (AF). Nevertheless, current experts' indications suggest the postprocedural administration of antithrombotic therapies to minimize the residual thromboembolic risk due to AF and to the need for device endothelialization. The aim of our study was to investigate the safety and effectiveness of LAA closure in preventing arterial thromboembolism in a very high-bleeding risk group, such as HHT patients, who are at risk not to tolerate even the mild postprocedural antithrombotic therapy usually recommended.BACKGROUND: Left atrial appendage (LAA) closure represents a novel therapeutic chance for patients with contra-indications to long-term anticoagulation therapy, such as those affected by hereditary hemorrhagic telangiectasia (HHT) and atrial fibrillation (AF). Nevertheless, current experts' indications suggest the postprocedural administration of an-tithrombotic therapies to minimize the residual thromboembolic risk due to AF and to the need for device endotheli-alization. The aim of our study was to investigate the safety and effectiveness of LAA closure in preventing arterial thromboembolism in a very high-bleeding risk group, such as HHT patients, who are at risk not to tolerate even the mild postprocedural antithrombotic therapy usually recommended. METHODS: Eight HHT-affected patients with non-valvular AF, high-bleeding risk and/or known intolerance to anti -platelet and anticoagulant therapy were treated with interventional LAA occlusion with the AmplatzerTM Cardiac PlugTM and AmplatzerTM AmuletTM devices. Device implantation was successful in all patients. RESULTS: Postprocedural antiplatelet/anticoagulation therapy was attempted in seven patients: adherence to therapy exceeded 6 months only for one, while four patients suspended all antithrombotic medications within 30 days from the procedure due to an increase in bleeding frequency and/or severity and the other two discontinued treatment within 6 months; a single patient was not prescribed any antithrombotic therapy. At a medium follow-up of 22.4 +/- 14.3 months no thromboembolic episodes attributable to AF or device related thrombosis were reported. Two deaths were recorded 1231 and 783 days after the procedure which were classified as unrelated to any cerebral or cardiovascular accident. CONCLUSIONS: Our study suggests that the percutaneous LAA closure in HHT patients with AF could be safe and effective in preventing arterial systemic thromboembolism, also in the presence of reduced or absent postinterventional antithrombotic treatment. LAA occluder implantation can represent a valid and potentially life-saving alternative to life-long anticoagulant therapy in HHT, as in other very high-bleeding risk patients