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Blanco I.,Board of the Alpha1 Antitrypsin Deficiency Spanish Registry | Lipsker D.,University of Strasbourg | Lara B.,Royal Exeter and Devon Hospital | Janciauskiene S.,Hannover Medical School
British Journal of Dermatology | Year: 2016

Neutrophilic panniculitis associated with alpha-1-antitrypsin deficiency (AATD) is a very rare disease. Its estimated prevalence is 1 in 1000 subjects with severe AATD (usually white individuals with a Pi∗ZZ genotype). It is manifested clinically by painful recurrent ulcerating subcutaneous nodules, and characterized histologically by dense infiltrates of neutrophils in the deep dermis and connective-tissue septae, with secondary lobular panniculitis. It may be the only clinical manifestation of AATD, although it can also occur together with the classical pulmonary or hepatic manifestations of the disease. AATD-associated panniculitis is not only very rare but may also be significantly underdiagnosed. The physician managing a case of panniculitis with a clinical presentation suggestive of AATD and a compatible skin biopsy should measure serum AAT concentration and, if low, determine the AAT phenotype by isoelectric focusing. If uncertainty remains, the SERPINA1 gene should be sequenced to identify the genotype. If AATD is diagnosed, AATD testing of first-degree family members should be performed in order to take appropriate preventive and therapeutic measures, including genetic counselling, education on inheritance, risk arising from tobacco smoke, occupational exposure to pollutants and hepatotoxic substances, and the provision of information on clinical management. Cases of panniculitis in which conventional therapy with dapsone has failed may be managed with intravenous augmentative therapy using human AAT. The current manuscript addresses the fundamental concepts of the pathogenesis of AATD-associated panniculitis and describes the clinical presentation and management of cases in order to reduce underdiagnosis and improve outcomes. © 2015 British Association of Dermatologists.

Lara B.,Royal Exeter and Devon Hospital | Miravitlles M.,CIBER ISCIII
COPD: Journal of Chronic Obstructive Pulmonary Disease | Year: 2015

Alpha-1 antitrypsin deficiency (AATD) is associated with an increased risk of pulmonary emphysema and liver disease. The growing interest in this deficiency in Spain led to the development of the Spanish Registry of Patients with Alpha-1 Antitrypsin Deficiency (REDAAT) in 1993. At present, the REDAAT is a network of more than 350 health care professionals and the database includes a total of 511 individuals. The adult population included consists of 469 individuals (91.8% of the total) and their phenotype distribution is: 348 PiZZ (74.2%), 100 PiSZ (21.3%) and 21 carriers of rare variants (4.5%). The most frequent diagnosis is lung disease (74.6%). Patients with chronic obstructive pulmonary disease (COPD) registered in the REDAAT constitute approximately 15% of the expected cases of AATD-related COPD in Spain. PiZZ showed more severe impairment in lung function and younger age at baseline compared with PiSZ. The mean decline in FEV1 in the PiZZ subgroup was-23 ml/year (SD:142.8), being-18 ml/year (SD:108.8) in PiSZ. Forty-five percent of the PiZZ individuals received augmentation therapy. A total of 61 deaths was recorded. The characteristics of the REDAAT population demonstrate some differential trends compared to other series: distribution of phenotypes, inclusion of children and patients treated with replacement therapy. Patients with the PiSZ phenotype were older and had milder lung function impairment. The most important challenge of this registry is to collect good quality long-term data that will allow better understanding of the natural history of the disease in real life. © Informa Healthcare USA, Inc.

Matamala N.,Instituto Of Investigacion Of Enfermedades Raras Iier | Martinez M.T.,Hospital 12 de Octubre | Lara B.,Royal Exeter and Devon Hospital | Perez L.,Instituto Of Investigacion Of Enfermedades Raras Iier | And 8 more authors.
Journal of Translational Medicine | Year: 2015

Background: SERPINA1 is the gene for alpha-1 antitrypsin (AAT), an acute phase protein with anti-protease and immunoregulatory activities. Mutations in SERPINA1 gene cause AAT deficiency and predispose individuals to early-onset emphysema and liver diseases. Expression of the SERPINA1 gene is regulated by different promoters and alternative splicing events among non-coding exons 1A, 1B and 1C. Methods: We have developed three quantitative PCR (QT-PCR) assays (1A, 1B and 1C). These assays were applied for the analysis of SERPINA1 alternative transcripts in: (1) 16 human tissues and (2) peripheral blood leukocytes from 33 subjects with AAT mutations and 7 controls. Results: Tissue-specific expression was found for the SERPINA1 transcripts. The 1A transcripts were mainly expressed in leukocytes and lung tissue while those detected with the 1B assay were highly restricted to leukocytes. Only 1B transcripts significantly correlated with serum AAT levels. The 1C transcripts were specifically found in lung, liver, kidney and pancreas. Furthermore, the expression of transcripts was related to AAT genotypes. While deficient variants of AAT had no pronounced effect on the transcript expression, null alleles were associated with significant reduction of different transcripts. Conclusions: The possibility to discriminate between SERPINA1 alternative splicing products will help us to understand better the regulation of SERPINA1 gene and its association with SERPINA1 mutations-related diseases. © 2015 Matamala et al.

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