Characterization of the plasma proteomic profile of Fabry disease: Potential sex- and clinical phenotype-specific biomarkers.

Fabry disease (FD) is a X-linked rare lysosomal storage disorder caused by deficient α-galactosidase A (α-GalA) activity. Early diagnosis and the prediction of disease course are complicated by the clinical heterogeneity of FD, as well as by the frequently inconclusive biochemical and genetic test results that do not correlate with clinical course. We sought to identify potential biomarkers of FD to better understand the underlying pathophysiology and clinical phenotypes. We compared the plasma proteomes of 50 FD patients and 50 matched healthy controls using DDA and SWATH-MS. The >30 proteins that were differentially expressed between the 2 groups included proteins implicated in processes such as inflammation, heme and haemoglobin metabolism, oxidative stress, coagulation, complement cascade, glucose and lipid metabolism, and glycocalyx formation. Stratification by sex revealed that certain proteins were differentially expressed in a sex-dependent manner. Apolipoprotein A-IV was upregulated in FD patients with complications, especially those with chronic kidney disease, and apolipoprotein C-III and fetuin-A were identified as possible markers of FD with left ventricular hypertrophy. All these proteins had a greater capacity to identify the presence of complications in FD patients than lyso-GB3, with apolipoprotein A-IV standing out as being more sensitive and effective in differentiating the presence and absence of chronic kidney disease in FD patients than renal markers such as creatinine, glomerular filtration rate and microalbuminuria. Identification of these potential biomarkers can help further our understanding of the pathophysiological processes that underlie the heterogeneous clinical manifestations associated with FD.

Genetic and clinical characterization of a novel FH founder mutation in families with hereditary leiomyomatosis and renal cell cancer syndrome.

BACKGROUND: Hereditary leiomyomatosis and renal cell cancer syndrome is a rare autosomal dominant hereditary syndrome. Previously, we published the largest cohort of FH mutation carriers in Spain and observed a highly recurrent missense heterozygous variant, FH(NM_000143.4):c.1118A > G p.(Asn373Ser), in 104 individuals from 31 apparently unrelated families. Here, we aimed to establish its founder effect and characterize the associated clinical phenotype. RESULTS: Haplotype analysis confirmed that families shared a common haplotype (32/38 markers) spanning 0.61-0.82 Mb, indicating this recurrent variant was inherited from a founder ancestor. Cutaneous and uterine leiomyomatosis were diagnosed in 64.6% (64/99) and 98% (50/51) of patients, respectively, and renal cell cancer was present in 10.4% (10/96). The pathogenic FH_c.1118A > G variant is a Spanish founder mutation that originated 12-26 generations ago. We estimate that the variant may have appeared between 1370 and 1720. Individuals carrying this founder mutation had similar frequency of renal cell cancer and a higher frequency of renal cysts and leiomyomas than those in other cohorts of this syndrome. CONCLUSIONS: In the Spanish province of Alicante there is a high prevalence of HLRCC because of the founder mutation FH c.1118A > G; p.(Asn373Ser). The characterization of founder mutations provides accurate and specific information regarding their penetrance and expressivity. In individuals with suspected HLRCC from the province of Alicante, genetic testing by direct analysis of the founder FH c.1118A > G; p.(Asn373Ser) mutation may be a faster and more efficient diagnostic tool compared with complete gene sequencing.

Current clinical spectrum of common variable immunodeficiency in Spain: The multicentric nationwide GTEM-SEMI-CVID registry.

Common variable immunodeficiency (CVID) constitutes a heterogenic group of primary immunodeficiency disorders with a wide-ranging clinical spectrum. CVID-associated non-infectious morbidity constitutes a major challenge requiring a full understanding of its pathophysiology and its clinical importance and global variability, especially considering the broad clinical, genetic, and regional heterogeneity of CVID disorders. This work aimed to develop a nationwide, multicenter, retrospective study over a 3-year period describing epidemiological, clinical, laboratory, therapeutic, and prognostic features of 250 CVID patients in Spain. The mean diagnostic delay was around 10 years and most patients initially presented with infectious complications followed by non-infectious immune disorders. However, infectious diseases were not the main cause of morbimortality. Non-infectious lung disease was extraordinarily frequent in our registry affecting approximately 60% of the patients. More than one-third of the patients in our cohort showed lymphadenopathies and splenomegaly in their follow-up, and more than 33% presented immune cytopenias, especially Evans' syndrome. Gastrointestinal disease was observed in more than 40% of the patients. Among biopsied organs in our cohort, benign lymphoproliferation was the principal histopathological alteration. Reaching 15.26%, the global prevalence of cancer in our registry was one of the highest reported to date, with non-Hodgkin B lymphoma being the most frequent. These data emphasize the importance of basic and translational research delving into the pathophysiological pathways involved in immune dysregulation and diffuse lymphocytic infiltration. This would reveal new tailored strategies to reduce immune complications, and the associated healthcare burden, and ensure a better quality of life for CVID patients.

Whipple's disease diagnosed during anti-tumor necrosis factor alpha treatment: two case reports and review of the literature.

INTRODUCTION: Whipple's disease is a rare infectious disease caused by Tropheryma whipplei with protean clinical manifestations. This infection may mimic chronic inflammatory rheumatisms. CASE PRESENTATION: We report two cases of Whipple's disease diagnosed in the context of an inflammatory disease with anti-tumor necrosis factor alpha failure. The first patient was a 58-year-old white man with psoriatic spondylarthritis, who was treated with adalimumab, etanercept, infliximab, tocilizumab and golimumab. The second was a 73-year-old white man with rheumatoid arthritis, who received treatment with infliximab, then etanercept and rituximab. CONCLUSIONS: Whipple's disease should be suspected in all patients diagnosed with chronic inflammatory rheumatism, partially controlled or not controlled by treatment with tumor necrosis factor alpha blockers, whose condition worsens after treatment.

Characteristics and outcome in nonagenarians admitted in general internal medicine and other specialties.

UNLABELLED: To describe the characteristics of nonagenarians admitted to the surgical and medical divisions at a tertiary hospital and compare them with nonagenarians admitted to other hospital care services. METHODS: A retrospective study of all hospital discharge episodes via the registry of the Basic Minimum Data Set at the Hospital General Universitario de Alicante from January 2007 until December 2011. RESULTS: Of the 165,870 hospitalizations, 2461 (1.5%) were nonagenarians. The highest number of admitted nonagenarians was in the Division of General Internal Medicine (DGIM) (n=751), followed by the short stay unit (SSU) (n=633). The rate of nonagenarians per 100 admissions to the DGIM was 10.2, significantly higher than that of those admitted to the SSU (6.2) (p<0.001), the service of orthopedic and trauma surgery (2.2) (p<0.001), and other specialties. Females comprised 64.8% of the nonagenarians. Mortality was 17% for the nonagenarians admitted, while for those admitted to the DGIM it was 27.7%. Those hospitalized in the SSU had a lower risk of death during hospitalization (8.1%) (odds ratio [OR] 0.23, 95% confidence interval [CI] 0.16-0.32) and a greater risk of being admitted for diseases and disorders of the circulatory system (OR: 1.58, 95% CI: 1.22-2.05), particularly for heart failure and shock (OR: 1.82, 95% CI: 1.30-2.53), and being discharged with home hospitalization (OR: 8.05, 95% CI: 5.5-11.8). CONCLUSIONS: Nonagenarian patients represent a tenth of those admitted to the DGIM. The profile of nonagenarians admitted to the DGIM is different from other hospital services. Hospital mortality for nonagenarians admitted to the DGIM is high and superior to other hospital services.