Clinical hints to diagnosis of attenuated forms of Mucopolysaccharidoses

The mucopolysaccharidoses (MPS) are clinically similar but also heterogeneous in terms of major or minor involvement of different organs/systems, burden of disease, and rate of progression. The attenuated forms of MPS, due to their less severe presentations, are more difficult to diagnose and often receive a significantly delayed diagnosis. On the other hand, the diagnosis is very important since the attenuated forms may benefit from earlier treatments. The aim of this paper is to describe the natural history and the clinical signs useful to arise a suspicion of an attenuated form of MPS. MPS patients usually show a cluster of signs and symptoms, one of which may be the trigger for an evaluation by a specialist. Individuals with attenuated MPS are mostly cognitively normal, and dysmorphisms of the facies may be mild or absent. The most frequently involved organs/systems are the osteoarticular system, heart, and eyes. These patients may also have hepatosplenomegaly, hearing loss, and respiratory problems. When they are referred to a specialist (rheumatologist, cardiologist, ophthalmologist, surgeon, orthopedist, etc.) for their main complaint, the other signs and symptoms are likely to be missed in the medical history. To avoid missing data and to save time, we propose a semistructured medical history form to be filled in by the patients or their caregivers while waiting for evaluation by a specialist

Anderson-Fabry’s Disease: A Rare but Treatable Case of Fever of Unknown Origin

Anderson-Fabry’s disease (AFD) is a rare, X-linked lysosomal storage disorder caused by the complete deficiency or attenuated activity of the enzyme α-galactosidase A, leading to progressive systemic intracellular accumulation of glycosphingolipids and subsequent cellular dysfunction, inflammation and fibrosis. Fever is a frequently misinterpreted symptom in the early stages of the disease, leading to diagnostic delay. We present the case of a 35-year-old man admitted to our Periodic Fever Research Centre for long-lasting recurrent episodes of fever of unknown origin. After extensive assessment, we diagnosed AFD associated with a novel GLA mutation. We started enzyme replacement therapy with clinical benefit and complete remission of fever

Macular Impairment in Fabry Disease: A Morpho-functional Assessment by Swept-Source OCT Angiography and Focal Electroretinography.

Purpose Fabry disease (FD) is a multiorgan X-linked condition characterized by a deficiency of the lysosomal enzyme alpha-galactosidase A, resulting in a progressive intralysosomal deposit of globotriaosylceramide. The aim of this study was to evaluate the macular ultrastructure of the vascular network using optical coherence tomography angiography (OCTA) and to evaluate macular function using focal electroretinography (fERG) in Fabry patients (FPs). Methods A total of 20 FPs (38 eyes, mean age 57 ± 2.12 SD, range of 27-80 years) and 17 healthy controls (27 eyes, mean age 45 years ± 20.50 SD, range of 24-65 years) were enrolled in the study. Color fundus photography, swept-source optical coherence tomography (SS-OCT), OCTA and fERG were performed in all subjects. The OCTA foveal avascular zone (FAZ), vasculature structure, superficial and deep retinal plexus densities (images of 4.5 × 4.5 mm) and fERG amplitudes were measured. Group differences were statistically assessed by Student's t-test and ANOVA. Results In the FP group, the FAZ areas of the superficial and deep plexuses were enlarged (P = 0.036, t = 2.138; P < 0.001, t = -3.889, respectively), the vessel density was increased in the superficial plexus, and the fERG amplitude was reduced (P < 0.001, t = -10.647) compared with those in healthy controls. No significant correlations were found between the structural and functional data. Conclusions OCTA vascular abnormalities and reduced fERG amplitudes indicate subclinical signs of microangiopathy with early retinal dysfunction in FPs. This study highlights the relevance of OCTA imaging analysis in the identification of abnormal macular vasculature as an ocular hallmark of FD

Transitional care management in patients with auto-inflammatory diseases: experience of cooperation of a paediatric and adult centre

Abstract Objectives Auto-inflammatory Diseases (AIDs) are a group of diseases with a strong genetic component, inducing an inappropriate activation of innate immunity. The patients with pediatric onset will face the transitional care (TC) from a pediatrician to an adult care setting, during the critical phase of the adolescence. That implies a risk of failure and drop out, due to the different approach of pediatrician compared to the adult doctor. To describe the model of TC for AIDs from a paediatric to adult centre of two hospitals in Rome, and to pointing out the different steps emerged from specific experiences. Methods In November 2020, a Board of paediatricians and internists discussed their experience to identify "hot topics" for a successful management of TC. Results The Board agreed on the optimal time for the transition (12–18 years). Specific elements to be considered are the reached level of emotional and intellectual maturity, and the clinical stability of the disease. Conclusions The TC of patients with chronic AIDs, requires a strong cooperation to define the adequate follow-up, and to guarantee the compliance to the treatment. This model allows us to investigate AIDs complex cases, requiring a long period of observations

Functional and pharmacological evaluation of novel GLA variants in Fabry disease identifies six (two de novo) causative mutations and two amenable variants to the chaperone DGJ

Abstract Background Allelic heterogeneity is an important feature of the GLA gene for which almost 900 known genetic variants have been discovered so far. Pathogenetic GLA variants cause alpha-galactosidase A (α-Gal A) enzyme deficiency leading to the X-linked lysosomal storage disorder Fabry disease (FD). Benign GLA intronic and exonic variants ( e.g. pseudodeficient p.Asp313Tyr) have also been described. Some GLA missense variants, previously deemed to be pathogenetic ( e.g. p.Glu66Gln and p.Arg118Cys), they have been reclassified as benign after re-evaluation by functional and population studies. Hence, the functional role of novel GLA variants should be investigated to assess their clinical relevance. Results We identified six GLA variants in 4 males and 2 females who exhibited symptoms of FD: c.159C>G p.(Asn53Lys), c.400T>C p.(Tyr134His), c.680G>C (p.Arg227Pro), c.815A>T p.(Asn272Ile), c.907A>T p.(Ile303Phe) and c.1163_1165delTCC (p.Leu388del). We evaluated their impact on the α-Gal A protein by bioinformatic analysis and homology modelling, by analysis of the GLA mRNA, and by site-directed mutagenesis and in vitro expression studies. We also measured their responsiveness to the pharmacological chaperone DGJ. Conclusions The six detected GLA variants cause deficient α-Gal A activity and impairment or loss of the protein wild-type structure. We found p.Asn53Lys and p.Ile303Phe variants to be susceptible to DGJ

Mesothelioma in Familial Mediterranean Fever With Colchicine Intolerance: A Case Report and Literature Review

A 65-year-old Italian physician affected by Familial Mediterranean fever (FMF) was hospitalized due to progressive abdominal enlargement, which had begun 6 months before admission. Physical examination revealed ascites and bilateral leg edema. Abdominal CT scan showed ascitic fluid and extensive multiple peritoneal implants; peritoneal CT-guided biopsy revealed an epithelial-type malignant mesothelioma. The patient\u2019s past medical history revealed recurrent episodes of abdominal pain and fever from the age of 2. Clinical diagnosis of FMF was suspected at the age of 25, while genetic analysis, performed at the age of 50, confirmed homozygosity for the M694I mutation in the MEFV gene. Treatment with the first line FMF drug colchicine was started and stopped several times because of worsened leukopenia. The patient in fact had a history of asymptomatic leukopenia/lymphopenia from an early age; the intake of colchicine aggravated his pre-existing problem until the definitive suspension of the drug. As for second-line drugs, canakinumab was first prescribed, but due to prescription issues, it was not possible to be administered. When he was given anakinra, there was a worsening of leukopenia leading to septic fever. Systematic literature review indicates that, in most cases, recurrent peritoneal inflammation results in benign peritoneal fibrosis or less commonly in encapsulating peritonitis. There are only a few reported cases of recurrent peritoneal inflammation progressing from FMF to peritoneal mesothelioma (MST). In such cases, intolerance to colchicine or its erratic intake may lead to long-term recurrent inflammation, which usually precedes the development of the tumor, while pre-existing leukopenia, as in our patient, could also be a factor promoting or accelerating the tumor progression. In conclusion, we suggest that in the presence of intolerance or resistance to colchicine, interleukin (IL)-1 inhibition could suppress peritoneal inflammation and prevent MSTs

A Snapshot on the On-Label and Off-Label Use of the Interleukin-1 Inhibitors in Italy among Rheumatologists and Pediatric Rheumatologists: A Nationwide Multi-Center Retrospective Observational Study.

Background: Interleukin (IL)-1 inhibitors have been suggested as possible therapeutic options in a large number of old and new clinical entities characterized by an IL-1 driven pathogenesis. Objectives: To perform a nationwide snapshot of the on-label and off-label use of anakinra (ANA) and canakinumab (CAN) for different conditions both in children and adults. Methods: We retrospectively collected demographic, clinical, and therapeutic data from both adult and pediatric patients treated with IL-1 inhibitors from January 2008 to July 2016. Results: Five hundred and twenty-six treatment courses given to 475 patients (195 males, 280 females; 111 children and 364 adults) were evaluated. ANA was administered in 421 (80.04%) courses, CAN in 105 (19.96%). Sixty-two (32.1%) patients had been treated with both agents. IL-1 inhibitors were employed in 38 different indications (37 with ANA, 16 with CAN). Off-label use was more frequent for ANA than CAN (p < 0.0001). ANA was employed as first-line biologic approach in 323 (76.7%) cases, while CAN in 37 cases (35.2%). IL-1 inhibitors were associated with corticosteroids in 285 (54.18%) courses and disease modifying anti-rheumatic drugs (DMARDs) in 156 (29.65%). ANA dosage ranged from 30 to 200 mg/day (or 1.0-2.0 mg/kg/day) among adults and 2-4 mg/kg/day among children; regarding CAN, the most frequently used posologies were 150mg every 8 weeks, 150mg every 4 weeks and 150mg every 6 weeks. The frequency of failure was higher among patients treated with ANA at a dosage of 100 mg/day than those treated with 2 mg/kg/day (p = 0.03). Seventy-six patients (14.4%) reported an adverse event (AE) and 10 (1.9%) a severe AE. AEs occurred more frequently after the age of 65 compared to both children and patients aged between 16 and 65 (p = 0.003 and p = 0.03, respectively). Conclusions: IL-1 inhibitors are mostly used off-label, especially ANA, during adulthood. The high frequency of good clinical responses suggests that IL-1 inhibitors are used with awareness of pathogenetic mechanisms; adult healthcare physicians generally employ standard dosages, while pediatricians are more prone in using a weight-based posology. Dose adjustments and switching between different agents showed to be effective treatment strategies. Our data confirm the good safety profile of IL-1 inhibitors

Development and implementation of the AIDA International Registry for patients with Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis syndrome

Objective: Aim of this paper is to illustrate the methodology, design, and development of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to patients with the Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome. Methods: This is a physician-driven, non-population- and electronic-based registry proposed to gather real-world demographics, clinical, laboratory, instrumental and socioeconomic data from PFAPA patients. Data recruitment is realized through the on-line Research Electronic Data Capture (REDCap) tool. This registry is thought to collect standardized information for clinical research leading to solid real-life evidence. The international scope and the flexibility of the registry will facilitate the realization of cutting-edge study projects through the constant updating of variables and the possible merging and transfer of data between current and future PFAPA registries. Results: A total of 112 centers have already been involved from 23 countries and 4 continents starting from August 24th, 2021, to April 6th, 2022. In total 56/112 have already obtained the formal approval from their local Ethics Committees. The platform counts 321 users (113 principal investigators, 203 site investigators, two lead investigators, and three data managers). The registry collects retrospective and prospective data using 3,856 fields organized into 25 instruments, including PFAPA patient's demographics, medical histories, symptoms, triggers/risk factors, therapies, and impact on the healthcare systems. Conclusions: The development of the AIDA International Registry for PFAPA patients will enable the on-line collection of standardized data prompting real-life studies through the connection of worldwide groups of physicians and researchers. This project can be found on NCT 05200715