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Prosthetic joint infections caused by Campylobacter are uncommon, with the majority of cases being attributed to C. fetus. This case report represents the third instance of a prosthetic hip infection caused by C. coli following an episode of gastroenteritis and, notably, in an immunocompetent patient. The infection was successfully managed by surgical debridement and lavage with retention of the prosthesis and 12 weeks of antibiotics. Furthermore, we present the first whole-genome sequence of a Campylobacter strain responsible for prosthetic joint infection and offer a comprehensive review of the literature on such infections. [ABSTRACT FROM AUTHOR]

Interferon regulatory factor 2 binding protein-like (IRF2BPL) encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals who carry damaging heterozygous variants in IRF2BPL and are affected with neurological symptoms. Five individuals who carry IRF2BPL nonsense variants resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The IRF2BPL bioinformatics signature based on population genomics is consistent with a gene that is intolerant to variation. We show that the fruit-fly IRF2BPL ortholog, called pits (protein interacting with Ttk69 and Sin3A), is broadly detected, including in the nervous system. Complete loss of pits is lethal early in development, whereas partial knockdown with RNA interference in neurons leads to neurodegeneration, revealing a requirement for this gene in proper neuronal function and maintenance. The identified IRF2BPL nonsense variants behave as severe loss-of-function alleles in this model organism, and ectopic expression of the missense variants leads to a range of phenotypes. Taken together, our results show that IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.

Background: Aicardi-Goutières syndrome (AGS) is a type I interferonopathy usually characterized by early-onset neurologic regression. Biallelic mutations in LSM11 and RNU7-1, components of the U7 small nuclear ribonucleoprotein (snRNP) complex, have been identified in a limited number of genetically unexplained AGS cases. Impairment of U7 snRNP function results in misprocessing of replication-dependent histone (RDH) pre-mRNA and disturbance of histone occupancy of nuclear DNA, ultimately driving cGAS-dependent type I interferon (IFN-I) release. Objective: We performed a clinical, genetic, and immunological workup of 3 unrelated patients with uncharacterized AGS. Methods: Whole exome sequencing (WES) and targeted Sanger sequencing of RNU7-1 were performed. Primary fibroblasts were used for mechanistic studies. IFN-I signature and STAT1/2 phosphorylation were assessed in peripheral blood. Cytokines were profiled on serum and cerebrospinal fluid (CSF). Histopathology was examined on brain and kidney tissue. Results: Sequencing revealed compound heterozygous RNU7-1 mutations, resulting in impaired RDH pre-mRNA processing. The 3′ stem-loop mutations reduced stability of the secondary U7 snRNA structure. A discrete IFN-I signature in peripheral blood was paralleled by MCP-1 (CCL2) and CXCL10 upregulation in CSF. Histopathological analysis of the kidney showed thrombotic microangiopathy. We observed dysregulated STAT phosphorylation upon cytokine stimulation. Clinical overview of all reported patients with RNU7-1-related disease revealed high mortality and high incidence of organ involvement compared to other AGS genotypes. Conclusions: Targeted RNU7-1 sequencing is recommended in genetically unexplained AGS cases. CSF cytokine profiling represents an additional diagnostic tool to identify aberrant IFN-I signaling. Clinical follow-up of RNU7-1-mutated patients should include screening for severe end-organ involvement including liver disease and nephropathy. [ABSTRACT FROM AUTHOR]

Dialysis-related amyloidosis (DRA) or β2microglobulin (β2m)-amyloidosis is a disorder caused by the inability to clear a protein called β2m in patients with chronic kidney disease. It results in deposition of β2m as amyloid fibrils, most commonly in bones and joints. Infrequently, visceral organs may be involved. With modern high-flux haemodialysis, DRA has become a rare disease, yet it may occur. We present a case of DRA in an 86-year- old woman. This case is particularly notable for its rare presentation as chronic intestinal pseudo-obstruction. It is of paramount importance to recognise this entity in order to reduce delay in treatment and avoid patients being frustrated not getting a diagnosis. [ABSTRACT FROM AUTHOR]

Abstract: Background: Patients with Fabry disease (FD) develop progressive left ventricular hypertrophy (LVH). In screening studies in patients with LVH, the prevalence of FD ranges from 0 to 12%. This variability is attributable to different factors like diverging inclusion and exclusion criteria, the evaluation of selected populations and suboptimal screening methods. In this study, we aimed to determine the prevalence of FD in an unselected population of everyday clinical practice presenting LVH, defined as a maximal end-diastolic septal or posterior wall thickness ≥13mm, without exclusion of patients with arterial hypertension or valvular pathology, and using optimal screening methods. Methods: In adult males, a two-tier approach was used; α-Galactosidase A (aGAL A) activity was measured using a dried bloodspot test (DBS) and diagnosis was confirmed by mutation analysis of the GLA gene. In females, mutation analysis was the primary screening tool. Results: 362 men and 178 women were screened. Six patients were diagnosed with a genetic sequence alteration of the GLA gene. One man had a novel mutation, GLA p.Ala5Glu (c.44C>A), presenting as classical FD. Another man and three women had the previously described GLA p.Ala143Thr (c.427G>A) mutation, which generally presents as an attenuated phenotype. One woman had a novel sequence alteration c.639+6A>C, which appeared to be a polymorphism. All true Fabry patients had arterial hypertension (AHT), and one had hypertrophic obstructive cardiomyopathy (HOCM). Conclusions: In a group of unselected patients with LVH, we found a prevalence of Fabry disease of 0.9%. AHT or type of hypertrophy should not be an exclusion criterion for screening for FD. [Copyright &y& Elsevier]

Fabry disease is an X-linked inherited lysosomal disorder that causes accumulation of glycosphingolipids in body fluids and tissues, leading to progressive organ damage and reduced life expectancy. It can affect both males and females and can be classified into classic or later-onset phenotypes. In classic Fabry disease, α-galactosidase A (α-Gal A) activity is absent or severely reduced and disease manifestations have an early onset that can affect multiple organs. In contrast, in later-onset Fabry disease, patients have residual α-Gal A activity and clinical features are primarily confined to the heart. Individualized therapeutic goals in Fabry disease are required due to varying phenotypes and patient characteristics, and the wide spectrum of disease severity. An international group of expert physicians convened to discuss and develop practical clinical recommendations for disease- and organ-specific therapeutic goals in Fabry disease, based on expert consensus and evidence identified through a structured literature review. Biomarkers reflecting involvement of various organs in adult patients with classic Fabry disease are discussed and consensus recommendations for disease- and organ-specific therapeutic goals are provided. These consensus recommendations should support the establishment of individualized approaches to the management of patients with classic Fabry disease by considering identification, diagnosis, and initiation of disease-specific therapies before significant organ involvement, as well as routine monitoring, to reduce morbidity, optimize patient care, and improve patient health-related quality of life. [ABSTRACT FROM AUTHOR]

Background and objectives Screening for Fabry disease (FD), an X-linked lysosomal storage disorder, reveals a significant number of individuals with a genetic variant of unknown significance without classical FD manifestations; these variants in the α-galactosidase A gene often result in a high residual leukocyte α-galactosidase A and it is unclear whether these individuals suffer from FD. Therefore, a structured diagnostic approach is warranted. We present a diagnostic algorithm on how to approach adults with chronic kidney disease and an uncertain diagnosis of FD nephropathy. Design, setting, participants, and measurements A modified Delphi procedure was conducted to reach consensus among 11 FD experts. A systematic review was performed to identify possible criteria that could confirm or exclude FD nephropathy. Results The gold standard for FD nephropathy was defined as characteristic storage on electron microscopy (EM) in a kidney biopsy in the absence of medication that may induce similar storage. The suggested criteria to confirm FD nephropathy are as follows: ‘renal cysts’, ‘Maltese cross sign’, ‘immunohistochemical staining of Gb3 in urine’ and ‘high urinary Gb3’; and to exclude FD nephropathy: ‘absence of renal cysts’, ‘small kidneys’ and ‘high protein excretion’ were rejected because of low or uncertain specificity. Urinary Gb3 may be increased in other kidney diseases and there was no agreement on this criterion, although a third of the panel indicated that it is sufficient to diagnose FD nephropathy. The ‘Maltese cross sign’ and ‘high urinary Gb3’ were selected as red flags to suggest the possibility of FD nephropathy, but are not sufficient for a definite diagnosis of FD nephropathy. Conclusions In adults with chronic kidney disease, an α-galactosidase A gene variant and an uncertain diagnosis of FD, a kidney biopsy with EM analysis should be performed to confirm or reject the diagnosis of FD nephropathy. Other criteria currently cannot substitute for a biopsy in these cases. [ABSTRACT FROM AUTHOR]

Purpose: To report on a rare case of intermediate uveitis occurring in a patient with common variable immunodeficiency (CVID) and a heterozygous TNFRSF13B variant., Methods: Observational case report., Results: A 23-year-old male presented with a 3-month history of increasing floaters and blurred vision to both eyes. He had been treated with topical and intravitreal corticosteroids by his local ophthalmologist nine months before. Ocular examination demonstrated bilateral intermediate uveitis with retinal vasculitis. He had been treated with intravenous immunoglobulins during childhood, due to primary humoral immunodeficiency. Systemic work-up for other causes of intermediate uveitis was unremarkable, notably no features of systemic sarcoid-like disease were detected. Initial treatment with mycophenolate mofetil showed insufficient response, and upon switching to adalimumab, clinical remission was achieved. Immunocytometry and genetic work-up revealed a smB+CD21norm subtype of CVID and a heterozygous TNFRSF13B variant., Conclusion: This report of CVID-associated intermediate uveitis in a patient with a heterozygous TNFRSF13B variant highlights the potential involvement of the eye within CVID-associated autoimmunity and the role for anti-TNF blockade in this challenging group of patients., Competing Interests: The authors have no conflicts of interest to disclose. No funding was obtained for this research.

Introduction: In recent decades, we witnessed a revolution in genetic technology. Some 20 years ago, analysing a single gene was quite laborious and time-consuming. In addition, diagnostic testing was only available for selected genes. Nowadays, whole exome analysis - a technique enabling sequencing of all protein coding sequences in the entire genome - is gradually introduced in a clinical setting. Whole genome sequencing forms the ultimate exponent of this evolution and offers an even broader application., Methods: A review of the application of these technologies in a diagnostic setting is presented., Results: Whole exome sequencing has a prominent place in modern clinical diagnostics. It offers a cost- and time-efficient way to interrogate all protein coding portions of the genome leading to a quick and adequate diagnosis, also in cases of phenotypic heterogeneity. As sequencing costs continue to drop, whole genome sequencing will take over in the near future guaranteeing a further improvement of the quality of genetic testing., Conclusion: Due to technological advances in the past decades, the field of clinical diagnostics has changed dramatically. With techniques such as whole exome and whole genome sequencing, the diagnostic yield increases serving both the patient and the health care system.

Cardiac masses are rare, the differential diagnosis includes infections with vegetations or abscesses, neoplasms, thrombi, and structural abnormalities. A pathology specimen is essential in therapeutic strategy planning for a cardiac mass, also if the primary imaging findings look dramatic at the start. Even in an inoperable setting, a life-saving therapy might be available. We report a case of a 49-year-old man, known with HIV-1, who was several times admitted with pericarditis. Now he was hospitalized with progressive lower limb edema, atrial fibrillation and detection of a giant cardiac mass in left and right atrium with infiltration of surrounding tissues. Given the extent and invasiveness of the mass, he was inoperable. Biopsy specimen was obtained and staging was performed by PET-CT scan. The diagnosis of stage IV Burkitt lymphoma with predominant extranodal cardiac involvement was withheld wherefore promptly aggressive therapy was started according to the GMALL B-NHL86 protocol. The therapy was downgraded to R-CHOP due to tolerance problems. He achieved a complete remission and during follow-up no relapse was detected.

Introduction: Fabry disease (FD) is a lysosomal storage disorder resulting in progressive nervous system, kidney and heart disease. Enzyme replacement therapy (ERT) may halt or attenuate disease progression. Since administration is burdensome and expensive, appropriate use is mandatory. We aimed to define European consensus recommendations for the initiation and cessation of ERT in patients with FD., Methods: A Delphi procedure was conducted with an online survey (n = 28) and a meeting (n = 15). Patient organization representatives were present at the meeting to give their views. Recommendations were accepted with ≥75% agreement and no disagreement., Results: For classically affected males, consensus was achieved that ERT is recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but may be considered in patients of ≥16 years in the absence of clinical signs or symptoms of organ involvement. Classically affected females and males with non-classical FD should be treated as soon as there are early clinical signs of kidney, heart or brain involvement, while treatment may be considered in females with non-classical FD with early clinical signs that are considered to be due to FD. Consensus was achieved that treatment should not be withheld from patients with severe renal insufficiency (GFR < 45 ml/min/1.73 m(2)) and from those on dialysis or with cognitive decline, but carefully considered on an individual basis. Stopping ERT may be considered in patients with end stage FD or other co-morbidities, leading to a life expectancy of <1 year. In those with cognitive decline of any cause, or lack of response for 1 year when the sole indication for ERT is neuropathic pain, stopping ERT may be considered. Also, in patients with end stage renal disease, without an option for renal transplantation, in combination with advanced heart failure (NYHA class IV), cessation of ERT should be considered. ERT in patients who are non-compliant or fail to attend regularly at visits should be stopped., Conclusion: The recommendations can be used as a benchmark for initiation and cessation of ERT, although final decisions should be made on an individual basis. Future collaborative efforts are needed for optimization of these recommendations.

Background: Anderson-Fabry disease (AFD) is an X-linked condition originating from a deficiency in alpha-galactosidase, a lysosomal enzyme. Multi-organ involvement ensues in early adulthood and vital organs are affected: the kidneys, brain, heart. Several reports however suggest that AFD is underdiagnosed., Methods: We screened a kidney transplant population using a two-tier approach. The first tier was the determination of alpha-galactosidase A (AGALA) activity using a dried blood spot on filter paper (DBFP); in the second tier, patients with the lowest alpha-galactosidase levels were further subjected to mutation analysis of the GLA gene., Results: From the database of 2328 patients, 1233 subjects met the inclusion criteria. Finally, after informed consent, 673 patients were screened (54.5%-395 women and 278 men). DBFP analysis resulted in a mean AGALA of 2.63 +/- 2.48 micromol/L/h (2.5 and 97.5 percentile were 0.0001 and 5.07 micromol/L/h, respectively). Eleven patients were subjected to further genetic analysis. In a male patient a pathogenic missense mutation p.Ala143Thr (c.427A>G) was identified., Conclusions: Our results show that the proposed approach can detect AFD patients in a until now seldomly screened high-risk group: kidney transplant patients. We conclude that screening for AFD in high-risk populations is a cost-effective, technically feasible and clinically valuable objective.

Phenytoin intoxication can result in major and possibly life-threatening disorders. Furthermore, the hepatic clearance can become saturated, thus, shifting the elimination from first- to zero-order kinetics. This results in a slow elimination of the compound in case of intoxication. The treatment modalities for phenytoin overdose are limited. Taking into account the high level of protein binding, the molecule is not easily eliminated from the body by means of extracorporal epuration. Although reports exist on the use of MARS (molecular adsorbents recirculating system) dialysis, peritoneal dialysis, and standard dialysis for the elimination, in practice, hemoperfusion, is the most often applied technique. The authors report the case of a hypoalbuminemic patient with severe neurologic signs of phenytoin intoxication (total concentration moderately elevated, free fraction high). A combination of high-flux dialysis and hemoperfusion resulted in a considerable extraction of the drug, accelerating the natural clearance from the body and ameliorating clinical signs of intoxication. In selected patients (with a high free fraction of phenytoin), high-flux dialysis may be a valuable alternative or adjuvant to hemoperfusion.