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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.

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.A review of the application of these technologies in a diagnostic setting is presented.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.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.

Patients with Fabry disease (FD) are at a high risk for developing chronic kidney disease and cardiovascular disease. The availability of specific but costly therapy has elevated the profile of this rare condition. This KDIGO conference addressed controversial areas in the diagnosis, screening, and management of FD, and included enzyme replacement therapy and nonspecific standard-of-care therapy for the various manifestations of FD. Despite marked advances in patient care and improved overall outlook, there is a need to better understand the pathogenesis of this glycosphingolipidosis and to determine the appropriate age to initiate therapy in all types of patients. The need to develop more effective specific therapies was also emphasized.

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.

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.

To report on the safety and adequacy of surveillance biopsy for detecting subclinical lesions in clinically stable renal grafts.We established an in-patient surveillance biopsy program with the elective performance of a renal transplant biopsy during the first year after renal transplantation. All biopsies in our centre were performed or supervised by the same operator. Patients were admitted to the hospital the day of biopsy and were discharged after 24h of observation. All patients were biopsied in supine position, using a 16-gauge needle with a spring-loaded gun (Bard) under real-time ultrasound guidance. Complication rates were retrospectively scored using the patients' charts and blood counts before and after biopsy. Major complications were defined as those requiring an intervention for resolution, a transfusion of blood products or an invasive procedure (angiography or surgery), and those that led to acute renal obstruction or failure, septicaemia, graft loss or death. In all other cases complications were considered minor. An adequate biopsy was defined as the presence of 7 or more glomeruli and at least one artery in the biopsy specimen.We performed 282 surveillance biopsies in 248 patients between January 2006 and December 2011. None of the complications were major. We observed 6% minor complications (n = 17). 5.6% (n = 16) of the complications were related to bleeding, with macroscopic haematuria as the most common condition (n = 10; 3.5%), followed by pain (n = 6; 2.1%) eighter due to a perinephric hematoma (n = 5) or a subcutaneous hematoma (n = 1). The biopsies contained a median number of 9 glomeruli (range 0-39) with 70% of biopsies containing at least 7 glomeruli and one artery.The procedure for taking surveillance biopsies was proven to be safe. There were no major complications and only rare minor complications. The majority of the samples were adequate for histological examination.

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.

Fabry disease (FD) is an X-linked disorder of glycosphingolipid catabolism resulting in the accumulation of glycolipids including globotriaosylceramide in cells of various tissues resulting in end-organ manifestations. Initially, FD is typically characterized by angiokeratoma and recurrent episodes of neuropathic pain in the extremities occurring during childhood or adolescence. Most affected patients also exhibit a decreased ability to sweat. Later in life, FD results in left ventricular hypertrophy, proteinuria, renal failure and stroke. These later disease manifestations are non-specific and also common in diabetes, hypertension and atheromatosis and thus for most practitioners do not point into the direction of FD. As a consequence, FD is under-diagnosed and screening of high-risk groups is important for case finding, as is a thorough pedigree analysis of affected patients. In the nephrology clinic, we suggest to screen patients for FD when there is unexplained chronic kidney disease in males younger than 50 years and females of any age. In men, this can be performed by measuring α-galactosidase A activity in plasma, white blood cells or dried blood spots. In women, mutation analysis is necessary, as enzyme measurement alone could miss over one-third of female Fabry patients. A multidisciplinary team should closely monitor all known Fabry patients, with the nephrologist screening kidney impairment (glomerular filtration rate and proteinuria) on a regular basis. Transplanted Fabry patients have a higher mortality than the regular transplant population, but have acceptable outcomes, compared with Fabry patients remaining on dialysis. It is unclear whether enzyme replacement therapy (ERT) prevents deterioration of kidney function. In view of the lack of compelling evidence for ERT, and the low likelihood that a sufficiently powered randomized controlled trial on this topic will be performed, data of all patients with FD should be collected in a central registry.

Ornithine transcarbamylase (OTC) deficiency is the most frequent innate urea cycle disorder (UCD) and is the only one with an X-linked inheritance. OTC deficiency leads to hyperammonemia and subsequent elevated cerebral pressure and brain damage. Most often, UCDs are described as acute onset hyperammonemia in the newborn; however, rare, it can present in adulthood. We present the case of a 61-year old Caucasian man with unexplained coma. He developed an acute hyperammonemic encephalopathy leading to mental problems, seizures and coma. Despite the classical treatment with hemodialysis and the administration of a combination of sodium phenylacetate and sodium benzoate, the patient unfortunately died of cerebral herniation. Postmortem, genetic analysis confirmed the presence of a c.662G > A (p.Ala208Thr) pathogenic mutation in the OTC gene in a hemizygous state. Synopsis: The association of neuropsychiatric symptoms or encephalopathy of unknown origin should lead, even in the absence of liver disease and even in late adulthood, to a high level of suspicion of hyperammonemia secondary to UCDs to ensure a timely diagnosis and life-saving treatment. UCD, an inborn error of metabolism, can present itself at an advanced age; attenuated phenotypes probably remain under-ascertained.

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 a-galactosidase A gene often result in a high residual leukocyte alpha-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 a-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. (C) 2014 Elsevier Inc All rights reserved

Axial gout is a well-documented but uncommon manifestation of gout. Its mimicking nature and the impracticality of axial joint aspiration might considerably delay its diagnosis. We report a case in a normouricemic renal transplant recipient, whereby the primary symptom of severe neck pain suggested pyogenic spondylodiscitis as an initial tentative diagnosis. Clinical findings included a high C-reactive protein concentration and elevated body temperature. The patient did not respond to empiric antibiotic treatment and suffered consecutive attacks of severe wrist and ankle pain in conjunction with a persistent fever. Blood and joint cultures were negative, but analysis of aspirated ankle joint fluid revealed monosodium urate crystals. A dual-energy computed tomography scan confirmed the presence of monosodium urate crystals in the costovertebral joints. Colchicine treatment dramatically improved the patient's clinical condition. Axial gout should be considered in transplant recipients with severe neck or back pain, fever, and increased inflammatory parameters with a high likelihood of an infectious etiology, despite the presence of paradoxically normal or even decreased serum urate concentrations. Dual-energy computed tomography is a noninvasive technique of possible benefit in the detection of axial gout when joint fluid aspiration is not deemed safe.

Delayed graft function is an important determinant of patient and graft survival. A complex of pathologic mechanisms intervenes in the pathophysiology of this outcome. This paper reviews the main processes involved in delayed graft function as they relate to five chronologically related stages: donor tissue quality, brain death and related stress, preservation variables, immune factors, and recipient variables.Dialyzed delayed graft function and nondialyzed slow graft function both have a negative impact on graft survival and on the incidence of acute rejection. Expanded-criteria donors, older donors, and non-heart-beating donors are more frequently used. The long-term results of the use of well-selected non-heart-beating donors are surprisingly good. The process of ischemia/reperfusion injury is already initiated in the brain-death donor and continues during preservation of the graft. Graft-infiltrating T cells, heat shock proteins, and heme oxygenase-1 are implicated in the process. Modifications in immunosuppressive therapy and pharmacologic modulations have an effect on delayed graft function. Delayed graft function plays a part in the incidence of acute rejection, impaired graft function, and survival of patients and grafts.This review discusses the current literature on several recent findings of pathophysiologic mechanisms of, and possible therapeutic interventions in, delayed graft function.

Fabry disease is an X-linked inborn error of glycosphingolipid metabolism caused by quantitative or qualitative defects in the lysosomal enzyme alfa-Galactosidase A (aGAL A), ultimately resulting in vital organ dysfunction. Mainly the kidneys, the heart, and the central nervous system are involved. While the classical phenotype of Fabry disease is readily recognizable, screening studies have identified clinical variants. Here, we report the phenotype associated with the GLA p.Ala143Thr (c.427G>A) mutation in 12 patients aged 42-83 years. None of the patients had classical Fabry signs or symptoms as angiokeratoma, hypohidrosis, acroparesthesia, or cornea verticillata. Possible Fabry manifestations were renal failure (5/12), stroke (7/12), and left ventricular hypertrophy (5/12), but these were not necessarily attributable to the p.Ala143Thr mutation, as a cardiac biopsy in one female and left ventricular hypertrophy and kidney biopsies in two males with renal failure and microalbuminuria lacked Gb-3 deposits. The literature data on this mutation as well as data collected in the Fabry Outcome Survey (FOS) database confirm these findings. The association of renal failure, stroke, and left ventricular hypertrophy with this mutation could be the result of selection bias, as most patients were detected in screening studies.We conclude that care should be taken with attribution of vital organ dysfunction to GLA sequence alterations. In case of the p.Ala143Thr mutation, and possibly also other mutations associated with an attenuated phenotype, diagnostic tools such as biopsy and imaging should critically evaluate the relation of end-organ failure with Fabry disease, as this has important consequences for enzyme replacement therapy.

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.

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 a determination of alphagalactosidase A activity (AGALA) 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 2,328 patients, 1,233 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 _mol/L/h (2.5 and 97.5 percentile were 0.0001 and 5.07 _mol/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. Key words Anderson-Fabry disease. Transplantation. Screening. Alpha-galactosidase.

Introduction. Fabry’s disease (AFD) is an X-linked lysosomal storage disease, resulting from a deficiency in alpha-galactosidase A (AGALA). Untreated, this leads to precocious failure of vital organ function and death. As enzyme replacement therapy is available, it is of vital importance that affected individuals can be traced. Materials and methods. We set up a screening in the Flemish haemodialysis population using a two-tier approach. The first tier was a determination of alphagalactosidase A activity using a dried blood spot on filter paper, in the second tier, patients with the lowest alpha-galactosidase levels were further subjected to mutation analysis of the GLA gene. Results. 1284 patients (1047 women, 237 men) were evaluated for inclusion, eliminating patients with definite renal diagnoses. Total 922 patients (71.8 %) were screened (742 women, 180 men). Fifty seven patients were subjected to further genetic analysis. Three GLA mutation carriers were identified: two apparently nonrelated female patients carry the missense mutation p.Ala143Thr (c.427G > A), a missense mutation p.Trp236Arg (c.706T > C) was identified in a man. While the male patient had been clinically diagnosed with AFD, the female patients had remained unrecognized. Additional family based screening resulted in the identification of nine mutation carriers (four males and five females). Discussion. We demonstrated that the prevalence of GLA mutation carriers in our haemodialysis population is 0.3%. Our results show that the proposed approach accurately detects AFD 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.

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 m2) 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