A defect in molybdenum cofactor binding causes an attenuated form of sulfite oxidase deficiency

Isolated sulfite oxidase deficiency (ISOD) is a rare recessive and infantile lethal metabolic disorder, which is caused by functional loss of sulfite oxidase (SO) due to mutations of the SUOX gene. SO is a mitochondrially localized molybdenum cofactor (Moco)- and heme-dependent enzyme, which catalyzes the vital oxidation of toxic sulfite to sulfate. Accumulation of sulfite and sulfite-related metabolites such as S-sulfocysteine (SSC) are drivers of severe neurodegeneration leading to early childhood death in the majority of ISOD patients. Full functionality of SO is dependent on correct insertion of the heme cofactor and Moco, which is controlled by a highly orchestrated maturation process. This maturation involves the translation in the cytosol, import into the intermembrane space (IMS) of mitochondria, cleavage of the mitochondrial targeting sequence, and insertion of both cofactors. Moco insertion has proven as the crucial step in this maturation process, which enables the correct folding of the homodimer and traps SO in the IMS. Here, we report on a novel ISOD patient presented at 17 months of age carrying the homozygous mutation NM_001032386.2 (SUOX):c.1097G > A, which results in the expression of SO variant R366H. Our studies show that histidine substitution of Arg366, which is involved in coordination of the Moco-phosphate, causes a severe reduction in Moco insertion efficacy in vitro and in vivo. Expression of R366H in HEK SUOX-/- cells mimics the phenotype of patient's fibroblasts, representing a loss of SO expression and specific activity. Our studies disclose a general paradigm for a kinetic defect in Moco insertion into SO caused by residues involved in Moco coordination resulting in the case of R366H in an attenuated form of ISO

An emerging molecular understanding and novel targeted treatment approaches in pediatric kidney diseases

The evaluation and treatment of the heterogeneous group of pediatric kidney diseases poses a challenging field in pediatrics. Many of the pediatric disorders resulting in severe renal affection are exceedingly rare and therapeutic approaches have remained symptomatic for most of these disease entities. The insights obtained from cellular and molecular studies of rare disorders by recent genetic studies have now substantially changed our mechanistic understanding of various important pediatric renal diseases and positive examples of targeted treatment approaches are emerging. Three fields of recent breathtaking developments in pediatric nephrology are the pathophysiology of nephrotic syndrome and proteinuria, the molecular mechanisms underlying atypical hemolytic uremic syndrome (aHUS), and the genetics and cellular biology of inherited cystic kidney diseases. In all three areas the combined power of molecular basic science together with deeply characterizing clinical approaches has led to the establishment of novel pathophysiological principles and to the first clinical trials of targeted treatment approaches

An emerging molecular understanding and novel targeted treatment approaches in pediatric kidney diseases

The evaluation and treatment of the heterogeneous group of kidney diseases poses a challenging field in pediatrics. Many of the pediatric disorders resulting in severe renal affection are exceedingly rare and therapeutic approaches have remained symptomatic for most of these disease entities. The insights obtained from cellular and molecular studies of rare disorders by recent genetic studies have now substantially changed our mechanistic understanding of various important pediatric renal diseases and positive examples of targeted treatment approaches are emerging. Three fields of recent breathtaking developments in pediatric nephrology are the pathophysiology of nephrotic syndrome and proteinuria, the molecular mechanisms underlying atypical hemolytic uremic syndrome, and the genetics and cellular biology of inherited cystic kidney diseases. In all three areas, the combined power of molecular basic science together with deeply characterizing clinical approaches has led to the establishment of novel pathophysiological principles and to the first clinical trials of targeted treatment approaches

Early clinical management of autosomal recessive polycystic kidney disease

Autosomal recessive polycystic kidney disease (ARPKD) is a rare but highly relevant disorder in pediatric nephrology. This genetic disease is mainly caused by variants in the PKHD1 gene and is characterized by fibrocystic hepatorenal phenotypes with major clinical variability. ARPKD frequently presents perinatally, and the management of perinatal and early disease symptoms may be challenging. This review discusses aspects of early manifestations in ARPKD and its clincial management with a special focus on kidney disease

Translational research approaches to study pediatric polycystic kidney disease

Polycystic kidney diseases (PKD) are severe forms of genetic kidney disorders. The two main types of PKD are autosomal recessive and autosomal dominant PKD (ARPKD, ADPKD). While ARPKD typically is a disorder of early childhood, patients with ADPKD often remain pauci-symptomatic until adulthood even though formation of cysts in the kidney already begins in children. There is clinical and genetic overlap between both entities with very variable clinical courses. Subgroups of very early onset ADPKD may for example clinically resemble ARPKD. The basis of the clinical variability in both forms of PKD is not well understood and there are also limited prediction markers for disease progression for daily clinical life or surrogate endpoints for clinical trials in ARPKD or early ADPKD.As targeted therapeutic approaches to slow disease progression in PKD are emerging, it is becoming more important to reliably identify patients at risk for rapid progression as they might benefit from early therapy. Over the past years regional, national and international data collections to jointly analyze the clinical courses of PKD patients have been set up. The clinical observations are complemented by genetic studies and biorepositories as well as basic science approaches to elucidate the underlying molecular mechanisms in the PKD field. These approaches may serve as a basis for the development of novel therapeutic interventions in specific subgroups of patients. In this article we summarize some of the recent developments in the field with a focus on kidney involvement in PKD during childhood and adolescence and findings obtained in pediatric cohorts

Autosomal recessive polycystic kidney disease (ARPKD)-lessons learned from the international ARPKD registry study ARegPKD

Autosomal recessive polycystic kidney disease (ARPKD) is rare but is one of the most important causes of kidney failure in childhood and adolescence. ARPKD is characterized by obligatory hepatorenal involvement and pronounced phenotypic variability. In most cases, it is caused by variants in the PKHD1 gene encoding the ciliary protein fibrocystin. The treatment of ARPKD is purely symptomatic. Targeted therapy has not yet been established. The prediction of clinical courses remains difficult in ARPKD. As ARPKD occurs significantly less frequently than autosomal dominant polycystic kidney disease (ADPKD), clinical or radiological risk markers for kidney disease progression could not be established for ARPKD in a similar manner. Genotype-phenotype correlations cannot fully explain the differences in the clinical courses. Clinical research in the field of ARPKD faces a number of challenges, such as rarity of the disease, complex disease courses, late, atypical or liver-predominant manifestations as well as incomplete understanding of the molecular pathogenesis. An exact longitudinal phenotypic characterization of large numbers of patients in international collaborations is helpful for the establishment of clinical, radiological and laboratory risk markers that are the basis for evaluation of first treatment options. In this setting, the European registry study ARegPKD was established. This article presents the evolution of the ARegPKD and extracts of lessons learned

Systematic review on outcomes used in clinical research on autosomal recessive polycystic kidney disease-are patient-centered outcomes our blind spot?

Background Autosomal recessive polycystic kidney disease (ARPKD) is a rare severe hepatorenal disease. Survivors of pulmonary hypoplasia and patients with milder presentations often achieve long-term survival but frequently require kidney and/or liver transplantation. Objective To examine the use of clinical, surrogate and patient-centered outcomes in studies on ARPKD with special attention to core outcomes of the Standardized Outcomes in NephroloGy project for children with chronic kidney disease (SONG-Kids). Data sources and study eligibility criteria A systematic MEDLINE literature search identified 367 ARPKD studies published since 1990; however, of these 134 were excluded because they did not report any clinical outcomes (e.g. only histopathological, genetic, protein structure or radiological markers), 19 studies because they only included prenatal patients and 138 because they were case reports with <= 3 patients. Study appraisal Seventy-six eligible studies were examined for study type, size, intervention, and reported outcomes by organ system and type, including all SONG-kids tier 1-3 outcomes. Participants There were 3231 patient-reports of children and adults with ARPKD. Results The overwhelming majority of studies reported clinical and surrogate outcomes (75/76 (98%) and 73/76 (96%)), but only 11/76 (14%) examined patient-centered outcomes and only 2/76 (3%) used validated instruments to capture them. Of the SONG-Kids core outcomes, kidney function was reported almost universally (70/76 (92%), infection and survival in three quarters (57/ 76 (75%), 55/76 (72%)) and measures of life participation (including neurological impairment) only rarely and inconsistently (16/76 (21%)). Limitations Thirty studies (39%) were of low quality as they were either narrative case reports (n = 14, 18%) and/or patients with ARPKD were an indistinguishable subgroup (n = 18, 24%). Only 28 trials compared interventions, but none were randomized. Conclusions and implications Studies that reported clinical outcomes in ARPKD usually covered the core outcome domains of kidney function, infections, and survival, but measures of life participation and patient-centered outcomes are distinctly lacking and require more attention in future trials

Recent Progress of the ARegPKD Registry Study on Autosomal Recessive Polycystic Kidney Disease

Autosomal recessive polycystic kidney disease (ARPKD) is a rare monogenic disease with a severe phenotype often presenting prenatally or in early childhood. With its obligate renal and hepatic involvement, ARPKD is one of the most important indications for liver and/or kidney transplantation in childhood. Marked phenotypic variability is observed, the genetic basis of which is largely unknown. Treatment is symptomatic and largely empiric as evidence-based guidelines are lacking. Therapeutic initiatives for ARPKD face the problem of highly variable cohorts and lack of clinical or biochemical risk markers without clear-cut clinical end points. ARegPKD is an international, multicenter, retro- and prospective, observational study to deeply phenotype patients with the clinical diagnosis of ARPKD. Initiated in 2013 as a web-based registry (www.aregpkd.org), ARegPKD enrolls patients across large parts of Europe and neighboring countries. By January 2017, more than 400 patients from 17 mostly European countries have been registered in the ARPKD registry study with significant follow-up data. Due to comprehensive retro- and prospective data collection and associated biobanking, ARegPKD will generate a unique ARPKD cohort with detailed longitudinal clinical characterization providing a basis for future clinical trials as well as translational research. Hence, ARegPKD is hoped to contribute to the pathophysiological understanding of the disease and to the improvement of clinical management

Recent Progress of the ARegPKD Registry Study on Autosomal Recessive Polycystic Kidney Disease

Autosomal recessive polycystic kidney disease (ARPKD) is a rare monogenic disease with a severe phenotype often presenting prenatally or in early childhood. With its obligate renal and hepatic involvement, ARPKD is one of the most important indications for liver and/or kidney transplantation in childhood. Marked phenotypic variability is observed, the genetic basis of which is largely unknown. Treatment is symptomatic and largely empiric as evidence-based guidelines are lacking. Therapeutic initiatives for ARPKD face the problem of highly variable cohorts and lack of clinical or biochemical risk markers without clear-cut clinical end points. ARegPKD is an international, multicenter, retro- and prospective, observational study to deeply phenotype patients with the clinical diagnosis of ARPKD. Initiated in 2013 as a web-based registry (www.aregpkd.org), ARegPKD enrolls patients across large parts of Europe and neighboring countries. By January 2017, more than 400 patients from 17 mostly European countries have been registered in the ARPKD registry study with significant follow-up data. Due to comprehensive retro- and prospective data collection and associated biobanking, ARegPKD will generate a unique ARPKD cohort with detailed longitudinal clinical characterization providing a basis for future clinical trials as well as translational research. Hence, ARegPKD is hoped to contribute to the pathophysiological understanding of the disease and to the improvement of clinical management.status: publishe