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Autosomal recessive polycystic kidney disease (ARPKD) is often associated with hepatobiliary disease in the form of hepatic fibrosis and/or Caroli disease. Combined liver–kidney transplantation (CLKT) is a transplant modality of choice in children with both end-stage renal disease (ESRD) and severe hepatic disease. However, there is no consensus on whether children with ARPKD-associated ESRD without severe hepatic disease can be treated with isolated kidney transplantation (KT) without the need for CLKT. We retrospectively studied the efficacy of isolated KT in children with ARPKD without severe hepatic disease, and followed the course of hepatic disease post KT. This is a single-center study of three children with ARPKD and ESRD who underwent isolated KT. None of them had severe hepatic disease at the time of KT. All children were clinically diagnosed with ARPKD in the immediate postnatal period. All had hepatic fibrosis of varying degrees and two had intrahepatic biliary duct (IHBD) dilatation. None had gastrointestinal (GI) bleed, portal hypertension or cholangitis. Two children had preemptive KT. Pre-transplant unilateral or bilateral native nephrectomy were performed for two children, and one underwent unilateral native nephrectomy at the time of KT. The median creatinine clearance at a median post-KT follow-up of 24 months was 60.3 mL/min/1.73 m2. The two-year graft and patient survival were both 100%. Post KT, all three patients continued to demonstrate evidence of hepatic fibrosis and IHBD on sonogram; however, none of them were either evaluated for or required liver transplantation given normal synthetic liver function and absence of portal hypertension or other severe hepatobiliary disease. There were no adverse events observed such as cholangitis, GI bleed, or multiorgan failure. Hence, an excellent short-term graft and patient survival was demonstrated in this study of children with ARPKD and mild to moderate hepatic disease who received isolated KT. Long-term follow-up and larger studies are important to assess the efficacy of isolated KT in this subset of children with ARPKD. [ABSTRACT FROM AUTHOR]

Renal cystic diseases (RCDs) can arise from utero to early adulthood and present with a variety of symptoms including renal, hepatic, and cardiovascular manifestations. It is well known that common RCDs such as autosomal polycystic kidney disease and autosomal recessive kidney disease are linked to genes such as PKD1 and PKHD1, respectively. However, it is important to investigate the genetic pathophysiology of how these gene mutations lead to clinical symptoms and include some of the less-studied RCDs, such as autosomal dominant tubulointerstitial kidney disease, multicystic dysplastic kidney, Zellweger syndrome, calyceal diverticula, and more. We plan to take a thorough look into the genetic involvement and clinical sequalae of a number of RCDs with the goal of helping to guide diagnosis, counseling, and treatment. [ABSTRACT FROM AUTHOR]

(1) Background: Autosomal recessive polycystic kidney disease (ARPKD) is a rare ciliopathy characterized by progressively enlarged kidneys with fusiform dilatation of the collecting ducts. Loss-of-function mutations in the PKHD1 gene, which encodes fibrocystin/polyductin, cause ARPKD; however, an efficient treatment method and drug for ARPKD have yet to be found. Antisense oligonucleotides (ASOs) are short special oligonucleotides which function to regulate gene expression and alter mRNA splicing. Several ASOs have been approved by the FDA for the treatment of genetic disorders, and many are progressing at present. We designed ASOs to verify whether ASOs mediate the correction of splicing further to treat ARPKD arising from splicing defects and explored them as a potential treatment option. (2) Methods: We screened 38 children with polycystic kidney disease for gene detection using whole-exome sequencing (WES) and targeted next-generation sequencing. Their clinical information was investigated and followed up. The PKHD1 variants were summarized and analyzed, and association analysis was carried out to analyze the relationship between genotype and phenotype. Various bioinformatics tools were used to predict pathogenicity. Hybrid minigene analysis was performed as part of the functional splicing analysis. Moreover, the de novo protein synthesis inhibitor cycloheximide was selected to verify the degraded pathway of abnormal pre-mRNAs. ASOs were designed to rescue aberrant splicing, and this was verified. (3) Results: Of the 11 patients with PKHD1 variants, all of them exhibited variable levels of complications of the liver and kidneys. We found that patients with truncating variants and variants in certain regions had a more severe phenotype. Two splicing variants of the PKHD1 genotypes were studied via the hybrid minigene assay: variants c.2141-3T>C and c.11174+5G>A. These cause aberrant splicing, and their strong pathogenicity was confirmed. We demonstrated that the abnormal pre-mRNAs produced from the variants escaped from the NMD pathway with the use of the de novo protein synthesis inhibitor cycloheximide. Moreover, we found that the splicing defects were rescued by using ASOs, which efficiently induced the exclusion of pseudoexons. (4) Conclusion: Patients with truncating variants and variants in certain regions had a more severe phenotype. ASOs are a potential drug for treating ARPKD patients harboring splicing mutations of the PKHD1 gene by correcting the splicing defects and increasing the expression of the normal PKHD1 gene. [ABSTRACT FROM AUTHOR]

Autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease, and nephronophthisis are hereditary disorders with the occurrence of numerous cysts in both kidneys, often causing chronic and end-stage renal failure. Animal models have played an important role in recent advances in research not only on disease onset and progressive mechanisms but also on the development of therapeutic interventions. For a long time, spontaneous animal models have been used as the primary focus for human diseases; however, after the identification of the nucleotide sequence of the responsible genes, PKD1, PKD2, PKHD1, and NPHPs, various types of genetically modified models were developed by genetic and reproductive engineering techniques and played the leading role in the research field. In this review, we present murine models of hereditary renal cystic diseases, discussing their potential benefits in the development of therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Hyperinsulinemic hypoglycemia (HH) is an important cause of persistent hypoglycemia in newborns and infants. Recently, PMM2 (phosphomannomutase 2) mutation has been associated with HH, especially in conjunction with polycystic kidney disease (PKD). PMM2 deficiency is one of the most common causes of congenital disorder of glycosylation (CDG). Renal involvement in PMM2-CDG manifests as cystic kidney disease, echogenic kidneys, nephrotic syndrome or mild proteinuria. Case Summary: Here, we describe a pair of siblings with HH associated with autosomal recessive polycystic kidney disease (ARPKD) and PMM2 mutation. Two siblings with ARPKD presented during infancy and early toddler years with severe hypoglycemia. Both had inappropriately elevated serum insulin, low β-hydroxybutyrate, a need for a high glucose infusion rate, positive glycemic response to glucagon, positive diazoxide response and PMM2 mutation. Conclusions: Although this combination of HH and PKD was recently described in patients of European descent who also had PMM2 mutation, our report is unique given that these non-consanguineous siblings were not exclusively of European descent. PMM2 mutation leading to abnormal glycosylation and causing cystic kidneys and the alteration of insulin secretion is the most likely pathogenesis of this clinical spectrum. [ABSTRACT FROM AUTHOR]

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cystic kidney disease, with patients often having a positive family history that is characterized by a similar phenotype. However, in atypical cases, particularly those in which family history is unclear, a differential diagnosis between ADPKD and other cystic kidney diseases is important. When diagnosing ADPKD, cystic kidney diseases that can easily be excluded using clinical information include: multiple simple renal cysts, acquired cystic kidney disease (ACKD), multilocular renal cyst/multilocular cystic nephroma/polycystic nephroma, multicystic kidney/multicystic dysplastic kidney (MCDK), and unilateral renal cystic disease (URCD). However, there are other cystic kidney diseases that usually require genetic testing, or another means of supplementing clinical information to enable a differential diagnosis of ADPKD. These include autosomal recessive polycystic kidney disease (ARPKD), autosomal dominant tubulointerstitial kidney disease (ADTKD), nephronophthisis (NPH), oral-facial-digital (OFD) syndrome type 1, and neoplastic cystic kidney disease, such as tuberous sclerosis (TSC) and Von Hippel-Lindau (VHL) syndrome. To help physicians evaluate cystic kidney diseases, this article provides a review of cystic kidney diseases for which a differential diagnosis is required for ADPKD. [ABSTRACT FROM AUTHOR]

The Special Issue "Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies" provides a collection of original research articles and systematic reviews focused on diverse conditions stemming from a pathogenic single gene mutation. Parahemophilia or Owren's disease, is an ultra-rare coagulation disorder associated with mutations in the factor V gene. -thalassemia is instead a blood cells disorder, linked to mutations of the -globin gene and reduced expression of the encoded adult hemoglobin (HbA) protein in erythrocytes. Trinucleotide repeat disorders, a group of neuropathological conditions caused by abnormal expansion of natural triplet repeats in a specific gene, are the focus of two systematic reviews. [Extracted from the article]

Niemann-Pick-disease type C1 (NPC1) is an autosomal-recessive cholesterol-storage disorder. Besides other symptoms, NPC1 patients develop liver dysfunction and hepatosplenomegaly. The mechanisms of hepatomegaly and alterations of lipid metabolism-related genes in NPC1 disease are still poorly understood. Here, we used an NPC1 mouse model to study an additive hepatoprotective effect of a combination of 2-hydroxypropyl-β-cyclodextrin (HPβCD), miglustat and allopregnanolone (combination therapy) with the previously established monotherapy using HPβCD. We examined transgene effects as well as treatment effects on liver morphology and hepatic lipid metabolism, focusing on hepatic cholesterol transporter genes. Livers of Npc1-/- mice showed hepatic cholesterol sequestration with consecutive liver injury, an increase of lipogenetic gene expression, e.g., HMG-CoA, a decrease of lipolytic gene expression, e.g., ppara and acox1, and a decrease of lipid transporter gene expression, e.g., acat1, abca1 and fatp2. Both, combination therapy and monotherapy, led to a reduction of hepatic lipids and an amelioration of NPC1 liver disease symptoms. Monotherapy effects were related to ppara- and acox1-associated lipolysis/β-oxidation and to fatp2-induced fatty acid transport, whereas the combination therapy additionally increased the cholesterol transport via abca1 and apoE. However, HPβCD monotherapy additionally increased cholesterol synthesis as indicated by a marked increase of the HMG-CoA and srebp-2 mRNA expression, probably as a result of increased hepatocellular proliferation. [ABSTRACT FROM AUTHOR]

Gaucher disease (GD) type I is an autosomal recessive disease caused by a genetic deficiency of lysosomal β-glucocerebrosidase that leads to accumulation of undergraded substrate glucocerebroside and other glycolipids, thus causing damage in different organs. GBA is the only gene in which mutations are known to cause GD. Nearly 300 mutations have been identified in GD patients, including frame-shift mutations, point mutations, deletions, insertions, splice site mutations and recombinants. The variety of phenotypes associated to GD shows imperfect correlation with mutations. GD encompasses a spectrum of clinical findings from a perinatal lethal form to an asymptomatic form. However the classification of GD by clinical subtype is still useful in describing the wide range of clinical findings and broad variability in presentation. Three major clinical types are delineated: type I (chronic non-neuropathic), type II (acute neuropathic), and type III (chronic neuropathic). Patients with type I GD present with visceromegaly, hematological complications, and bone disease. Cardiac and pulmonary complications are rare. Type I GD adult patients have elevated risk of malignancies, Parkinson's disease or Parkinsonism. Neuropathic forms of GD are rare and clinically ranging from lethal perinatal form to very mild form limited to abnormalities of horizontal ocular saccades. Diagnosis of acid β-glucosylceramidase relies on enzyme activity in peripheral blood leukocytes or skin fibroblasts and/or identification of GBA mutations. Enzyme replacement therapy is an effective treatment for non-neuropathic GD. Substrate inhibitor is the alternative therapy for some patients with GD is miglustat, iminosugar inhibitor of glucocerebroside synthase. [ABSTRACT FROM AUTHOR]

Background: Approximately fifteen percent of patients with tuberous sclerosis complex (TSC) phenotype do not have any genetic disease-causing mutations which could be responsible for the development of TSC. The lack of a proper diagnosis significantly affects the quality of life for these patients and their families. Methods: The aim of our study was to use Whole Exome Sequencing (WES) in order to identify the genes responsible for the phenotype of nine patients with clinical signs of TSC, but without confirmed tuberous sclerosis complex 1/ tuberous sclerosis complex 2 (TSC1/TSC2) mutations using routine molecular genetic diagnostic tools. Results: We found previously overlooked heterozygous nonsense mutations in TSC1, and a heterozygous intronic variant in TSC2. In one patient, two heterozygous missense variants were found in polycystic kidney and hepatic disease 1 (PKHD1), confirming polycystic kidney disease type 4. A heterozygous missense mutation in solute carrier family 12 member 5 (SLC12A5) was found in one patient, which is linked to cause susceptibility to idiopathic generalized epilepsy type 14. Heterozygous nonsense variant ring finger protein 213 (RNF213) was identified in one patient, which is associated with susceptibility to Moyamoya disease type 2. In the remaining three patients WES could not reveal any variants clinically relevant to the described phenotypes. Conclusion: Patients without appropriate diagnosis due to the lack of sensitivity of the currently used routine diagnostic methods can significantly profit from the wider application of next generation sequencing technologies in order to identify genes and variants responsible for their symptoms. [ABSTRACT FROM AUTHOR]

Autosomal recessive polycystic kidney disease (ARPKD) is a rare disorder and one of the most severe forms of polycystic kidney disease, leading to end-stage renal disease (ESRD) in childhood. PKHD1 is the gene that is responsible for the vast majority of ARPKD. However, some cases have been related to a new gene that was recently identified (DZIP1L gene), as well as several ciliary genes that can mimic a ARPKD-like phenotypic spectrum. In addition, a number of molecular pathways involved in the ARPKD pathogenesis and progression were elucidated using cellular and animal models. However, the function of the ARPKD proteins and the molecular mechanism of the disease currently remain incompletely understood. Here, we review the clinics, treatment, genetics, and molecular basis of ARPKD, highlighting the most recent findings in the field. [ABSTRACT FROM AUTHOR]

Ciliopathies are a group of multi-organ diseases caused by the disruption of the primary cilium. This event leads to a variety of kidney disorders, including nephronophthisis, renal cystic dysplasia, and renal cell carcinoma (RCC). Primary cilium contributes to the regulation of the cell cycle and protein homeostasis, that is, the balance between protein synthesis and degradation by acting on the ubiquitin-proteasome system, autophagy, and mTOR signaling. Many proteins are involved in renal ciliopathies. In particular, fibrocystin (PKHD1) is involved in autosomal recessive polycystic kidney disease (ARPKD), while polycystin-1 (PKD1) and polycystin-2 (PKD2) are implicated in autosomal dominant polycystic kidney disease (ADPKD). Moreover, primary cilia are associated with essential signaling pathways, such as Hedgehog, Wnt, and Platelet-Derived Growth Factor (PDGF). In this review, we focused on the ciliopathies associated with kidney diseases, exploring genes and signaling pathways associated with primary cilium and the potential role of cilia as therapeutic targets in renal disorders. [ABSTRACT FROM AUTHOR]

Autosomal recessive and autosomal dominant polycystic kidney disease (ARPKD, ADPKD) are systemic disorders with pronounced hepatorenal phenotypes. While the main underlying genetic causes of both ARPKD and ADPKD have been well-known for years, the exact molecular mechanisms resulting in the observed clinical phenotypes in the different organs, remain incompletely understood. Recent research has identified cellular metabolic changes in PKD. These findings are of major relevance as there may be an immediate translation into clinical trials and potentially clinical practice. Here, we review important results in the field regarding metabolic changes in PKD and their modulation as a potential target of systemic treatment. [ABSTRACT FROM AUTHOR]

Mutations of the Pkhd1 gene cause autosomal recessive polycystic kidney disease (ARPKD). Pkhd1 encodes fibrocystin/polyductin (FPC), a ciliary type I membrane protein of largely unknown function, suggested to affect adhesion signaling of cells. Contributions of epithelial cell adhesion and contractility to the disease process are elusive. Here, we link loss of FPC to defective epithelial morphogenesis in 3D cell culture and altered cell contact formation. We study Pkhd1-silenced Madin-Darby Canine Kidney II (MDCKII) cells using an epithelial morphogenesis assay based on micropatterned glass coverslips. The assay allows analysis of cell adhesion, polarity and lumen formation of epithelial spheroids. Pkhd1 silencing critically affects the initial phase of the morphogenesis assay, leading to a reduction of correctly polarized spheroids by two thirds. Defects are characterized by altered cell adhesion and centrosome positioning of FPC-deficient cells in their 1-/2-cell stages. When myosin II inhibitor is applied to reduce cellular tension during the critical early phase of the assay, Pkhd1 silencing no longer inhibits formation of correctly polarized epithelia. We propose that altered sensing and cell interaction of FPC-deficient epithelial cells promote progressive epithelial defects in ARPKD. [ABSTRACT FROM AUTHOR]

Here we report novel mutations in ABCA4 with the underlying phenotype in a large French cohort with autosomal recessive Stargardt disease. The DNA samples of 397 index subjects were analyzed in exons and flanking intronic regions of ABCA4 (NM_000350.2) by microarray analysis and direct Sanger sequencing. At the end of the screening, at least two likely pathogenic mutations were found in 302 patients (76.1%) while 95 remained unsolved: 40 (10.1%) with no variants identified, 52 (13.1%) with one heterozygous mutation, and 3 (0.7%) with at least one variant of uncertain significance (VUS). Sixty-three novel variants were identified in the cohort. Three of them were variants of uncertain significance. The other 60 mutations were classified as likely pathogenic or pathogenic, and were identified in 61 patients (15.4%). The majority of those were missense (55%) followed by frameshift and nonsense (30%), intronic (11.7%) variants, and in-frame deletions (3.3%). Only patients with variants never reported in literature were further analyzed herein. Recruited subjects underwent complete ophthalmic examination including best corrected visual acuity, kinetic and static perimetry, color vision test, full-field and multifocal electroretinography, color fundus photography, short-wavelength and near-infrared fundus autofluorescence imaging, and spectral domain optical coherence tomography. Clinical evaluation of each subject confirms the tendency that truncating mutations lead to a more severe phenotype with electroretinogram (ERG) impairment (p = 0.002) and an earlier age of onset (p = 0.037). Our study further expands the mutation spectrum in the exonic and flanking regions of ABCA4 underlying Stargardt disease. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant genetic diseases. It is caused by mutations in the NF1 gene encoding for the large protein, neurofibromin. Genetic testing of NF1 is cumbersome because 50% of cases are sporadic, and there are no mutation hot spots. In addition, the most recognizable NF1 clinical features—café-au-lait (CALs) spots and axillary and/or inguinal freckling—appear early in childhood but are rather non-specific. Thus, the identification of causative variants is extremely important for early diagnosis, especially in paediatric patients. Here, we aimed to identify the underlying genetic defects in 72 index patients referred to our centre for NF1. Causative mutations were identified in 58 subjects, with 29 being novel changes. We evaluated missense and non-canonical splicing mutations with both protein and splicing prediction algorithms. The ratio of splicing mutations detected was higher than that reported in recent patients’ series and in the Human Gene Mutation Database (HGMD). After applying in silico predictive tools to 41 previously reported missense variants, we demonstrated that 46.3% of these putatively missense mutations were forecasted to alter splicing instead. Our data suggest that mutations affecting splicing can be frequently underscored if not analysed in depth. We confirm that hamartomas can be useful for diagnosing NF1 in children. Lisch nodules and cutaneous neurofibromas were more frequent in patients with frameshifting mutations. In conclusion, we demonstrated that comprehensive in silico analysis can be a highly specific method for predicting the nature of NF1 mutations and may help in assuring proper patient care. [ABSTRACT FROM AUTHOR]