Gaucher disease

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Using induced pluripotent stem cells to investigate the mechanistic link between Gaucher disease and Parkinson related synucleinopathies

Using induced pluripotent stem cells to investigate the mechanistic link between Gaucher disease and Parkinson related synucleinopathies

Gaucher Disease (GD) FiPS 4F 21C is an induced pluripotent stem cell line derived from fibroblasts of a female Gaucher Disease patient. It has a compound heterozygote mutation in the GBA1 gene in which one allele has a 721 G->A mutation and the other a 1448 T->C mutation rendering the β-glucocerebrosidase protein disfunctional. In order to analyze the effect of β-glucocerebrosidade on α-synuclein protein levels we first tried rescuing β-glucocerebrosidade through the use of chaperone compounds which led to highly variable results. We then tried rescuing β- glucocerebrosidade through infection of the neuronal cultures with a 3rd generation lentiviral vector expressing WT β-glucocerebrosidade but this method implied doing an infection before any experiment. Therefore we went on to generate stable transduced GD FiPS 4F 21C overexpressing WT β-glucocerebrosidade cell lines to provide us with a powerful tool for the study of β-glucocerebrosidade effects and to facilitate future experiments. We achieved this by dissociating the iPS colonies, getting a single cell suspension, transducing cells with several MOI’s of the lentiviral vector expressing WT β-glucocerebrosidade and finally seeding the cells under normal iPS culture conditions.
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Pulmonary involvement in siblings with Gaucher disease type III

Pulmonary involvement in siblings with Gaucher disease type III

Introduction. Pulmonary involvement has been described in all types of Gaucher disease (GD) but it is considered as relatively rare manifestation. There are reports suggesting that homozygosity for L444P mutation in GBA gene is as- sociated with a substantial risk for developing primary pul- monary disease in GD. Case report. We reported sisters with pulmonary involvement in GD type III. Respiratory failure with fatal outcome at 3 years and 4 months of age occurred in K.K. due to pulmonary complications of GD. At the time enzyme replacement therapy (ERT) was not available in Serbia. J.K., homozygous for L444P mutation,
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Pharmacokinetics of Novel Plant Cell-Expressed Taliglucerase Alfa in Adult and Pediatric Patients with Gaucher Disease.

Pharmacokinetics of Novel Plant Cell-Expressed Taliglucerase Alfa in Adult and Pediatric Patients with Gaucher Disease.

17. Pastores GM, Petakov M, Giraldo P, Rosenbaum H, Szer J, Deegan PB, et al. (17 June 2014) A phase 3, multicenter, open-label, switchover trial to assess the safety and efficacy of taliglucerase alfa, a plant cell expressed reconbinant human glucocerebrosidase, in adult and pediatric patients with Gaucher disease previously treated with imiglucerase. Blood Cells Mol Dis [Epub ahead of print].

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High frequency of mutation G377S in Brazilian type 3 Gaucher disease patients

High frequency of mutation G377S in Brazilian type 3 Gaucher disease patients

Gaucher disease (GD), the most prevalent lysosome storage disorder, presents an autosomal recessive mode of inheritance. It is a paradigm for therapeutic intervention in medical genetics due to the existence of effective enzyme replacement therapy. We report here the analysis of GD in 262 unrelated Brazilian patients, carried out in order to establish the frequency of the most common mutations and to provide prognostic information based on genotype-phenotype correlations. Among 247 type 1 GD patients, mutation N370S was detected in 47% of all the alleles, but N370S/N370S homozygosity was found in only 10% of the patients, a much lower frequency than expected, suggesting that most individuals presenting this genotype may not receive medical attention. Recombinant alleles were detected at a high frequency: 44% of the chromosomes bearing mutation L444P had other mutations derived from the pseudogene sequence, present in 25% of patients. Three neuronopathic type 2 patients were homozygous for L444P, all present- ing additional mutations (E326K or recombinant alleles) that probably lead to the more severe phenotypes. Six children, classified as type 1 GD patients, had a L444P/L444P genotype, showing that neuronopathic symptoms may only manifest later in life. This would indicate the need for a higher treatment dose during enzyme replacement therapy. Finally, mutation G377S was present in 4 homozygous type 1 patients and also in compound heterozygosity in 5 (42%) type 3 patients. These findings indicate that G377S cannot be unambiguously classified as mild and suggest an allele-dose effect for this mutation.
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Coenzyme Q(10) partially restores pathological alterations in a macrophage model of Gaucher disease

Coenzyme Q(10) partially restores pathological alterations in a macrophage model of Gaucher disease

In order to mimic the pathological phenotype of the disease, an in vitro cellular model of Gaucher disease was developed by treating the THP-1, a human mono- cytic cell line differentiated into macrophage, with a spe- cific inhibitor of GCase, conduritol beta epoxide (CBE) [5] and the concomitant supplementation with exogen- ous GlcCer (chemically-induced Gaucher THP-1 macro- phages). Autophagy flux, mitochondrial dysfunction, inflammasome activation and efferocitosis capacity were examined in chemically-induced Gaucher THP-1 macro- phages. In addition, as mitochondrial dysfunction and/or impaired mitochondria elimination may be associated with alterations of lysosome-dependent processes, treat- ment with coenzyme Q 10 (CoQ), an antioxidant and
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The prognostic value of the serum ferritin in a southern Brazilian cohort of patients with Gaucher disease

The prognostic value of the serum ferritin in a southern Brazilian cohort of patients with Gaucher disease

The clinical utility of serum ferritin as a biomarker of disease severity and prognosis in Gaucher disease (GD) is still debated. Here, we aimed to evaluate ferritin and its relation to clinicolaboratory parameters of GD patients seen at the Reference Center for Gaucher Disease of Rio Grande do Sul, Brazil, so as to gather evidence on the utility of ferritin as a biomarker of this condition. A retrospective chart review was performed collecting pre- and post- treatment data from GD patients. Eighteen patients with ferritin levels available before and after treatment were in- cluded in the study. Nine of these participants were males, and seventeen had type I GD. All patients were given ei- ther enzyme replacement (n = 16) or substrate reduction therapy (n = 2), and ferritin was found to decrease from 756 [318-1441] ng/mL at baseline to 521 [227-626] ng/mL (p = 0.025) after 28.8 months of treatment. Serum ferritin levels did not correlate with measures of disease severity, but showed an association with age at onset of treatment (r = 0.880; n = 18; p < 0.001). In conclusion, although serum ferritin did not correlate with disease severity, after a median 28.8 months of treatment, clinical outcomes had clearly improved, and ferritin levels had decreased.
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Isofagomine in vivo effects in a neuronopathic Gaucher disease mouse.

Isofagomine in vivo effects in a neuronopathic Gaucher disease mouse.

The pharmacological chaperone, isofagomine (IFG), enhances acid b-glucosidase (GCase) function by altering folding, trafficking, and activity in wild-type and Gaucher disease fibroblasts. The in vivo effects of IFG on GCase activity, its substrate levels, and phenotype were evaluated using a neuronopathic Gaucher disease mouse model, 4L;C* (V394L/V394L + saposin C-/-) that has CNS accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) as well as progressive neurological deterioration. IFG administration to 4L;C* mice at 20 or 600 mg/kg/day resulted in life span extensions of 10 or 20 days, respectively, and increases in GCase activity and protein levels in the brain and visceral tissues. Cerebral cortical GC and GS levels showed no significant reductions with IFG treatment. Increases of GC or GS levels were detected in the visceral tissues of IFG treated (600 mg/kg/day) mice. The attenuations of brain proinflammatory responses in the treated mice were evidenced by reductions in astrogliosis and microglial cell activation, and decreased p38 phosphorylation and TNFa levels. Terminally, axonal degeneration was present in the brain and spinal cord from untreated and treated 4L;C* mice. These data demonstrate that IFG exerts in vivo effects by enhancing V394L GCase protein and activity levels, and in mediating suppression of proinflammation, which led to delayed onset of neurological disease and extension of the life span of 4L;C* mice. However, this was not correlated with a reduction in the accumulation of lipid substrates.
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The effect of chaperone compounds on glucocerebrosidase stability and activity in fibroblasts from Gaucher Disease patients with different genotypes

The effect of chaperone compounds on glucocerebrosidase stability and activity in fibroblasts from Gaucher Disease patients with different genotypes

Esta   patologia   divide-­‐se   principalmente   em   três   tipos:   o   tipo   1   que   se   caracteriza   por   afectar   tanto   crianças   como   adultos,   podendo   estes   indivíduos   viver   apenas   durante   a   sua   infância   ou   eventualmente   atingir   a   idade   adulta.   Uma   das   principais   características   que   identificam   o   tipo   1   e   diferem-­‐no   dos   outros  tipos  da  doença  de  Gaucher  é  o  facto  de  o  sistema  nervoso  central  não  ser   afectado.   O   tipo   2   caracteriza-­‐se   por   afectar   maioritariamente   crianças,   possuindo  uma  esperança  média  de  vida  curta,  tendo  em  conta  que  os  indivíduos   vivem   em   média   cerca   de   nove   meses.   Ocorre   no   tipo   2,   entre   outras   complicações,  o  envolvimento  severo  do  sistema  nervoso  central.  O  tipo  3  afecta   tanto  crianças  como  adultos,  sendo  a  esperança  média  de  vida  dos  indivíduos  o   período  da  infância  e,  em  alguns  casos,  a  idade  jovem  adulta.  No  tipo  3  o  sistema   nervoso   central   está   afectado,   assim   como   no   tipo   2.   Existe   ainda   o   tipo   intermediário,  entre  o  tipo  2  e  o  tipo  3,  que  se  inicia  com  idade  avançada,  porém   com  rápida  progressão  de  complicações  neurológicas  (Grabowski,  2008).  
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BIOCHEMICAL AND MOLECULAR GENETIC STUDIES ON GAUCHER DISEASE IN PORTUGAL

BIOCHEMICAL AND MOLECULAR GENETIC STUDIES ON GAUCHER DISEASE IN PORTUGAL

patients are secondary to systemic complications of the illness), and the age of onset of clinical symptoms and the severity can differ to a large extent. Symptomatic patients exhibit variable splenomegaly (4 to 70 times normal), with accompanying haematological abnormalities like anaemia, thrombocytopenia, and ocasionally, leukopenia. The spleen is known for it specialised vascular structure: it contains lymphocytes and macrophages that serve unique filtering, scavenging and immune functions. The enlarged spleen in GD causes cytopenias by haemodilution, sequestration and premature destruction of the blood elements in phagocytes that line its expanded sinusoids and cords. Increased haematopoiesis may initially compensate but continuing enlargement of the spleen and local effects of Gaucher cells in the bone marrow ultimately lead to the syndrome of hypersplenism. Severe abdominal pain due to infarcts, mechanical interference with adjoining organs, growth retardation (in children), or cachexia (in adults) occur; in severely afflicted patients, even high cardiac output failure may occur. Easy bruising, epistaxis, and bleeding from gums are common. Low haemoglobin levels lead to dyspnea, tachypnea, and fatigue. Hepatomegaly (1.5 to 10 times normal) is another common manifestation. Hepatic function may be impaired, resulting in elongation of prothrombin time and partial thromboplastin time. Skeletal involvement is frequent in patients and can cover the spectrum from osteopenia to severe destruction of bone. Erlenmeyer flask-like deformities of the distal femur are characteristic of the disorder but occur in about 30% of patients. Aseptic necrosis of femoral head is the most common destructive bony lesion (reviewed in Beutlerand Grabowski, 1995).
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Glucosylsphingosine is a highly sensitive and specific biomarker for primary diagnostic and follow-up monitoring in Gaucher disease in a non-Jewish, Caucasian cohort of Gaucher disease patients.

Glucosylsphingosine is a highly sensitive and specific biomarker for primary diagnostic and follow-up monitoring in Gaucher disease in a non-Jewish, Caucasian cohort of Gaucher disease patients.

Current diagnostic steps comprise the measurement of b- glucocerebrosidase enzyme activity in fibroblasts and leucocytes, supported by the detection of the mutation and determination of chitotriosidase and CCL18/PARC [8]. However, enzyme activity levels cannot be used to reliably determine disease severity. The routinely available biomarkers, chitotriosidase and CCL-18, are epiphenomena caused by activation of macrophages after uptake of glucosylceramide. Therefore, they do not reflect the patho- physiology of the disease and reflect only to a limited extent the disease activity or response to therapy. While GD patients display a massive increase in chitotriosidase, patients with other LSDs exhibit elevated chitotriosidase levels to a lesser extent. However this limits the significance and value of this measurement [9]. In male Fabry patients Vedder and colleagues found evidence of elevated chitotriosidase levels which was reduced to normal after onset of treatment reflecting the lipid accumulation in Fabry patients in macrophages prior to therapy [10]. Not only lysosomal storage disorders may cause an increase in chitotriosidase, peroxisomal disorders like the X-linked cerebral adrenoleukodys- trophy may also cause an elevation of this biomarker, which recently was reported to be able to monitor and predict the prognosis of patients with X-linked cerebral adrenoleukodystrophy receiving allogeneic hematopoietic stem cell transplantation [11]. Furthermore, subjects, including those with GD, may have a chitotriosidase activity deficiency due to a 24–base pair (bp) duplication in the chitotriosidase gene. Obviously, these individ- uals cannot be monitored by the measurement of plasma chitotriosidase activity [12–13]. The frequency of the homozygous 24-bp duplication in the chitotriosidase gene depends on the ethnicity and can vary between 6% and nearly 35% in the Latino population (unpublished data). In these cases the marker CCL18 is used [14–15]. However, elevated levels of CCL18 were also found to be associated with a variety of diseases, such as different types of cancer and inflammation of joints, lungs and skin (e.g. rheumatoid arthritis, hypersensitivity pneumonitis and atopic dermatitis, for details see review by Schutyser and colleagues) [16]. For example, the ascitic fluid of patients suffering from ovarian cancer contains a significantly elevated level of CCL18 compared to patients without this carcinoma (Budd-Chiari syndrome) [17]. Since it attracts and activates specific immune cells CCL18 plays a role in tumor suppression. Furthermore, children having acute lymphocytic leukemia are found to exhibit elevated levels of CCL18 [18]. Hence, plasma levels of CCL18 do not reflect one particular clinical symptom, but are rather a reflection of the total body burden of Gaucher cells.
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Estudo da doença de Gaucher em Santa Catarina.

Estudo da doença de Gaucher em Santa Catarina.

Gaucher Disease (GD) was the first described and is the most common lysosomal deposit disease. It is characterized byahereditary deficiency of glucocerebrosidase lysosomal enzyme activity which blocks the metabolism of glucocerebrosideo. The aim of this work was to study the clinical, laboratorial and radiological characteristics, the main mutations correlating them with the clinical form of the disease and evaluating the response to enzymatic replacement therapy in patients with GD in Santa Catarina. Ten GD patients were studied at a University Hospital between 1998 and 2003. The disease was diagnosed by measurement of the beta- glucosidase enzyme in leukocytes. Investigation of mutations used samples of blood and oral mucus. The average age at diagnosis was 19.6 years. Type 1 GD was diagnosis in 80% of the cases and type 2 in 20%. Four patients had a family history of GD. Hepatosplenomegaly was the most common clinical manifestation. Anemia and thrombocitopenia occurred in all cases. Bone pain was reported by 75% of the patients. The mutanted alleles identified were N370S and L444P. The hemoglobina levels were elevated in all patients with type 1 GD. In conclusion, type 1 GD is the most common clinical form and anemia, thrombocitopenia, hepatosplenomegaly and osteopenia were the most common characteristics of GD patients. The N370S allele is the most common mutation and is related with type 1 GD 1. Homozygosity of the L444P allele suggests early death. Enzyme replacement therapy is safe and efficacious in type 1 GD. Rev. bras. hematol. hemoter. 2008;30(1):5-11.
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Tratamento da doença de Gaucher: um consenso brasileiro

Tratamento da doença de Gaucher: um consenso brasileiro

Banerjee TK, McKee MA et al. Enzyme therapy in Type 1 Gaucher disease: Comparative efficacy of mannose- terminated glucocerebrosidase from natural and recombinant sources. Ann Intern Med 1995;122:33-39. 20. Pastores GM, Sibille AR, Grabowski GA. Enzyme Therapy in Gaucher disease Type 1: Dosage efficacy and adverse effects in 33 patients treated for 6 to 24 months. Blood 1993;82:408-416.

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Ressonância magnética e o escore BMB na avaliação do acometimento ósseo em pacientes com doença de Gaucher.

Ressonância magnética e o escore BMB na avaliação do acometimento ósseo em pacientes com doença de Gaucher.

3. Wenstrup RJ, Roca-Espiau M, Weinreb NJ, et al. Skeletal aspects of Gaucher disease: a review. Br J Radiol. 2002;75 Suppl 1:A2–12. 4. Stowens DW, Teitelbaum SL, Kahn AJ, et al. Skeletal complica- tions of Gaucher disease. Medicine (Baltimore). 1985;64:310–22. 5. Maas M, van Kuijk C, Stoker J, et al. Quantification of bone in- volvement in Gaucher disease: MR imaging bone marrow burden score as an alternative to Dixon quantitative chemical shift MR imaging – initial experience. Radiology. 2003;229:554–61. 6. Robertson PL, Maas M, Goldblatt J. Semiquantitative assessment
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Aspectos clínicos e nutricionais da doença de Gaucher: estudo prospectivo de 13 crianças em um único centro.

Aspectos clínicos e nutricionais da doença de Gaucher: estudo prospectivo de 13 crianças em um único centro.

Methods: thirteen patients were prospectively followed up. Gaucher disease was confirmed in all patients through the use of an enzyme assay test to measure glucocerebrosidase enzyme activity. Demographic and nutritional data, and biochemical findings obtained on admission, were studied. Genetic testing was performed in 7 patients. The median age of follow-up was 5.3 years. Z scores for weight and height on admission and at the end of observation period were calculated. The standardized prevalence for malnutrition was calculated using the Mora method.

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DOENÇA DE GAUCHER TIPO 1 NO ESQUELETO: REVISÃO DA AMÉRICA LATINA.

DOENÇA DE GAUCHER TIPO 1 NO ESQUELETO: REVISÃO DA AMÉRICA LATINA.

Gaucher disease (GD) is the most prevalent lysosomal storage disease, and is characterized by the accumulation of glucosylceramide and glucosylsphingosine in tissues throughout the body. With the advent of enzyme replacement therapy, the prognosis for patients with GD has dramatically improved. Still, the skeletal manifestations associated with GD respond slowly to enzyme replacement therapy and are the most significant contributor of disease related patient morbidity. This review of bone manifestations in GD presents the most recent theories on its pathophysiology, and gives a systematic review of studies with Latin American patients that report the frequency of bone manifestations and the effects of enzyme replacement therapy on their treatment. We conclude by emphasizing the importance of early identification and proper management at appropriate dosage levels of enzyme replacement therapy to reduce the morbidity caused by GD. Keywords: Gaucher disease; Skeleton; Prevalence; Latin America.
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Rastreamento populacional para Doença de Gaucher em Tabuleiro do Norte-CE

Rastreamento populacional para Doença de Gaucher em Tabuleiro do Norte-CE

Background. Gaucher Disease (GD) is a hereditary lysosomal storage disorder characterized by the accumulation of glucosylceramide, mainly in the cells of the reticuloendothelial system, due to a deficiency of the enzyme acid β-glucosidase (GBA). Diagnosis is usually based on measurement of GBA activity in peripheral leukocytes. The purpose of this study was to evaluate the ability of screening for GBA and chitotriosidase activity using Dried Blood Spots on Filter Paper (DBS-FP) to identify individuals at high risk for GD in high-risk populations such as that of Tabuleiro do Norte, a small town in Northeastern Brazil. Methods. Between June 1, 2007 and May 31, 2008, 740 consented residents and descendants of traditional families from Tabuleiro do Norte were submitted to screening with DBS-FP. Subjects with GBA activity <2.19 nmol/h/mL were referred to analysis of GBA and chitotriosidase activity in peripheral leukocytes and in plasma, respectively. Subjects at highest risk for GD (GBA activity in peripheral leukocytes <5.6 nmol/h/mg protein) were submitted to molecular analysis to confirm diagnosis. Results. Screening with DBS-FP identified 135 subjects (18.2%) with GBA activity <2.19 nmol/h/mL, 131 of whom remained in the study. In 10 of these (7.6%), GBA activity in leukocytes was 2.6 –5.5 nmol/h/mg protein. Subsequent molecular analysis confirmed 6 cases of heterozygosity and 4 normals for GD. Conclusion. DBS-FP assay was shown to be an effective initial GD screening strategy for high-prevalence populations in developing regions. Diagnosis could not be established from GBA activity in leukocytes alone, but required confirmation with molecular analysis.
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Evolução do estado nutricional na doença de Gaucher tipo I em tratamento com reposição enzimática - relato de dois casos.

Evolução do estado nutricional na doença de Gaucher tipo I em tratamento com reposição enzimática - relato de dois casos.

Discussion: the two patients were of low height for age on diagnosis and had experienced an increase in fat mass during treatment, with one patient also presenting with an increase in fat free mass. Energy consumption and macronutrients remained fairly constant during the follow-up period in both patients. Key words Gaucher disease, Nutritional status, Food consumption, Body weight

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Medicamentos de alto custo para doenças raras no Brasil: o exemplo das doenças lisossômicas.

Medicamentos de alto custo para doenças raras no Brasil: o exemplo das doenças lisossômicas.

Abstract This paper approaches in a critical way aspects of Brazilian public policies for drugs, em- phasizing those classified as high cost and for rare diseases. The lysosomal storage diseases was taken as an example because of their rarity and the in- ternational trend for the development of new drugs for their treatment, all at high costs. Three lysos- omal storage diseases were approached: Gaucher disease, Fabry disease and mucopolysaccharido- sis type I. Gaucher disease has its treatment drug licensed in Brazil and guidelines for its use are established through a clinical protocol by the Min- istry of Health. The others have their drug treat- ments registered in Brazil; however, no treatment guidelines for them have been developed by the government. The objective of the paper was to foster the discussion on the role of health technol- ogy assessment for high-cost drugs for rare diseas- es in Brazil, emphasizing the need for establish- ing health policies with legitimacy towards these diseases. Despite the difficulties in establishing a health policy for each rare disease, it is possible to create rational models to deal with this growing challenge.
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Doença de Gaucher: uma desordem subdiagnosticada

Doença de Gaucher: uma desordem subdiagnosticada

Comments: This was the only documented case of Gaucher disease diagnosis in the General Hospital of Uberlândia Federal University, between 1999 and 2008, which assists a population of approximately 3 million people in 86 municipalities, indicating underdiagnosis of this inborn metabolic error. Thus, it is important to consider Gaucher disease as a differential diagnosis on patients with chronic anemia and splenomegaly during childhood.

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Autosomal Dominant Polycystic Kidney Disease: Review and Management Update

Autosomal Dominant Polycystic Kidney Disease: Review and Management Update

Genetic testing should not be used as a screening tool when imaging diagnosis is clear. It is only indicated in speciic situations: diagnosis of exclusion in younger at-risk individuals with a family history of ADPKD (such as a potential living-related kidney donor), patients with cystic disease but without afected relatives, individuals with early onset of PKD in families with ADPKD, and couples who wish a prenatal or preimplantation genetic diagnosis. 17

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