Sara Nuovo1,2, Laura Fuiano3, Alessia Micalizzi1, Roberta Battini4,5, Enrico Bertini6, Renato Borgatti7, Gianluca Caridi8, Stefano D'Arrigo9, Elisa Fazzi10,11, Rita Fischetto12, Gian Marco Ghiggeri8, Lucio Giordano10, Vincenzo Leuzzi13, Romina Romaniello7, Sabrina Signorini14, Gilda Stringini3, Ginevra Zanni6, Marta Romani15, Enza Maria Valente1,16, Francesco Emma3. 1. Neurogenetics Unit, IRCCS Santa Lucia Foundation, Rome, Italy. 2. Department of Medicine and Surgery, University of Salerno, Salerno, Italy. 3. Department of Nephrology and Urology, Unit of Nephrology and Dialysis, IRCCS Bambino Gesù Children's Hospital, Rome, Italy. 4. Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Pisa, Italy. 5. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. 6. Laboratory of Molecular Medicine, Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, IRCCS Bambino Gesù Children's Hospital, Rome, Italy. 7. Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy. 8. Laboratory of Molecular Nephrology, Istituto Giannina Gaslini IRCCS, Genoa, Italy. 9. Developmental Neurology Division, Foundation IRCCS Neurological Institute Carlo Besta, Milan, Italy. 10. Child and Adolescent Neurology and Psychiatry Unit, Children Hospital, ASST Spedali Civili of Brescia, Brescia, Italy. 11. Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. 12. Clinical Genetics Unit, Department of Paediatric Medicine, Giovanni XXIII Children's Hospital, Bari, Italy. 13. Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy. 14. Unit of Child Neurology and Psychiatry, IRCCS C. Mondino Foundation, Pavia, Italy. 15. Molecular Genetics Laboratory, Eurofins GENOMA Group, Rome, Italy. 16. Deparment of Molecular Medicine, University of Pavia, Pavia, Italy.
Abstract
Background: Joubert syndrome (JS) is an inherited ciliopathy characterized by a complex midbrain-hindbrain malformation and multiorgan involvement. Renal disease, mainly juvenile nephronophthisis (NPH), was reported in 25-30% patients although only ∼18% had a confirmed diagnosis of chronic kidney disease (CKD). NPH often remains asymptomatic for many years, resulting in delayed diagnosis. The aim of the study was to identify a biomarker able to quantify the risk of progressive CKD in young children with JS. Methods: Renal features were investigated in 93 Italian patients, including biochemical tests, ultrasound and 1-deamino-8D-arginine vasopressin test in children with reduced basal urine osmolality. A subset of patients was followed-up over time. Results: At last examination, 27 of 93 subjects (29%) presented with CKD, ranging from isolated urinary concentration defect (UCD) to end-stage renal disease. Both normal and pathological urine osmolality levels remained stable over time, even when obtained at very early ages. Follow-up data showed that the probability of developing CKD can be modelled as a function of the urine osmolality value, exceeding 75% for levels <600 mOsm/kg H2O, and significantly increased in patients with an early diagnosis of isolated UCD. Conclusions: We conclude that the frequency of CKD in JS increases with age and is higher than previously reported. Urine osmolality represents an early sensitive quantitative biomarker of the risk of CKD progression.
Background: Joubert syndrome (JS) is an inherited ciliopathy characterized by a complex midbrain-hindbrain malformation and multiorgan involvement. Renal disease, mainly juvenile nephronophthisis (NPH), was reported in 25-30% patients although only ∼18% had a confirmed diagnosis of chronic kidney disease (CKD). NPH often remains asymptomatic for many years, resulting in delayed diagnosis. The aim of the study was to identify a biomarker able to quantify the risk of progressive CKD in young children with JS. Methods: Renal features were investigated in 93 Italian patients, including biochemical tests, ultrasound and 1-deamino-8D-arginine vasopressin test in children with reduced basal urine osmolality. A subset of patients was followed-up over time. Results: At last examination, 27 of 93 subjects (29%) presented with CKD, ranging from isolated urinary concentration defect (UCD) to end-stage renal disease. Both normal and pathological urine osmolality levels remained stable over time, even when obtained at very early ages. Follow-up data showed that the probability of developing CKD can be modelled as a function of the urine osmolality value, exceeding 75% for levels <600 mOsm/kg H2O, and significantly increased in patients with an early diagnosis of isolated UCD. Conclusions: We conclude that the frequency of CKD in JS increases with age and is higher than previously reported. Urine osmolality represents an early sensitive quantitative biomarker of the risk of CKD progression.
Authors: Ruxandra Bachmann-Gagescu; Jennifer C Dempsey; Sara Bulgheroni; Maida L Chen; Stefano D'Arrigo; Ian A Glass; Theo Heller; Elise Héon; Friedhelm Hildebrandt; Nirmal Joshi; Dana Knutzen; Hester Y Kroes; Stephen H Mack; Sara Nuovo; Melissa A Parisi; Joseph Snow; Angela C Summers; Jordan M Symons; Wadih M Zein; Eugen Boltshauser; John A Sayer; Meral Gunay-Aygun; Enza Maria Valente; Dan Doherty Journal: Am J Med Genet A Date: 2019-11-11 Impact factor: 2.802
Authors: Simon A Ramsbottom; Peter E Thelwall; Katrina M Wood; Gavin J Clowry; Laura A Devlin; Flora Silbermann; Helena L Spiewak; Shirlee Shril; Elisa Molinari; Friedhelm Hildebrandt; Meral Gunay-Aygun; Sophie Saunier; Heather J Cordell; John A Sayer; Colin G Miles Journal: Proc Natl Acad Sci U S A Date: 2019-12-26 Impact factor: 11.205