Lowe Syndrome and Dent Disease: Long term outcomes

Detlef Bockenhauer for Marcin Zaniew and the International OCRL consortium

Nephrol Dial Transplant (2016) 0: 1–11doi: 10.1093/ndt/gfw350

Original Article

Long-term renal outcome in children with OCRL mutations:retrospective analysis of a large international cohort

Marcin Zaniew1,2, Arend Bökenkamp3, Marcin Kołbuc1, Claudio La Scola4, Federico Baronio5,

Anna Niemirska6, Maria Szczepańska7, Julia Bürger8, Angela La Manna9, Monika Miklaszewska10,

Anna Rogowska-Kalisz11, Jutta Gellermann12, Argyroula Zampetoglou13, Anna Wasilewska14,

Magdalena Roszak15, Jerzy Moczko15, Aleksandra Krzemień16, Dariusz Runowski6, Grzegorz Siteń17,

Iga Załuska-Leśniewska18, Patrizia Fonduli19, Franca Zurrida19, Fabio Paglialonga20, Zoran Gucev21,

Dusan Paripovic22, Rina Rus23, Valerie Said-Conti24, Lisa Sartz25, Woo Yeong Chung26, Se Jin Park27,

Jung Won Lee28, Yong Hoon Park29, Yo Han Ahn30, Przemysław Sikora2,31, Constantinos J. Stefanidis13,

Velibor Tasic21, Martin Konrad8, Franca Anglani32, Maria Addis33, Hae Il Cheong34, Michael Ludwig35,*

and Detlef Bockenhauer36,*1Children’s Hospital, Poznan, Poland, 2Polish Registry of Inherited Tubulopathies (POLtube), Polish Society of Pediatric Nephrology, Poland,3Department of Pediatrics, VUMedical Center, Amsterdam, The Netherlands, 4Nephrology and Dialysis Unit, Department of Woman, Child and

Urological Diseases, Azienda Ospedaliero-Universitaria ‘Sant’Orsola-Malpighi’, Bologna, Italy, 5Endocrinology Unit, Department of Woman,

Child and Urological Diseases, Azienda Ospedaliero-Universitaria ‘Sant’Orsola-Malpighi’, Bologna, Italy, 6Department of Nephrology, Kidney

Transplantation and Hypertension, The Children’s Memorial Health Institute, Warsaw, Poland, 7Chair and Clinical Department of Pediatrics,

SMDZ in Zabrze, SUM in Katowice, Katowice, Poland, 8Department of General Pediatrics, University Children’s Hospital, Münster, Germany,9Department of Pediatrics, II University of Naples, Naples, Italy, 10Department of Pediatric Nephrology, Collegium Medicum of the Jagiellonian

University, Cracow, Poland, 11Department of Pediatrics, Immunology and Nephrology, Polish Mothers Memorial Hospital Research Institute,

Łódź, Poland, 12Department of Pediatric Nephrology, Charité Universitätsmedizin Berlin, Charité Children’s Hospital, Berlin, Germany,13Pediatric Nephrology, ‘A. and P. Kyriakou’Children’s Hospital, Athens, Greece, 14Department of Pediatrics and Nephrology, Medical University

of Białystok, Białystok, Poland, 15Department of Computer Science and Statistics, Poznan University of Medical Sciences, Poznan, Poland,16Department of Nephrology, Children’s Hospital, Katowice, Poland, 17Dialysis Center, District Hospital, Rzeszów, Poland, 18Department of

Pediatrics, Medical University of Gdansk, Nephrology and Hypertension, Gdańsk, Poland, 19Pediatric Nephrology, Hospital G.Brotzu, Cagliari,

Italy, 20Pediatric Nephrology andDialysis Unit, Fondazione IRCCS Ca’Granda OspedaleMaggiore Policlinico,Milan, Italy, 21University Children’s

Hospital, Medical Faculty Skopje, Skopje, Macedonia, 22Nephrology Department, University Children’s Hospital, Belgrade, Serbia, 23Division of

Nephrology, University Children’s Hospital, Ljubljana, Slovenia, 24Mater Dei Hospital, Msida, Malta, 25Department of Pediatric and Adolescent

Medicine, Skåne University Hospital, Lund, Sweden, 26Department of Pediatrics, Inje University Busan Paik Hospital, Busan, Korea, 27Department

of Pediatrics, Ajou University Daewoo Hospital, Geoje, Korea, 28Department of Pediatrics, Ehwa University Mokdong Hospital, Seoul, Korea,29Department of Pediatrics, Yeungnam University College of Medicine, Daegu, Korea, 30Department of Pediatrics, Hallym University Kangnam

Sacred Heart Hospital, Seoul, Korea, 31Department of Pediatric Nephrology, Medical University of Lublin, Lublin, Poland, 32Laboratory of

Histomorphology and Molecular Biology of the Kidney, Department of Medicine, University of Padova, Padova, Italy, 33Department of Public

Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy, 34Department of Pediatrics, Seoul National University Children’s

Hospital, Seoul, Korea, 35Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany and 36University

College London, Institute of Child Health and Great Ormond Street Hospital for Children, National Health Service Trust, London, UK

© The Author 2016. Published by Oxford University Presson behalf of ERA-EDTA. All rights reserved.

1

NDT Advance Access published October 5, 2016

at University C

ollege London on Decem

ber 1, 2016http://ndt.oxfordjournals.org/

Dow

nloaded from

Lowe syndrome

First described in 1952 by C. U. Lowe et al: �Organic Aciduria, Decreased Renal Ammonia Production, Hydrophthalmus and Mental Retardation; a clinical entity�

Genetics

• Underlying gene identified in 1992: called “OCRL(1)”(Nature. 1992 Jul 16;358(6383):239-42)

• In 2005: Identification of OCRL Mutations in a subset of patients with Dent disease(Am J Hum Genet. 2005 Feb;76(2):260-7)

=> “Dent2” disease vs “Dent1” (CLCN5)

Lowe Syndrome vs Dent2 disease

Lowe syndrome Dent2 DiseaseEyes: cataracts, glaucomaCNS: mental impairment, hypotonia

Kidney: proximal tubulopathy, progressive CKDGenetics: OCRL

severity

The international OCRL cohort

• 106 patients from 11 countries

Lowe DentN 88 18Median age (range) last f/u 9 (4-16) 13 (7-17)Mutation identified 98% 83%Median height SDS -3.98 -2.11Nephrocalcinosis (%) 45 (51) 9 (50)

Exon 1

Exon 2

Exon 3

Exon 4

Exon 5

Exon 6

Exon 7

Exon 8

Exon 9

Exon 10

Exon 11

Exon 12

Exon 13

Exon 14

Exon 15

Exon 16

Exon 17

Exon 18

Exon 19

Exon 20

Exon 21

Exon 22

Exon 23

Exon 24

c.1484C>Tc.1490G>Ac.1495_1496ins21c.1499G>Ac.1539T>G#c.1571A>G

c.1900T>Cc.1925delCc.1927_28delGTc.1987C>T c.2083C>T (n=7)**c.2071A>T (n=2)*

c.940-11G>A (consequence: c.939_940insAACTCATAG) (n=3)**c.940-1G>A

c.2581+1G>A (n=2)*c.2582-2A>Gc.2290_2291GA>TT

c.2313T>A#

c.724_729insT (n=2)#c.734G>Ac.812T>A#

c.982G>Cc.953C>T#c.962G>Ac.1000C>T (n=4)**

c.2396C>Tc.2418G>Tc.2428C>Tc.2455delC#c.2464C>T (n=4)**

c.1602+1G>Ac.1603-2A>C

c.1621C>T

c.723-1G>Ac.1879+5G>A

c.1067G>A#c.1070G>Tc.1123C>Tc.1120T>C

c.829C>Gc.829C>Tc.836T>Cc.891G>C

c.2530C>Tc.2581G>C (n=2)*

c.621_624delGAAG#c.643C>Tc.688C>T

c.2341+1_+6delGTATCCc.2341+1G>C#

c.413insA (n=3)*/**

c.1262G>Ac.1300 G>A c.2168_2175delTGGATGAA

c.2603T>G

c.259_260insTc.260delA (n=2)**

c.506delA c.728T>C

c.1431T>G

c.1817insA#

c.1133C>T (n=2)*/#

c.952C>T (n=2)*c.953G>T#

c.1477C>Tc.1567G>A (n=3)*/**

c.214_215delCT#

RhoGAP

Del exons 1-24

Del exons 1-3

Del exons 1-2

c.1453_1466/c.1466+1_+13delinsTCTAAAACAGACTCTAA (n=4)*/§

PH 5-phosphatase ASH

Genetics

Kidney function (all)

Kidney function (longitudinal)

Kaplan-Meier Analysis

0 2 4 6 8 10 12 14 16 18 20

Age (years)

0,0

0,2

0,4

0,6

0,8

1,0

Surv

ival

free

from

CK

D s

tage

3

Lowe syndrome Dent-2 disease

A

Patients at riskLowe syndrome 83 62 53 44 34 27 19 12 5 2Dent-2 disease 18 18 17 13 10 10 10 6 4 3

Genotype-Phenotype

Conclusions

• Largest cohort reported of patients with OCRL mutations

• Patients with Lowe syndrome have faster CKD progression than Dent2

• No striking genotype-phenotype effect

• 3 LS patients reached CKD5 age 14, 16 and 17 y. 1 received RRT

(Korea) and one died of complications.

• No patient with Dent 2 reached ESKD

• Collaboration with adult nephrologists needed to get longer term

data