Abstract
OCRL mutations, which are a hallmark of Lowe syndrome, have recently been found in patients with isolated renal phenotype (Dent-2 disease). In this report, we describe clinical and laboratory features in five Macedonian children with mutations in the OCRL gene. Children with a clinical diagnosis of Lowe syndrome or Dent disease underwent complete neurological and ophthalmological examination, imaging of the kidney and urinary tract, assessment of renal tubular function, and mutation analysis of the OCRL gene. Two children (18 months and 11 years, respectively) were diagnosed with Lowe syndrome on the basis of congenital cataracts, severe psychomotor retardation, and renal dysfunction. Both children had low molecular weight proteinuria (LMWP) and hypercalciuria, but not Fanconi syndrome. The older one had bilateral nephrolithiasis due to associated hypocitraturia and mild hyperoxaluria. Three children with asymptomatic proteinuria were diagnosed with Dent-2 disease; none had cataracts or neurological deficit. One child showed mild mental retardation. All had LMWP, hypercalciuria, and elevated enzymes (creatine phosphokinase, lactic dehydrogenase). All three children had an abnormal Tc-99m DMSA scan revealing poor visualization of the kidneys with a high radionuclide content in the bladder; none had nephrolithiasis or nephrocalcinosis. In conclusion, children with OCRL mutations may present with very mild phenotype (asymptomatic proteinuria with/without mild mental retardation) or severe classic oculocerebrorenal syndrome of Lowe. Elevated enzymes and abnormal results on the Tc-99m DMSA scan may be useful indicators for Dent-2 disease.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Lowe CU, Terrey M, Maclachan EA (1952) Organic aciduria, decreased renal ammonia production, hydrophthalmos, and mental retardation: A clinical entity. Am J Dis Child 83:164–184
Kruger SJ, Wilson ME Jr, Hutchinson AK, Peterseim MM, Bartholomew LR, Saunders RA (2003) Cataracts and glaucoma in patients with oculocerebrorenal syndrome. Arch Ophthalmol 121:1234–1237
Röschinger W, Muntau AC, Rudolph G, Roscher AA, Kammerer S (2000) Carrier assessment in families with Lowe oculocerebrorenal syndrome: novel mutations in the OCRL1 gene and correlation of direct DNA diagnosis with ocular examination. Mol Genet Metab 69:213–222
Charnas LR, Bernardini I, Rader D, Hoeg JM, Gahl WA (1991) Clinical and laboratory findings in the oculocerebrorenal syndrome of Lowe, with special reference to growth and renal function. N Engl J Med 324:1318–1325
Schramm L, Gal A, Zimmermann J, Netzer KO, Heidbreder E, Lopau K, Gröne H, Wanner C (2004) Advanced renal insufficiency in a 34-year-old man with Lowe syndrome. Am J Kidney Dis 43:538–543
Tricot L, Yahiaoui Y, Teixeira L, Benabdallah L, Rothschild E, Juquel JP, Satre V, Grünfeld JP, Chauveau D (2003) End-stage renal failure in Lowe syndrome. Nephrol Dial Transplant 18:1923–1925
Choudhury R, Diao A, Zhang F, Eisenberg E, Saint-Pol A, Williams C, Konstantakopoulos A, Lucocq J, Johannes L, Rabouille C, Greene LE, Lowe M (2005) Lowe syndrome protein OCRL1 interacts with clathrin and regulates protein trafficking between endosomes and the trans-Golgi network. Mol Biol Cell 16:3467–3479
Erdmann KS, Mao Y, McCrea HJ, Zoncu R, Lee S, Paradise S, Modregger J, Biemesderfer D, Toomre D, De Camilli P (2007) A role of the Lowe syndrome protein OCRL in early steps of the endocytic pathway. Dev Cell 13:377–390
Hoopes RR Jr, Shrimpton AE, Knohl SJ, Hueber P, Hoppe B, Matyus J, Simckes A, Tasic V, Toenshoff B, Suchy SF, Nussbaum RL, Scheinman SJ (2005) Dent disease with mutations in OCRL1. Am J Hum Genet 76:260–267
Utsch B, Bökenkamp A, Benz MR, Besbas N, Dötsch J, Franke I, Fründ S, Gok F, Hoppe B, Karle S, Kuwertz-Bröking E, Laube G, Neb M, Nuutinen M, Ozaltin F, Rascher W, Ring T, Tasic V, van Wijk JA, Ludwig M (2006) Novel OCRL1 mutations in patients with the phenotype of Dent disease. Am J Kidney Dis 48(942):e1–14
Matos V, van Melle G, Boulat O, Markert M, Bachmann C, Guignard JP (1997) Urinary phosphate/creatinine, calcium/creatinine, and magnesium/creatinine ratios in a healthy pediatric population. J Pediatr 131:252–257
Böckenhauer D, Bökenkamp A, van't Hoff W, Levtchenko E, Kist-van Holthe JE, Tasic V, Ludwig M (2008) Renal phenotype in Lowe Syndrome: a selective proximal tubular dysfunction. Clin J Am Soc Nephrol 3:1430–1436
Bökenkamp A, Böckenhauer D, Cheong HI, Hoppe B, Tasic V, Unwin R, Ludwig M (2009) Dent-2 disease: a mild variant of Lowe syndrome. J Pediatr 155:94–99
Sekine T, Nozu K, Iyengar R, Fu XJ, Matsuo M, Tanaka R, Iijima K, Matsui E, Harita Y, Inatomi J, Igarashi T (2007) OCRL1 mutations in patients with Dent disease phenotype in Japan. Pediatr Nephrol 22:975–980
Cho HY, Lee BH, Choi HJ, Ha IS, Choi Y, Cheong HI (2008) Renal manifestations of Dent disease and Lowe syndrome. Pediatr Nephrol 23:243–249
Shrimpton AE, Hoopes RR Jr, Knohl SJ, Hueber P, Reed AA, Christie PT, Igarashi T, Lee P, Lehman A, White C, Milford DV, Sanchez MR, Unwin R, Wrong OM, Thakker RV, Scheinman SJ (2009) OCRL1 mutations in Dent 2 patients suggest a mechanism for phenotypic variability. Nephron Physiol 112:p27–36
Tosetto E, Addis M, Caridi G, Meloni C, Emma F, Vergine G, Stringini G, Papalia T, Barbano G, Ghiggeri GM, Ruggeri L, Miglietti N, D’Angelo A, Melis MA, Anglani F (2009) Locus heterogeneity of Dent’s disease: OCRL1 and TMEM27 genes in patients with no CLCN5 mutations. Pediatr Nephrol 24:1967–1973
Kaneko K, Hasui M, Hata A, Hata D, Nozu K (2010) Focal segmental glomerulosclerosis in a boy with Dent-2 disease. Pediatr Nephrol 25:781–782
Ludwig M, Utsch B, Monnens LA (2006) Recent advances in understanding the clinical and genetic heterogeneity of Dent's disease. Nephrol Dial Transplant 21:2708–2717
Frishberg Y, Dinour D, Belostotsky R, Becker-Cohen R, Rinat C, Feinstein S, Navon-Elkan P, Ben-Shalom E (2009) Dent's disease manifesting as focal glomerulosclerosis: Is it the tip of the iceberg? Pediatr Nephrol 24:2369–2373
Suzuki S, Suzuki J, Kume K, Yoshida K, Suyama H, Kawasaki Y, Nozawa R, Suzuki H, Fujiki T, Kamiyama S, Suzuki A (1999) Poor renal accumulation of 99mTc-DMSA in idiopathic tubular proteinuria. Nephron 81:49–54
Lee BH, Lee SH, Choi HJ, Kang HG, Oh SW, Lee DS, Ha IS, Choi Y, Cheong HI (2009) Decreased renal uptake of (99m)Tc-DMSA in patients with tubular proteinuria. Pediatr Nephrol 24:2211–2216
van Luÿk WH, Ensing GJ, Piers DA (1983) Low renal uptake of 99mTc-DMSA in patients with proximal tubular dysfunction. Eur J Nucl Med 8:404–405
de Lange MJ, Piers DA, Kosterink JG, van Luijk WH, Meijer S, de Zeeuw D, van der Hem GK (1989) Renal handling of technetium-99m DMSA: evidence for glomerular filtration and peritubular uptake. J Nucl Med 30:1219–1223
Kim SE, Cho JT, Lee DS, Chung JK, Kim S, Lee MC, Lee JS, Koh CS (1995) Poor renal uptake of Tc-99m DMSA and Tc-99m MDP in a patient with Fanconi syndrome and near normal glomerular filtration rate. Clin Nucl Med 20:215–219
Caglar M, Topaloğlu R (2002) Reduced Tc-99m DMSA uptake in a patient with renal tubular acidosis: effect of acid-base imbalance. Ann Nucl Med 16:499–501
Hecht H, Ohlsson J, Starck SA (1996) Poor renal uptake of 99mtechnetium-dimercaptosuccinic acid and near-normal 99mtechnetium-mercaptoacetyltriglycine renogram in nephronophthisis. Pediatr Nephrol 10:167–170
Jänne PA, Suchy SF, Bernard D, MacDonald M, Crawley J, Grinberg A, Wynshaw-Boris A, Westphal H, Nussbaum RL (1998) Functional overlap between murine Inpp 5b and Ocrl1 may explain why deficiency of the murine ortholog for OCRL1 does not cause Lowe syndrome in mice. J Clin Invest 101:2042–2053
Conflict of interests
None
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Tasic, V., Lozanovski, V.J., Korneti, P. et al. Clinical and laboratory features of Macedonian children with OCRL mutations. Pediatr Nephrol 26, 557–562 (2011). https://doi.org/10.1007/s00467-010-1758-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00467-010-1758-9