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Oculocerebrorenal Syndrome

  • Author: Deborah M Alcorn, MD; Chief Editor: Hampton Roy, Sr, MD  more...
 
Updated: Dec 17, 2014
 

Background

Oculocerebrorenal syndrome (OCRS) is an X-linked recessive metabolic disorder described by Lowe and coworkers in 1952.[1] It is a multisystem disorder that primarily affects the eyes, nervous system, and kidneys. It is characterized by congenital cataracts, infantile glaucoma, neonatal or infantile hypotonia, intellectual impairment, and renal tubular dysfunction (Fanconi syndrome).

The oculocerebrorenal syndrome is so named because of the prominent involvement of the 3 major organ systems; however, involvement of bone, gonads, muscle, skin, and connective tissue, as well as stereotypic behavior, also can occur. Additional manifestations include corneal keloids, growth retardation, areflexia, metabolic acidosis, proteinuria, aminoaciduria, and noninflammatory arthropathy. These patients often exhibit the characteristic facial appearance of frontal bossing, deep set eyes, and full cheeks, although the characteristic phenotype is often difficult to identify in neonates.

Female carriers manifest characteristic lens opacities, but they typically have normal renal and neurologic function. See the image below.

Classic lenticular opacities in a female carrier fClassic lenticular opacities in a female carrier for Lowe syndrome. Note the punctate cortical opacities in radical wedges. Image courtesy of Otis Paul, MD.
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Pathophysiology

OCRL is caused by a mutation of the OCRL1 gene mapped to the chromosomal locus of Xq26.1.[2] The gene encodes a phosphatidylinositol (4,5) bisphosphate 5 phosphatase, localized to the trans-Golgi complex involved in actin polymerization.[2, 3] It is a key enzyme in the cellular phosphoinositide pathway, important in cellular trafficking. Deficiency of the enzyme causes the protean manifestations of Lowe syndrome. The reduced enzyme activity results in increased enzyme substrate and abnormal actin-binding proteins important in neuronal morphogenesis.[4, 5]

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Epidemiology

Frequency

International

The estimated prevalence is 1/500,000.

Mortality/Morbidity

See the list below:

  • Ocular: The hallmark feature is congenital cataracts. Left untreated, the cataracts will cause nystagmus and eventual blindness. Glaucoma develops in 50-70% of patients, typically manifesting in the first year of life, but it may present at any age.[6] Patients also may develop corneal leukomas. Amblyopia may occur secondary to poor compliance with treatment and secondary strabismus. Corrected visual acuity is infrequently better than 20/70 despite optimal management. The visual impairment represents a combination of the morphologic changes in the eye, retinal dysfunction, and cortical functioning.
  • Renal: If untreated, the proximal renal tubular acidosis leads to failure to thrive and metabolic collapse. By the second to third decade, gradual loss of creatinine clearance occurs, with progressive renal failure.
  • Growth: At birth, these patients are within the normal growth curve but fall off in length, height, and weight in subsequent years.
  • Neurological: Neonatal hypotonia may contribute to poor feeding and delayed motor development.
  • Life expectancy: Patients with appropriate therapy may live to be 30-40 years of age, generally dying from renal failure, respiratory distress, status epilepticus, or infection. With improved medical treatment, infection as a cause for death has declined dramatically. The expected life span has not yet been defined.

Sex

Oculocerebrorenal syndrome occurs almost exclusively in males. It is an X-linked recessive disorder. The female carrier state is identifiable by characteristic lenticular opacities.

A few cases have been reported in females, often having X-autosome translocations involving the OCRL1 locus, explained by the inactivation of the normal X chromosome by the translocation.[2]

Age

Oculocerebrorenal syndrome is congenital.

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Contributor Information and Disclosures
Author

Deborah M Alcorn, MD Associate Professor, Departments of Ophthalmology and Pediatrics, Stanford University School of Medicine; Director of Pediatric Ophthalmology and Strabismus, Lucile Packard Children's Hospital

Deborah M Alcorn, MD is a member of the following medical societies: American Academy of Ophthalmology, International Society for Genetic Eye Diseases and Retinoblastoma, American Association for Pediatric Ophthalmology and Strabismus

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Hampton Roy, Sr, MD Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Hampton Roy, Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, Pan-American Association of Ophthalmology

Disclosure: Nothing to disclose.

Additional Contributors

Andrew W Lawton, MD Neuro-Ophthalmology, Ochsner Health Services

Andrew W Lawton, MD is a member of the following medical societies: American Academy of Ophthalmology, Arkansas Medical Society, Southern Medical Association

Disclosure: Nothing to disclose.

Acknowledgements

Brian R Younge, MD Professor of Ophthalmology, Mayo Clinic School of Medicine

Brian R Younge, MD is a member of the following medical societies: American Medical Association, American Ophthalmological Society, and North American Neuro-Ophthalmology Society

Disclosure: Nothing to disclose.

References
  1. Lowe CU, Terrey M, MacLachlan EA. Organic-aciduria, decreased renal ammonia production, hydrophthalmos, and mental retardation. Am J Dis Child. 1952. 83:164-184.

  2. Loi M. Lowe syndrome. Orphanet J Rare Dis. 2006 May 18. 1:16. [Medline].

  3. Luo N, Kumar A, Conwell M, Weinreb RN, Anderson R, Sun Y. Compensatory Role of Inositol 5-Phosphatase INPP5B to OCRL in Primary Cilia Formation in Oculocerebrorenal Syndrome of Lowe. PLoS One. 2013. 8(6):e66727. [Medline]. [Full Text].

  4. Kim HK, Kim JH, Kim YM, Kim GH, Lee BH, Choi JH, et al. Lowe syndrome: a single center's experience in Korea. Korean J Pediatr. 2014 Mar. 57(3):140-8. [Medline]. [Full Text].

  5. Sugimoto K, Nishi H, Miyazawa T, Fujita S, Okada M, Takemura T. A novel OCRL1 mutation in a patient with the mild phenotype of lowe syndrome. Tohoku J Exp Med. 2014. 232(3):163-6. [Medline].

  6. Walton DS, Katsavounidou G, Lowe CU. Glaucoma with the oculocerebrorenal syndrome of Lowe. J Glaucoma. 2005 Jun. 14(3):181-5. [Medline].

  7. Topaloglu R, Ludwig M, Çelebi Tayfur A. Selective proximal renal tubular involvement and dyslipidemia in two cousins with oculocerebrorenal syndrome of Lowe. Turk J Pediatr. 2013 May-Jun. 55(3):331-4. [Medline].

  8. Pirruccello M, De Camilli P. Inositol 5-phosphatases: insights from the Lowe syndrome protein OCRL. Trends Biochem Sci. 2012 Apr. 37(4):134-43. [Medline]. [Full Text].

  9. Kühbacher A, Dambournet D, Echard A, Cossart P, Pizarro-Cerdá J. Phosphatidylinositol 5-phosphatase oculocerebrorenal syndrome of Lowe protein (OCRL) controls actin dynamics during early steps of Listeria monocytogenes infection. J Biol Chem. 2012 Apr 13. 287(16):13128-36. [Medline]. [Full Text].

  10. Attree O, Olivos IM, Okabe I, Bailey LC, Nelson DL, Lewis RA. The Lowe's oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase. Nature. 1992 Jul 16. 358(6383):239-42. [Medline].

  11. Cibis GW, Waeltermann JM, Whitcraft CT, Tripathi RC, Harris DJ. Lenticular opacities in carriers of Lowe's syndrome. Ophthalmology. 1986 Aug. 93(8):1041-5. [Medline].

  12. Kenworthy L, Charnas L. Evidence for a discrete behavioral phenotype in the oculocerebrorenal syndrome of Lowe. Am J Med Genet. 1995 Nov 20. 59(3):283-90. [Medline].

  13. Kruger SJ, Wilson ME Jr, Hutchinson AK, Peterseim MM, Bartholomew LR, Saunders RA. Cataracts and glaucoma in patients with oculocerebrorenal syndrome. Arch Ophthalmol. 2003 Sep. 121(9):1234-7. [Medline].

  14. Lavin CW, McKeown CA. The oculocerebrorenal syndrome of Lowe. Int Ophthalmol Clin. 1993 Spring. 33(2):179-91. [Medline].

  15. Lin T, Lewis RA, Nussbaum RL. Molecular confirmation of carriers for Lowe syndrome. Ophthalmology. 1999 Jan. 106(1):119-22. [Medline].

  16. Nussbaum RL, Orrison BM, Janne PA, Charnas L, Chinault AC. Physical mapping and genomic structure of the Lowe syndrome gene OCRL1. Hum Genet. 1997 Feb. 99(2):145-50. [Medline].

  17. Suchy SF, Nussbaum RL. The deficiency of PIP2 5-phosphatase in Lowe syndrome affects actin polymerization. Am J Hum Genet. 2002 Dec. 71(6):1420-7. [Medline]. [Full Text].

  18. Tripathi RC, Cibis GW, Tripathi BJ. Pathogenesis of cataracts in patients with Lowe's syndrome. Ophthalmology. 1986 Aug. 93(8):1046-51. [Medline].

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Classic lenticular opacities in a female carrier for Lowe syndrome. Note the punctate cortical opacities in radical wedges. Image courtesy of Otis Paul, MD.
 
 
 
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