Oculocerebrorenal Dystrophy (Lowe Syndrome)

Updated: Dec 02, 2014
  • Author: Amira Al-Uzri, MD, MCR; Chief Editor: Luis O Rohena, MD  more...
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Overview

Background

In 1952, Lowe and colleagues described an infant with congenital cataracts and mental retardation. When more patients were described, the phenotype was expanded to include the renal tubular defects that comprise Fanconi syndrome, and an X-linked inheritance pattern was noted. In 1992, Nussbaum and colleagues reported that mutations of OCRL1 caused the rare X-linked disorder oculocerebrorenal syndrome of Lowe (OCRL), or Lowe syndrome, which includes the diagnostic triad of congenital cataracts, neonatal or infantile hypotonia with subsequent mental impairment, and renal tubular dysfunction.

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Pathophysiology

Lowe syndrome is caused by an inherited mutation in the OCRL gene, mapped to chromosome Xq 26.1, which encodes the OCRL1 protein. The OCRL1 protein is an inositol polyphosphate 5-phosphatase primarily located in the trans- Golgi network (TGN), on endosomes, and at the endocytic clathrin coated pits. It can also translocate to plasma membrane ruffles upon stimulation with growth-factors.

The main substrates for Lowe syndrome are two phosphoinositides (Ptdln): PtdIn4,5P2 and PtdIn3,4,5P3. OCRL1 has been localized to the trans -Golgi network and various compartments of the endocytic pathway (traffic), where it is found in the clathrin-coated pits, clathrin-coated vesicles, variable functioning endosomes (early, signaling, recycling), and the basal body of primary cilia. Therefore, OCRL1 affects several cellular processes, namely membrane trafficking, actin cytoskeleton remodeling, cell migration, cell polarity, and phagocytosis. Cytokine defects have also been reported in mammalian cell lines lacking OCRL1 attributed to dysregulation of actin assembly.

In addition, OCRL1 plays an important role in ciliogenesis by modulating trafficking of ciliary components into the cilium, presumably through binding with Rab8. Studies in zebrafish demonstrated defects in cell migration, cell spreading, and primary cilia assembly in the presence of mutant OCRL1. [1] These studies provide strength to the classification of Lowe syndrome as part of the ciliopathy-associated diseases.

For a more thorough review of the role of phosphatidylinositol and the cellular and physiological functions of OCRL1 please refer to the following 2 reviews: (1) McCrea HJ, De Camilli P. Mutations in phosphoinositide metabolizing enzymes and human disease. Physiology (Bethesda). Feb 2009;24:8-16 [2] and (2) Mehta ZB, Pietka G, Lowe M. The cellular and physiological functions of the Lowe syndrome protein OCRL1. Traffic. May 2014;15(5):471-87. [3]

Membrane trafficking defects caused by mutation in OCRL may explain renal tubular defects observed in Lowe syndrome, including the inability of proximal tubular cells (PTC) to reabsorb low-molecular weight (LMW) proteins and other solutes such as phosphorus and bicarbonate from the glomerular filtrate. The absorption of LMW proteins occurs in the PTC through clathrin-mediated endocytosis via 2 multiligand receptors (megalin and cubilin) present in the PTC apical border.

Megalin is internalized by endocytosis and delivered to vacuolar endosomes, which then sort megalin into recycling tubules and deliver it back to the plasma membrane, thus keeping an abundant number of megalin receptors at the apical surface of PTC for further endocytosis and recycling. In OCRL1 deficiency, megalin trafficking and recycling by the endosome is impaired, leading to accumulation of megalin in the endosome. The low number of megalin at the PTC apical border explains the reduced endocytosis of low-molecular weight proteins that occur in Lowe syndrome. [3] Proteomic analysis of urine from patients with Lowe syndrome typically show low levels of megalin and cubilin denoting a decrease in the number of these multiligand receptors in the PTC. [4]

The OCRL gene is located on Xq25-q26 and consists of 24 exons occupying 52kb. Sequence analysis detects mutations in 95% of males and 95% of female carriers. Several mutations in the OCRL gene have been described, including truncation mutations, missense mutations, and large deletions. New mutations do occur in about 32% of cases, and germline mosaicism is not uncommon. For more detailed genetic information, please refer to the Online Mendelian Inheritance in Man website catalog (OMIM).

Recently, mutations in the OCRL gene have also been identified with renal tubular reabsorption defects in a subset of patients with another X-linked disease called Dent-2 disease, characterized by LMW proteinuria, hypercalciuria, and nephrocalcinosis. [5, 6] Classic Dent disease (also called Dent-1 disease) typically does not include renal tubular acidosis or extra renal manifestations. It occurs due to a mutation in the CLCN5 gene located in Xp11.22 and encodes the chloride channel 5 (ClC-5). These CIC-5 channels are predominantly expressed in the proximal tubule and in the intercalated cells of the distal nephron.

Patients with Dent-2 disease can be easily differentiated from patients with Lowe syndrome based on their lack of major extra-renal manifestations such as cataracts and hypotonia. However, mildly elevated serum muscle enzyme levels, mild cognitive or behavioral impairment, growth retardation, and cryptorchidism have been reported in Dent-2 disease. Lowe syndrome and Dent-2 disease both share defective endocytic trafficking due to loss of OCRL1 function; therefore, cells that are highly polarized with a high rate of endocytosis, such as PTC, lens epithelium, and neurons, are expected to be more sensitive to the effects of OCRL1 nonfunctions.

However, despite recent advances in molecular genetics, the exact mechanism by which the mutations in OCRL gene causes the phenotypic characteristics of Lowe syndrome or the limited renal manifestations of Dent-2 disease remains poorly understood. Among possible theories for this phenotypic variability include presence of modifier loci in the gen and epigenetic factors.

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Epidemiology

Frequency

International

Lowe syndrome is an uncommon, panethnic disorder with the prevalence of 1:200,000-1:500,000 births. In the United States, as of the year 2000, 190 living affected males were known to the Lowe Syndrome Association (LSA), which estimates this number to represent approximately 50% of all cases.

Mortality/Morbidity

The high mortality rate observed in the first few months of life is attributed to the severe metabolic derangements associated with Fanconi syndrome. These patients are predisposed to failure to thrive, severe metabolic acidosis, electrolyte imbalances, and dehydration. Patients with Lowe syndrome also have a tendency to develop pneumonia due to hypotonia and poor cough reflex. Other causes of death include infection and status epilepticus. Sudden unexplained death can also occur. Death usually occurs in the second or third decade of life. A few patients with Lowe syndrome are reported to have survived into the fourth and fifth decades of life with chronic kidney failure.

Sex

Lowe syndrome is inherited in an X-linked fashion. Thus, the vast majority of patients are males. Few cases have been reported in females. Most affected females have X-autosomal translocations involving the OCRL1 locus, which permits full expression of the Lowe syndrome phenotype.

Age

Although the diagnosis is not always straightforward, virtually all patients have some degree of hypotonia with the absence of deep tendon reflexes and cataracts present at birth. Other nervous system manifestations and mental retardation become obvious later. Renal tubular function may essentially be normal at birth, but the typical abnormalities often are detectable by age 1 year. Serum creatinine levels remain normal, with normal urinary creatinine clearance during the first decade of life. Chronic kidney disease with an increase in the serum creatinine levels develops slowly, starting in the second decade of life in some patients.

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