The oculocerebrorenal syndrome of Lowe: an update

Abstract

The oculocerebrorenal syndrome of Lowe is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, intellectual disability, and proximal renal tubular dysfunction. Whereas the ocular manifestations and severe muscular hypotonia are the typical first diagnostic clues apparent at birth, the manifestations of incomplete renal Fanconi syndrome are often recognized only later in life. Other characteristic features are progressive severe growth retardation and behavioral problems, with tantrums. Many patients develop a debilitating arthropathy. Treatment is symptomatic, and the life span rarely exceeds 40 years. The causative oculocerebrorenal syndrome of Lowe gene (OCRL) encodes the inositol polyphosphate 5-phosphatase OCRL-1. OCRL variants have not only been found in classic Lowe syndrome, but also in patients with a predominantly renal phenotype classified as Dent disease type 2 (Dent-2). Recent data indicate that there is a phenotypic continuum between Dent-2 disease and Lowe syndrome, suggesting that there are individual differences in the ability to compensate for the loss of enzyme function. Extensive research has demonstrated that OCRL-1 is involved in multiple intracellular processes involving endocytic trafficking and actin skeleton dynamics. This explains the multi-organ manifestations of the disease. Still, the mechanisms underlying the wide phenotypic spectrum are poorly understood, and we are far from a causative therapy. In this review, we provide an update on clinical and molecular genetic findings in Lowe syndrome and the cellular and physiological functions of OCRL-1.

Receptor-Mediated Endocytosis in the Proximal Tubule

“…The renal abnormalities in Lowe syndrome, which include renal tubular acidosis and LMW proteinuria, are virtually identical to those observed in patients with Dent disease. Lowe syndrome patients typically develop end-stage renal disease within the first 20 years of life, and this is the primary cause of mortality (see 133 for a review). As noted above, a subset of patients with OCRL mutations manifest with milder extrarenal symptoms and are classified as having Dent2 disease.…”

“…Patients with Lowe syndrome have increased plasma and urinary levels of lysosomal hydrolases (133, 141). It is still unclear, however, whether the elevated urinary secretion of lysosomal hydrolases is due to defective M6P-receptor trafficking in cells lacking OCRL1 (142, 143) or to impaired uptake of filtered hydrolases from the tubule lumen, as observed in megalin and ClC-5 knockout mice (144).…”

Mutations In PIK3C2A Cause Syndromic Short Stature, Skeletal Abnormalities, and Cataracts Associated With Ciliary Dysfunction

“…However, the phenotype associated with mutations in INPP5E is quite distinct, and includes cerebellar vermis hypodysplasia, coloboma, hypotonia, ataxia, and neonatal breathing dysregulation (Travaglini et al, 2013). In contrast, the phenotypes associated with Lowe's syndrome share many of the same features with PIK3C2A deficiency including congenital cataracts, secondary glaucoma, kidney defects, skeletal abnormalities, developmental delay, and short stature (Bökenkamp and Ludwig, 2016;Staiano et al, 2015). The enzyme defective in Lowe's syndrome, OCRL, is functionally similar to PIK3C2A as well, as it is also required for membrane trafficking and ciliogenesis (Mehta et al, 2014).…”

Incidental Detection of Dent-2 Disease in an Infant with Febrile Proteinuria

“…Dent-2 disease should be differentiated from oculocerebrorenal syndrome of Lowe, which is a multisystem disorder characterized by congenital cataracts, hypotonia, severe neurologic deficits, intellectual disability, and renal Fanconi syndrome [9,10]. Mild intellectual disability and peripheral cataracts may be seen in some patients with Dent-2 disease, therefore one should consider both entities within the spectrum of OCRL mutations.…”