The Oculocerebrorenal Syndrome of Lowe

Publisher Summary The oculocerebrorenal syndrome of Lowe (OCRL) is a rare human X-linked disorder manifested clinically by congenital cataracts, severe mental retardation, and renal tubular dysfunction (Fanconi’s syndrome). Several mutations, including truncation mutations (nonsense, splicesite, frame-shift), missense and occasionally, somatic mutations have been identified as causative for OCRL. Nucleotide mutations are concentrated in the 3' part of the gene, whereas most of the large genomic deletions occur in the 5' part of the gene. Ninety-three percent of mutations are concentrated in only half of the 24 exons. Fifty-two percent of mutations are in five exons, and 20% have mutations in exon 15. The gene product of OCRL1, referred to as ocrl1, a 105 kD protein, deficient in Lowe syndrome, was identified to be the enzyme phosphatidylinositol-4,5-biphosphate 5-phosphatase. A variety of mutations of the OCRL1 gene lead to a loss of function of its product, the enzyme phosphatidylinositol (4,5) biphosphate 5-phosphatase (orcl1), which leads to accumulation of phosphatidylinositol (4,5) biphosphate. Most patients with OCRL have some degree of mental retardation, most with moderate to severe impairment. A small percentage of individuals (10%) have IQs in the normal or borderline range. OCRL results in proximal tubule dysfunction (Fanconi syndrome) and progressive renal failure. The onset of renal dysfunction usually is manifest a few weeks to months after birth, presenting with renal tubular acidosis, proteinuria, phosphaturia, and aminoaciduria and carnitine wasting. Most patients with OCRL have proteinuria, with almost two-thirds having nephrotic range proteinuria, but do not have other characteristics of the nephrotic syndrome.