Excerpt from Oculocerebrorenal Dystrophy (Lowe Syndrome)

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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. The diagnostic triad of the oculocerebrorenal syndrome of Lowe (OCRL) includes congenital cataracts, neonatal or infantile hypotonia with subsequent mental impairment, and renal tubular dysfunction.

Pathophysiology

OCRL is caused by an inherited mutation in OCRL1, which has been mapped to chromosome Xq26. OCRL1 contains 24 exons and encodes the OCRL1 protein. The OCLR1 protein is a phosphatidylinositol 4,5-bisphosphate (PtdIns[4,5]P2) 5 phosphatase that is localized in the Golgi apparatus and appears to play a role in cytoskeleton remodeling and cellular trafficking. Several mutations have been described in this gene, including truncation mutations, missense mutations, and large deletions. New mutations have been reported, and germline mosaicism is common. OCRL1 deficiency may impair proper intracellular protein sorting, especially within polarized cells such as the renal epithelium and the optic lens. This impairment may explain the epithelial cell phenotype (ie, congenital cataracts and renal tubular dysfunction).

Frequency

International

OCRL is a panethnic disease that has an estimated prevalence of 1 per 500,000 population (Loi, 2006).

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 OCRL 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 OCRL are reported to have survived into the fourth and fifth decades of life with chronic kidney failure.

Sex

OCRL 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 OCRL 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.

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