Chapter 252

## Abstract

Abstract

1. The oculocerebrorenal syndrome of Lowe (OCRL) is a multisystem disorder with major abnormalities in the eyes, the nervous system, and the kidneys. Prenatal development of cataracts is universal, and other ocular abnormalities, including glaucoma, microphthalmos, decreased visual acuity, and corneal keloid formation, are frequent. Neonatal or infantile hypotonia, intellectual impairment, and areflexia are also cardinal features. Mental retardation, although very common, is not universal. Stereotypic behaviors, including tantrums and aggressiveness, are some of the more difficult management problems in the disease. Fanconi syndrome of the renal tubule (bicarbonaturia, renal tubular acidosis, aminoaciduria, phosphaturia, tubular proteinuria, and impaired urine-concentrating ability) is also a major feature, but the severity and age of onset of the tubular dysfunction are variable. Slowly progressive renal failure can also occur in the second to fourth decade of life. Musculoskeletal abnormalities such as joint hypermobility, dislocated hips, and fractures may develop as secondary consequences of hypotonia or renal tubular acidosis and hypophosphatemia, but nontender joint swelling and subcutaneous nodules are also frequently seen and may reflect a primary abnormality of excessive connective tissue growth.

2. OCRL is a rare X-linked disorder with an estimated prevalence of only a few cases per 100,000 males. The only significant manifestation in carriers is in the lens and is characterized by many smooth, off-white micropunctate cataracts clustered in a radial wedge pattern, and, occasionally, a dense posterior cortical cataract. The sensitivity of carrier detection by slit-lamp exam is >90 percent but, as with most X-linked conditions, penetrance is unlikely to ever be 100 percent in female carriers because the proportion of cells in the lens that have an inactivated Lowe syndrome allele can vary by chance between carriers. Germ line or somatic mosaicism has been documented.

3. The gene for OCRL (OCRL1), termed OCRL1, located at Xq25-q26, was identified by positional cloning in the Xq25-q26 region of the X chromosome, and encodes a phosphatidylinositol -4,5- bisphosphate 5-phosphatase (PtdIns-4,5-P2) localized to the Golgi complex. How a deficiency of this enzyme results in the clinical phenotype remains obscure.

4. Clinical diagnosis of OCRL depends on the cardinal ophthalmologic, neurologic, and renal abnormalities, while X-linked inheritance is extremely helpful when present. Carrier detection by slit-lamp examination has high but not perfect sensitivity. Biochemical assay for deficiency of PtdIns(4,5)P2 5-phosphatase is the definitive laboratory test for diagnosing patients and for prenatal diagnosis, but its role in carrier detection is unproved.

5. Over two dozen mutations have been described in the OCRL1 gene in Lowe syndrome patients. Most are unique to a family and are either nonsense mutations or deletions that cause frameshifts and premature termination, although missense mutations in domains conserved among all the known PtdIns(4,5)P2 5-phosphatases are also seen. Carrier detection can be done by direct detection of mutations when known and by linked markers when the mutation is unknown.

6. Treatment includes cataract extraction, refraction for aphakia, control of glaucoma, speech and physical therapy for developmental delay, anticonvulsants or behavior-modifying medications if needed, and replacement of urinary bicarbonate, water, and phosphate losses if indicated by the development of acidosis or bone disease.

Sign in to your MyAccess profile while you are actively authenticated on this site via your institution (you will be able to verify this by looking at the top right corner of the screen - if you see your institution's name, you are authenticated). Once logged in to your MyAccess profile, you will be able to access your institution's subscription for 90 days from any location. You must be logged in while authenticated at least once every 90 days to maintain this remote access.

Ok

## Subscription Options

### OMMBID Full Site: One-Year Subscription

Connect to the full suite of OMMBID content including new and revised chapters that reflect the latest research, image galleries, clinical phenotypes, and more.