Oculocerebrorenal syndrome

Oculocerebrorenal syndrome

Description, Causes and Risk Factors:

A congenital syndrome with hydrophthalmia, cataracts, mental retardation, aminoaciduria, reduced ammonia production by the kidney, and vitamin D-resistant rickets; X-linked recessive inheritance, caused by mutation in the oculocerebrorenal gene (OCRL) on Xq.

The syndrome was first described by Lowe, Terrey and MacLachlan in 1952. It is an X-linked condition due to a mutation on the Xq26.1 gene. The gene encodes a phosphatidylinositol (4,5) bisphosphate 5 phosphatase, localized to the trans-Golgi complex involved in actin polymerization. It is a key enzyme in the cellular phosphoinositide pathway, important in cellular trafficking. Deficiency of the enzyme causes the protean manifestations of Lowe syndrome. The reduced enzyme activity results in increased enzyme substrate and abnormal actin-binding proteins important in neuronal morphogenesis.

The oculocerebrorenal syndrome is so named because of the prominent involvement of the 3 major organ systems; however, involvement of bone, gonads, muscle, skin, and connective tissue, as well as stereotypic behavior, also can occur. Additional manifestations include corneal keloids, growth retardation, areflexia, metabolic acidosis, proteinuria, aminoaciduria, and noninflammatory arthropathy. These patients often exhibit the characteristic facial appearance of frontal bossing, deep set eyes, and full cheeks, although the characteristic phenotype is often difficult to identify in neonates.

It is a rare condition that usually affects just males, with female carriers. There are three recorded cases of the disease affecting females. This might be due to mutation on an autosome rather than the X chromosome or it may represent "infelicitous lyonization in heterozygous females". This relates to the Lyon hypothesis that in females, one of the X chromosomes is suppressed.

Oculocerebrorenal syndrome is an uncommon, pan ethnic disorder with a prevalence of only a few individuals per 100,000 births. In the USA, as of the year 2000, 190 living affected males were known to the Oculocerebrorenal syndrome, which estimates this number to represent approximately 50% of all cases.


Symptoms may include the following:

    Bilateral dense congenital cataracts.

  • Infantile congenital hypotonia.

  • Delayed development.

  • Proximal renal tubular transport dysfunction of the Fanconi type characterized by varying degrees of bicarbonaturia and acidosis, phosphaturia, aminoaciduria, and low molecular-weight (LMW) proteinuria (including retinol binding protein, N-acetyl glucosaminidase, and albumin); except for LMW proteinuria, the Fanconi syndrome features do not appear until after the first few months of life.

Other frequently noted findings may include:

    Infantile glaucoma (in ~50% of males).

  • Seizures.

  • Absent deep tendon reflexes (DTR).

  • Maladaptive behaviors, especially stubbornness, tantrums, stranger anxiety, and stereotypy (complex repetitive behaviors).

  • Short stature.

    Mild ventriculomegaly and multiple, periventricular, variably sized, small cysts on MRI in approximately one third of affected individuals.

  • Hypercalciuria with nephrocalcinosis and nephrolithiasis.

  • Pathologic fractures and bone demineralization in the presence of normal serum concentrations of calcium, phosphorus, and vitamin D metabolites.

  • Dental cysts and dysplastic dentin formation of the teeth.

  • Skin cysts similar to eruptive vellus hair cysts.

  • Prolonged or delayed bleeding following surgery, such as cataract extraction.


The classical diagnostic triad includes:

    Congenital cataracts.

  • Neonatal or infantile hypotonia with subsequent mental impairment.

  • Renal tubular dysfunction progressing to chronic renal failure.

The diagnosis is established in affected individuals by demonstrating reduced (<10% of normal) activity of inositol polyphosphate 5-phosphatase OCRL-1 in cultured skin fibroblasts. Such testing is available clinically. Molecular genetic testing of OCRL detects mutations in approximately 95% of affected males and a similar proportion of carrier females. Molecular genetic testing is available clinically.

Clinical Signs:

    Elevated serum enzyme levels.

  • Enzyme test (phosphatidylinositol-4,5-bisphosphate phosphatase; >99% sensitivity) in males who are affected.

  • Mild elevations of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK).

  • Increased serum glutamic-oxaloacetic transaminase (SGOT) and lactate dehydrogenase (LDH).

  • Serum protein electrophoresis shows a markedly elevated alpha-2-band, and total serum protein concentration is elevated frequently in patients older than 4 years.

  • Acid phosphatase is elevated in most patients.

  • Increased alkaline phosphatase.

  • Increased creatinine.

  • Hypokalemia.


    Low urine osmolality and elevated 24-hour volumes

  • Proteinuria.

  • Aminoaciduria

  • Hyperphosphaturia, frequently present, but may be variable.

  • Calciuria.

  • Check urine pH.

  • Check L-carnitine (may be lost in urine).

Blood gas - Metabolic acidosis secondary to urinary loss of bicarbonate.

Imaging: Ocular ultrasound: B-scan is indicated if posterior pole cannot be visualized secondary to the cataract.Cranial MRI: Mild ventriculomegaly is evident in about one third of patients. Additionally, in a periventricular and centrum semiovale distribution, increased signal intensity may occur on T2-weighted scans. These areas correspond to cysts of variable size and number and are yet of no known clinical significance.

Because of the allelic heterogeneity of the OCRL gene, prenatal diagnosis by molecular analysis is limited to families in which the mutation is already known or in which linkage is informative. A more generally applicable diagnostic test based on biochemical testing is reported for prenatal diagnosis of Lowe's syndrome by measuring phosphatidylinositol 4,5-bisphosphate 5-phosphatase activity in cultured amniocytes.7


Early removal of cataracts; nasogastric tube feedings or feeding gastrostomy with or without fundoplication to achieve appropriate nutrition; occupational or speech therapy to address feeding problems; standard measures for gastroesophageal reflux; programs to promote optimal psychomotor development, including services for the visually handicapped, beginning in early infancy; behavior modification plan with antidepressant and/or antipsychotic medications as needed.

For those with renal Fanconi syndrome/type 2 renal acidosis: oral supplements of sodium and potassium bicarbonate or citrate to correct acidosis and hypokalemia, and oral phosphate and oral calcitriol (1,25-dihydroxyvitamin D3) to correct hypophosphatemia and renal rickets; consider treatment of ESRD (end stage renal disease) with chronic dialysis and renal transplant in selected individuals; consider human growth hormone therapy to improve growth velocity; resection of fibromas and cutaneous cysts if painful or impairing function.

Prevention of secondary complications: Intravenous fluids, bicarbonate, and electrolytes during illness or when fasting.

Surveillance: Routine eye evaluations with attention to measurement of intraocular pressure; routine monitoring of kidney function, growth, developmental progress; annual evaluation for scoliosis and joint problems; semiannual dental examinations.

Circumstances to avoid: Corneal contact lenses because of associated risk of corneal keloid formation and complexities of contact lens care; artificial lens implants because of probable increased risk of glaucoma.

Other: Despite appropriate medical and surgical measures, glaucoma is often difficult to control.

NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.

DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.


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