LOWE SYNDROME

The Oculo-Cerebro-Renal Syndrome of Lowe (OCRL) is a rare X-linked disorder characterized by congenital cataracts, neuromuscular hypotonia, mental retardation, infantile glaucoma in half of affected males, vitamin D-resistant rickets, and renal tubular dysfunction. Affected males have a mean IQ in the moderate mental retardation range, and most exhibit maladaptive behaviors. Heterozygote carrier females have distinctive mild "snowflake" lenticular opacities that are detectable by slit-lamp ocular examination after pupillary dilation. The Lowe Syndrome gene at chromosome Xq25-q26 is OCRL1, which encodes a phosphatidylinositol 4,5 bisphosphate (PtdIns[4,5]P2) 5-phosphatase that has been localized to the trans-Golgi network. The complex phenotype of Lowe Syndrome is due to an inborn error of inositol phosphate metabolism, and diagnostic testing in affected males is available through biochemical enzyme analysis. Multiple mutations in the OCRL1 gene have been identified including missense and nonsense mutations, small deletions and insertions, and larger genomic deletions. The gene consists of 24 exons, of which 23 are coding. Approximately 97% of males with a definite clinical diagnosis of Lowe Syndrome have mutations identified in the OCRL1 gene (Monnier et al., 2000). These mutations are detectable by PCR-based DNA sequence analysis in affected males.

Molecular genetic testing for the Lowe Syndrome OCRL1 gene is available at the Baylor DNA Diagnostic Laboratory. Symptomatic males will be tested by automated fluorescent DNA sequence analyses of the OCRL1 gene coding region. DNA sequencing of an affected male is recommended to provide the highest sensitivity; the identification of a mutation would provide the most efficient carrier test for female relatives by targeted DNA sequencing. In cases where a male proband is not available, DNA carrier testing can be performed in families with a definite enzyme-confirmed diagnosis of Lowe syndrome in conjunction with careful ophthalmological examination of suspected carrier females. Approximately 6% of known mutations involve partial or complete deletions of the OCRL1 gene, which will not be detected in carrier females by DNA sequencing.

Prenatal biochemical enzymatic testing for Lowe Syndrome in a male fetus (without prior mutation data) is available at the Baylor Biochemical Genetics Laboratory*.

Recommended Flowchart for Lowe Syndrome Diagnostic Testing

Reasons For Referral:

• Lowe Syndrome DNA testing for individuals with phenotypic features. Unusual phenotypes (such as Lowe syndrome in a female, or Dent syndrome) should be discussed in advance.
• Carrier testing in females with a definite family history of Lowe Syndrome (in conjunction with a careful ophthalmological examination).
• Prenatal diagnosis in families with an identified mutation in the OCRL1 gene.*Note: Prenatal biochemical enzymatic testing on male fetuses can be performed in cases where a familial mutation has not been identified.

Testing Methodology:

Genomic DNA from this individual was used for PCR amplification of all exons contained in the coding region of the OCRL1 gene.  Primers for these exons flank the respective portions of the OCRL1 coding region and the appropriate intron/exon junctions. Direct sequence analysis of PCR products corresponding to the entire OCRL1 gene coding region is performed in both the forward and reverse directions using automated fluorescence dideoxy sequencing methods.

Sensitivity:

DNA Sequence Analysis: 99% detection of mutations in OCRL1 gene when present in an affected male. (~91% sensitivity for sequence analysis of carrier females).

Specimen Requirements:

Blood: EDTA (purple-top) tubes: Adults: 14 cc; Child: 6 cc; Infant: 2-3 cc
Requisition form must accompany specimen. Prior to any genetic testing, we recommend genetic counseling and require that the subject, or the legal guardian, sign our Consent Statement and submit it with the sample. Please contact the laboratory for specific requirements for prenatal testing.

Turnaround Time:

4 weeks

CPT Codes and Prices:

A 20% up-front payment is required for the index case before specimen can be processed.
Index: 83904x23, 83912, 83909x66, 83898x12, 83894, 83891
Known Familial Mutation: 83904x2, 83912, 83909x2, 83898, 83891, 83894

Shipping Information

Forms:

 >> Molecular Diagnostic Requisition
 >> Prenatal Requisition

References:

1. 1. Monnier, et al. (2000) Hum. Mut. 16: 157-165; Lowe Syndrome Mutation Database: http://www.nhgri.nih.gov/DIR/GDRB/Lowe/

Test Codes:

Index: 6039
Known Familial Mutation: 6102
Prenatal: 6101

Medical Genetics Laboratories
Baylor College of Medicine · Houston, TX 77030
Phone: 1-800-411-GENE · Fax: 713-798-2787
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