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Lowe syndrome

NORD is very grateful to Richard Alan Lewis MD, MS, Professor, Departments of Ophthalmology, Medicine, Pediatrics, and Molecular and Human Genetics, Baylor College of Medicine, for assistance in the preparation of this report.

Synonyms of Lowe syndrome

  • OCRL
  • oculocerebrorenal syndrome
  • oculocerebrorenal syndrome of Lowe

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Lowe syndrome is characterized by vision problems including clouding of the lenses of the eyes (cataracts) that are present at birth, kidney problems that usually develop in the first year of life, and brain abnormalities that are associated with intellectual disabilities. Lowe syndrome is inherited as an X-linked genetic condition.

Symptoms

Boys with Lowe syndrome have cataracts that are present at birth in each eye. With only extremely rare exceptions, these require surgery early in life, as soon as health allows for anesthesia to perform it. But even in optimal circumstances, corrected visual acuities when recordable are rarely better than 20/100. Approximately half of eyes will develop high pressure in the eye (glaucoma) that can damage the optic nerve and lead to blindness if not controlled. Infants with Lowe syndrome have poor muscle tone (hypotonia) at birth and experience delayed motor development. Almost all boys with Lowe syndrome have developmental and intellectual disability that can range from mild (~10%-25%) to severe (~50%-65%). Seizures occur in approximately half of those by six years of age, and behavioral problems are present in some boys with Lowe syndrome. A fraction of affected males develop growths on the corneas of one or both eyes called keloids during late childhood and adolescence. These growths are progressive and can lead to blindness.

The kidney problem associated with Lowe syndrome is called proximal tubular dysfunction of the Fanconi type. This abnormality results in the loss of certain substances (amino acids, bicarbonates, and phosphates) into the urine that are normally filtered prior to excretion into the urine or reabsorbed by the body. However, as mentioned, the spilling of amino acids into the urine seldom begins until the end of the first year of life, sometimes delaying and confounding the diagnosis. The filters in the kidney (glomeruli) usually begin to fail in boys with Lowe syndrome after 10 years of age. Kidney failure is slow and progressive and results in a reduced life expectancy of approximately 30-40 years.

Other signs frequent in boys with Lowe syndrome include short stature, dental cysts and abnormal dentin formation of the teeth, skin cysts, and vitamin D deficiency that can lead to soft bones, skeletal changes (rickets), bone fractures, scoliosis, and degenerative joint disease.

Causes

Lowe syndrome is an X-linked genetic disorder caused by a mutation in the OCRL1 gene that results in reduced activity of the inositol polyphosphate 5-phosphatase OCRL1 enzyme. About a third of affected males have a new mutation in the OCRL gene; in most of the rest, the disorder is inherited from a mother who is a genetic carrier of the condition.

X-linked genetic disorders are conditions caused by an abnormal gene on the X-chromosome and occur mostly in males. Females who have a disease gene present on one of their X-chromosomes are carriers for that disorder. As in other X-linked disorders, carrier females have two X chromosomes, and one is inactivated so that the genes on that chromosome are nonfunctioning. Although in many X-linked disorders, carrier females usually do not display features because the activity of the product of the normal gene is sufficient to prevent abnormalities, such is not true for Lowe syndrome. Essentially every female carrier for Lowe syndrome aver the age of 10 years will show characteristic changes in the lenses of her eyes, different from any other metabolic cataract. Some carriers will develop visually significant cataracts even in their early 30’s, sufficient to require cataract surgery, and may be missed by the operating surgeon.

A male has only one X-chromosome that he inherits from his mother; if a male inherits an X-chromosome that contains a disease gene, he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son. Each pregnancy, of course, is independent of the last and does not influence the outcome of the next pregnancy.

No males with Lowe syndrome have been reported to have children.

Affected Populations

Lowe syndrome is a rare genetic disorder that occurs almost exclusively in males. The prevalence is estimated to be between 1 and 10 males per 1,000,000 people. This condition has been reported in North and South America, Europe, Japan, and India.

Related Disorders

Signs of the following disorders can be similar to those of Lowe syndrome. Comparisons may useful for a differential diagnosis:

Congenital rubella (German measles) is a syndrome that occurs when a fetus has been infected with the rubella virus while in the uterus. It is primarily characterized by abnormalities of the heart and nervous system, the eyes, and the ears. The fetus is most vulnerable to the virus during the first three months of pregnancy, although pregnant women are advised to avoid exposure to rubella virus at all times. Women who contract rubella during pregnancy have a high risk of having a baby with congenital rubella. (For more information on this disorder, choose "rubella congenital" as your search term in the rare disease database.)

Peroxisome biogenesis disorders, Zellweger syndrome spectrum, are a group of genetic disorders of variable severity characterized by low muscle tone (hypotonia), feeding difficulty, and abnormal facial features. Other symptoms may include vision and hearing deficits, seizures, and liver dysfunction. Mutations in several different genes have been found to be associated with the reduction or elimination of cell structures called peroxisomes that break down toxic substances in the body. High levels of iron and copper in the blood lead to the symptoms associated with this condition. However, congenital cataracts are not a feature. (For more information on this disorder, choose "Zellweger" as your search term in the rare disease database.)

Cataract-dental syndrome (Nance-Horan syndrome) is an extremely rare genetic disorder that may be evident at birth (congenital). It is primarily characterized by abnormalities of the teeth and clouding of the lens of the eyes (congenital cataracts), resulting in poor vision. Additional eye abnormalities are also often present, such as unusual smallness of the front, clear portion of the eye through which light passes (microcornea) and involuntary, rapid, rhythmic eye movements (nystagmus). In some cases, the disorder may also be associated with additional physical abnormalities (simple ears turned forward, short fourth and fifth fingers and toes, and highly abnormal teeth that are barrel-shaped and widely spaced, and possibly intellectual disability. The range and severity may vary greatly from case to case, even among affected members of the same family. (For more information on this disorder, choose "cataract-dental syndrome" as your search term in the rare disease database.)

Smith-Lemli-Opitz syndrome (SLOS) is a variable genetic disorder that is characterized by slow growth before and after birth, small head (microcephaly), mild to moderate mental retardation, and multiple birth defects including particular facial features, cleft palate, heart defects, fused second and third toes, extra fingers and toes and underdeveloped external genitals in males. The severity of SLOS varies greatly in affected individuals, even in the same family, and some have normal development and only minor birth defects. SLOS is caused by a deficiency in the enzyme 7-dehydrocholesterol reductase that results in an abnormality in cholesterol metabolism. SLOS is inherited as an autosomal recessive genetic disorder. Aminoaciduria and rickets and other features are not present, even though hypotonia is. (For more information on this disorder, choose "Smith-Lemli-Opitz" as your search term in the rare disease database.)

Dent disease 2 is an X-linked disorder with overlapping features of kidney stones (nephrolithiasis), hypophosphatemic rickets, and excessive calcium, phosphate, protein, and amino acids in the urine. Many males with Dent disease also have mild developmental delay. About two-thirds of males with Dent disease have mutations in a chloride channel gene called CLCN5, but most of the others have mild mutations in OCRL, interestingly without the typical face, the behavioral features, the metabolic acidosis, and without cataracts of classical Lowe syndrome.

Standard Therapies

Diagnosis
Lowe syndrome is diagnosed when a reduced activity of the inositol polyphosphate 5-phosphate OCRL-1 enzyme is demonstrated in cultured skin cells (fibroblasts). Molecular genetic testing for OCRL gene mutations is also available and accurately detects more than 95% of affected males.

Carrier testing for female relatives is available. Approximately 95% of carrier females older than 10 years of age have specific and distinctive abnormalities of the lens of the eye that can be diagnosed by an experienced ophthalmologist. Molecular genetic testing for carrier status is available if a specific OCRL gene mutation has been identified in a male relative. Biochemical testing for inositol polyphosphate 5-phosphate OCRL-1 enzyme activity is not reliable for carrier testing for Lowe syndrome.

Prenatal diagnosis is available with biochemical testing (enzyme assay) or molecular genetic testing if the OCRL gene mutation has been determined in an affected male relative.

Treatment
Treatment of Lowe syndrome usually requires a team of medical professionals including a pediatric ophthalmologist, nephrologist, geneticist, nutritionist, endocrinologist, neurologist, child development specialist, general surgeon, orthopedist, and dentist.

Low muscle tone (hypotonia) can sometimes result in feeding problems and may require tube feeding and standard measures for gastroesophageal reflux.

Early removal of cataracts is recommended to promote optimum development of vision. Eyeglasses and contact lenses help to improve vision. Glaucoma sometimes can be treated with medication (eyedrops) but usually requires surgery which is not always successful with a single operation. If they occur, corneal keloids can sometimes be surgically removed but often recur. There is no consistent proven therapy to eradicate corneal keloids.

Proximal tubular dysfunction of the Fanconi type is treated with oral supplements of sodium and potassium bicarbonate or citrate. Doses must be determined on an individual basis.

Oral phosphate and oral calcitriol are used to treat (or prevent) rickets. Seizure disorders are treated with anticonvulsant medications. Behavior problems are treated with behavior modification and medications.

Early intervention programs that include physical therapy, occupational therapy, speech and language therapy, special education services, and services for visually impaired are recommended and should begin in early infancy.

Boys with Lowe syndrome should be monitored regularly for vision problems (especially later onset glaucoma), kidney function, growth, developmental progress, scoliosis, and joint problems, and dental problems.

Treatment of end-stage renal disease has been successfully treated with dialysis and kidney transplantation in some adult men.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Contact for additional information about Lowe syndrome:

Richard Alan Lewis, MD, MS
Cullen Eye Institute NC-206
Baylor College of Medicine
One Baylor Plaza
Houston, Texas 77030
Tel: (713) 798-3030
Fax: (713) 798-3042

Organizations related to Lowe syndrome

References

TEXTBOOKS
Nussbaum RL, Suchy SF: The oculocerebrorenal syndrome of Lowe (Lowe syndrome). In: The Metabolic and Molecular Bases of Inherited Disease Volume CH. 252. 8th edition. Edited by: Scriver CR, Beadet Al, Sly WS, Valle D. McGraw Hill, New York: 2001;6257-6266.

McSpadden K. Living with Lowe syndrome: A Guide for Families, Friends and Professionals, 3rd ed. Lowe Syndrome Association, Inc.; 2000.

JOURNAL ARTICLES
Hichri H, Rendu J, Monnier N, et al. From Lowe syndrome to Dent Disease: correlations between mutations of the OCRL1 gene and clinical and biochemical phenotypes. Hum Mutat. 2011;32:379-388.

Schurman SJ, Scheinman SJ Inherited cerebrorenal syndromes.. Nat Rev Nephrol. 2009;5(9):529-38.

Ruellas AC, Pithon MM, Oliveira DD, Oliveira AM. Lowe syndrome: literature review and case report. J Orthod. 2008;35(3):156-60.

Loi M. Lowe syndrome. Orphanet Journal of Rare Diseases. 2006;1:16.

Tricot L, Yahiaoui Y, Teixeira L et al. End-stage renal failure in Lowe syndrome. Nephrol Dial Transplant. 2003;18:1923-5.

Roschinger W, Muntau AC, Rudolph G, et al. Carrier assessment in families with Lowe oculocerebrorenal syndrome: novel mutations in the OCRL1 gene and correlation of direct DNA diagnosis with ocular examination. Mol Genet Metab. 2000;69:213-22.

Nussbaum RL, Orrison BM, Janne PA, et al. Physical mapping and genomic structure of the Lowe syndrome gene OCRL1. Hum Genet. 1997;99:145-50.

Kenworthy L, Park T, Charnas LR: Cognitive and behavioral profile of the oculocerebrorenal s yndrome of Lowe. Am J Med Genet. 1993;46:297-303.

INTERNET
Lewis RA, Nussbaum RL,Brewer ED. (Updated February 23, 2012). Lowe Syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1993-2012. Available at http://www.genetests.org. Accessed February 23, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Lowe Oculocerebrorenal Syndrome; OCRL. Entry No: 309000. Last Edited April 2, 2007. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed February 23, 2012.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2012/03/13 00:00:00 GMT+0

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