Information on the following diseases can be found in the Related Disorders section of this report:

• Cystinosis
• Cystinuria
• Vitamin D Resistant Rickets
• Hypophosphatemic Rickets
• Renal Fanconi Syndrome
• Polycystic Kidney Disease-Cataract-Blindness

Boys with Lowe syndrome have cataracts in both eyes that are present at birth. These almost invariably require surgery early in life, but even in optimal circumstances visual acuities when recordable are rarely better than 20/100. Approximately half of those affected develop high pressure in the eye (glaucoma) that can damage the optic nerve and lead to blindness. Infants with Lowe syndrome have poor muscle tone (hypotonia) at birth and experience delays in motor development. Almost all boys with Lowe syndrome have some degree of mental retardation that can range from mild to severe. Seizures occur in approximately half of those by six years of age and severe 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. 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 common 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 joint

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 carrier mother.

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. Carrier females usually do not display features because females have two X chromosomes and one is inactivated so that the genes on that chromosome are nonfunctioning. It is often the X chromosome with the abnormal gene that is inactivated. A males has only one X chromosome that is inherited from his mother, and 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.

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

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

Signs ofthe 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. (For more information on this disorder, choose "Zellweger" as your search term in the rare disease database.) However, congenital cataracts are not a feature.

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 and/or mental retardationThe range and severity may vary greatly from case to case, including 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. (For more information on this disorder, choose "Smith-Lemli-Opitz" as your search term in the rare disease database.) but aminoaciduria and rickets and other features are not present, even though hypotonia is.

Cystinosis is an autosomal recessive genetic disorder characterized by the accumulation of cystine in tissues throughout the body that can cause certain organs to malfunction. One of the major complications of cystinosis is renal tubular Fanconi syndrome that is characterized by impaired kidney function resulting in a loss of essential nutrients in the urine. Three distinct forms of cystinosis are recognized. Infantile nephropathic cystinosis is the most severe form of the disease. Symptoms include growth problems and kidney abnormalities that appear as early as 6 to 12 months of age. This form of the disease may lead to kidney failure by 10 years of age. Intermediate cystinosis has a later age of onset and can result in kidney failure between 15 and 25 years of age. Non-nephropathic cystinosis is characterized by sensitivity to light only. (For more information on this disorder, choose "cystinosis" as your search term in the rare disease database.)
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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 detects approximately 95% of affected males.

Carrier testing for female relatives is available. Approximately 95% of carrier females older than 15 years of age have a specific abnormality 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.

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 but usually requires surgery which is not always successful. Corneal keloids can sometimes be surgically removed but often recur. There is no consistent proven therapy for 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.

For information on eye examinations for carrier testing for Lowe syndrome, contact:

Dr. Richard Lewis
Cullen Eye Institiute
Baylor College of Medicine
(713) 798-3030

An investigation on Lowe syndrome is under way at the National Human Genome Research Institute. For information on this study, patients may wish to have their physicians contact:

Robert L. Nussbaum, M.D.
Chief, Laboratory of Genetic Disease Research
NIH/National Human Genome Research Institute
Building 49/4A72
49 Covenant Drive, MSC 4472
Bethesda, MD 20892-4472
Tel (301) 402-2039

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

Lewis RA, Nussbaum RL and Brewer ED. (Updated 1/5/07) Lowe Syndrome In: GeneReviews at Genetests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2007. Available at http://www.genetests.org. Accessed 6/07.

McKusick VA, ed. Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University; Entry No. 30900; Last Update: 4/2/07.

Al-Uzri A. Oculocerebrorenal Dystrophy (Lowe syndrome). EMedicine 2/7/07.

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

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.

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

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.

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.

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.

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