NORD gratefully acknowledges Richard Alan Lewis MD, MS, Professor, Departments of Molecular and Human Genetics, Ophthalmology, Medicine, Pediatrics, and Molecular and Human Genetics, Baylor College of Medicine, and Robert L. Nussbaum MD, Professor, Institute for Human Genetics, University of California, San Francisco, for assistance in the preparation of this report.
Boys with Lowe syndrome have cataracts that are present at birth in each eye (and detectable by high resolution ultrasound prenatally in suspect cases). 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 or leakage 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 non-inflammatory degenerative joint disease. Some patients have shown a delayed bleeding diathesis following surgery characterized by normal hemostasis and clot formation, only to be followed a few hours later by sudden recurrence of bleeding. This may be an important consideration with any surgery but especially both cataract surgery and glaucoma surgery in which bleeding inside the eye may have considerable consequences.
Lowe syndrome is an X-linked genetic disorder caused by a mutation in the OCRL gene that results in reduced activity of the phosphatidylinositol polyphosphate 5-phosphatase OCRL enzyme. About a third of affected males have a new mutation in the 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 over 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. However, these highly informative and distinctive changes in the lenses of a carrier female should lead the ophthalmologist suspecting this diagnosis in an infant male to dilate the pupils and to reflexively examine the mother of the child under consideration.
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.
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.
Lowe syndrome is diagnosed when a reduced activity of the phosphatidylinositol polyphosphate 5-phosphatase OCRL 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 phosphatidylinositol polyphosphate 5-phosphatase OCRL enzyme activity is not reliable for carrier testing for Lowe syndrome because the range of enzyme activity spreads over the normal range.
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 or carrier mother.
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 occurring in half of males sometimes may 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 removed surgically but often recur more aggressive than before. 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. Bone density should be monitored periodically. 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.
End-stage renal disease has been treated successfully with dialysis and kidney transplantation in some late-adolescent adult men.
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Contact for additional information about Lowe syndrome:
Richard Alan Lewis, MD, MS
Ben Taub Research Building Room T803
Department of Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza
Houston, Texas 77030
Tel: (713) 798-3030
Fax: (713) 798-3042
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Lewis RA, Nussbaum RL, Brewer ED. Lowe Syndrome. 2001 Jul 24 [Updated 2012 Feb 23]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1480/ Accessed September 12, 2016.
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://omim.org/entry/309000 .Accessed September 12, 2016.
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