Lowe Oculocerebrorenal Syndrome

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Lowe oculocerebrorenal syndrome

Definition

Lowe oculocerebrorenal syndrome is a rare genetic condition that affects males. It is caused by an enzyme deficiency. It affects many body systems including the eyes, the kidneys, and the brain.

Description

Lowe oculocerebrorenal syndrome was first described by Dr. Charles Lowe in 1952. The syndrome is caused by a change (mutation) in the OCRL1 gene . This gene is responsible for the production of the enzyme phosphatidylinositol 4,5-bisphosphate 5-phosphatase. A mutation in the OCRL1 gene leads to a decrease in enzyme activity. This decrease in the activity of phosphatidylinositol 4,5-bisphosphate 5-phosphatase is responsible for the physical and mental problems associated with Lowe oculocerebrorenal syndrome. The reason why a deficiency of this enzyme causes Lowe oculocerebrorenal syndrome is still unknown. Phosphatidylinositol 4,5-bisphosphate 5-phosphate phosphatase is thought to be limited to a specific part of the cell called the "Golgi apparatus." The relationship between the function of the Golgi apparatus, the enzyme deficiency, and the features of Lowe oculocerebrorenal syndrome is unclear.

The name Lowe oculocerebrorenal syndrome describes the body systems most commonly affected by this genetic disease. The term "oculo" refers to the eye problems commonly seen in individuals with the disease. Cataracts (cloudiness of the lens of the eye) are a classic feature and are usually present at birth (congenital). Other eye problems are also common. The term "cerebro" refers to the brain dysfunction commonly seen in the disease. The majority of affected males have mental retardation and behavior disturbances. The term "renal" represents the associated kidney problems, which can interfere with normal bone development and eventually lead to kidney failure.

Genetic profile

Changes (mutations) in the OCRL1 gene decrease the activity of the enzyme phosphatidylinositol 4,5-bisphosphate 5-phosphatase. There have been many different mutations identified in the OCRL1 gene. These mutations may be different between families. The OCRL1 gene is located on the X chromosome . Since the OCRL1 gene is located on the X chromosome, Lowe oculocerebrorenal syndrome is considered to be X-linked. This means that it only affects males.

A person's sex is determined by his or her chromosomes. Males have one X chromosome and one Y chromosome, while females have two X chromosomes. Males who possess a mutation in their OCRL1 gene will develop Lowe oculocerebrorenal syndrome. Females who possess a mutation in their OCRL1 gene will not; they are considered to be carriers. This is because females have another X chromosome without the mutation that allows normal function, and prevents them from getting this disease. If a woman is a carrier, she has a 50% risk with any pregnancy to pass on her X chromosome with the mutation. Therefore, with every male pregnancy she has a 50% risk of having an affected son, and with every female pregnancy she has a 50% risk of having a daughter who is a carrier.

Demographics

Lowe oculocerebrorenal syndrome affects approximately one in 100,000 live births. It occurs evenly among ethnic groups. Almost always, only male children are affected. Women carriers usually do not have physical or mental problems related to the disease.

Signs and symptoms

The signs and symptoms of Lowe oculocerebrorenal syndrome are variable. Some individuals with Lowe oculocerebrorenal syndrome have many severe symptoms, while other affected individuals have fewer, more mild symptoms.

Eye problems are a common feature of Lowe oculocerebrorenal syndrome. Congenital cataracts are a classic feature of the disorder. These cataracts may be one of the first symptoms noticed during infancy. Approximately 50% of males with Lowe oculocerebrorenal syndrome will develop increased pressure behind the eye (glaucoma ). This pressure can damage the eye. Other eye problems include strabismus (crossed or divergent eyes), nystagmus (uncontrollable rhythmic eye movements), and microphthalmia (small eyes).

The nervous system (brain and nerves) is also typically affected by Lowe oculocerebrorenal syndrome. Mental retardation is a common feature of Lowe oculocerebrorenal syndrome. It can vary between mild and severe. Some males with Lowe oculocerebrorenal syndrome have normal intelligence. Seizures and behavior disturbances can also be seen in individuals with Lowe oculocerebrorenal syndrome. Behavior disturbances can include temper tantrums, aggression, obsessions, and repetitive hand movements. One of the first signs of brain dysfunction caused by Lowe oculocerebrorenal syndrome is muscle weakness (hypotonia) during infancy.

Kidney problems are another common finding in individuals with Lowe oculocerebrorenal syndrome. The kidneys normally filter chemicals and acids from the body. The kidneys allow the body to keep needed substances and to remove unneeded substances through the urine. Individuals with Lowe oculocerebrorenal syndrome cannot do this properly, allowing needed substances (calcium, phosphate, etc.) to be excreted in the urine. This kidney disturbance can ultimately lead to kidney failure.

Individuals with Lowe oculocerebrorenal syndrome frequently have slow growth and have short stature. Problems with bones can also develop due to the loss of certain substances through the kidneys. Rickets and easily breakable bones are common features. Joints may also become inflamed in individuals with Lowe oculocerebrorenal syndrome.

Diagnosis

The diagnosis of Lowe oculocerebrorenal syndrome is based initially on the presence of the symptoms of the disorder. Lowe oculocerebrorenal syndrome is definitively diagnosed by measuring the activity of the enzyme phosphatidylinositol 4,5-bisphosphate 5-phosphatase. When the activity of this enzyme is very low it is diagnostic of Lowe oculocerebrorenal syndrome. In order to perform this test a small piece of skin must be removed from the patient's body (skin biopsy). The enzyme is then measured from cells in this skin sample. In some cases it is also possible to look for a mutation in the OCRL1 gene. The presence of mutation confirms the diagnosis of Lowe oculocerebrorenal syndrome in males.

Determining if a woman is a carrier of Lowe oculocerebrorenal syndrome can be done several different ways. Females who carry a mutation in their OCRL1 gene commonly have changes in the lens of the eye. These changes can only be detected by an ophthalmologist with a special eye examination. These changes do not cause vision problems. The eye difference seen in carriers of Lowe oculocerebrorenal syndrome is best observed once females reach adulthood. Recent reports suggest that a detailed eye exam can detect 90% of carriers. In addition to eye examinations, carrier detection can also be performed with DNA testing. If the OCRL1 mutation has been identified in an affected male in the family, the females in the family can undergo DNA testing.

Prenatal diagnosis is possible by measuring the activity of phosphatidylinositol 4,5-bisphosphate 5-phosphatase in fetal tissue drawn by amniocentesis or chorionic villus sampling (CVS). In cases where the mutation is known, DNA testing can be used in prenatal diagnosis. Fetuses should be tested if the mother is a carrier of a Lowe oculocerebrorenal syndrome. A woman is at risk of being a carrier if she has a son with Lowe oculocerebrorenal syndrome or someone in her family with Lowe oculocerebrorenal syndrome. Any woman at risk of being a carrier can undergo testing to determine if she is at risk to have a son with Lowe oculocerebrorenal syndrome.

Treatment and management

There is currently no cure for Lowe oculocerebrorenal syndrome. Individuals with Lowe oculocerebrorenal syndrome benefit from therapies and regular medical care. Physical therapy, occupational therapy, and speech therapy may be recommended due to developmental delays. Regular eye exams by an ophthalmologist are also recommended. Patients with Lowe oculocerebrorenal syndrome should be followed by a nephrologist (kidney doctor). Dialysis may ultimately be recommended for kidney failure.

Prognosis

The life span of males with Lowe oculocerebrorenal syndrome is limited by their multiple medical problems. Death by middle age is common. However, medical advances are improving the quality of life for individuals with this genetic condition.

Resources

BOOKS

Nussbaum, Robert L., and Sharon Suchy. "The Oculocerebrorenal Syndrome of Lowe (Lowe Syndrome)." The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw Hill, 2001.

PERIODICALS

Monnier, Nicole, V. Satre, E. Lerouge, F. Berthoin, and J. Lunardi. "OCRL1 Mutation Analysis in French Lowe Syndrome Patients: Implications for Molecular Diagnosis Strategy and Genetic Counseling." Human Mutation 16 (2000) :157–65.

Roschinger, Wulf, A. Muntau, G. Rudolph, A. Roscher, and S. Kammerer. "Carrier Assessment in Families with Lowe Oculocerebrorenal Syndrome: Novel Mutations in the OCRL1 Gene and Correlation of Direct DNA Diagnosis with Ocular Examination." Molecular Genetics and Metabolism 69 (2000): 213–22.

ORGANIZATIONS

Alliance of Genetic Support Groups. 4301 Connecticut Ave. NW, Suite 404, Washington, DC 20008. (202) 966-5557. Fax: (202) 966-8553. <http://www.geneticalliance.org>.

Lowe Syndrome Association. 222 Lincoln St., West Lafayette, IN 47906-2732. (765) 743-3634. <http://www.lowesyndrome.org>.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.