Lowe syndrome

Medical quality assurance by Dr. Albrecht Nonnenmacher, MD at December 2, 2016
StartDiseasesLowe syndrome

Lowe syndrome, also known as oculocerebrorenal syndrome is a rare genetic disorder that mostly affects the brain, kidneys, and eyes. Lowe syndrome almost exclusively affects males as it is inherited via an X-linked pattern. Symptoms first appear in infancy.

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Definition & Facts

Lowe syndrome is an X-linked inherited disorder that affects males, causing a variety of mental and physical issues. First described by Dr. Lowe in Boston in 1952, the disease affects three major organ systems: the eyes, the brain, and the kidneys. This is why it is also known as oculocerebrorenal syndrome.

It is unknown exactly how many people have Lowe syndrome, but the prevalence is estimated at 1 to 10 people per million in the United States. Hallmarks of the disorder include congenital cataracts, or thick clouding of the lenses, infantile glaucoma, renal problems, and weakened muscle tone. 

Symptoms & Complaints

Boys with Lowe syndrome are born with cataracts in both eyes that are typically removed early in infancy. Most children are fitted with eyeglasses and/or contact lenses.

While it is usually not present at birth, about 50% of people with Lowe syndrome develop glaucoma. By the age of one, many boys with Lowe syndrome develop kidney problems, including the loss of substances like bicarbonate, sodium, amino acids, albumin, potassium, glucose, and phosphate in the urine. This issue is known as renal Fanconi syndrome.

Kidney issues may be mild and involve the loss of only a few substances or it can be severe. People with Lowe syndrome may also display other common symptoms, such as intellectual disabilities that range from borderline to severe, behavioral problems that may be moderate to severe, searching nystagmus (or involuntary eye movements), poor muscle tone, delayed motor development, seizures, and an increased risk of bone fractures, scoliosis, and rickets.

Many also have facial abnormalities, including frontal bossing (a prominent forehead); deep-set eyes; a fair complexion with blonde hair; protracted retention of the primary teeth; and large, round cheeks.

About 10-15% of cases result in mild disability while 50-65% result in severe disability. Seizures typically affect about half of boys by the time they are six years old. Some affected males develop keloid growths on the corneas in late childhood and adolescence that are progressive and eventually lead to blindness.

Causes

Oculocerebrorenal syndrome is caused by genetic mutations in the gene called OCRL1. This defective gene prevents the production of an important enzyme called PIP2-5 phosphatase that helps modify fat molecules called membrane phospholipids, although the exact mechanism is unknown.

It is known that this enzyme is vital to normal metabolic processes in the area of the cell called the Golgi apparatus. Normal levels of the enzyme help control the levels of membrane phospholipids to regulate transportation to and from the cell membrane. This enzyme deficiency causes abnormal cell functions controlled by the Golgi apparatus, including developmental defects.

Lowe syndrome almost always affects males, although females are the genetic carriers. A male has just one X chromosome that is inherited from the mother. If a male inherits an X chromosome with the mutated gene, he will develop Lowe's disease. If a female inherits a copy of the X-chromosome with the mutation, she will be a carrier.

While very rare, it is possible for Lowe syndrome to occur in females due to X-chromosome translocation, or a defect that occurs when a piece of one chromosome sticks to another broken chromosome, or non-random X inactivation, which occurs when only one X-chromosome is activated in all or most of the female's cells. 

Diagnosis & Tests

While an official diagnosis of Lowe syndrome is usually made by a geneticist, there are several early symptoms that may lead a physician to suspect Lowe syndrome. A clinical diagnosis is often used as a precursor to a genetic test in which the male's symptoms are compared to the classic symptoms of Lowe syndrome.

If there is a suspicion of Lowe syndrome, the boy's mother may be checked by an ophthalmologist for the classic "snowflake" lenticular opacities of the eye. Following this, an enzyme test will likely be ordered. People with Lowe syndrome have a deficiency in the production of the PIP2-5 phosphatase enzyme that can be detected through an enzyme test. This test is done using a skin sample that is cultured and sent to a lab.

Finally, a DNA analysis may offer a definitive diagnosis. A DNA blood test will check for the defective OCRL1 gene with a diagnosis that is 99% accurate. Prenatal testing for Lowe syndrome may also be done. In this case, an enzyme deficiency analysis or DNA test may be useful. Ultrasound examination is the most common strategy to check for cataracts on the fetus, particularly when there is a strong family history of Lowe syndrome. 

Treatment & Therapy

There is no cure for Lowe syndrome, but many symptoms can be effectively treated and managed with a combination of special education, physical therapy, medication, and surgery. Regular care is recommended which includes blood tests at least every 6 months to check levels of chloride, potassium, sodium, magnesium, phosphorus, calcium, and other compounds that may be lost through urine. Kidney function urinalysis is typically done every six months to monitor a Lowe syndrome patient's kidney health.

One of the earliest forms of intervention is cataract surgery within the first few years of life to avoid amblyopia, or lazy eye, in which vision in the eye is reduced because the eye and brain do not work together. Ocular tone will also need to be tested often to diagnose and manage glaucoma.

Physical therapy is typically recommended to treat hypotonia, or weak muscle tone, whereas seizures can be controlled with symptom-specific prescription medication. Surgery and/or prescription eye drops may be necessary to maintain correct eye pressure in those diagnosed with glaucoma. 

Prevention & Prophylaxis

There is no way to prevent Lowe syndrome, but genetic testing can reveal if parents are carriers and at risk of having a child with the disorder. Genetic testing is used to determine if females are at-risk carriers of Lowe disease. Family planning options are available, such as prenatal testing, to reduce the risk.