Oculocerebrorenal Syndrome

What is Oculocerebrorenal Syndrome?

In the early 1950s, a team of researchers led by Lowe identified a new health condition in children. This condition was characterized by a number of unique features such as intellectual disability, the presence of a certain type of urine abnormality (organic aciduria), a decreased ability to make a chemical called ammonia in the kidneys, double-sided cataracts, and glaucoma.

Since that time, more studies have helped us understand this disorder better. We now know it includes other conditions like a type of kidney disease (`Fanconi-type proximal renal tubulopathy`), a lack of normal reflex responses (`areflexia`), and joint disease (`arthropathy`).

Today, what we call Lowe syndrome is recognized as a genetic disorder that is passed down through families (`X-linked recessive disorder`). It impacts key processes within body cells, which is why it can affect multiple organs. Diagnosing this syndrome early and providing essential supportive care can help avoid severe, potentially life-threatening complications and ensure the best possible quality of life for the patient.

What Causes Oculocerebrorenal Syndrome?

Oculocerebrorenal syndrome, a condition affecting the eyes, brain, and kidneys, is caused by a mutation, or change, in the OCRL gene located on chromosome X. This gene produces an enzyme, primarily found on the cell surface and within some cell compartments, mainly those involved in sorting and processing of molecules within the cell.

This enzyme plays an important role in transforming a molecule, called phosphatidylinositol 4,5-bisphosphate, into a different form. This process is crucial for various cell functions including the movement and sorting of proteins within the cell, transmitting signals within the cell, cell movement, and changing the cell’s shape.

More than 200 different variations of mutations in the OCRL gene have been discovered. The type of mutation usually doesn’t predict the features or severity of the syndrome.

The changed OCRL gene is passed down from parents to children in a pattern called X-linked recessive, which mostly affects males. A mother who carries the mutation can pass it to her children, even if there’s no history of the condition in the family. Although women who carry this changed gene don’t usually have the full syndrome, they can have changes in their eyes that can be identified during an eye examination. Some women showing features of oculocerebrorenal syndrome have been reported, especially if they have certain chromosomal abnormalities.

Risk Factors and Frequency for Oculocerebrorenal Syndrome

Oculocerebrorenal syndrome is a rare condition, with an estimated occurrence of 1 in 500,000 people. This disorder mostly affects males. In fact, in the United States, it affects between 1 to 10 males per 1 million people.

Signs and Symptoms of Oculocerebrorenal Syndrome

Oculocerebrorenal syndrome is a condition that affects multiple body systems. Including the nervous system, ocular system, renal system, musculoskeletal system, and has some other findings related to the skin and teeth.

• Nervous system: People with this condition often experience severe hypotonia, or decreased muscle tone, and absence of deep tendon reflexes. This may lead to difficulties with motor milestones and feeding. Additional symptoms include seizures, intellectual disability, and conduct disorders with possible aggressive or obsessive-compulsive behaviors.
• Ocular system: Vision problems are common, due to the formation of bilateral cataracts in the womb, necessitating surgery in infancy. Other less common eye issues include glaucoma, increased intraocular pressure, the development of corneal keloids, and strabismus. Females who carry the gene related to the condition often have opacities, or cloudiness, in the lens of the eye.
• Renal system: Kidney disease characterized by Fanconi syndrome, proximal tubular dysfunction, and renal failure is typical in patients with this condition. Symptoms can include low-molecular-weight proteinuria, risk of developing hyperchloremic metabolic acidosis, elevated urinary levels of amino acids and calcium, and kidney stones. By the fourth decade of life, most patients have severe chronic kidney disease.
• Musculoskeletal system: Common issues relate to thinning of the bones (osteopenia), inflammation of the tendon sheath (tenosynovitis), and degenerative joint disease (arthropathy). Patients may also have stunted growth and experience scoliosis.
• Other findings: Various additional symptoms can include skin cysts, dental anomalies like delayed tooth eruption or enamel hypoplasia, and cryptorchidism in about a third of males, or undescended testicles. Some people may also exhibit dysfunction of primary hemostasis, suggested to be due to delayed platelet activation.

Testing for Oculocerebrorenal Syndrome

If a baby shows symptoms of Lowe syndrome, such as slow growth, there are several tests doctors could suggest. These tests may involve taking a blood sample or collecting urine. Such tests can help doctors identify certain signs of Lowe syndrome like low potassium levels, high acid levels in the blood, increased levels of creatinine (a waste product your body produces), presence of proteins or high levels of calcium in urine, or an increased level of certain amino acids in the urine.

The doctor might also want to look at the baby’s brain if they observe any neurological abnormalities. In such situations, they may use a method called magnetic resonance imaging (MRI), which uses strong magnetic fields and radio waves to create detailed images inside the body. The MRI might show certain abnormalities such as overly bright areas deep inside the brain, or a slight enlargement of the brain’s fluid-filled spaces (ventricles).

If the baby shows other unusual signs or symptoms, the doctor may suggest additional tests. The surefire method of diagnosing Lowe syndrome, however, is through genetic testing. In particular, examining skin cells under a microscope can show if there’s less activity than normal of a certain enzyme called inositol polyphosphate-5-phosphatase. A gene test can also identify if there’s a harmful change (pathogenic variant) in a specific gene linked with Lowe syndrome, known as the OCRL gene.

If doctors suspect Lowe syndrome before the baby is born, there are tests they can carry out. An ultrasound scan of the unborn baby might reveal eye conditions like cataracts. And by testing the pregnant woman’s blood or the fluid inside the womb, doctors can measure the levels of a substance known as alpha-fetoprotein – high levels might suggest Lowe syndrome.

Treatment Options for Oculocerebrorenal Syndrome

The oculocerebrorenal syndrome is a health condition that can affect various parts of your body, leading to health complications. The treatment aims to improve the function of impacted organs and prevent sudden illness.

The Nervous and Musculoskeletal Systems

If you are experiencing low muscle tone (hypotonia), early physical therapy and rehabilitation are essential. Keeping your joints flexible can help avoid stiffening of the joints (contractures). Osteomalacia, a weakening of the bones due to vitamin deficiency, can be prevented or treated with vitamin D, calcitriol and phosphate supplements. If your low muscle tone affects your ability to swallow (dysphagia), you might need to get your nutrition through a feeding tube.

If you experience seizures, you’ll need medication to control them. For behavioral and mental health challenges, a team of professionals, including special education educators, occupational therapists, and speech-language pathologists, can help manage them. Medication such as stimulants, antipsychotics, and antidepressants can also be beneficial.

The Ocular System

To prevent lazy eye (amblyopia), it’s important to remove any cataracts in infant’s eyes within the first three months of life. Babies are often left without a lens (aphakic) and are given glasses or contact lenses to correct their vision. If you develop glaucoma, a disease that damages your eye’s optic nerve, controlling the internal pressure of your eye might be challenging with medication alone. In many cases, surgery is necessary.

Common surgeries performed in glaucoma patients include trabeculectomy and goniotomy, as well as aqueous tube shunt implantation. Eye patching or muscle surgery are used to correct misaligned eyes (strabismus). Thick scars on your eye’s cornea (corneal keloids) can also be surgically removed, especially if they disrupt your vision. Some people might experience corneal scarring or need a corneal transplant. Reduced vision due to corneal scarring also increases the risk of lazy eye.

The Renal System

If you have acidemia, an excess amount of acid in your blood, you will need a supplement that is alkaline, like sodium bicarbonate. Your calcium levels and your Parathyroid Hormone (PTH), which controls calcium and phosphate levels in your blood, should be monitored to avoid too much Vitamin D supplementation, which could increase the risk of high calcium in urine (hypercalciuria) and kidney stones (nephrolithiasis).

If your kidney disease progresses to end-stage kidney disease (ESRD), you will need dialysis, a procedure that helps your body filter waste products from your blood when your kidneys can’t. In rare cases, patients with the oculocerebrorenal syndrome might need a kidney transplant.

What else can Oculocerebrorenal Syndrome be?

There are several diseases a doctor might consider if they suspect a patient has Fanconi syndrome. These include:

• Disease type 2 of a rare genetic disorder called Dent disease
• A rare genetic eye disorder known as Nance-Horan syndrome
• Congenital Rubella – a condition caused by maternally transmitted rubella virus
• Smith-Lemli-Opitz syndrome (SLOS), a developmental disorder that affects multiple parts of the body
• Zellweger spectrum disorders, which are a group of rare genetic disorders affecting many body systems
• Cystinosis, a genetic disorder that can lead to damage in different organs and tissues
• Myotonic dystrophy, a type of muscular dystrophy
• Mucopolysaccharidoses, a group of metabolic disorders
• Mitochondrial diseases, a group of disorders caused by dysfunctional mitochondria
• Others diseases known to cause Fanconi syndrome, like Wilson disease, tyrosinemia, galactosemia, and glycogen storage diseases

What to expect with Oculocerebrorenal Syndrome

People with Lowe syndrome often have poor vision prognosis because they may develop amblyopia, or ‘lazy eye’, and severe glaucoma, a condition that damages the optic nerve in the eye. Both of these conditions can greatly affect sight.

People with this condition might also experience dysphagia, which is a fancy term for difficulty in swallowing, due to lack of muscle tone or strength (hypotonia). In severe cases, this could need tube feeding. On top of this, difficulty swallowing can make a person more prone to lung infections.

Renal (or kidney) disease is also a factor of Lowe syndrome. Its severity changes from patient to patient and usually gets worse as they get older. Most people with this condition live into their 20s to 40s. Kidney failure, as a result of the progressing renal disease, is often the primary factor in lessened life expectancy. Other common causes of death include lung diseases, seizures, and infections.

Possible Complications When Diagnosed with Oculocerebrorenal Syndrome

The Lowe syndrome affects multiple parts of the body. It can cause eye and muscle-related complications which significantly affect the patient’s lifestyle. Babies born with cataracts can develop a condition known as ‘lazy eye’, but the surgery to remove the cataracts can also lead to ‘aphakic glaucoma’. This is a severe and hard-to-manage type of eye disease.

People with this disorder are susceptible to seizure disorders and fever-related convulsions. A condition known as ‘hypotonia’ can lead to swallowing difficulties, eventually resulting in lung infections and complications. The kidney problems associated with Lowe syndrome can cause a loss of essential minerals. This loss can result in symptoms like delayed growth and a type of rickets caused by low phosphate levels. Issues with blood clotting might also cause complications during surgeries.

Common Complications:

• Eye and muscle complications
• Cataracts leading to ‘lazy eye’
• Aphakic glaucoma after cataract surgery
• Seizure disorders and fever-related convulsions
• Swallowing difficulties which can cause lung infections
• Mineral losses due to kidney problems, causing delayed growth and specific type of rickets
• Risk of complications during surgeries due to blood clotting issues

Preventing Oculocerebrorenal Syndrome

Lowe syndrome is a very rare inherited disease that is usually passed on following an X-linked recessive pattern. This means that the condition primarily affects men, and there are no recorded cases of men with this syndrome having children. About one-third of men with Lowe syndrome have new (de novo) genetic changes that were not inherited.³⁰

Family members of the patient with Lowe syndrome are recommended to receive genetic counseling. This means talking with a healthcare professional trained to help you understand genetic disorders, how they’re passed on, and what risks you might have. Prenatal genetic tests are available to help with this counseling process. These tests can examine your baby’s genes before he or she is born. It’s advised that women who already have children affected by Lowe syndrome should get prenatal genetic testing to assess for “germline mosaicism”, which means they could still pass on the condition even if they appear healthy.

Because Lowe syndrome is linked with many different health problems, it’s essential to have careful and thorough check-ups and monitoring. Parents should also be taught about possible problems associated with muscle weak (hypotonia), such as difficulty feeding and delayed development of motor skills, starting from birth. Behavioral problems, especially those tied to poor vision and intellectual difficulties, can lead to self-destructive behaviors. Treatment for these conditions includes programs to modify behavior, personalized therapy, and the use of medication to control symptoms of psychosis, a type of severe mental disorder.