What are the other Names for this Condition? (Also known as/Symptoms)

• Cerebrooculorenal Syndrome
• Oculocerebrorenal Syndrome of Lowe (OCRL)
• Phosphatidylinositol-4,5-Bisphosphate-5-Phosphatase Deficiency

What is Lowe Syndrome? (Definition/Background Information)

• Lowe Syndrome is a rare congenital disorder mostly occurring in males. The disorder predominantly affects the eyes, brain, and kidneys of the affected individuals
• Lowe Syndrome is caused by mutations in the OCRL gene, which codes for an enzyme known as inositol polyphosphate-5-phosphatase. This enzyme is ubiquitous (present everywhere) and regulates the transport of substances through cell membranes, both into and out of the cells. The enzyme is also involved in the regulation of the actin cytoskeleton, which is involved in the structural integrity and movement of cells
• Having a family history of Lowe Syndrome is a known risk factor for being born with the condition. However, there are reported cases of the disorder developing without any preceding family history. The risk factors associated with spontaneous mutations leading to the disorder are being researched upon
• Lowe Syndrome is inherited in an X-linked manner. In this type of inheritance, the genetic mutation is carried on the X chromosome, leading to the manifestation of the symptoms only in males, since they carry only one X chromosome
• Newborn baby boys with Lowe Syndrome show present cataract in both eyes. Additionally, the affected individuals also develop skeletal abnormalities, increased urination, dehydration, acidic blood, and are intellectually deficit
• The disorder is diagnosed with the help of physical examination, assessment of symptoms, evaluation of family medical history, blood tests, kidney function tests and imaging studies. Genetic testing may be used to confirm the presence of OCRL gene mutations
• Complications from the disorder include glaucoma, kidney disorder, bone abnormalities resulting in stature and movement problems, delay in achieving developmental milestones, seizures, behavioral issues, and reduced life expectancy
• A team of professionals belonging to different specialties is often needed to help an affected individual to lead as normal a life as possible. Treatment options for the disorder include surgery to repair cataracts, medication to address kidney malfunction and behavioral issues, physiotherapy to help with movement, as well as speech therapy
• The prognosis of Lowe Syndrome is typically poor. The affected individuals do not generally live beyond the age of 40 years. The quality of life depends upon the severity of disorder, timely and sustained treatment, as well as supportive care

Who gets Lowe Syndrome? (Age and Sex Distribution)

• Lowe Syndrome is a rare genetic condition affecting 1-10 individuals in every million population
• With very few exceptions, the disorder occurs only in males
• The condition has been more often noted in North and South America, European countries, and Asian countries (such as India and Japan)

What are the Risk Factors for Lowe Syndrome? (Predisposing Factors)

• Since Lowe Syndrome is an inherited disorder, having a family history of the disorder is the biggest risk factor
• However, some individuals develop the condition without any family history. In such cases, the risk factors for the disorder are not known

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Lowe Syndrome? (Etiology)

• Lowe Syndrome is caused by mutations in the OCRL gene. This gene localizes on the X chromosome. Thus, the condition is inherited in an X-linked recessive fashion
• Under normal circumstances, the OCRL gene codes for an enzyme known as inositol polyphosphate-5-phosphatase, which is ‘present everywhere’
  • This enzyme modulates the membrane-bound phospholipids. By doing so, it regulates the transport of specific substances in and out of the cells
  • The enzyme also regulates the actin cytoskeleton. The actin filaments, in combination with microfilaments, maintain the shape, structural integrity and organization of organelles inside the cells. Additionally, they are also involved in cellular movement during cell division and multiplication
• Mutations in the OCRL gene can lead to the following:
  • Loss of inositol polyphosphate-5-phosphatase production
  • Modification of the enzyme in such a way that it is unable to catalyze reactions

Both the above possibilities can lead to an individual developing symptoms of Lowe Syndrome.

X-linked recessive: X-linked recessive conditions are traits or disorders that occur when two copies of an abnormal gene are inherited on a sex chromosome (X or Y chromosome). All X-linked recessive traits are fully evident in males, because they have only one copy of the X chromosome. This means that there is no normal gene present to mask the effects of the mutant copy. All males who are affected will pass the mutated gene onto their female offspring, because they must inherit one copy of the X chromosome from each parent. This means that they will be unaffected carriers. Females are rarely affected by X-linked recessive disorders because they have two copies of the X chromosome. In the rare case that they inherit two mutated copies of the gene, they will inherit the condition.

• In some cases, an individual can develop the OCRL gene mutation without any preceding family history of the condition. The exact cause of such mutations is not known
• Although the mutation in the OCRL gene (and consequent enzyme dysfunction/malfunction) has been identified as the cause of the disorder, the mechanism by which the symptoms occur is still unclear and under scientific investigation

What are the Signs and Symptoms of Lowe Syndrome?

The signs and symptoms of Lowe Syndrome may include the following:

• Cataract in both eyes, often seen at birth
• Development of corneal keloids (encroachment of scar tissue in the cornea)
• Feeding problems
• Increased susceptibility to infections
• Signs and symptoms similar to Fanconi syndrome that include:
  • Dehydration owing to increased urination; increased thirst
  • Presence of glucose, phosphates, and protein in urine
  • Bone pain
  • Reduced phosphate and increased chlorine in the body
  • Fatigue, weakness
• Metabolic acidosis (acidic blood)
• Bone abnormalities because of loss of nutrients through urination
• Hypophosphatemic rickets (softening and bowed appearance of bones)
• Scoliosis; fractures of bones
• Weak or low muscle tone (hypotonia)
• Joint problems
• Abnormalities in teeth development
• Formation of cysts on skin
• Difficulty reaching developmental milestones
• Short stature
• Intellectual deficiency (may be mild, moderate, or severe)

How is Lowe Syndrome Diagnosed?

Lowe Syndrome is diagnosed with information obtained from the following tests and procedures:

• Complete physical examination with assessment of symptoms
• Evaluation of family medical history
• Eye exams
• Assays for inositol polyphosphate 5-phosphate enzyme activity using cultured fibroblast tissue from affected individual
• Blood tests
• Imaging tests for checking bone densities and abnormalities
• Ultrasound examination of the kidneys
• Tests to evaluate kidney function
• Tests to rule out other medical conditions with similar symptoms
• Prenatal testing of fetal cells in case of a family history of the condition
• Molecular genetic testing to confirm mutation(s) in the OCRL gene
• Genetic testing of family members to check for “carrier of mutation” status

What are the possible Complications of Lowe Syndrome?

Some potential complications of Lowe Syndrome include:

• Progressive eye abnormalities that may lead to blindness
• Severe intellectual deficiency
• Seizures
• Delayed development of motor skills, leading to difficulty in normal/ordinary movements such as standing up or walking
• Renal failure and end-stage renal disorder

How is Lowe Syndrome Treated?

For the treatment of Lowe Syndrome, a team of professionals from various disciplines working in coordination is necessary in order for the affected individual/child to lead as normal a life as possible. The treatment for Lowe Syndrome may involve:

• Surgical removal of cataracts
• Devices (glasses) to improve vision
• Medication to control progression of glaucoma
• Replenishment of lost fluids through intravenous or oral modes
• Nutritional supplements and dietary changes to replace lost minerals and vitamins
• Anticonvulsant medication for seizures
• Medication for behavioral issues
• Speech therapy
• Physiotherapy
• Special education for the intellectually-challenged
• Occupational therapy

In case of renal failure or end-stage renal disorder:

• Dialysis
• Kidney transplantation

How can Lowe Syndrome be Prevented?

• Currently, there are no specific methods or guidelines to prevent Lowe Syndrome, since it is a genetic condition
• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Lowe syndrome

Regular medical screening at periodic intervals with tests and physical examinations are advised.

What is the Prognosis of Lowe Syndrome? (Outcomes/Resolutions)

• The prognosis of Lowe Syndrome is guarded; typically the life expectancy of affected individuals does not exceed 40 years
• Many individuals with Lowe Syndrome, between the ages of 20 and 40 years, succumb to the condition
• The quality of life may be severely affected owing to mobility problems, behavioral issues, and intellectual deficits. Blindness, renal failure and end-stage renal disorder can severely interfere with the quality of life as well

Additional and Relevant Useful Information for Lowe Syndrome:

Since the disorder predominantly affects the eyes, brain, and kidneys of the affected individuals. It is also known as Oculocerebrorenal Syndrome of Lowe (OCRL).