Lowe syndrome, also known as oculocerebrorenal syndrome, is a rare genetic disorder that primarily affects males. This condition impacts three major body systems: the eyes, the brain, and the kidneys. The syndrome leads to a variety of physical and developmental challenges that require ongoing medical care and support throughout an individual’s life.
Genetic Causes and Inheritance
Lowe syndrome is caused by mutations in the OCRL gene, located on the X chromosome. This gene provides instructions for making an enzyme called phosphatidylinositol polyphosphate 5-phosphatase. This enzyme is involved in regulating cell membrane transport and the cell’s structural framework.
The condition is inherited in an X-linked recessive pattern, meaning it occurs almost exclusively in males who have only one X chromosome. If this X chromosome carries the mutated OCRL gene, the male will develop the syndrome.
Female individuals have two X chromosomes. One normal copy of the OCRL gene can compensate for a mutated copy, so females with one altered copy are usually carriers and do not develop severe symptoms. However, approximately 95% of female carriers over age 10 may exhibit characteristic changes in the lens of their eyes, detectable by an ophthalmologist, though these changes usually do not impair vision. About a third of affected males have a new mutation not inherited from their parents; in other cases, the mutation is inherited from a carrier mother.
Key Symptoms and Affected Body Systems
Lowe syndrome causes a range of symptoms affecting multiple body systems, with varying severity among individuals. These symptoms become apparent early in life, typically within the first year.
Eyes
Individuals with Lowe syndrome are born with congenital cataracts, a clouding of the eye lenses. These cataracts often impair vision and usually require surgical removal within the first few months of life. About half of affected infants also develop infantile glaucoma, a condition with increased eye pressure that can further reduce vision. Other issues include corneal keloids, strabismus (misaligned eyes), and nystagmus (involuntary eye movements), contributing to poor visual outcomes, with corrected acuity rarely better than 20/100.
Brain (Central Nervous System)
Neurological impacts are common, beginning with hypotonia (weak muscle tone) at birth. This low muscle tone can lead to difficulties with feeding, breathing, and significant delays in achieving motor milestones like sitting, standing, and walking. Developmental delays are widespread, and intellectual ability ranges from near normal to severely impaired; many individuals have mild-to-moderate or severe-to-profound intellectual disability. Seizures occur in about half of affected children, and common behavioral issues like stubbornness, temper tantrums, and aggressive or self-abusive behaviors are also reported.
Kidneys
Kidney dysfunction, specifically renal Fanconi syndrome, frequently develops, usually by one year of age. In this condition, the kidneys are unable to properly reabsorb essential nutrients and minerals back into the bloodstream. Instead, substances such as amino acids, bicarbonate, phosphate, potassium, sodium, glucose, and L-carnitine are excreted in the urine. This loss of nutrients can lead to increased urination, dehydration, abnormally acidic blood (metabolic acidosis), and impaired growth, sometimes resulting in soft, bowed bones (hypophosphatemic rickets). Over time, these progressive kidney problems can lead to chronic kidney disease and, in adulthood, end-stage renal disease.
The Diagnosis Process
Diagnosis often begins with clinical suspicion based on characteristic symptoms in a male infant. The consistent appearance of congenital bilateral cataracts at birth is a strong early indicator. An ophthalmological examination confirms these eye abnormalities.
Further investigation involves laboratory tests of blood and urine. These tests reveal signs of Fanconi syndrome, such as low-molecular-weight proteinuria, aminoaciduria, bicarbonaturia, and phosphaturia, indicating the kidneys’ inability to reabsorb these substances. Elevated levels of certain enzymes like creatine kinase, lactate dehydrogenase, and transaminases in plasma can also be observed.
Definitive diagnosis is confirmed through molecular genetic testing, which identifies a pathogenic mutation in the OCRL gene. This genetic testing accurately detects mutations in over 95% of affected males. For families with a known OCRL gene mutation, prenatal diagnosis is available through genetic testing. Ultrasound may also reveal fetal cataracts or elevated alpha-fetoprotein in maternal serum or amniotic fluid.
Management of Lowe Syndrome
There is no cure for Lowe syndrome, so management focuses on addressing the symptoms to improve quality of life and prevent complications. A multidisciplinary team of medical professionals, including ophthalmologists, nephrologists, neurologists, and therapists, typically provides care.
Medical Management
Cataract removal surgery is performed early in life to improve vision, often followed by corrective glasses or contact lenses. Glaucoma, if present, is managed with pressure-lowering medications or surgical interventions like goniotomy or trabeculotomy. Seizures are controlled with anticonvulsant medications.
Kidney dysfunction, specifically Fanconi syndrome, requires regular monitoring of acid-base status and electrolyte levels. Oral supplements of sodium bicarbonate, potassium citrate, and phosphate are administered to correct metabolic acidosis, hypokalemia, and hypophosphatemia, and to prevent rickets. Vitamin D supplementation, often with calcitriol, is also given to support bone health.
Therapeutic Support
Physical therapy is started in infancy to address hypotonia and aid in developing motor skills like head control, sitting, and walking. Occupational therapy helps individuals develop skills for daily living. Speech therapy is important for communication delays, which are common due to hypotonia, a high palate, and intellectual delays. Feeding difficulties caused by low muscle tone may necessitate tube feedings if oral intake is insufficient.
Educational and Behavioral Support
Children with Lowe syndrome often require specialized educational plans tailored to their learning abilities and developmental delays. Behavioral interventions and support from psychologists can help manage challenging behaviors such as temper tantrums, aggression, or self-abusive actions. Many affected boys exhibit behaviors consistent with the autistic spectrum, requiring specific strategies to support their communication and social development.