Oculocerebrorenal Syndrome

Etiology

The oculocerebrorenal syndrome is caused by a mutation in the OCRL gene on chromosome Xq25-26. This gene encodes an inositol 5-phosphatase enzyme (OCRL-1), which is found primarily within clathrin-coated pits on the cell surface as well as within cellular organelles, particularly endosomes and the Golgi apparatus.[4] 

The enzyme converts phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 4-phosphate.[5] The proper function of OCRL-1 is essential for cellular processes such as protein trafficking, cell signaling, cell motility, and actin cytoskeleton remodeling.

At least 200 mutations in the OCRL gene have been identified, most of which are frameshift, nonsense, and splice mutations. The OCRL variant type has not been shown to have a direct or reliable correlation with the phenotype or severity of the disease.[6]

The OCRL gene mutation is transmitted in an X-linked recessive fashion, predominantly to males with a carrier mother. De novo OCRL mutations can arise in patients with no prior family history.[7] Although female carriers of an altered OCRL gene do not have the classic features of oculocerebrorenal syndrome, they have characteristic lenticular changes that can be seen on ophthalmologic examination.[8] Females with oculocerebrorenal manifestations have been reported, such as in patients with 45,X karyotype.[9]

Epidemiology

The prevalence of oculocerebrorenal syndrome in the general population has been estimated at 1 in 500,000.[3] This disorder occurs almost exclusively in males and, in the United States, affects 1 to 10 males per 1 million people.

History and Physical

Patients with oculocerebrorenal syndrome present with abnormalities in multiple organ systems. These clinical findings will be reviewed in detail by the system.

The Nervous System

The burden of illness in patients with oculocerebrorenal syndrome is heavily based on the involvement of the peripheral and central nervous systems. Severe hypotonia and absence of deep tendon reflexes are some early clinical manifestations.[3] 

Infants may have impaired feeding as a consequence of weak or ineffective sucking. Hypotonia in infants also delays the achievement of motor milestones, such as ambulating independently. Patients are also prone to developing seizures, which can vary in type and severity. Intellectual disability is typical in most patients with Lowe syndrome and can range from mild to severe.[10] 

Patients tend to develop conduct disorders, such as aggression and obsessive-compulsive behavior. This maladaptive behavior interferes with daily functioning and can lead to self-injury.[11] Patients with low vision are particularly susceptible to conduct disorders and aggression.

The Ocular System

The visual potential in patients with oculocerebrorenal syndrome is low due to multiple phenotypic findings. The classic ocular manifestation is the presence of bilateral cataracts, which form in-utero and are often managed by cataract surgery in infancy.[12][13] 

Cataract formation in these patients is thought to be secondary to a genetic defect that affects the migration of the crystalline lens epithelial cells.[14] Less common ocular manifestations include X-linked infantile glaucoma, with or without buphthalmos. Glaucoma develops within the first few decades of life and is difficult to treat.[15] It has been reported as one of the main etiologies of blindness in patients with Lowe syndrome.[16] 

Intraocular pressures can be challenging to treat, and patients are often on multiple topical medications. Surgical intervention may be required for more aggressive intraocular pressure control. Developing conjunctival or corneal keloids has been reported in Lowe syndrome, sometimes leading to vision-threatening corneal scars. Other ophthalmic findings include nystagmus and strabismus. 

Characteristic lenticular opacities, distributed radially in all layers of the cortex, have been linked to carriers of the OCRL gene.[17][8] This highlights the importance of ophthalmologic examination in ascertaining a female’s carrier status. 

The Renal System

In patients with oculocerebrorenal syndrome, the characteristic renal disease is characterized by Fanconi syndrome with proximal tubular dysfunction and progressive renal failure. Renal disease may not be present at birth but may manifest in early infancy. Impaired endocytosis in the proximal tubules results in low-molecular-weight (LMW) proteinuria, often in the nephrotic range.[4] 

Patients are also at risk of developing hyperchloremic metabolic acidosis.[18] Elevated urinary levels of amino acids and calcium have also been commonly reported in Lowe syndrome. As a result of hypercalciuria, approximately half of patients will develop nephrolithiasis. Stones are often composed of both calcium oxalate and calcium phosphate.[18] Renal phosphate wasting increases the risk for rickets and osteomalacia.[19] 

Chronic, progressive renal failure is a hallmark of Lowe syndrome and requires close monitoring of kidney function. By the fourth decade of life, most patients have stage 4-5 chronic kidney disease (CKD).[18][20]

The Musculoskeletal System

Osteopenia, tenosynovitis, and debilitating arthropathy are frequent musculoskeletal manifestations of oculocerebrorenal syndrome. Hypophosphatemia and metabolic acidosis can exacerbate osteopenia and lead to pathologic fractures.[4] Patients also present with stunted growth and short stature, which has been postulated to be the result of growth hormone deficiency.[21] Scoliosis has been reported in patients with Lowe syndrome and may worsen with age.[22]

Other Findings

Certain dermatologic findings reported in patients with Lowe syndrome include benign cystic lesions, thought to originate from hair follicles.[23] The etiology of these skin lesions is poorly understood but has been attributed to elevated levels of lysosomal enzymes in extracellular tissue.[24] Dental anomalies - such as delayed tooth eruption, enamel hypoplasia, and tooth impaction - have been linked to Lowe syndrome.[25] 

While puberty and testosterone levels are reportedly normal in most patients with Lowe syndrome, about one-third of males have cryptorchidism.[26] Dysfunction of primary hemostasis has been recognized in Lowe syndrome and is postulated to be secondary to delayed platelet activation.[27]

Evaluation

Infants with typical clinical findings of Lowe syndrome should undergo laboratory testing, particularly if presenting with failure to thrive. Serum and urine testing may reveal metabolic acidosis, hypokalemia, elevated creatinine, proteinuria, hypercalciuria, and/or aminoaciduria. In the presence of neurologic abnormalities, imaging may be warranted. Typical findings include periventricular and deep hyperintense lesions on T2-weighted magnetic resonance imaging (MRI). Mild ventriculomegaly may also be present.[4] Additional diagnostics may be indicated if other systemic symptoms or findings are present.

The definitive diagnosis of Lowe syndrome is based on molecular genetic testing. Cultured skin fibroblasts demonstrate the reduced activity of inositol polyphosphate-5-phosphatase. Genetic testing can reveal a pathogenic variant of the OCRL gene. Antenatal testing is also available if Lowe syndrome is suspected. Ultrasound may reveal the presence of fetal cataracts.[12] Testing of maternal serum and amniotic fluid may show elevated levels of alpha-fetoprotein.[28]

Treatment / Management

The oculocerebrorenal syndrome has systemic manifestations that can impact patient morbidity and mortality. Treatment focuses on optimizing function and preventing acute illness.

The Nervous and Musculoskeletal Systems

Treatment of hypotonia requires early physical therapy and rehabilitation. Maintaining articular mobility reduces the development of contractures. Prevention or treatment of osteomalacia involves oral supplementation of Vitamin D, calcitriol, and phosphate. Hypotonia resulting in dysphagia may necessitate tube feeding.

Anticonvulsant therapy is required if seizures are present. Treatment of behavioral and psychiatric disorders is best managed by multidisciplinary team care, which may include special education services, occupational therapy, and speech/language therapy. Some pharmacologic agents that have shown benefits in patients include stimulants, antipsychotics, and antidepressants.[3]

The Ocular System

Early cataract removal within the first three months of life is important to prevent amblyopia. Infants are often left aphakic and provided with spectacles or contact lenses to correct refractive error. In patients with infantile and/or aphakic glaucoma, intraocular pressures are often difficult to control with medical therapy alone. In many cases, surgical management is necessary.

The most commonly reported glaucoma surgeries performed in this patient population are trabeculectomy and goniotomy. The next most common glaucoma surgery in these patients is aqueous tube shunt implantation. Patching or extraocular muscle surgery are used to treat patients with strabismus. Corneal keloids can be surgically removed, particularly if they compromise visual acuity. However, some patients suffer from corneal scarring or require corneal transplantation.[16] Decreased vision secondary to corneal scarring also increases the risk of amblyopia.(B3)

The Renal System

Alkali supplementation, including sodium bicarbonate, is critical for patients with acidemia. Monitoring calcium and Parathyroid Hormone (PTH) helps prevent excess Vitamin D supplementation, which could increase hypercalciuria and the risk of nephrolithiasis.[3] 

Dialysis is necessary for patients who advance to ESRD. Kidney transplantation in patients with oculocerebrorenal syndrome has been rarely reported in the literature.[29](B3)

Differential Diagnosis

• Dent disease type 2
• Nance-Horan syndrome
• Congenital Rubella
• Smith-Lemi-Opitz syndrome (SLOS)
• Zellweger spectrum disorders
• Cystinosis
• Myotonic dystrophy
• Mucopolysaccharidoses
• Mitochondrial diseases
• Other diseases causing Fanconi syndrome (e.g., Wilson disease, tyrosinemia, galactosemia, glycogen storage diseases)

Prognosis

Visual prognosis is poor in patients with Lowe syndrome due to the high likelihood of amblyopia and glaucoma severity. Dysphagia resulting from hypotonia may be severe enough to require tube feeding. It also increases patient susceptibility to respiratory infections.

Renal disease severity varies among patients and worsens with age. Patients typically live until the 2nd to 4th decade of life. Reduced life expectancy is most often a consequence of renal failure. Other frequent causes of death include respiratory illness, seizures, and infections.

Complications

The oculocerebrorenal syndrome of Lowe affects multiple organ systems. The visual and neuromuscular complications in this patient population significantly impact the patient's quality of life. Congenital cataracts may lead to amblyopia, but treatment with cataract surgery can also lead to secondary aphakic glaucoma, which can be severe and difficult to control.

Patients are at risk for seizure disorders and febrile convulsions. Hypotonia may result in dysphagia, leading to respiratory infections and complications. Mineral loss secondary to renal disease can result in complications such as failure to thrive and hypophosphatemic rickets. Impaired hemostasis may lead to intra-operative complications in patients requiring surgery.