Lowe syndrome, also called oculocerebrorenal syndrome of Lowe, is a rare congenital metabolic disorder. It is caused by mutations in the OCRL gene on the X chromosome, and because it is X-linked recessive, it almost exclusively affects males.
The incidence is about 1 in 100,000 male births. However, some reports from overseas suggest 1 in 500,000. Cases can also occur as de novo mutations without a family history.
The three main features of this syndrome are as follows.
Ocular symptoms: congenital cataracts, glaucoma, etc.
In female carriers, although they do not develop the disease, over 90% of those aged 10 years or older have lens opacities. These are characteristically observed as “snowflake”-shaped cortical radial opacities, which are useful for evaluating family history.
The main complaints are decreased visual acuity and photophobia from infancy. If nystagmus is present, oscillatory eye movements are observed. Motor developmental delay due to hypotonia and feeding difficulties are often noted from early infancy.
They are categorized into ocular and systemic symptoms.
Ocular Symptoms
Congenital cataract: Present at birth, bilateral. The lens is thin and often presents as total cataract. It may also be recognized as lamellar cataract.
Posterior lenticonus (posterior conical lens): Often associated with cataracts.
Glaucoma: Occurs in about 50% of cases. Caused by angle dysgenesis, presenting with elevated intraocular pressure and buphthalmos. Gonioscopy reveals decreased visibility of the scleral spur and narrowing of the ciliary body band.
Nystagmus: Caused by visual deprivation, aphakia, or retinal abnormalities. It may persist even after early surgery.
Others: Miosis, enophthalmos. Strabismus and corneal keloid are observed in approximately 25–35% of patients, further worsening visual prognosis.
Systemic symptoms
Hypotonia: Severe from birth. Accompanied by loss of deep tendon reflexes, causing feeding difficulties and respiratory problems.
Intellectual disability: Ranges from mild to severe. About 70% of patients achieve independent walking by ages 6–13.
Epilepsy: Present in over 50% of adult patients. Type and severity vary.
Fanconi syndrome: Presents with metabolic acidosis, growth impairment, dehydration, and rickets due to proximal tubular dysfunction. Appears from early infancy.
Chronic kidney failure: Progresses with age; most patients reach stage 4–5 chronic kidney disease by their 40s.
QWhat is the visual prognosis?
A
The visual prognosis for patients with Lowe syndrome is generally poor. Because multiple visual impairment factors such as congenital cataracts, glaucoma, nystagmus, and corneal keloid overlap, the best corrected visual acuity rarely exceeds 0.2. Early cataract surgery and amblyopia treatment are important, but many cases do not achieve sufficient vision.
Lowe syndrome is caused by mutations in the OCRL gene located on the X chromosome at Xq25-26. This gene encodes the inositol-5-phosphatase enzyme (OCRL-1).
The main functions of OCRL-1 are as follows:
Lipid metabolism: Converts phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 4-phosphate (PI4P)
Intracellular localization: Mainly present in clathrin-coated pits, endosomes, and Golgi apparatus
Involvement in cellular functions: Essential for protein transport, cell signaling, and actin cytoskeleton polymerization
Because the inheritance pattern is X-linked recessive, the disease almost exclusively affects males. Females can be carriers and pass the mutation to the next generation. Cases without a family history, occurring as de novo mutations, also exist.
A definitive diagnosis of Lowe syndrome is made by genetic testing or enzyme activity measurement. This syndrome should be actively suspected in boys with congenital cataracts, hypotonia, and developmental delay.
The main diagnostic steps are shown below.
Test
Description
Genetic testing
Mutation analysis of the OCRL gene; identifies over 95% of affected males
Enzyme activity assay
Demonstrates reduced OCRL-1 activity in cultured skin fibroblasts
Prenatal diagnosis
Detection of cataract by fetal ultrasound, elevated alpha-fetoprotein in amniotic fluid
Ophthalmic examination is useful for diagnosing female carriers, and snowflake-like lens opacities are observed in over 90% of female carriers aged 10 years or older.
MRI (T2-weighted imaging) may show periventricular and deep white matter hyperintensities and mild ventricular enlargement. If epilepsy is suspected, an electroencephalogram (EEG) should be performed.
Cataract surgery within 3 months of birth is recommended to minimize deprivation amblyopia. In infancy, the eye is often left aphakic due to the risk of complications, and visual development is supported with aphakic glasses or contact lenses. Contact lens management may be difficult in cases with behavioral issues or complications such as glaucoma or corneal disease.
There is no established consensus on the surgical procedure, and selection should be made on a case-by-case basis. Regular glaucoma screening every 6 months is necessary.
Surgical excision may be possible, but recurrence is common and often more invasive than the initial lesion. There is no established treatment for eradication.
Hypotonia: Early intervention with physical therapy and occupational therapy
Neurological and psychiatric symptoms: Reports suggest clomipramine, paroxetine, and risperidone show some efficacy
Renal tubular acidosis: Correction with alkaline agents such as sodium bicarbonate
Rickets prevention: Vitamin D supplementation, regular monitoring of parathyroid hormone and calcium
Dehydration management: Intravenous fluids may be necessary for dehydration in infancy
QCan an intraocular lens be inserted after cataract surgery?
A
In infantile cataract surgery, intraocular lenses are traditionally not inserted, leaving the eye aphakic, due to high complication risks and potential need for additional surgery. Later in life, intraocular lens insertion may be considered, but concurrent glaucoma or corneal pathology complicates management.
The underlying pathology of Lowe syndrome is the loss of function of the OCRL-1 enzyme. OCRL-1 is an inositol 5-phosphatase that catalyzes the dephosphorylation of PIP2 to PI4P, and its dysfunction leads to excessive accumulation of intracellular PIP2.
Accumulation of PIP2 impairs the following cellular functions:
Impaired protein transport: Proper transport of proteins in endosomes and the Golgi apparatus is inhibited. Multiple transporters in the proximal renal tubules become dysfunctional, resulting in Fanconi syndrome.
Abnormal actin cytoskeleton: PIP2 regulates actin polymerization, and its accumulation affects cell morphology and motility.
Mechanism of ocular symptoms: Normal OCRL-1 activity is required for epithelial cell migration and differentiation in the eye; its impairment causes defective migration of lens epithelial cells, leading to congenital cataracts. Abnormal development of the iridocorneal angle causes glaucoma.
OCRL-1 is localized in clathrin-coated pits, endosomes, and the Golgi apparatus, and plays a central role in intracellular membrane trafficking. This broad involvement is thought to cause diverse symptoms in different organs such as the eyes, brain, and kidneys.
7. Latest Research and Future Prospects (Research-stage Reports)
Complementary effects of rapamycin and statins are being studied to regulate the mTOR pathway and intervene in cholesterol metabolism for cytoskeletal and transport dysfunction caused by OCRL-1 deficiency. Currently, this is limited to animal experiments and basic research, and has not reached clinical application.
Possibility of Gene Therapy and Enzyme Replacement Therapy
Basic research on gene therapy approaches to introduce functional copies of the OCRL gene into target cells is underway. However, due to the wide range of target organs, there are significant challenges to practical application, and it has not yet reached the clinical trial stage.
