Oculocerebrorenal syndrome of Lowe (OCRL) is a multisystem disorder characterized by congenital cataracts, glaucoma, intellectual disabilities, postnatal growth retardation and renal tubular dysfunction with chronic renal failure.
The estimated prevalence is 1/500,000 and males are almost exclusively affected.
OCRL is a neonatal disorder characterized by ocular abnormalities (bilateral congenital discoid cataracts, glaucoma with or without buphthalmos, strabismus, hypermetropia and corneal and conjunctival cheloids), neurological involvement (developmental delay, seizures, hypotonia present at birth typically with absence of deep tendon reflexes), stereotypic behavior (temper tantrums, aggressiveness and obsessive compulsive behavior), postnatal growth retardation, mild to severe intellectual disability, stereotypic hand movements, renal dysfunction of the Fanconi type (proximal tubular acidosis; phosphate wasting leading to renal rickets, osteomalacia and pathological fractures) and progressive decline in kidney function leading to end-stage renal failure in adulthood. Subtle cataracts are obligate findings in female carriers after puberty. Other clinical manifestations include facial dysmorphism (frontal bossing, deep-set eyes, chubby cheeks, fair complexion), destructive teno-synovitis in older patients, short stature, mucocutaneous anomalies (eruptive vellus hair cysts, tricoepithiloma, excess skin folds and eruption cysts in oral cavity), dental malformations, cryptorchidism and bleeding tendency due to platelet dysfunction.
OCRL results from mutations in OCRL (Xq25), leading to phosphatidylinositol (4,5) bisphosphate accumulation. OCRL is involved in multiple intracellular processes including endocytic trafficking, actin skeleton dynamics and cell signaling. In the eye, this leads to disorganization of embryonic lens epithelium and abnormal development of the trabecular meshwork that regulates aqueous humor outflow from the eye.
Diagnosis of OCRL is based on specific ophthalmologic, neurologic and renal abnormalities. Laboratory findings reveal features of renal Fanconi syndrome (hypercalciuria, with nephrocalcinosis and nephrolithiasis; generalized hyperaminoaciduria; hypokaliemia; low-molecular weight proteinuria) and elevations in plasma creatine kinase, lactate dehydrogenase and transaminases levels. Brain imaging reveals brain atrophy, delayed myelination, pachygyrias, hydrocephalus as well as gliotic lesions suggestive of periventricular leukomalacia. Perinatal diagnosis may be achieved by detection of low molecular weight proteinuria. Diagnosis is confirmed by genetic screening of OCRL.
Differential diagnosis includes Dent disease type 2 which is allelic to OCRL, congenital infections (such as congenital rubella syndrome), Nance-Horan syndrome, Smith-Lemli-Opitz syndrome, muscle-eye-brain disease and cystinosis (see these terms) and peroxisomal disorders.
Prenatal testing is possible and unless the mutation in the family has been defined previously, assay of enzyme activity is preferred. Cataract has been demonstrated on prenatal ultrasound.
OCRL is transmitted by an X-linked mode of inheritance. De novo mutations are reported in 30% of affected males.
Treatment of OCRL includes early cataract extraction to avoid amblyopia, glaucoma control by either medications or surgery and postoperatively, eye glasses or contact lenses to improve visual function. Nasogastric tube feedings or feeding gastrostomy may be required. Physical and speech therapy, use of drugs (clomipramine, paroxetine and risperidone) for behavioral problems, correction of tubular dysfunction by alkali supplements, phosphate, potassium and water. Potassium citrate may be useful to prevent nephrocalcinosis.
Quality of life depends on extent of neurological and renal manifestations. Life span rarely exceeds 40 years and death occurs between 20-40 years, as a consequence of renal disease, hypotonia, increased susceptibility to infectious disease, seizures and sudden death. Glaucoma is often difficult to control.
Last update: October 2015