eMedicine Specialties > Ophthalmology > Metabolic Disorders

Oculocerebrorenal Syndrome

Author: Deborah M Alcorn, MD, Associate Professor, Departments of Ophthalmology and Pediatrics, Stanford University School of Medicine; Director of Pediatric Ophthalmology and Strabismus, Lucile Packard Children's Hospital
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Updated: Jun 2, 2006

Introduction

Background

Oculocerebrorenal syndrome (OCRS) is an X-linked recessive metabolic disorder described by Lowe and coworkers in 1952. It is a multisystem disorder that primarily affects the eyes, nervous system, and kidneys. It is characterized by congenital cataracts, infantile glaucoma, neonatal or infantile hypotonia, intellectual impairment, and renal tubular dysfunction (Fanconi syndrome). The oculocerebrorenal syndrome is so named because of the prominent involvement of the 3 major organ systems; however, involvement of bone, gonads, muscle, skin, and connective tissue, as well as stereotypic behavior, also can occur. Additional manifestations include corneal keloids, growth retardation, areflexia, metabolic acidosis, proteinuria, aminoaciduria, and noninflammatory arthropathy. These patients often exhibit the characteristic facial appearance of frontal bossing, deep set eyes, and full cheeks, although the characteristic phenotype is often difficult to identify in neonates.

Female carriers manifest characteristic lens opacities, but they typically have normal renal and neurologic function.

Pathophysiology

OCRS is caused by a mutation of the OCRL1 gene located in the chromosomal locus of Xq26.1 The gene encodes a phosphatidylinositol (4,5) bisphosphate 5-phosphatase, localized in the Golgi complex. It is a key enzyme in the cellular phosphoinositide pathway, important in cellular trafficking. Deficiency of the enzyme causes the protean manifestations of Lowe syndrome. The reduced enzyme activity results in increased enzyme substrate and abnormal actin-binding proteins important in neuronal morphogenesis.

Frequency

International

The incidence rate is 1 in 200,000 live births.

Mortality/Morbidity

• Ocular: The hallmark feature is congenital cataracts. Left untreated, the cataracts will cause nystagmus and eventual blindness. Glaucoma develops in 50-70% of patients, typically manifesting in the first year of life, but it may present at any age. Patients also may develop corneal leukomas. Amblyopia may occur secondary to poor compliance with treatment and secondary strabismus. Corrected visual acuity is infrequently better than 20/70 despite optimal management. The visual impairment represents a combination of the morphologic changes in the eye, retinal dysfunction, and cortical functioning.
• Renal: If untreated, the proximal renal tubular acidosis leads to failure to thrive and metabolic collapse. By the second to third decade, gradual loss of creatinine clearance occurs, with progressive renal failure.
• Growth: At birth, these patients are within the normal growth curve but fall off in length, height, and weight in subsequent years.
• Neurological: Neonatal hypotonia may contribute to poor feeding and delayed motor development.
• Life expectancy: Patients with appropriate therapy may live to be 30-40 years of age, generally dying from renal failure, respiratory distress, status epilepticus, or infection. With improved medical treatment, infection as a cause for death has declined dramatically. The expected life span has not yet been defined.

Sex

This condition occurs almost exclusively in males. It is an X-linked recessive disorder. The female carrier state is identifiable by characteristic lenticular opacities. A few cases have been reported in females, often having X; autosome translocations involving the OCRL1 locus.

Age

This condition is congenital.

Clinical

History

• Family history - Family members with congenital cataracts, nystagmus, infantile glaucoma, developmental delay, neurological problems, seizures, or Lowe syndrome. Attempt to identify any potentially affected male relatives through the maternal side.
• Pregnancy - Complications, consanguinity, birth weight, and Apgar scores
• Medical
  • Failure to thrive; recurrent infections
  • Aminoaciduria, phosphaturia, proteinuria, or acidosis
  • Ocular concerns (eg, nystagmus, leukocoria, abnormal globe size, corneal haze, epiphora)
  • Renal problems
  • Neurologic problems; particularly, any hypotonia, areflexia, seizures, neuroimaging abnormalities, or behavioral abnormalities
  • Joint hypermobility, joint contractures, recurrent fractures, tenosynovitis, arthropathy, joint swelling, or genu valgum
• Surgery - Previous ocular surgery, cataract extraction, or glaucoma procedure
• Developmental - Delay in milestones, particularly motor milestones

Physical

• Ocular
  • Congenital cataracts are the hallmark of this disease. The abnormal lens development begins early (8 weeks' gestation) because of a disrupted migration of the embryonic lens epithelium and not as a result of a systemic metabolic imbalance. Lens abnormalities have been described in 20- to 24-week fetuses by the presence of necrosis and the disorganization of embryonic lens epithelium.
  • Bilateral leukocoria is evident at birth, often with miosis, shallow chamber, and microphthalmos. These clinically characteristic cataractous lenses are small and discoid. Histopathologically, they show an absence of demarcation between the nucleus and the cortex, indicating a retarded maturation. The anterior capsule may be thickened irregularly, often with anterior subcapsular plaques. The posterior capsule is irregular, with warty excrescences, indicating abnormal function of the posterior lens epithelium.
  • Glaucoma usually is not present at birth, but it is detected within the first year of life, associated with buphthalmos. Glaucoma develops in 50-70% of patients with OCRS, usually by age 6 years. It is generally bilateral and is usually the result of a primary developmental filtration angle anomaly rather than secondary to cataract extraction.
  • The pupils of patients with Lowe syndrome are typically miotic secondary to a hypoplastic dilator muscle.
  • Nystagmus is usually not noted at birth, but rather it develops shortly thereafter as a sensory nystagmus from poor visual development.
  • Corneal keloids may develop in up to 25% of patients, usually after age 5 years. They extend through the entire thickness of the cornea. They are progressive and may become visually significant.
• Neurologic
  • A cardinal feature of this disease is infantile hypotonia with a delay in motor milestones. The children may have feeding difficulties. After age 1 year, deep tendon reflexes are absent.
  • Up to 50% of patients have seizures, but no characteristic seizure type is evident. Infantile spasms, myoclonic seizures, partial complex seizures, and generalized convulsions have been reported. Seizures usually are present by age 6 years.
  • A poor prognosis exists for intellectual development with early-onset seizures and inadequately controlled seizures. The diagnosis of OCRS is compatible with normal intelligence. Approximately 10-25% of patients have an intelligence quotient (IQ) in the reference range, although mental deficiency is common. Intelligence appears to be stable over their lifetime, excluding decline due to interceding illness or progressive renal disease.
  • A high incidence (>80%) of behavioral abnormalities, including tantrums; aggressive and self-injurious behavior; irritability; and repetitive, nonpurposeful movements, occurs.
• Renal
  • Abnormal renal function is part of the clinical triad and a cardinal feature of the disease. In OCRS, impairment of both tubular and glomerular function occurs.
  • Renal function and histology are apparently normal in utero. Renal function may be normal at birth. Proximal tubular dysfunction usually begins at age 3-12 months. Aminoaciduria, proteinuria, phosphaturia, metabolic acidosis, and impaired urine concentrating ability develop subsequently. The severity and the age of onset of the renal tubular dysfunction may be quite variable.
  • Proteinuria is seen frequently but with variability of age of onset and amount of urinary protein loss. Acidosis is present and of the proximal renal tubular type. This condition may lead to failure to thrive and recurrent infections.
  • The renal dysfunction may lead to calcium and phosphorus loss, resulting in bone resorption. Bone resorption from long-term loss of phosphorous may lead to rickets and osteomalacia. Nephrocalcinosis and nephrolithiasis may result from hyperphosphaturia and hypercalciuria. Generally, tubular phosphate wasting worsens progressively with age.
  • In addition to the renal tubular dysfunction, by the second to third decade, impairment of glomerular filtration and gradual loss of creatinine clearance with progressive renal failure occurs.
• Musculoskeletal
  • Patients may exhibit noninflammatory arthropathy, joint swelling, and contractures. Scoliosis is frequently seen.
  • One half of patients older than 20 years have diffuse swellings of both small and large joints, focal nodules of fingers, and/or bilateral plantar masses, occasionally requiring resection. These manifestations may result from excessive growth of fibroblasts.
• Sexual development
  • The onset of puberty is generally at the appropriate age, but fertility may be reduced secondary to peritubular fibrosis and azoospermia.
  • Up to 40% of patients may have unilateral or bilateral cryptorchidism.
• Carrier state
  • Slit lamp examination of the lenses of female carriers of OCRS is very specific. These carriers manifest multiple (15 to >100) punctate gray-white cortical opacities observed by slit lamp evaluation. They usually are wedge-shaped aggregates located outside the nucleus in anterior cortical wedges. They are seen in increasing numbers with increasing age. The numbers of punctate cortical lenticular opacities are less relevant than their shape and distribution. These lenticular opacities usually have no visual impact.
  • They also may exhibit subcapsular cataracts, which increase in size and density with age.
  • The female carriers are otherwise asymptomatic and classically have normal renal and neurologic function.
  • DNA diagnosis is the most accurate method to identify carriers of Lowe syndrome when the mutation in the family is known.

Causes

• Genetic
  • OCRS has been mapped to chromosome locus Xq26.1.
  • The OCRS1 gene has been cloned and encodes the protein product of the OCRS1 gene, a phosphatidylinositol (4,5) bisphosphate 5-phosphatase that is deficient in OCRS patients.
  • To date, more than 70 different mutations have been identified, with most of them being private mutations restricted to one family. A common mutation in the OCRS gene has not been identified among OCRS patients.

• Search for CME/CE on This Topic »

• Oculocerebrorenal Dystrophy (Lowe Syndrome) (Pediatrics: Genetics and Metabolic Disease)
• Fanconi Syndrome (Pediatrics: General Medicine)
• Renal Glucosuria (Pediatrics: General Medicine)
• Carnitine Deficiency (Pediatrics: Genetics and Metabolic Disease)