Norrie Disease

Norrie disease is a rare, inherited eye disorder that causes blindness in male infants and can lead to progressive hearing loss and developmental delays.

Overview

Norrie disease is an inherited condition that leads to blindness in male infants at birth or soon after birth. It causes abnormal development of the retina, the layer of sensory cells that detect light and color, resulting in masses of immature retinal cells accumulating at the back of the eye. As a result, the pupils appear white when light is shone on them, a sign called leukocoria. The irises (colored portions of the eyes) or the entire eyeballs may shrink and deteriorate during the first months of life, and cataracts (cloudiness in the lens of the eye) may eventually develop.

Beyond vision, the condition affects other systems:

• About 30 percent of individuals develop progressive hearing loss.
• 30 to 50 percent of people affected experience developmental delays in motor skills, such as sitting up and walking.
• Other problems may include mild to moderate intellectual disability, often with psychosis.
• Abnormalities can affect circulation, breathing, digestion, excretion, or reproduction.

Frequency

Norrie disease is a rare disorder; more than 400 cases have been reported in the scientific literature.

Causes

Mutations in the NDP gene cause Norrie disease. The NDP gene provides instructions for making a protein called norrin. Norrin participates in the Wnt cascade, a sequence of steps that affect the way cells and tissues develop. In particular, norrin plays a critical role in the specialization of retinal cells for their unique sensory capabilities. It is also involved in the establishment of a blood supply to tissues of the retina and the inner ear, as well as the development of other body systems.

To initiate the Wnt cascade, norrin must bind to another protein called frizzled-4. Mutations in the norrin protein interfere with its ability to bind to frizzled-4, resulting in the signs and symptoms of Norrie disease.

Inheritance

This condition is inherited in an X-linked recessive pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes.

• Males (who have only one X chromosome) are affected if they have one altered copy of the gene in each cell.
• Females (who have two X chromosomes) must have a mutation present in both copies of the gene to cause the disorder.
• Fathers cannot pass X-linked traits to their sons.

In X-linked recessive inheritance, a female with one altered copy of the gene is called a carrier. She can pass on the gene but generally does not experience signs and symptoms of the disorder. However, in rare cases, carrier females have shown some retinal abnormalities or mild hearing loss associated with Norrie disease.

X-inactivation

Females with one NDP gene mutation who show features of Norrie disease do so because of a process called X-inactivation. Early in embryonic development in females, one of the two X chromosomes is permanently turned off (inactivated) in somatic cells (cells other than egg and sperm cells). This ensures that females, like males, have only one active copy of the X chromosome in each body cell.

Usually, X-inactivation occurs randomly, so each X chromosome is active in about half the body's cells. In females with an NDP gene mutation, the X chromosome with the mutation is active in about half of cells, and the X chromosome with the normal NDP gene is active in about half. Because X-inactivation leads to some cells that produce functional norrin protein and some cells that do not, females can have some features of Norrie disease.

Other Names for This Condition

• Anderson-Warburg syndrome
• Atrophia bulborum hereditaria
• Congenital progressive oculo-acoustico-cerebral degeneration
• Episkopi blindness
• Fetal iritis syndrome
• Norrie syndrome
• Norrie's disease
• Norrie-Warburg syndrome
• Oligophrenia microphthalmus
• Pseudoglioma congenita
• Whitnall-Norman syndrome